FDA-2010-N-0477-0012

202-234-4433Neal R. Gross & Co., Inc.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS)

+ + + + +

FOOD AND DRUG ADMINISTRATION (FDA) + + + + + PART 15 PUBLIC HEARING ON APPROVAL PATHWAY FOR BIOSIMILAR AND INTERCHANGEABLE BIOLOGICAL PRODUCTS

+ + + + +

WEDNESDAY, NOVEMBER 3, 2010 + + + + +

The Panel convened at 8:30 a.m. inBuilding 31, Room 1503 of the White Oak Campusof the Food and Drug Administration, locatedat 10903 New Hampshire Avenue, Silver Spring,Maryland, Rachel Behrman, Presiding Officer,presiding.

PANEL MEMBERS PRESENT:RACHEL BEHRMAN, M.D., M.P.H., PresidingOfficerDENISE ESPOSITO, J.D.JOHN K. JENKINS, M.D.

STEVEN KOZLOWSKI, M.D.DIANE MALONEY, J.D.HEIDI C. MARCHAND, Pharm.D.MARK I. SCHWARTZ, J.D.ROBERT A. YETTER, Ph.D.


PRESENTERS:

JAY P. SIEGEL, M.D.

JAMES ROACH, M.D.

DIRK REITSMA, M.D.

ANSHUMAN PATWARDHAN, Ph.D., M.B.A.

MARK McCAMISH, M.D., Ph.D.

NIKHIL MEHTA, Ph.D.

MICHAEL WENGER, M.D.

CHARLES D. EBERT, Ph.D.

CRAWFORD BROWN, Ph.D.

VIJAY TAMMARA, Ph.D., F.A.A.P.S.

TERENCE E. RYAN, Ph.D.

ARTHUR TZIANABOS, Ph.D.

JOSEPH P. MILETICH, M.D., Ph.D.

RICHARD KINGHAM

JUDY RUCKMAN, Ph.D.

BRUCE BABBITT, Ph.D.

ROBERT BAKIN, Ph.D.

BERNARD RHEE, R.Ph., ESQ.

MARY GUSTAFSON

JOERG WINDISCH, Ph.D.

MARIE VODICKA, Ph.D.

RASMUS ROJKJAER, M.D., Ph.D.

SARA RADCLIFFE


TABLE OF CONTENTSPresiding Officer Opening Remarks - Rachel Behrman. . . . . . . . . . . . . .5

Johnson & Johnson Jay Siegel. . . . . . . . . . . . . . . 12

Momenta Pharmaceuticals, Inc. James Roach . . . . . . . . . . . . . . 32PPD Dirk Reitsma. . . . . . . . . . . . . . 52Dr. Reddy's Laboratories, Inc. Anshuman Patwardhan . . . . . . . . . . 66

Novartis Mark McCamish . . . . . . . . . . . . . 87

Merck and Company Nikhil Mehta. . . . . . . . . . . . . .108Hoffman-La Roche, Ltd. Michael Wenger. . . . . . . . . . . . .123

Watson Pharmaceuticals

Crawford Brown. . . . . . . . . . . . .140 Charles Ebert . . . . . . . . . . . . .144Nuron Biotech, Inc. Vijay Tammara . . . . . . . . . . . . .155

iBio, Inc.

Terence Ryan. . . . . . . . . . . . . .167

Shire Human Genetic Therapies Arthur Tzianabos. . . . . . . . . . . .182Amgen, Inc. Joseph Miletich . . . . . . . . . . . .199

Covington & Burling, LLP Richard Kingham . . . . . . . . . . . .217


TABLE OF CONTENTS (CONTINUED)

CBR International Corporation

Judy Ruckman. . . . . . . . . . . . . .238

PAREXEL Consulting

Bruce Babbit. . . . . . . . . . . . . .255

Technology & Business Law Advisors, LLC

Bernard Rhee. . . . . . . . . . . . . .274

Robert Bakin. . . . . . . . . . . . . .275

Plasma Protein Therapeutics Association

Mary Gustafson. . . . . . . . . . . . .292

European Generic Medicines Association

Joerg Windisch. . . . . . . . . . . . .301

PhRMA

Marie Vodicka . . . . . . . . . . . . .317

Generic Pharmaceutical Association

Rasmus Rojkjaer . . . . . . . . . . . .328

Biotechnology Industry Organization

Sara Radcliffe. . . . . . . . . . . . .339

Open Public Comments

Russ Lehrman, Lehrman Consulting. . . .360

Eric Katz, Katz and Company . . . . . .364

Closing Remarks/Adjournment

Rachel Behrman. . . . . . . . . . . . .373


1 P-R-O-C-E-E-D-I-N-G-S

2 8:32 a.m.

3 DR. BEHRMAN: Good morning to both

4 the attendees in the conference center and

5 those viewing the hearing through our live

6 webcast. Welcome to the Part 15 hearing on

7 the approval pathway for biosimilar and

8 interchangeable biological products, the

9 second day.

10 I am Rachel Behrman, Associate

11 Director for Medical Policy, Center for Drug

12 Evaluation and Research. I will serve as the

13 presiding officer for this hearing.

14 Before we begin, I will provide a

15 few housekeeping announcements. Please turn

16 off any mobile devices as they may interfere

17 with audio in this room.

18 We ask that all attendees sign in

19 on both days. I guess you already know this.

20 The doors were opened at 7:30 a.m. and we're

21 beginning promptly at 8:30. We are scheduled

22 until 4:30 p.m. today.


1 The restrooms are located in the

2 lobby to the left and right of the hallways.

3 We are planning for one 15-minute break during

4 the morning and one 15-minute break during the

5 afternoon session.

6 Please note there are trash

7 receptacles located in the back of the

8 conference room and the in the hallways and

9 please we encourage you to use them.

10 Today's lunch break is scheduled

11 from 11:55 to 12:55. There will be

12 sandwiches, salads, beverages for purchase in

13 the lobby.

14 Concerning the hearing, the

15 purpose of the hearing today is to create a

16 form for interested stakeholders to provide

17 input regarding the Agency's implementation of

18 the subtitle of the Patient Protection and

19 Affordable Care Act, the Biological Price,

20 Competition and Innovations Act of 2009.

21 The BPCI Act amends the Public

22 Health Service Act and other statutes to


1 create an abbreviated approval pathway for

2 biological products shown to be biosimilar to

3 or interchangeable with an FDA licensed

4 reference biological product.

5 FDA will take the information

6 obtained from the public hearing into account

7 in its implementation of the BPCI Act.

8 The Agency's interested in hearing

9 from stakeholders regarding the Agency's

10 implementation of the statute on all issues.

11 Chief among them, scientific and technical

12 factors related to a determination of

13 biosimilarity or interchangeability, the type

14 of information that may be used to support a

15 determination of biosimilarity or

16 interchangeability, development of a framework

17 for optimal pharmacovigilance for biosimilar

18 and interchangeable biological products, scope

19 of the revised definition of a biological

20 product, priorities for guidance development,

21 scientific and technical factors related to

22 reference product exclusivity, scientific and


1 technical factors that may inform the Agency's

2 interpretation of a product class as it

3 relates to available regulatory pathways for

4 certain protein products during the ten-year

5 transition period following enactment of the

6 BPCI Act and the establishment of a user fee

7 program for biosimilar and interchangeable

8 biological products.

9 I would now like to ask the FDA

10 Panel Members to introduce themselves.

11 DR. KOZLOWSKI: Hi, Steven

12 Kozlowski, Director of the Office of

13 Biotechnology Products in CDER.

14 MS. ESPOSITO: Denise Esposito,

15 CDER Office of Regulatory Policy.

16 DR. JENKINS: John Jenkins. I'm

17 the Director of the Office of New Drugs in

18 CDER and also the Chair of the CDER

19 Biosimilars Review Committee.

20 MS. MALONEY: I'm Diane Maloney.

21 I'm the Associate Director for Policy in CBER.

22 DR. MARCHAND: I'm Heidi Marchand.


1 I'm the Director of Health Professional

2 Liaison Program in the Office of Special

3 Health Issues in the Office of the

4 Commissioner.

5 MR. SCHWARTZ: Mark Schwartz,

6 Associate Chief Counsel, Drugs and Biologics.

7 DR. YETTER: Bob Yetter. I'm the

8 Associate Director for Review Management in

9 the Center for Biologics Evaluation and

10 Research and the Chair of CBER's Biosimilars

11 Committee.

12 DR. BEHRMAN: Turning now to the

13 speakers on the agenda. We have an agenda of

14 speakers from 21 organizations today with

15 scheduled presentation slots.

16 In order to keep to the agenda as

17 closely as possible, I will go over some

18 ground rules.

19 First, this meeting is informal.

20 The rules of evidence do not apply. No

21 participant may interrupt the presentation of

22 another participant. Only FDA Panel Members


1 will be allowed to question a presenter.

2 FDA may recall a presenter for

3 additional questions assuming time allows and

4 the presenter remains available.

5 Public hearings under Part 15 are

6 subject to FDA policy and procedures for

7 electronic media coverage of FDA public

8 administrative proceedings. Representatives

9 of the electronic media may be permitted

10 subject to certain limitations to videotape,

11 film or otherwise record FDA public

12 administrative proceedings including a

13 presentation of the speakers today.

14 The meeting will be transcribed

15 and copies of the transcript may be ordered

16 through the docket or accessed on our website

17 approximately 30 days after this public

18 hearing.

19 Each registered speaker has been

20 given an eight-minute time slot on the agenda

21 with seven additional minutes allotted for FDA

22 panel members to ask questions. If a speaker


1 goes over the eight-minute time slot, the time

2 allotted for questions will be reduced

3 accordingly.

4 For those of you who did not

5 register to make an oral presentation but

6 would like to present your comments, you may

7 speak during the open comment period at that

8 conclusion of the hearing if time permits and

9 I would just ask you at some point to see

10 Sandy Benton who's standing in the back of the

11 room and waiving her hand just so we have a

12 sense of how many people want to speak so we

13 can allot the time accordingly and I'll remind

14 you of that at the lunch break.

15 This hearing is not your last

16 chance to comment. The docket will stay open

17 until December 31st and we strongly encourage

18 all interested parties to comment. We take

19 these comments obviously very seriously and

20 study them very closely.

21 Please see the Federal Register

22 notice for details. The majority of speakers


1 will be addressing the questions listed in

2 Section 2 of the Federal Register notice for

3 this hearing.

4 And again, given the full agenda,

5 we request that each speaker keep to the

6 allotted time so that we are able to keep to

7 our tight time schedule.

8 We thank you for your interest and

9 your participation. We look forward to a very

10 productive public hearing.

11 We will proceed with the

12 presentations and our first speaker is Jay

13 Siegel from Johnson & Johnson.

14 DR. SIEGEL: Thank you and I want

15 to thank the entire panel and the FDA for

16 holding this hearing on this very important

17 matter and seeking broad public input.

18 I'll address a select subset of

19 the issues raised and questions asked in the

20 Federal Register notice and I want to start

21 with if I might paraphrase one of those

22 questions.


1 In a determination of

2 biosimilarity, what differences in analytic

3 testing may be acceptable?

4 We firmly believe that a standard

5 should be that biosimilar should be as similar

6 as is reasonably achievable. The standard of

7 sameness has worked well for generics, but as

8 we all know, it's neither achievable nor

9 measurable or demonstrable for biosimilar.

10 So, the legal standard in order to increase

11 access and affordability has been set at

12 highly similar.

13 Now, the highly similar standard

14 has some intrinsic risk. Any differences

15 between products could have some clinical

16 significance. When applied properly, that

17 risk can be appropriately controlled and

18 managed so that we can ensure that access is

19 improved and it's access to safe and effective

20 products.

21 But, intentional differences,

22 avoidable, unnecessary differences create


1 unnecessary risks and should not be permitted.

2 Another question asked when are

3 clinical data unnecessary? When might the

4 requirement for clinical data be waived?

5 We believe that some clinical

6 testing will be essential always to exclude or

7 detect clinically meaningful differences.

8 Even for major manufacturing changes by a

9 innovator, clinical data are often needed and

10 the types of differences that can arise when

11 you completely change the manufacturer are

12 quite major.

13 What types of clinical data would

14 be needed? Well, immunogenicity is something

15 that now and I think for the foreseeable

16 future, certainly the next few years, cannot

17 be predicted without clinical data. So, it

18 would be important to test immunogenicity and

19 other parameters when there are tests I should

20 add in head-to-head clinical trials and in the

21 case of immunogenicity, also important to

22 determine whether any antibodies that do arise


1 against the products cross react between the

2 biosimilar and the innovator and whether they

3 give rise to antibodies to the same or

4 different epitopes.

5 Human pharmacokinetics is

6 important. Relatively easy to measure. It's

7 unpredictable from structure and it's

8 relatively sensitive to some changes that may

9 exist between products. So, it should also be

10 measured.

11 The amount of safety data needed

12 may vary depending on the setting, but it's

13 hard to conceive of allowing a product to be

14 broadly marketed to large numbers of patients

15 before some collection of safety data in the

16 controlled setting particularly as clinical

17 studies will be done for immunogenicity and PK

18 in any case.

19 The issue of the desired or

20 intended effects or efficacy if you will is a

21 very complex issue in terms and many of the

22 answers will need to be on a product by


1 product or product class by product class

2 basis. But, there are some general points

3 that I would like to make in this regard.

4 One is that clinical outcome

5 endpoints are the most meaningful ones and

6 often relied upon as the most meaningful ones

7 and thus are important to measure, but in this

8 setting, pharmacodynamic endpoints even when

9 they're not validated surrogates play a very

10 important role.

11 Because these measures, lab tests,

12 cell count changes that occur with many

13 biologics are often more precisely measured

14 and more rapidly measured and as such, they

15 can be much more sensitive measures of whether

16 there are or are not differences than clinical

17 outcomes endpoints which often require

18 extremely large and long trials in order to

19 exclude all differences that might be

20 clinically meaningful.

21 An issue that has had much

22 discussion in Europe with implementation and


1 here has been about whether when there are

2 clinical data supporting a finding about a

3 similarity and one of an innovator's

4 indications, there might be extrapolation to

5 another indication without additional clinical

6 data and it's been noted that that indication

7 would have to have the same mechanism of

8 action.

9 We would assert that the same

10 mechanism of action is necessary but not

11 sufficient. It's one critical determination,

12 but there are other scientific determinations

13 that need to be considered.

14 Experience both with biosimilars

15 in Europe and with drug products of the same

16 class have shown that two highly similar

17 products with similar clinical effects in one

18 indication may have differences that emerge in

19 a new indication when, for example, the dose

20 or route differs and that's been seen in

21 Europe with biosimilars. A biosimilar EPO.

22 A deemed biosimilar by the IV route had


1 additional safety issues when given by the

2 subcutaneous route.

3 Differences may also emerge when

4 the new target population has different

5 susceptibility to an effect. For example, is

6 or is not immunosuppressed. When different

7 concombinant medications are used. When the

8 effects of the drug depend on multiple parts

9 of a molecule such as is the case with

10 antibodies where in one indication may rely on

11 similarity in one area. A new indication may

12 require a similarity in other areas as well

13 and when tissue penetration to the sites of

14 action differs as can happen with modest

15 changes to any molecule.

16 In different diseases, the same

17 product may be necessary to arrive in

18 different -- may be required to be present in

19 different tissues.

20 A few comments on the much

21 discussed issues of switching

22 interchangeability in front of covigilance.


1 Switching can increase immunogenicity risk

2 compared with taking either product alone.

3 So, we welcome the requirement to test for

4 switching as part of a determination of

5 interchangeability.

6 Switching can also impair both the

7 detection and the attribution of

8 pharmacovigilant signals, of safety signals

9 that can and will emerge even years after

10 products are on the market.

11 With our own experience with the

12 erythropoietins in Thailand, we have found

13 that in settings where patients have been

14 switched across many products, where all those

15 products are called by the same name, it's

16 extremely difficult to determine any

17 meaningful information about changes in

18 adverse profile trends, attribution of new

19 cases and so forth.

20 That should be avoided here.

21 Naming should discourage inadvertent switching

22 of patients. Naming should facilitate


1 tracking signals and with regard to comments

2 that perhaps numbers, NDCs, lot numbers could

3 be included in adverse event reports to ensure

4 appropriate tracking. Something that I'm not

5 sure the implementation of is really feasible.

6 I would note that we need to focus

7 for pharmacovigilance not only on adverse

8 event reports. That increasingly electronic

9 medical records, insurance claim databases can

10 be powerful sources of information where we

11 might even be able to look at large numbers of

12 patients receiving an innovative product, a

13 biosimilar for differences in safety effect.

14 We will only be able to use that

15 if all of those databases enable us to know

16 which product the patient had received.

17 I see I have a yellow light and

18 I'm near the end of the my talk.

19 So, I'll just say quickly that we

20 strongly support the development of FDA

21 guidance through a transparent, timely and

22 open scientific product. We believe these are


1 important public issues that should have

2 public input. That the sponsors of innovator

3 products can greatly help in understanding

4 what are the critical attributes of a product.

5 That the manufacturers of biosimilars will

6 also benefit from such guidance.

7 And I will forego reiterating my

8 key points at the end in order to allow time

9 for questioning.

10 Thank you very much.

11 DR. BEHRMAN: Thank you for your

12 comments. Are there questions from the panel?

13 Dr. Jenkins.

14 DR. JENKINS: Thanks for that

15 presentation. Yesterday, we heard about the

16 approvals in Europe and that included some

17 products that I think J&J either markets or

18 manufactures.

19 So, I'm interested in hearing

20 what's your perspective on the European

21 experience? I think they have approved upward

22 of close to 20 biosimilars. What's your view


1 on any safety or efficacy concerns,

2 immunogenicity concerns of the products

3 already approved under their system?

4 DR. SIEGEL: I would say in

5 general in almost all regards we have a very

6 positive view of the European system. The

7 process for developing it was an open one.

8 It's a science-driven system. There's been

9 substantial public commentary and input and

10 those have been considered well in developing

11 the system.

12 You know, one could find

13 individual aspects of it that one might wish

14 were done differently, but I think in general

15 they've done a good job in implementing a

16 biosimilars program.

17 DR. JENKINS: If I could just

18 follow up, one of the suggestions we heard

19 yesterday is that the data that were used to

20 support the approvals in Europe should be

21 applicable and usable here in the United

22 States.


1 So, do you have a view on that?

2 On use of non-U.S. approved reference products

3 for some or all of the data packets that would

4 come to the U.S. for approval and any problems

5 you've seen with the approved biosimilars in

6 Europe that should give us pause?

7 DR. SIEGEL: Well, with regard to

8 the first part of your question, you know, the

9 issue will depend on how similar the reference

10 product is to the product sold in the U.S.

11 That's a determination I suppose could be

12 made.

13 It does raise certain pragmatic

14 issues. Because if you can approve a product

15 on the basis of being similar to a product

16 that's marketed in Europe but not in the U.S.,

17 than that product that's marketed in Europe

18 but not in the U.S. would also seem to be

19 indirectly deemed to be marketable in the U.S.

20 because it's quite similar to itself.

21 Could a European product show

22 biosimilarity to itself and thereby get


1 approved in the U.S.? That's a question I

2 think that would arise.

3 I think the second part of your

4 question was --

5 DR. JENKINS: Whether you're aware

6 of any problems that have been identified with

7 the European approved biosimilars? Safety

8 problems, efficacy problems, immunogenicity

9 concerns?

10 DR. SIEGEL: Yes, and I alluded to

11 one of those which is erythropoietin that was

12 approved only for use by the intravenous route

13 which subsequently was tested by the

14 subcutaneous route to support potentially that

15 use and in the subcutaneous route, there were

16 a couple of cases of PRCA which is a far

17 higher incidence than when it's used with the

18 innovator product and so, that was not

19 approved.

20 As to approved uses and

21 indications, I'm not aware of any problems

22 that have arisen. That was pre-market testing


1 that determined that.

2 DR. BEHRMAN: Dr. Kozlowski.

3 DR. KOZLOWSKI: Dr. Siegel, you

4 mentioned mechanism of action is not

5 sufficient to extrapolate indications and you

6 listed some potential factors. So, do you

7 feel that if there's appropriate consideration

8 of the right risk-based factors that

9 indications can be extrapolated?

10 DR. SIEGEL: Yes, I didn't mean to

11 imply that if any of those factors exist you

12 need to do full and complete clinical trials.

13 I think this is a matter of scientific

14 judgment. I think careful consideration needs

15 to be given to any of those potential

16 differences in the indication. You know,

17 we've gone from a immunosuppressed population

18 to an immunocompetent population. Might there

19 be an immunogenicity.

20 What would be needed clinically or

21 otherwise to address those. So,

22 extrapolation, it could be possible, but not


1 simply based on mechanism of action.

2 DR. KOZLOWSKI: And another

3 question. You mentioned a standard -- you

4 know, as similar is reasonably possible and

5 you stated one of the purposes of that is to

6 avoid intentional changes. But, as similar as

7 reasonably possible will vary with the type of

8 product, how easy it is to characterize, its

9 complexity.

10 So, do you envision, therefore,

11 very different standards across different

12 products?

13 DR. SIEGEL: Well, not

14 necessarily. I think as the law envisions,

15 there may be some classes where as similar as

16 reasonably possible cannot meet the standard

17 of excluding clinically meaningful differences

18 and you may not be able to go there.

19 I do think, however, that there

20 will be cases where standard may even in that

21 sense migrate over time. Where it might be

22 acceptable to have certain types of


1 differences, but as one learns how to avoid

2 those differences, you know, it might be

3 acceptable and it might create a risk that as

4 I said is a risk that can managed with some

5 amount of clinical testing, the

6 pharmacovigilance. But, if it can be avoided,

7 it should be avoided.

8 MS. ESPOSITO: Dr. Siegel, in your

9 presentation, you indicated that early and

10 transparent guidance from the Agency would be

11 very useful to the industry.

12 Has Johnson & Johnson given

13 thought to what topics would be most useful

14 and what topics you believe would facilitate

15 the use of the biosimilars pathway in terms of

16 issuing early guidance?

17 DR. SIEGEL: Well, I don't know

18 that we have a company position on that, but

19 I would say this -- and, of course, some of

20 the comments yesterday I think we all know

21 that the law appropriately precludes guidance

22 delaying the FDA's ability to implement, which


1 we support and also regarding another comment,

2 we all know that guidance is guidance. It's

3 not binding.

4 But, one area, you know, if you --

5 one of the things they talked about is product

6 specific guidance and I think in that regard

7 it is through the experience of making a

8 product, through the experience of seeing

9 variations in that product, the experience of

10 clinical testing, that one develops insights

11 that often go beyond the published

12 specifications about what really matters in

13 terms of the quality of the product. We

14 believe that the sponsor can communicate that

15 information through an open process to the FDA

16 that will assist the FDA in assuring that the

17 biosimilars manufacturers know what they need

18 to do.

19 So, that's an area in particular

20 that we'd have interest in doing.

21 MS. ESPOSITO: One follow-up

22 question. Are there particular product


1 classes that you would view as ripe for early

2 guidance from the Agency?

3 DR. SIEGEL: Well, I think that it

4 would be a general and reasonable expectation

5 that policy would begin with some of the

6 simpler, smaller, less complicated in

7 structure biologics.

8 That's what has happened in Europe

9 and Europe is now having discussions for

10 policy development regarding antibodies.

11 But, I do think that it's not a

12 bad idea to start with those better defined,

13 better characterized antibodies and products

14 and so, that would probably be the first

15 places to look to issue guidance. But, part

16 will be what demand you're seeing in terms of

17 what companies want to make biosimilars for.

18 DR. BEHRMAN: I'm going to ignore

19 the red light and ask you one question. Do

20 you have any comments on the discussions we

21 had yesterday on drift in terms of

22 interchangeability?


1 DR. SIEGEL: Yes. Products can

2 drift apart. Products that are the same can

3 drift apart. Products manufactured by the

4 same company in two different facilities can

5 drift apart. That's something that we pay

6 close attention to monitoring for.

7 Even when you do comparability

8 testing, comparability is not transitive.

9 Meaning, you know, A may be biosimilar to B or

10 interchangeable with B. But, when A becomes

11 A prime, they may be comparable. A double

12 prime may be comparable to A prime, but you

13 can no longer know that A double prime is

14 interchangeable or similar to B.

15 Because depending on the nature of

16 comparability, it generally will allow some

17 margin. If you're talking PK20 to 20 percent

18 in PK parameters, the next change may also

19 increment change and other drifts occur over

20 time.

21 So, I do think it's an important

22 issue. I think it's an important issue for


1 interchangeability. Because

2 interchangeability requires a determination at

3 a single point in time that they're

4 interchangeable and that switching is safe.

5 I think consideration needs to be given as to

6 whether that will hold up over time.

7 I do not think the solution as one

8 speaker proposed, however, is to therefore not

9 let products change once there is a biosimilar

10 on the market. Many of the changes reflect --

11 how products are made reflect new technologies

12 that often bring new efficiencies and if we're

13 interested in affordability, we shouldn't be

14 locking into old technologies for our

15 products.

16 DR. BEHRMAN: Okay. Thank you for

17 your comments.

18 DR. SIEGEL: You're welcome.

19 Thank you.

20 DR. BEHRMAN: Our next speaker is

21 James Roach from Momenta Pharmaceuticals.

22 DR. ROACH: Good morning. I am


1 Jim Roach, Chief Medical Officer at Momenta

2 Pharmaceuticals.

3 Momenta is a biotechnology company

4 that belongs to both GPhA and BIO and we

5 develop analytical tools and methods that

6 advance the science of thorough product and

7 process characterization and knowledge.

8 We apply these methods to develop

9 generic versions of complex products such as

10 enoxaparin and glatiramer acetate and also to

11 develop biosimilar and potentially

12 interchangeable products.

13 We seek to further define product

14 structure and use this enhanced product

15 knowledge to lead to an increased

16 understanding of structure function and

17 process product relationships, tighter control

18 of process development and greater assurance

19 of purity, potency and sameness.

20 We believe that innovation in the

21 analytical methods and tools offers the

22 biologics industry the opportunity to improve


1 the quality of all biologics whether branded

2 or biosimilar. A goal that all should pursue.

3 The industry has historically

4 taken the approach to characterizing proteins

5 by evaluating identity, size, charge and

6 glycosylation profile into various methods.

7 We believe generally this is limited and

8 perhaps doesn't capture the complexity of most

9 glycoprotein products.

10 Though it is beyond the scope of

11 this forum to delve into a detailed technical

12 presentation, or spend too much time on slides

13 like this, we believe that the ability does

14 exist to much more thoroughly characterize the

15 entire structural space of the biologic by

16 applying a variety of additional and

17 orthogonal high resolution analytical methods

18 and data integration techniques.

19 As an example of how this

20 technology may be applied, I would refer you

21 to a paper being published in the next week or

22 two in Nature Biotechnology entitled Chinese


1 Hamster Ovary Cells Can Produce Galactose-

2 Alpha-1,3-Galactose Antigens on Proteins by

3 Carlos Bosques, Brian Collins, James Meador,

4 et al.

5 Patient access to biologics is

6 increasingly limited by high cost and growing

7 demand. Many emphasize the potential risks to

8 patients if we rush too quickly to bring

9 biosimilars to the market.

10 However, equal emphasis should be

11 placed on the potential benefit to patients by

12 implementing the pathway in a way that ensures

13 the introduction of safe and effective

14 biosimilars into the marketplace.

15 The BPCI Act offers the

16 opportunity to extend the significant benefits

17 that the Hatch-Waxman legislation provided to

18 patients in need of biologics by permitting

19 appropriate reliance on what is already known

20 about an existing biologic. Unnecessary

21 duplication of human or animal testing can be

22 avoided and access to these potentially life


1 altering or lifesaving medications will be

2 significantly increased.

3 With this in mind, I would like to

4 emphasize the following points. If the rules

5 establish burdensome limitations on the

6 application of new scientific approaches, the

7 goals of this legislation will be undermined

8 and investment will be further directed away

9 from the development of technologies intended

10 to enhance product understanding and safety.

11 The Agency's statutory scientific

12 discretion was presumably enacted for

13 precisely this purpose: To accept

14 applications that may offer new solutions and

15 scientific approaches to the traditional drug

16 development paradigm.

17 It is critically important to

18 allow the Agency the broad scientific

19 discretion needed to make determinations on

20 data required for approval on a case-by-case

21 basis and not to implement unnecessary

22 obstacles to use of the pathway such as


1 issuing guidances which perhaps mandate

2 certain requirements for approval.

3 To offer the most potential

4 benefit to patients, the Agency's

5 implementation of the BPCI Act must allow for

6 the practical and feasible development of both

7 biosimilars and potentially interchangeable

8 biologics. It will only make sense for

9 companies to pursue approval via the 351(k)

10 pathway if requirements for pre-clinical and

11 clinical studies are reduced relative to a

12 traditional BLA pathway.

13 The degree of analytical data and

14 knowledge of product quality attributes will

15 help to inform the Agency in deciding the

16 nature and scope of pre-clinical and clinical

17 trials required to support approval.

18 The state of the science with

19 respect to the enhancement of product

20 understanding has evolved considerably in the

21 last decade and will continue to do so. We

22 need to set policy that is flexible enough to


1 allow the Agency to consider scientific

2 advancements on an ongoing and real-time

3 basis.

4 Pre-clinical and clinical trials

5 clearly have an essential role in assuring the

6 safety and efficacy of novel products. It is

7 certainly appropriate for both pre-clinical

8 and clinical trials to potentially play a role

9 in determination of similarity.

10 However, this data requirement

11 should be implemented in the context of the

12 existing product knowledge data set. Clinical

13 trials could be positioned as supportive and

14 designed to provide adequate safety and

15 efficacy information to establish

16 comparability to the reference product.

17 These trials must also be feasible

18 to conduct. Establishing statistical non-

19 inferiority or equivalence of a biosimilar

20 relative to a branded product in clinical

21 studies may be impractical for many products

22 and indications.


1 Additionally, switching studies to

2 assess the potential immunogenicity, efficacy

3 and/or safety of a biosimilar relative to a

4 branded product may neither be feasible nor

5 particularly informative in certain

6 circumstances.

7 Immunogenic responses and other

8 safety-related issues may not manifest

9 themselves until well after initial exposure

10 making it difficult to determine the product

11 that may be causing a biological response and

12 similarly biological efficacy may be the

13 result of a long-term cumulative affect with

14 exposure. Again, making it difficult to

15 envision the concept of switching. For

16 example, in oncology studies designed to

17 demonstrate an effect on survival.

18 There is certainly lessons to be

19 learned from novel biologics as to how

20 similarity and comparability may be defined.

21 It is important to recognize that existing

22 products may exhibit a considerable amount of


1 lot-to-lot variability for a number of product

2 quality attributes.

3 However, as long as each lot falls

4 within certain predefined specifications for

5 these variables, they are considered the same

6 or sufficiently similar to be interchangeable

7 and treated as the same.

8 We believe that the principles

9 articulated in the ICH Q5E Guidance on

10 Comparability of Biologic Products are very

11 relevant to determining the type of data that

12 may be required case-by-case to support

13 approval of a biosimilar product.

14 To quote the guidance,

15 "Determinations of product comparability can

16 be based solely on quality considerations if

17 the manufacturer can provide assurance of

18 comparability through analytical studies and

19 additional evidence from non-clinical or

20 clinical studies as appropriate when quality

21 data are insufficient to establish

22 comparability."


1 We support this approach. As the

2 comparison of a very thoroughly characterized

3 biosimilar to a reference product can be

4 thought of in many instances as analogous to

5 the comparison between a pre-change and post-

6 change product. The burden, of course, will

7 be on the sponsor to demonstrate that the

8 variability of the biosimilar or potentially

9 interchangeable product falls within a

10 comprehensive set of prospectively defined

11 product quality attributes so that one can

12 reasonably expect that the product will have

13 the same clinical activity as the brand

14 product.

15 Biotechnology companies that have

16 successfully commercialized products are often

17 referred to as innovators. Many of these

18 companies state the process is the product and

19 replicating biologics is impossible and appear

20 to be advocating for policy requirements that

21 if implemented could effectively render the

22 351(k) pathway unusable. Many people stated


1 that replicating enoxaparin was impossible as

2 well.

3 I find it interesting generally

4 that an industry which has always prided

5 itself on innovation and the ability to solve

6 complex problems is to quick to emphatically

7 conclude that something is impossible and

8 can't be done.

9 I submit that the technology

10 platforms that we and other biotechnology

11 companies have developed in the interest of

12 advancing product knowledge are every bit as

13 innovative as more traditional drug

14 development platforms and if appropriately

15 applied and supported have the potential to

16 translate into very substantial benefit to

17 patients.

18 So, in summary, there's no arguing

19 with the concept that patient safety is of

20 paramount concern. However, this phrase is

21 often positioned to support the foregone

22 conclusion that comprehensive non-clinical and


1 clinical trials must, therefore, be conducted

2 to ensure patient safety.

3 I submit that the patient is of

4 paramount concern and we may not be

5 benefitting patients by conducting redundant

6 and arguably unethical trials should criteria

7 for similarity and/or sameness be otherwise

8 met.

9 I sincerely hope that as the

10 debate moves forward that sound bites and

11 rhetoric will be replaced with fact,

12 objectivity and solid science that enables the

13 use of this pathway in a responsible way.

14 Although the pathway presents

15 challenges to both sponsors and regulators, it

16 also presents a tremendous opportunity for all

17 involved. Most importantly patients.

18 In conclusion, I would like to

19 borrow a quote from a presentation given by

20 Dr. Daniela Verthelyi, Chief of Laboratory of

21 Immunology in the Division of Therapeutic

22 Proteins and OBP at FDA.


1 "The regulatory process must

2 render a balance between the desire for

3 rapidly available novel therapeutics and the

4 need the carefully evaluate potential safety

5 risks and clinical efficacy."

6 We agree, and hope the Agency

7 finds these comments useful as you move

8 forward to implement the BPCI pathway and

9 thank you very much.

10 Happy to answer any questions.



13 Dr. Kozlowski.

14 DR. KOZLOWSKI: Dr. Roach, one

15 should use a standard of within manufacturer

16 comparability for doing a biosimilar

17 evaluation and the previous speaker mentioned

18 in his presentation some issues that are

19 different like access to intermediates.

20 So, could you comment a little on

21 the actual differences or lack of differences

22 in your view within manufacturer change and a


1 biosimilarity evaluation?

2 DR. ROACH: Sure. It's a great

3 question and I think we would have to evaluate

4 certainly on a product by product basis the

5 differences that we're observing.

6 But, I think the main point is if

7 you can apply analytical technologies at

8 various points in time in process development

9 with your own biosimilar, you learn certain

10 things about how the process may affect the

11 product. Such that by the time you get to

12 drug product, you can see certain structural

13 fingerprints that you think perhaps were

14 influenced by the process.

15 So that, by the time you get to

16 drug product through these learnings, you may,

17 in fact, have a drug product that may be more

18 similar to the reference product that the

19 differences you observed between lot-to-lot in

20 the reference product.

21 Obviously, this is an evolving

22 science, but that's kind of how I would


1 approach it.

2 DR. KOZLOWSKI: So, to follow up,

3 that assumes that you can characterize

4 anything of importance.

5 DR. ROACH: I don't know that I

6 want to be so bold as to make that statement

7 here today, but what I will say is that our

8 technology platform and I'm sure other people

9 that are working on this bring a whole other

10 degree of resolution to these compounds.

11 DR. KOZLOWSKI: And to follow up

12 on another note, in your first slide, you had

13 sort of Dr. Nasr's wheel of quality by design.

14 DR. ROACH: Yes.

15 DR. KOZLOWSKI: And I think the

16 concept of more advanced pharmaceutical

17 manufacturing that can deliver targeted sets

18 of attributes very consistently I think is

19 something the Agency would like everybody to

20 do. You know, innovators and biosimilar

21 industries.

22 And I guess if manufacturing can


1 really advance to be much more targeted, how

2 do you think that relates to the question of

3 drift? Because that's something which has

4 come up I guess yesterday and today.

5 DR. ROACH: No, absolutely and I

6 think I made the point early on that I think

7 these technologies that we and others are

8 working on can be applied certainly both to

9 development of biosimilars and to ensure a

10 higher degree of quality for branded products.

11 So, to me the product drift

12 question, I think if I'm the manufacturer, I

13 would embrace these kind of technologies to

14 ensure that your product is not drifting very

15 much rather than to try and position it as

16 what happens if you get a biosimilar on the

17 market and the reference product drifts.

18 To me, the problem or the

19 potential situation could be that there's more

20 issues with product drift than there is from

21 the biosimilar being comparable to the

22 reference product that's approved.


1 DR. BEHRMAN: Dr. Jenkins.

2 DR. JENKINS: I'd like to follow

3 up on some of your comments about the role of

4 clinical data.

5 You said that clinical trials in

6 this context should be positioned as

7 supportive to the existing data set and

8 designed to provide adequate safety and

9 efficacy information to establish

10 comparability to the referenced product.

11 We heard a lot of comments

12 yesterday from patient groups and prescribers

13 that they wanted to be very certain that the

14 biosimilar would be highly similar to the

15 clinical effect of the branded product. So,

16 I'm interested, how do you reconcile those two

17 viewpoints as far as where we should set the

18 bar on determining the role of the clinical

19 trials in establishing, you know, that there's

20 no clinically meaningful difference as the

21 statute requires between the biosimilar and

22 the reference product?


1 DR. ROACH: Yes. Well, I do think

2 again it would be on a case-by-case basis.

3 But, I also think that as you

4 develop more product knowledge through various

5 analytical and biocharacterization techniques,

6 we can't underestimate the benefit to

7 patients, right, by getting the products on

8 the market without having to replicate trials

9 conducted by the sponsor or in some instances,

10 quite frankly, depending on how you set this,

11 you could envision a scenario where if you're

12 requiring establishment of non-inferiority or

13 equivalence, you might end up having to run a

14 trial that's 4X or 5X greater in size than

15 what the innovator needed to do to get the

16 product approved in the first place.

17 So, I would emphasize that the

18 burden is clearly on the sponsor to make the

19 arguments as to why it is that their

20 collective package including, you know,

21 certainly all the analytical and

22 biocharacterization data, in vivo data animal


1 studies support a more limited clinical data

2 set.

3 At the end of the day, I think

4 everybody needs to be very comfortable with

5 the understanding that if sponsors are

6 presenting package X and the FDA has reviewed

7 it and in your opinion based on this

8 collective data set, it's safe and effective,

9 I mean I think you'll be the ultimate arbiter

10 of where you draw the line based on that

11 package.

12 But, I do think it's possible to

13 provide a limited clinical data set in

14 conjunction with the entire existing data

15 package to get a product approved.

16 DR. JENKINS: There is a model

17 that's used in the Office of Generic Drugs in

18 certain situations where you can't determine

19 bioequivalents for small molecules based on

20 either pharmacokinetics which is their

21 preferred approach or pharmacodynamics.

22 DR. ROACH: Yes.


1 DR. JENKINS: They do use clinical

2 trials in some settings such as for topical

3 products.

4 Are you familiar with that model

5 and if you are, do you have any thoughts how

6 that should apply to biosimilars?

7 DR. ROACH: I'm only vaguely

8 familiar with that model. I understand the

9 model in concept, but I think the concept

10 still applies that you work out -- you know,

11 the sponsor will propose a study that they

12 think makes sense in conjunction with their

13 package to support approval.

14 Above and beyond that, I guess I'm

15 not that, you know, familiar with the

16 specifics of the model.

17 But, it is a limited -- it's not

18 necessarily the same kind of study that de

19 novo you would be obviously putting forth for

20 an NCE.

21 DR. KOZLOWSKI: One more follow up

22 on that.


1 So, you do mention that there

2 should be supportive clinical trials, but you

3 suggest a non-inferiority trial or a two-sided

4 equivalence trial or a switching trial may be

5 inappropriate.

6 So, I guess I'm wondering what

7 would you envision the design of a supportive

8 trial other than those looking like?

9 DR. ROACH: You know, how much is

10 enough and where do you set the bar I think

11 relative to the package that you submit?

12 I guess to be clear, I'm not

13 suggesting that non-inferiority or equivalence

14 are necessarily not appropriate for products

15 like this, but it may be, as an example, how

16 you define the non-inferiority or equivalence

17 margin for a product like this relative to an

18 NCE. Might you allow a wider margin as an

19 example to provide evidence of comparability.

20 DR. BEHRMAN: Just a quick

21 question on your slide eight. It seems to

22 imply that you believe that interchangeability


1 can be established without any clinical data.

2 Is that your position?

3 DR. ROACH: I guess my position is

4 I would like to believe that over time as the

5 science evolves that it's certainly possible

6 at some point in time and maybe for some

7 products very soon and maybe for others not so

8 soon that possibility exists and so, my main

9 point was more to allow the policy to be

10 flexible enough to able to respond to that

11 kind of data package.

12 DR. BEHRMAN: That's very helpful.

13 Thank you for your comments.

14 DR. ROACH: Thank you.


16 Dirk Reitsma from PPD.

17 DR. REITSMA: Good morning. My

18 name is Dirk Reitsma. I am the Vice President

19 of Global Product Development at PPD and I

20 would like to thank the FDA and particularly

21 the panel for this public comment meeting on

22 the Approval Pathway for Biosimilar and


1 Interchangeable Biological Products.

2 As a Global CRO, PPD has become

3 involved in the development of biosimilars and

4 to further the interest of our clients, we

5 hope to be able to contribute to the

6 discussion about feasible trial designs for

7 the developments of biosimilar and

8 interchangeable biological products.

9 We were curious what would happen

10 if you actually tried to design a biosimilar

11 trial to show interchangeability. We wanted

12 to find out if it would be feasible numbers-

13 wise and what the assumptions would be that

14 you would need guidance on as you went

15 through.

16 So, the key definitions that we

17 took were that an interchangeable obviously

18 first has to be a biosimilar which means it

19 has to be highly similar as the definition

20 states with minor differences in clinically

21 inactive components. There should be no

22 meaningful differences in safety, purity, or


1 potency, and that the same mechanism, vaccinal

2 mechanism, actions should apply as the

3 referenced biologic product.

4 So, once the biosimilarity has

5 been established, you would then add the

6 criteria that if administered more than once

7 or switched, there would be no decrease, no

8 loss of safety or activity or increase of

9 immunogenicity as compared to the reference

10 biologic product.

11 And so, the first point that we

12 discussed was the switch itself. We assumed

13 that that meant the patient would be receiving

14 one treatment and then would be switched to

15 the other and for the purpose of the

16 discussion, the exercise, we said the patient

17 would switch once. We didn't go into

18 alternating back and forth and we also didn't

19 think that that would be as common a clinical

20 situation.

21 We also discussed the point at

22 which you would switch. You'd need to switch


1 at a point when the patient had had adequate

2 exposure to the first compound before going to

3 the second one, but they would also have to

4 have sufficient exposure to the second

5 compound before they had their assessment.

6 So, the timing of the switch is

7 something that you would need to discuss and

8 need to understand.

9 As Dr. Chow pointed out yesterday,

10 there are issues about the pharmacokinetic and

11 pharmacodynamic profiles of biosimilars that

12 you would need to take into account. By and

13 large, the first generation of biosimilars has

14 been characterized for having a short half-

15 life and in many cases, you're able to explore

16 single dose pharmacokinetics and single dose

17 pharmacodynamics. Which does allow cross-over

18 designs which are feasible and which should be

19 conducted particularly if the subject can

20 serve as their own control. It allows for

21 fairly compact designs.

22 On the other hand, the monoclonal


1 antibody biosimilars that are coming through

2 tend to be characterized by having a long

3 half-life. Because of the indications being

4 treated, there's the need to sustain minimal

5 blood levels so that you cannot stop and have

6 a washout period between repeated

7 ministrations. Not always feasible and so,

8 that means that a perfectly satisfactory trial

9 design may not always be possible.

10 But, in going through this

11 exercise, we did refer back to some of Dr.

12 Chow's publications.

13 So, on the interchangeability

14 criteria, the ones that we focused on for this

15 exercise were, of course, safety. Any

16 clinical trial needs to have safety first and

17 foremost and then we also took into account

18 pharmacokinetic and pharmacodynamic

19 comparability as well as activity or efficacy

20 for the clinical.

21 We didn't take into account non-

22 clinical or manufacturing comparability


1 although we understand that the degree of

2 comparability influences the type of clinical

3 trial you would do and the type of data you'd

4 go after. Particularly, if you don't have

5 very tight comparability, you might even need

6 to do some sort of dose escalation before you

7 actually compare the drug at the level the

8 referenced drug is used at and there have been

9 many comments at this meeting about the impact

10 of product variability on the selection of

11 which biologic reference compound which you

12 use.

13 So, this outlines our thoughts on

14 the trial design for interchangeability.

15 Because it's a clinical trial, it has to be

16 relatively simple and robust. What we

17 selected was the four parallel design trial

18 with a crossover point in two of the arms and

19 the crossover point is somewhat arbitrary, but

20 we selected that to be at steady state because

21 then at least there would be full exposure to

22 the minimal trough level for the first


1 compound.

2 And so, we have four sequences.

3 The first two sequences are that the patient

4 stays on the reference compound so it goes

5 from to A to A past the switching point. The

6 second is that the patient receives the

7 biosimilar all the way through going from B to

8 B through the switching point.

9 And then we have the two switch

10 arms. So, the one that we thought was most

11 clinically relevant was the switch from the

12 reference compound to the biosimilar since

13 that is probably what would happen most often

14 in practice. But, we also thought that once

15 the biosimilar's available patients might

16 start out on the biosimilar, have a

17 disappointing benefit or result from being on

18 the treatment and might be switched to the

19 reference compound. So, we felt that to be

20 complete we should include that change in the

21 trial as well.

22 Just as a model to get our heads


1 around, we selected a rheumatoid arthritis

2 model because it has fairly early and clear

3 outcome and we selected Humira as the drug to

4 think about which gives us a switching point

5 for steady state at about 12 weeks.

6 So, the endpoint we selected was a

7 measure of joint inflammation, ACR 20,

8 response at 24 weeks. Of the

9 interchangeability endpoints that we could

10 pick from acute and chronic safety, early

11 activity and immunogenicity, for the purposes

12 of this exercise, we looked at early activity.

13 So, if you would power the trial

14 at 80 percent and you were to take a 5 percent

15 significance level and an equivalence margin

16 which you probably need to do with a compound

17 like this where you could go up in dose and

18 perhaps increase the activity, of 12 percent

19 which is half of the lower limit of the 95

20 percent confidence interval of the difference

21 between Humira and placebo in the original

22 trials, and we did a pulled analysis for this,


1 if you do all of that, you come up with a

2 sample size of exactly 1228, but about 1200

3 patients.

4 So, we then asked what would

5 change about that because you want to try to

6 get your head around whether these trials

7 would even be feasible. If you went from

8 equivalence to non-inferiority in this

9 setting, you would drop the patients sample

10 size by about 300.

11 Depending on the type of analysis

12 you do, the patient numbers could go up. We

13 assumed a sequential analysis where you would

14 first do the biosimilarity comparison. Then

15 compare the reference to biosimilar switch and

16 then the biosimilar to reference switch.

17 If you want to do a really deluxe

18 trial and you wanted to do 90 power and you

19 wanted to do a multiplicity analysis where you

20 could do all the comparisons, your trial would

21 end up being about 2,000 patients and that

22 would be about 2 to 4 times the size of trials


1 we're seeing for biosimilarity in these

2 indications.

3 So, I think what we and our

4 clients would benefit from as priorities

5 through guidances is first good guidance on

6 what needs to be demonstrated for PK and PD

7 and clinical comparability in

8 interchangeability and then also in non-

9 clinical and manufacturing in order to set the

10 type of clinical trials you would need to do

11 in the first place.

12 We then would need to know what's

13 acceptable as far as the reference compound

14 goes. There's been a lot of discussion about

15 that, whether ex-U.S. base could be taken.

16 And then specifically as it was

17 referenced this morning, there are guidelines

18 in existence for the earlier biosimilars, but

19 there are no guidelines yet for monoclonal

20 antibody. So, we'd be very eager to receive

21 those as well.

22 Thank you for your attention.




3 I have one. You made a decision

4 to think about only a single switch.

5 DR. REITSMA: Yes.

6 DR. BEHRMAN: Although that's not

7 quite what the statute anticipates and

8 certainly, we have said publicly we're very

9 concerned in terms of the way health care is

10 delivered in this country. That switching, in

11 fact, would be repeated.

12 Can you explain a little bit why

13 you chose a single switch?

14 DR. REITSMA: Basically, it was to

15 get through a feasibility exercise. We

16 weren't sure when we started out whether we

17 would even come up with a number that would

18 work. Because in our experience in modeling

19 these studies, you sometimes come up with very

20 high numbers.

21 I'm not sure whether the numbers

22 per se would change very much if you allowed


1 alternating. It was just for the ease of

2 setting the switching points so that we could

3 get on the exercise that we picked one.

4 DR. BEHRMAN: Dr. Kozlowski and

5 Dr. Jenkins.

6 DR. KOZLOWSKI: The calculation

7 you I assume would have been valid had these

8 products not had any biochemical similarity

9 demonstrated. It was basically what you would

10 need to do to compare switching from one

11 product to another.

12 So, I want to ask do you think

13 there is any way in which the prior knowledge,

14 you know, as you mentioned, the level of

15 characterization and the level of similarity

16 could somehow be utilized in the design of the

17 clinical trial?

18 DR. REITSMA: I think that is a

19 very interesting and a very relative question

20 and I think it's something that I hope to see

21 as we get more into development of

22 biosimilars. Which is being able to take the


1 existing information as it was discussed

2 yesterday and again this morning and

3 incorporating that into your assessment of

4 biosimilarity and interchangeability and

5 perhaps even extrapolation and obviously,

6 Bayesian techniques would lend themselves very

7 well to that.

8 So, I would be very interested to,

9 you know, take some of that information and

10 see what modeling would deliver on that and

11 whether it would save you significantly on

12 sample size.


14 DR. JENKINS: Staying on that same

15 slide where you developed a model for both

16 biosimilarity and interchangeability, I was

17 confused. Are you thinking that would be 24-

18 week study or a 48-week study? So, just

19 taking you're doing to A to A. You switch it

20 24 weeks or you switch it 12 weeks?

21 DR. REITSMA: The switch in this

22 example would be at 12 weeks because that's


1 more or less when steady stage is reached and

2 we picked the 24-week endpoint as something we

3 would measure across the arms for the primary

4 activity.

5 In reality, the trial would

6 probably continue. You would look at the time

7 code of response to make sure that that was

8 the same because that's well known and there

9 are many ancillary measures you would take

10 including PK/PD measures to support the

11 biosimilarity and interchangeability of the

12 compound.

13 DR. JENKINS: We heard a comment

14 earlier about concerns that the standards for

15 biosimilars might lead to a program that so

16 much larger than what it took to get the

17 innovator approved and it might drive people

18 away from the 351(k) pathway.

19 I don't know how much data were

20 required for the original Humira approval, but

21 what's your thinking about whether this would

22 be such a large trial that might drive


1 sponsors away from this pathway.

2 DR. REITSMA: It is possible if

3 you can't apply mitigating factors to bring

4 the trial size down and I'd be surprised if

5 you couldn't do that because now we just look

6 at the clinical data.

7 Generally, when a drug gets

8 approved, there are more studies done

9 obviously than just the pivotal study. In

10 this development, the pivotal study itself may

11 be bigger than individual pivotal study for

12 some of the originator approvals, but I think

13 the total size of the program by the nature of

14 the biosimilarity development and the spirit

15 of that might still be smaller.

16 DR. BEHRMAN: Other questions?


18 DR. REITSMA: Thank you.


20 Anshuman Patwardhan.

21 DR. PATWARDHAN: Good morning,

22 everyone.


1 My name is Anshuman Patwardhan.

2 I'm here representing Dr. Reddy's

3 Laboratories.

4 I would like to begin by thanking

5 by FDA for giving us a chance to put forward

6 some of our thoughts on the biosimilars

7 pathway in the United States.

8 Dr. Reddy's is a diversified

9 health care organization with global presence

10 and the United States is our largest market.

11 The biologics business of Dr.

12 Reddy's is currently focused on biosimilars

13 where our business strategy is quite simple.

14 We plan to and will launch our biosimilars in

15 every market where the unmet is defined by

16 either limited patient access to lifesaving

17 medications as is the case in emerging markets

18 or there is a disproportionate cross burden on

19 the health care system as in the case in many

20 developed markets.

21 This slide shows an overview of

22 our biosimilars pipeline. We specialize in


1 tackling complex biologics. Our GCSF and

2 rituximab are already marketed in Asia, Latin

3 America, Middle East and the CIS bloc and our

4 darbepoetin alfa has recently been launched in

5 India.

6 As many of you might know, we have

7 been the first in several of these markets to

8 have gained an approval for a similar version

9 of the originator product and have made

10 significant impact on patient access in these

11 countries as I'll show in my next slide.

12 We launched our GCSF in India in

13 2001. Today, with ten-plus place in the

14 market, the number of cancer patients

15 receiving GCSF has increased more than 30-fold

16 in India. Similarly in case of rituximab,

17 just within three years of launch of our

18 Reditux brand, the number of patients

19 receiving this lifesaving therapy has already

20 gone up more than sixfold in India.

21 The evidence is indisputable.

22 Competition does lead to patient benefits


1 especially in countries like India where there

2 is a wide income disparity and individuals

3 have to bear practically the entire burden of

4 the cost of therapy. Pharmaceutical

5 monopolies really have no reason to insure

6 affordability of drugs even for lifesaving

7 mediations.

8 The only way to make this happen

9 is for regulatory agencies to create science-

10 based pragmatic regulatory frameworks that can

11 encourage healthy competition in the

12 marketplace. We think that the United States

13 is not too different from India in this

14 regard.

15 In fact, the best example of this

16 phenomenon is right here in our backyard where

17 the FDA's implementation of the Hatch-Waxman

18 law has demonstrated amazing efficiency of the

19 U.S. market and has saved the system literally

20 hundreds of billions of dollars.

21 Before I move into our positions,

22 I wanted to leave you with some snapshots from


1 the basis of the original approval of Reditux

2 in India which was based on a limited single-

3 arm clinical trial, but with the expectation

4 of an extensive post-marketing surveillance in

5 which we now have close to a thousand

6 patients.

7 The figure on the left shows that

8 the objective response rate with Reditux in

9 patients with an aggressive form of non-

10 Hodgkin's lymphoma is highly consistent with

11 that shown with the originator product and the

12 graph on the right shows our post-marketing

13 surveillance data where we continue to see not

14 a single case of immunogenic response in any

15 patient.

16 The point I'm trying to make is

17 that today's advancement in process and

18 analytical sciences, it is possible to design

19 biosimilars to be therapeutically

20 indistinguishable from the RMP. Thus, health

21 care cost savings and patient benefits are no

22 longer expected to be mutually exclusive


1 propositions assuming that the regulatory

2 framework for the approval of biosimilars is

3 made competition-friendly based on science,

4 common sense and pragmatic approach to risk

5 benefit for the patient.

6 With that preamble, I would like

7 to now present our position on three key

8 questions that we have chosen to speak about

9 today.

10 Question A3 asks, "What the

11 acceptable range of structural differences may

12 be in the absence of any clinically meaningful

13 differences?"

14 We believe that the goal of

15 clinical testing is to separate relevant

16 structural differences from irrelevant ones.

17 Presuming that the development was designed to

18 present a biosimilar product via the use of

19 identical host species to produce identical

20 amino acid sequence and a highly similar

21 glycosignature.

22 Thus, while similarity in the key


1 critical quality attributes should be a pre-

2 condition for IND approval, we believe that

3 minor differences in post-translational

4 modifications need not serve as a hurdle to

5 begin clinical testing and we want to

6 reiterate this is for beginning the clinical

7 testing not for the approval of the product.

8 So, here we have shown an example

9 of how such differences in post-translational

10 modifications may be delineated by the FDA on

11 the basis of key considerations. Such as, the

12 presence of all isoforms in the biosimilar

13 that are present in the RMP, no introduction

14 of any new isoform for the first time in the

15 biosimilar, in the presence of all mechanisms

16 of action in the biosimilar and finally, a

17 detailed explanation and investigation of any

18 quantitative structural differences by the

19 biosimilar sponsor along with the adequate

20 justification of how these differences may not

21 lead to any clinically meaningful differences.

22 We'll go on to the next question.


1 Question A4 asked, "When can animal toxicology

2 studies not considered necessary?"

3 Well, we know that animal tox

4 studies are not statistically powered and do

5 not always predict clinical toxicity. Even

6 so, we believe that their use as a

7 prerequisite to clinical trials may be

8 justified in case of novel biologics where

9 significant potential risks exist from unknown

10 unknowns.

11 For biosimilars, however, which

12 have been demonstrated to be highly similar to

13 the RMP and the RMP itself has had a long

14 history safe human use, the value of requiring

15 unpowered animal tox studies as a prerequisite

16 for clinical trials in our opinion is marginal

17 and especially so when the biosimilar has

18 already been marketed in other jurisdictions

19 where it has gathered significant clinical

20 post-marketing safety, efficacy and

21 immunogenicity data.

22 We believe that the only time non-


1 clinical tox studies may be justified is when

2 there exists a relevant animal model for the

3 indication that can differentiate between the

4 toxicities of two highly similar molecules.

5 An example of this may be a case

6 where a mouse model is found to be relevant

7 and can ethically be used with sufficient

8 power.

9 Moving on to the last question on

10 our list, Question D asked "When would studies

11 against RMP approved in other jurisdictions

12 may be considered acceptable to the FDA?"

13 We all know that clinical costs

14 represent by far the largest proportion of the

15 cost for biosimilars development and that the

16 burden of having to repeat clinical trials for

17 every major market is guaranteed to be a major

18 entry barrier for a majority of biosimilar

19 manufacturers.

20 We fully realize that it is not

21 the job of the FDA, but the job of lawmakers

22 to create competition in the marketplace.


1 However, we also know that the BPCI Act as it

2 is worded today is fairly broad and thus at

3 the end of the day, it will be the FDA

4 guidelines that will define whether or not

5 health care savings and the patient benefits

6 envisioned in the BPCI Act are brought to

7 reality.

8 Specifically in this case, our

9 position is that studies with a RMP approval

10 in other jurisdictions should be acceptable to

11 the FDA based on (1) a clear demonstration by

12 the sponsor using high resolution in vitro

13 structural and functional assays that the two

14 RMPs are similar and (2) the quality of the

15 studies conducted in other jurisdictions is

16 acceptable to the FDA based on compliance with

17 GMPs, GLPs and GCPs.

18 I would like to begin my summary

19 with this graph that shows health care

20 spending in various countries and say

21 something that we all already know. That the

22 U.S. patient pays more for health care that


1 any other patient in the world. With current

2 monopoly pricing routinely in the range of

3 $10,000 to $100,000 per patient per year,

4 biologics truly represent the extreme end of

5 the health care costs spectrum.

6 Dr. Reddy's has first-hand

7 experience that health competition in the

8 biologics market even without automatic

9 substitution can result in dramatic increase

10 in patient benefits without affecting the

11 quality of care.

12 I would like to reiterate the 30-

13 fold and sixfold expansion in patient access

14 in India after the launch of similar GCSF and

15 rituxima versions respectively in combination

16 with the excellent safety, efficacy and

17 immunogenicity profile of our similar

18 biologics without extensive post-marketing

19 surveillance.

20 I would like to conclude by saying

21 that we fully support the FDA in adopting

22 biosimilar approval guidelines that employ


1 science to realize the goal of the BPCI Act of

2 creating health competition to cause a

3 reduction in monopoly pricing of biologics and

4 a break to the runaway cost of our health

5 care.

6 I would like to end my

7 presentation with this slide and I thank you.


9 comments. Questions from the panel? Dr.

10 Jenkins.

11 DR. JENKINS: I'd like to go back

12 to your slide where you describe the approval

13 pathway for your rituximab product in India

14 and try to better understand what the clinical

15 trial database actually consisted of. I think

16 you said it was a single-arm trial. So, can

17 you say more about the figure on the left?

18 I'm having trouble sorting through exactly

19 what I'm seeing there.

20 DR. PATWARDHAN: Yes. Basically,

21 in the figure on the left, we are showing in

22 blue the objective response rate with our


1 trial in 67 patients in India. It was a

2 single-arm trial and in, I guess, orange

3 boxes, we are showing all the literature with

4 the originator product and what objective

5 response rate they have gotten in the same

6 indication.

7 The point of the slide was that

8 yes, we had to go to a single-arm trial, but

9 that objective response rate is basically

10 identical to what has been MabThera Rituxan

11 experience.

12 Regarding your point about single-

13 arm trial, I just want to out that when we

14 launched or when we were trying to launch

15 Reditux in India, because of the price of

16 Rituxan or MabThera in India, the number of

17 patients, overall number of patients in India

18 receiving Rituxan was less than a thousand.

19 So, in a country like India, for

20 the regulatory agencies to mandate powered

21 clinical trials against the brand was just

22 simply not possible and, in fact, I mean, we


1 wouldn't be -- in fact, in India, that wasn't

2 the standard of care at that time.

3 Of course, now that we have

4 launched, the prices have come down and as I

5 said, the patient access has increased sixfold

6 since the time we launched. So, that was a

7 justification why the single-arm trial was

8 asked.

9 However, there was an expectation

10 that there will be extensive post-marketing

11 surveillance in which we now have a thousand

12 patients.

13 DR. JENKINS: So, basically, on

14 this slide, the 94 that's in the blue box is

15 your single-arm trial data and the other boxes

16 represent other historical trials --

17 DR. PATWARDHAN: Articles --

18 DR. BEHRMAN: -- published.

19 DR. PATWARDHAN: Correct.

20 DR. JENKINS: Then what's the

21 dotted-line box that captures some of the

22 smaller boxes, but not all? What does that


1 refer to?

2 DR. PATWARDHAN: Yes, the dotted

3 line is the confidence interval around our

4 objective response.

5 What we are saying is that that

6 confidence interval, 95 percent confidence

7 interval, around our objective response is

8 falling within the range of the historically

9 observed. So, it's not just the 94 percent,

10 but even the variation of our -- although, I

11 guess, some measure of variability of our

12 objective responses falling within the

13 historical range.

14 DR. JENKINS: Okay. So, would you

15 be advocating for a noncomparative trial for

16 U.S. registration?

17 DR. PATWARDHAN: What we would be

18 advocating is an eye on the benefit versus the

19 risk.

20 So, in India, for example, the

21 benefit was clearly that patients were not

22 receiving the product and it was impossible to


1 do a power trial because the number of

2 patients on the branded version was just

3 simply not enough.

4 In the U.S., the risk/benefit

5 ratio may be different, but always eye on the

6 benefit has to be there before requesting the

7 trials. So, we're not envisioning a single-

8 arm trial. We think, in fact, that that

9 probably won't fly with the FDA.

10 But, again, the size of the trial,

11 the endpoints, the length of the trial, these

12 things have to be kept in perspective of a new

13 -- vis-a-vis the benefits to the patients as

14 opposed to just sticking with the prior

15 practice.

16 DR. BEHRMAN: Could I just follow

17 up on Dr. Jenkins' question before we get to

18 Dr. Kozlowski.

19 So, patients were not on in the

20 post-market setting or in the clinical

21 practice the product, but you would not have

22 been prohibited from doing a randomized trial.


1 DR. PATWARDHAN: Correct.

2 DR. BEHRMAN: So, you made a

3 decision to do a single-arm trial. Is that

4 correct?

5 DR. PATWARDHAN: No, so the

6 requirement in India for approval was that we

7 can be marketed with a single-arm trial.

8 DR. BEHRMAN: You would not have

9 been prohibited from doing a --

10 DR. PATWARDHAN: No.

11 DR. BEHRMAN: -- comparative

12 trial?

13 DR. PATWARDHAN: No.

14 DR. BEHRMAN: Okay. Thanks.

15 DR. PATWARDHAN: But, doing a

16 power trial at that time in India with less

17 than a thousand patients on the brand was just

18 even for us -- even you wanted to, wouldn't

19 have been possible.

20 DR. BEHRMAN: Thank you. Dr.

21 Kozlowski.

22 DR. KOZLOWSKI: To keep to this


1 same slide, so on the right of this slide, you

2 talk about evaluation from immunogenicity.

3 So, just to clarify, is that using

4 an assay for antibody or is that looking for

5 immune-related adverse events?

6 DR. PATWARDHAN: No, this is assay

7 against Reditux.

8 DR. KOZLOWSKI: Okay. And did you

9 have controls to sort of make sure the

10 sensitivity of that assay was similar to, for

11 instance, what the innovator would be using to

12 get their data?

13 DR. PATWARDHAN: The assay has

14 been validated in our shop, but I don't think

15 we have done a comparison with the assay that

16 has been used by the branded company.

17 DR. KOZLOWSKI: You wouldn't have

18 access to that, but --

19 DR. PATWARDHAN: Right.

20 DR. KOZLOWSKI: -- based on their

21 sensitivity to their product.

22 DR. PATWARDHAN: Yes.


1 DR. KOZLOWSKI: And then, you

2 know, in your presentation you had mentioned,

3 you know, making sure that you have the same

4 isoforms. So, is there an extensive

5 biochemical characterization to look for

6 differences in glycoforms in other post-

7 translational modifications?

8 DR. PATWARDHAN: Sure. So, the

9 effect of -- well, our position is that all

10 glycoforms must be present in the biosimilar

11 that are present in the RMP. There should not

12 be any new isoforms that we have introduced

13 and you can expect a high level of similarity

14 in the major isoforms between the -- in the

15 quantitativeness of the major isoforms between

16 the RMP and the biosimilar.

17 But, to expect even a minor

18 isoform that they have to be exactly on top of

19 each other is -- in our opinion is not

20 consistent with the biosimilar concept.

21 Regarding the position, you can

22 always do functional. You always have


1 functional bioassays that can measure the

2 impact of differences in minor glycoforms on

3 the bioactivity and even beyond that, you also

4 have biomarker studies that without going into

5 patients or animals, you can still predict the

6 effect of differences in minor glycoforms on

7 the activity and on the PD markers. So, we

8 can recreate using those studies.

9 DR. BEHRMAN: Dr. Marchand.

10 DR. MARCHAND: Thank you for your

11 comments today.

12 I wanted to ask the question with

13 regard to the single-arm clinical trial, you

14 have an n of 67. You made the comment --

15 mention that in your post-marketing trial.

16 It's extensive that you have a thousand

17 patients enrolled.

18 Can you talk a little bit about

19 that trial? If it's a registry or if it's an

20 actual trial and would you advocate that for

21 products as we implement biosimilar in the

22 U.S.? A similar type of system.


1 DR. PATWARDHAN: Yes, so

2 definitely, we would advocate. In fact, in

3 our opinion, clinical trials are really

4 designed to separate -- the resolution of

5 clinical trials -- while the relevance is very

6 high, the resolution of clinical trials is

7 significantly lower than the very high

8 resolution bioanalytical techniques we use in

9 the front of the development.

10 So, our view is that the clinical

11 development is really designed to separate or

12 see kind of major differences. If there are

13 any major differences between -- at the

14 clinical level between the RMP and the

15 biosimilar. The final proof of whether

16 they're exactly the same or whether there are

17 any minor differences are only going to come

18 from post-marketing studies.

19 So, our view is that the clinical

20 studies can be designed in a pragmatic fashion

21 with the expectation that there should be

22 extension post-marketing surveillance so that


1 over time the FDA has the ability to take

2 further action if necessary.

3 And the same thing probably can

4 apply towards some of the other questions that

5 have been posed before regarding the drift of

6 interchangeables. I mean you can approve, you

7 know, A prime based on all the due diligence,

8 but then there should be an expectation on the

9 sponsor that in post-marketing phase whole

10 studies they show clear differences between A

11 prime and B and very well would be that, then

12 interchangeability will be taken away for the

13 brand.


15 comments. Our next speaker is Mark McCamish

16 from Novartis.

17 DR. MCCAMISH: Thank you. It's my

18 privilege to represent the Novartis Group of

19 companies and sharing with you our worldwide

20 experience in development and

21 commercialization of biosimilars.

22 I'll be addressing three items


1 today: biosimilarity, interchangeability and

2 use of non-U.S. licensed products in support

3 of clinical development programs. We'll

4 address all remaining issues in our support to

5 the document.

6 Novartis speaks with 30 years of

7 experience in development of biologics

8 including functioning as a contract

9 manufacturer, developing diagnostics,

10 vaccines, novel products as well as

11 biosimilars. We feel that competing in all

12 sectors is completely compatible and that in

13 doing so, we will encourage innovation.

14 Access is an unmet public health

15 need that lower-cost biosimilars will and have

16 already addressed.

17 I have to pause here and just

18 address the access issue. It's a fundamental

19 stimulus for me and many families that you are

20 aware of deal with this issue in terms of

21 decrease access.

22 My wife of 35 years has ankylosing


1 spondylitis for the past 30 years. We have

2 had good health care coverage in the U.S., now

3 in Europe. She's never qualified for use of

4 an anti-TNF biologic due to cost issues as a

5 primary factor.

6 So, it's a personal issue for me

7 and from a Novartis perspective, we feel that

8 dealing with all aspects of novel as well as

9 biosimilar products meet unmet medical needs

10 including access moving forward.

11 A theme we will have is that

12 standards should apply. High standards should

13 apply to biologics equally. That biosimilars

14 that demonstrate a high similarity to a U.S.-

15 referenced product should have an abbreviated

16 clinical program.

17 A key is that scientific and

18 regulatory consistency should be applied by

19 FDA fairly and irrespective of sponsor.

20 You have got excellent experience

21 with product comparison whether it's in

22 looking at generic products and establishing


1 equivalents such as the recent approval of

2 enoxaparin by Sandoz and Momenta or looking at

3 manufacturing changes, making a judgment of

4 comparability or with the new legislation

5 looking at high degree of similarity within a

6 biosimilar. Our point is that identical

7 science applies in these applications and the

8 science is fundamental and universally

9 applicable.

10 This pyramid taken from the

11 published literature shows our foundational

12 principle. That is degree of similarity is

13 based on analytical characterization and

14 iterative improved processes.

15 You can see that the base of the

16 pyramid is formed by physical chemical

17 biologic characterization supported by world-

18 class analytics and what we do is reiterate in

19 terms of process development. We change the

20 process to achieve these highly similar

21 product attributes including post-

22 translational modifications.


1 So, we modify the process to

2 achieve the post-translation modifications

3 that we feel are similar to the reference

4 product and that way it is a pyramid and will

5 require less pre-clinical, PK, PD, or clinical

6 trials than would be expected in a traditional

7 BLA approach.

8 Once we achieve what we consider

9 highly similar, then we should have a

10 streamlined pre-clinical and clinical program

11 and if the product quality attributes deviate

12 from the reference product, then more pre-

13 clinical and clinical studies should be

14 required.

15 You're very familiar with

16 manufacturing process changes. You've

17 evaluated that as being highly similar in the

18 past. Whether these encompass new master cell

19 banks, different cell lines, new manufacturing

20 facilities or different purification

21 processes, you've made a judgment call about

22 the pre-change and post-change product being


1 comparable and in doing so, they achieve a

2 level of high similarity in an analytical

3 level and sometimes that requires additional

4 work.

5 When you've made that judgment and

6 the pre and post-change products are deemed

7 comparable, they are interchangeable. The

8 U.S. market physicians, pharmacists, payers,

9 patients are not even informed about the shift

10 in the product attributes because you've made

11 a judgment that they're comparable.

12 We suggest that similar scientific

13 and technical factors should be used to make

14 a similar decision with biosimilars and that

15 that biosimilar product quality attributes

16 that are within a referenced product goalpost

17 which I'll justify an abbreviated pathway.

18 This slide is probably the

19 critical slide in the deck and it outlines the

20 view of the quality range of the originator

21 that sets the product goalpost.

22 We have an ongoing sophisticated


1 analytical characterization program for

2 reference products. We follow them over time

3 through batch-to-batch variability as well as

4 through a process change.

5 There's been a lot of discussion

6 about drift today and yesterday. In our

7 experience, we don't see "drift". We see

8 batch-to-batch variability and then we see

9 jumps and those jumps are usually sudden. We

10 assume they're associated with manufacturing

11 changes and we outline here in this graph, for

12 example, the initial originator quality that

13 we look at, batch-to-batch variability. Then

14 we see new originator quality that's usually

15 associated with manufacturing changes.

16 We feel that this sets up,

17 depicted by this graph here, this arrow, the

18 complete quality range for claiming

19 comparability for a biosimilar and we utilize

20 that as our goalpost to achieve a highly

21 similar biosimilar product and then we iterate

22 that process development as well as analytical


1 characterization to achieve that.

2 In fact, it takes us twice as long

3 to develop a biosimilar product than it does

4 a novel product because of those iterations

5 and process change to achieve this.

6 Once this is achieved, again, we

7 establish narrow release specs and follow that

8 product through commercialization and then if

9 this is achieved, we petition for an

10 abbreviated clinical development program.

11 In terms of interchangeability, we

12 would use the same scientific approach that

13 I've just outlined in terms of looking at

14 product quality attributes as a core.

15 However, the statute does refer to switching

16 studies. So, accordingly, we feel that we'll

17 have to demonstrate safety, purity and potency

18 that are not impacted by switching going

19 forward.

20 In this slide, we just outline an

21 approach that we would suggest. We think that

22 it is scientifically plausible to assess risk


1 of switching in a phased restudy design.

2 However, it is not scientifically feasible to

3 do this looking at immunogenicity alone. In

4 other words, we can't power study if

5 immunogenicity's one or two or three percent

6 in terms of a non-inferiority approach.

7 So, what we proposed and what

8 we've done is we use efficacy as a surrogate

9 for significant clinical immunogenicity. If

10 the efficacy is impacted by immunogenicity,

11 you can pick that up through a traditional

12 non-inferiority design and here we're simply

13 using an oncology approach using supportive

14 products such as EPO or GCSF.

15 Patients undergo multiple cycles

16 of chemotherapy with such support and we look

17 at subjects that have been assigned to the

18 reference or the biosimilar product without

19 switching and compare and contrast the

20 efficacy over multiple switches to those

21 patients exposed to switching from the

22 reference to the biosimilar product over time.


1 You can establish a non-

2 inferiority margin in interactions with

3 regulatory authorities to agree upon that and

4 then do such a study to give you confidence in

5 this moving forward.

6 Again, we look at immunogenicity

7 of each of the patients, but it's not powered

8 to show a difference in immunogenicity.

9 The use of supportive data. It is

10 key to be able to use data from non-U.S.

11 licensed products in moving forward. It's key

12 to have a global development program and we

13 would again take the same approach.

14 We can utilize the same analytical

15 characterization of the non-U.S. licensed

16 product. Compare that to the U.S. licensed

17 product and if they have overlapping product

18 attributes based on formal analytical

19 characterization and comparability, then we

20 feel that that data can be used in support of

21 a file including pivotal program.

22 The other aspect that can be done,


1 you in collaboration with EMA can look at

2 where products have been manufactured and make

3 a determination of whether it's in the same

4 manufacturing site for drug product growths

5 drug substance and that could be helpful in

6 limiting repeated development in every region.

7 So, finally, in summary, Novartis

8 urges FDA to use past experience with

9 comparability exercises to evaluate

10 biosimilars. Foundational principle is that

11 the product attributes within the origin

12 product variability should mandate an

13 abbreviated clinical development program.

14 Current analytical technologies

15 allow robust analytical and biologic

16 characterization of even complex biologics.

17 They can't pick up everything, but they pick

18 up most issues that can be looked at and

19 certainly the same issues you've evaluated

20 with comparability exercises.

21 Solid regulatory science is a

22 basis for determinations of what additional


1 data beyond characterization is necessary and

2 for biosimilars, the product attributes that

3 are within the distribution of the product

4 attributes of the reference product would

5 justify an abbreviated pre-clinical and

6 clinical program to address biosimilarities,

7 use of supportive data and interchangeability.

8 The more it drifts, the more data is

9 necessary.

10 Thanks for your time.


12 comments. Questions from the panel? Mr.

13 Schwartz.

14 MR. SCHWARTZ: Thank you for the

15 presentation. Just a quick seeking

16 clarification in this admission that you made.

17 Can you elaborate a little bit on

18 why you take issue with the reference to

19 interchangeability being a higher standard in

20 the statute towards the end of your

21 submission?

22 DR. MCCAMISH: Yes, sir. The main


1 issue there is that we don't create a product

2 from an analytical perspective or actual

3 development of the product. That would be

4 different for the biosimilar or the


6 So, the higher standard that is

7 referred to is really more data necessary to

8 get that approval, but it's not a higher

9 standard for the product per se. Because when

10 we develop the biosimilar, we don't anticipate

11 developing a lower standard biosimilar for

12 biosimilarity and then a higher standard

13 product for interchangeability.

14 So, it's mainly around there's

15 more data required based on the statute for

16 justification of interchangeability, but the

17 product itself is high quality moving forward.

18 MR. SCHWARTZ: It's just that it's

19 a more exacting standard, not a higher or

20 lower standard.

21 DR. MCCAMISH: Correct. Correct.



1 DR. KOZLOWSKI: So, I want to

2 follow up on your comment on goalposts.

3 DR. MCCAMISH: Yes.

4 DR. KOZLOWSKI: So, you're

5 suggestion is the entire range of attributes

6 that the product has had throughout the market

7 are a legitimate target for biosimilarity.

8 So, would that also in your view be a

9 legitimate target for interchangeability?

10 DR. MCCAMISH: Yes, and the issue

11 there is that the products as illustrated

12 here, they've been exposed to patient

13 populations and so, the product attributes

14 that you're looking at have been exposed in

15 patient populations and so, when that

16 originator changes in terms of manufacturing

17 process, you've made a determination of the

18 comparability of those products. Those

19 products at times have been on the market at

20 the same time depending on the expiry date of

21 the old versus new, et cetera.

22 Those have been used


1 interchangeably. They've been exposed to

2 patients and we feel that entire area is not

3 only valuable from a biosimilar perspective,

4 but also for an interchangeable biosimilar.

5 But, again, that's an analytical base

6 approach.

7 DR. KOZLOWSKI: So, to follow up

8 on your answer, so, if you make a

9 manufacturing change, you have a step function

10 change and you have crossover for a short

11 period of time. So, the patient population

12 would be exposed to the different products for

13 some level of time and then, you know, much

14 more similar batch-to-batch variation within

15 products.

16 So, when you have two products on

17 the market at the same time though that have

18 that same range of difference, you're exposing

19 the population to this larger difference

20 between products all at once and I guess I

21 want your sense about whether that's a

22 consideration for interchangeability.


1 DR. MCCAMISH: And again, my

2 response would be it is a consideration that

3 should be evaluated, but when we're talking

4 about this, this is not an easy thing to be

5 able to create a product that has all

6 attributes within this range. This is not a

7 huge range going forward. This is not

8 products that are licensed outside of highly

9 regulated areas or regions.

10 So, it is very difficult and

11 challenging to get these product attributes

12 within this range and the expectation is that

13 not often can you achieve that. If you do

14 achieve it, it should give you more comfort in

15 terms of the biosimilarity, extrapolation and



18 Ms. Maloney.

19 MS. MALONEY: It was on the slide

20 before this. I just want to make sure I

21 understand. Where you talk about for

22 manufacturing process changes and how and I


1 think your opinion is that they're actually

2 for the same company's product treated as

3 interchangeable.

4 My understanding is when the

5 change is made the old product is no longer on

6 the market. So, I'm not sure if I understand

7 the interchangeability.

8 DR. MCCAMISH: Simply that

9 interchangeability meaning that you could use

10 either and for a period of time, again,

11 depending on the expiry of the products

12 because when a manufacturer changes, there is

13 usually a lifetime of the product, the pre-

14 product and the post-product and depending on

15 whether that's in Europe or the U.S., there is

16 the potential for being exposed to both of

17 those products.

18 And there's no labeling. First,

19 there's no labeling that says the product's

20 been changed. So, it's not communicated to

21 the clinician or the user or the payer and

22 secondly, there's no difference in terms of


1 whether you order a product pre and post-

2 change. They can be interchangeable because

3 the pharmacist doesn't know that that batch or

4 whatever is the new product quality.


6 DR. JENKINS: A couple of

7 questions along that same line. First, within

8 innovator changes, they have access not only

9 to the product, but also to the API which will

10 be different for the biosimilar who's trying

11 to compare himself to the innovator. They

12 only have access to the product.

13 So, does that have any

14 implications in your mind about the ability to

15 demonstrate comparability?

16 And secondly, I think it's on your

17 next slide. If you could advance to your next

18 slide. How will the biosimilar product know

19 about those ranges of changes that have

20 occurred to the innovator? How will know that

21 range? You're saying that's a range that you

22 should be able to target your biosimilar to


1 fit in, but how will you know what those

2 ranges are? Those are not publicly available

3 information I don't think. Are they?

4 DR. MCCAMISH: Good questions.

5 Let me address the first -- the second first.

6 In terms of the range, what I

7 mentioned is we have an ongoing screening

8 program. So, we follow this over time. I can

9 only comment about what we do and so, we have

10 access to our own characterization of products

11 over years, over batches, over manufacturing

12 changes.

13 So, we accumulate this data. This

14 is not publicly available data. It's data

15 that we generate and accumulate in comparison

16 to our product as it's going through the

17 development phases.

18 Biosimilar takes about seven years

19 to develop. It's not an overnight development

20 program. So, we do this over time and so, it

21 is not a public database. It's our own that

22 we generate and compare.


1 In terms of the first question, in

2 terms of looking at the API or the drug

3 substance, what we use is a fairly

4 sophisticated deformulation strategies. We

5 have our product that we have made. We put

6 that product in the identical formulation of

7 the originator product and then we deformulate

8 that and we look at if there's any product

9 changes to that based on our API drug

10 substance compared to what we utilize and then

11 we modify that deformulation process to

12 achieve that with the originator to give us

13 confidence in that capability.

14 DR. BEHRMAN: Okay. We're not

15 doing as well as yesterday. Dr. Kozlowski has

16 more questions.

17 DR. KOZLOWSKI: So, in your

18 switching study for immunogenicity basically

19 relying on decreased efficacy, so, I think you

20 had a number of 50 patients per arm. So, that

21 would be sensitive only to a very large

22 percentage of patients having neutralizing


1 antibody.

2 So, I guess I'm wondering where

3 that number came from and what level of

4 sensitivity to neutralizing immunogenicity do

5 you think is appropriate?

6 DR. MCCAMISH: Sure and that's a

7 great question. What we're trying to

8 demonstrate is a pragmatic scientific approach

9 going forward. We've recognized and I've

10 mentioned that you cannot feasibly do a study

11 powered on immunogenicity. So, this is not

12 powered on immunogenicity. This is powered on

13 whether there's a significant effect that

14 immunogenicity alters the efficacy.

15 And you're absolutely correct that

16 you would not be able to pick up from such a

17 small study issues regarding immunogenicity if

18 there's a 1 or 2 or 3 percent, but you can

19 pick up a major impact in terms if it has an

20 efficacy.

21 Each patient would be monitored

22 for screening antibodies as well as


1 neutralizing antibodies if the screening

2 antibody test is positive.

3 But, the question becomes how can

4 you balance moving forward with developing a

5 biosimilar in a efficacious and efficient way.

6 Because it takes about $200 million to develop

7 these and even the cost of the originator

8 product that we have to purchase can be

9 between $70 and $100 million.

10 So, these are the issues we have

11 to deal with.


13 your comments.

14 We're going to take a break.

15 We'll resume at 10:15. Thank you.

16 (Whereupon, at 10:03 a.m. the

17 above-entitled matter went off the record

18 until 10:18 a.m.)

19 DR. BEHRMAN: Our first speaker

20 will be Nikhil Mehta.

21 DR. MEHTA: Good morning. My name

22 is Nikhil Mehta and I'm here on behalf of


1 Merck and Company.

2 We appreciate the opportunity to

3 comment on the approval pathway for

4 biosimilars and interchangeable products.

5 Merck has a broad portfolio of

6 biologics products. We have been and continue

7 to be a leader in the disease prevention space

8 through the development of vaccines including

9 several that are listed here and many others

10 that aren't.

11 In the innovative biologic space,

12 our products include Intron A, Remicade

13 outside the U.S. and Follistim. We also have

14 significant experience in development of

15 second generation products in each case. They

16 include PEG Intron, Simponi and Elonva.

17 Merck is our business here that

18 focuses on the development and

19 commercialization of biosimilars. We

20 currently have several biosimilars in

21 development and anticipate having five

22 biosimilar programs in advance development by


1 2012.

2 Our approach is to develop both

3 innovative biologics and biosimilars to the

4 same consistent high quality standards and

5 scientific standards.

6 We believe that consistent high

7 scientific integrity standards should be used

8 in assessment of similarity in the development

9 of biosimilars and innovative biologics. Have

10 the experience that industrial agencies have

11 had over the years.

12 In the biosimilars, however, you

13 should keep in mind and factor in the

14 extensive nature of the change which includes

15 cell lines, manufacturing processes,

16 manufacturing facilities, analytics and

17 process controls and on and on. That's a

18 significant change and based on that, the

19 rigor of the comparability exercise should be

20 significantly higher.

21 We'll focus today on showing our

22 perspective on three key issues which are


1 likely to have a major impact on the

2 development of biosimilars from our

3 perspective: Establishment of quality

4 standards, the need for clinical trials for

5 approved biosimilars and clear and stringent

6 basis for extrapolation of indications and the

7 use of ex-U.S. supporting data.

8 Setting private quality standards

9 for comparability demonstration poses a

10 challenge for biosimilar development and the

11 previous speaker Dr. McCamish also shared the

12 same thinking. We have similar thought

13 process actually.

14 Product variabilities inherent to

15 biologics and this includes both batch-to-

16 batch variability and product micro-

17 originating. Further, more reference product

18 quality attributes change over time due to

19 drift and manufacturing process changes.

20 From a perspective of developing

21 biosimilars, we can say that it starts with a

22 -- it's a very targeted activity with a


1 thorough analysis over the years of multiple

2 lots of reference products to generate a range

3 of results. We believe that the entire

4 analytical range for reference products that

5 we have been able to generate from those

6 analysis should constitute a private window

7 for the development of biosimilars as the

8 originator has already qualified them through

9 their clinical or other trials or other

10 studies as relates to patient exposure.

11 We also acknowledge that the

12 actual range of the quality attributes for the

13 biosimilar would be a subset of this window

14 keeping in mind the quality attributes within

15 the manufacturing capability of the biosimilar

16 process.

17 In spite of these targeted efforts

18 to insure product comparability, it's likely

19 that differences will be observed due to

20 complexity of the products and the process and

21 analytics.

22 The current state of science does


1 not allow to credit the impact of these

2 changes. Therefore, we strongly believe that

3 beyond the determination of CMC comparability

4 demonstration of similarity of safety and

5 efficacy profile for the biosimilar should be

6 required.

7 To that end, clinical trials

8 demonstrated bioequivalence necessary. We

9 also believe that a robust non-inferiority

10 study comparing biosimilar to reference

11 products should be required in one key

12 sensitive indication.

13 Extrapolation to other indications

14 could be supported by open and safety studies

15 in each of these indications as the mechanism

16 of action is well understood.

17 Regarding the use of supporting

18 data from studies with ex-U.S. comparator,

19 it's important to note that in most cases the

20 originator product approval is in different

21 regions especially the ICH regions and notably

22 in the EU are based on the set of trials by


1 the innovator and consequently use the same

2 drug product, i.e., a common original

3 reference product.

4 We also have to keep in mind that

5 over time there's a risk of divergence of

6 quality attributes that can be U.S. and ex-

7 U.S. product and the differences in approved

8 indications and patient populations.

9 With that in mind, the biosimilar

10 sponsor should be required to justify their

11 allowance update out of the ex-U.S. sponsor.

12 It will be very valuable to insure that the

13 ex-U.S. reference product could have been

14 approved based on the same set of clinical

15 trials at least in the initial case as a U.S.

16 reference product as that insures good -- of

17 a common reference to the biosimilar.

18 Bridging data furthermore between

19 the biosimilar and the U.S. and ex-U.S.

20 reference should be provided and this could

21 include CMC comparability using sensitive

22 physicochemical and biophysical and in vitro


1 testing.

2 Clinical PK, PD and immunogenicity

3 comparability will also be valuable to

4 demonstrate.

5 And finally, it's also important

6 that the studies with the non-U.S.-licensed

7 comparator be performed on the same

8 population, U.S. population, for the same

9 indication using the same administration as

10 those of the U.S. as to make them into

11 critical.

12 Finally, on the subject of safety,

13 biosimilar manufacturers should have a robust

14 PVG system capable of tracing adverse events

15 at the patient level with individual lots of

16 products and some solutions were provided

17 yesterday and I realize it's a complex

18 problem, but I think it's an important one.

19 The use of proprietary unique

20 identifiers and physician/pharmacist education

21 programs should mitigate inadvertent

22 substitution or interchangeability.


1 And finally, all constituents

2 should receive educational updates to manage

3 the unique nature of pharmacovigilance as we

4 embark on this effort to introduce biosimilars

5 into this system.

6 In conclusion, patient safety is

7 certainly paramount in our efforts to

8 commercialize biosimilars. Regulations should

9 be based on clear scientific and clinical

10 evidence of similarity and safety.

11 We believe that one positive

12 control clinical trial and a key indication

13 should be required to support the approval of

14 a biosimilar and that there could be ways

15 including the one which we suggested, possible

16 way, whereby we could allow the ex-U.S. data

17 to support the approval in the U.S.

18 And finally, extrapolation of

19 indications should be allowed for all that

20 clinical evidence including control trial and

21 indication and supplemented with open-label

22 safety studies and other indications.


1 Thank you.



4 Jenkins.

5 DR. JENKINS: I'm trying not to.

6 Unfortunately, they took away your last slide,

7 but okay, there it's back.

8 That one positive controlled

9 clinical trial that you're recommending for

10 the initial approval, what's your proposal for

11 how that should be designed and analyzed?

12 We've heard various proposals

13 yesterday and today. Some concerns about a

14 strict non-inferiority or equivalence analysis

15 leading to a sample size that would be not

16 feasible or economically a disincentive. So,

17 what's Merck's proposal for how that one

18 positive clinical trial would be designed and

19 analyzed?

20 DR. MEHTA: We believe that the --

21 we do believe that it is feasible to run a

22 control trial and we believe that the non-


1 inferiority margin that essentially preserves

2 a substantial portion of the difference in a

3 trial of potential biosimilar and referenced

4 products should be essential.

5 I take that a equivalence trial is

6 certainly also -- from our experience, an

7 equivalence trial is not going to be

8 substantially larger and certainly provides a

9 greater assurance that the product is going to

10 be biosimilar.

11 DR. JENKINS: Does Merck have any

12 thoughts on how we would set those margins?

13 You know, I mentioned yesterday

14 non-inferiority analyses are often used in the

15 setting of active control trials to establish

16 that the new product is safe and effective for

17 approval. Which is different from saying that

18 it's not clinically meaningfully different

19 from the active control.

20 So, are you talking about

21 retaining 50 percent of the estimated effect

22 size of the active 80 percent/90 percent?


1 Have you given any thought to where you would

2 set that bar to be a reasonable standard for

3 not clinically meaningfully different, but

4 also not so burdensome that it would be

5 infeasible to conduct the study?

6 DR. MEHTA: We think that it's --

7 I don't believe we are -- the exact number

8 where the bar should be set. However, we do

9 acknowledge that if the bar is set too low and

10 your trial comes out at the lower end and

11 passes through, it will still be difficult to

12 convince prescribers to use the product.

13 So, I think that needs to be a

14 reasonable balance. I don't think we have an

15 actual number in mind as to where it should

16 be.

17 DR. KOZLOWSKI: To follow up on

18 the idea of one trial for a key sensitive

19 indication, so, I'm assuming by key sensitive

20 indication that there is one indication most

21 sensitive to structural variation and

22 potential differences between the biosimilar


1 and the innovator. So, is there always a key

2 sensitive indication?

3 Because you can worry about

4 different adverse events in different

5 populations. You know, you might have

6 different mechanisms of efficacy.

7 DR. MEHTA: I think the selection

8 of the key sensitive indication would be

9 dependent on the response in that indication.

10 I think some are very sensitive through the

11 dose response. Would be one way to look at it

12 from our perspective.

13 Certainly, it will also be useful

14 to pick it in an indication where there's a

15 substantial uptake of the product.

16 DR. KOZLOWSKI: And would

17 mechanism or other potential safety risks in

18 a population play a role in that?

19 DR. MEHTA: Absolutely, yes.


21 Ms. Maloney.

22 MS. MALONEY: I just wanted to go


1 to the slide that had to do with safety and

2 monitoring and the naming issue. I'm not sure

3 if I heard you take a position on the need for

4 a unique name or not from a pharmacovigilance

5 point of view.

6 We've heard some people speak to

7 the fact that maybe the NDC number is

8 sufficient because it's detailed enough.

9 So, can you just comment on that?

10 DR. MEHTA: We believe that having

11 a unique name is valuable. I think it's going

12 to prevent inadvertent substitution and

13 certainly, we also believe that it's useful

14 for patients' awareness of what they are using

15 as well as physicians awareness.

16 There are NDC codes and other ways

17 where we can track pharmacovigilance, but I

18 think having unique names provides other

19 benefits other than just pharmacovigilance.


21 DR. JENKINS: I want to follow up

22 on that because I misread your slide earlier.


1 It says the use of proprietary unique

2 identifiers.

3 Yesterday, we were talking about

4 nonproprietary unique identifiers. So, are

5 you suggesting that they would have the same

6 nonproprietary names. Say Filgrastim, but you

7 would differentiate by the trade name?

8 DR. MEHTA: I think that we should

9 have -- it would actually be useful to have

10 different names other than -- not just the

11 proprietary name, but even the --

12 DR. BEHRMAN: I have one question

13 back to drift or jump or whatever term.

14 To you have any recommendations to

15 the agency in terms of how we can assure over

16 time that if, indeed, products were determined

17 to be interchangeable that the soundness of

18 that decision remained?

19 DR. MEHTA: I think it's a

20 challenging question for an interchangeable

21 product. I'm not sure that we have an answer.

22 DR. BEHRMAN: Okay. Thank you.



2 Our next speakers, we have four.

3 Still four? Oh, just one. Okay. Michael

4 Wenger.

5 DR. WENGER: Yes.

6 DR. BEHRMAN: Hoffman-La Roche and

7 Genentech.

8 DR. WENGER: That's correct. My

9 name is Michael Wenger. I work in late-stage

10 development for La Roche and Genentech and I

11 would like to thank the FDA for giving us the

12 opportunity to express our views on this

13 guideline.

14 So, many speakers have already

15 alluded to that safety should be the primary

16 concern. We concur with this.

17 La Roche supports the development

18 of a regulatory framework for biosimilars and

19 the approval process for biosimilars in our

20 view must be based on the concept of

21 similarity. Comparison with the reference and

22 innovative product, i.e., a rigorous head-to-


1 head quality non-clinical and clinical

2 evaluation.

3 Extrapolation of safety and

4 efficacy across indications should not be

5 supported without adequate clinical trials,

6 but a similar entrance must meet the firm

7 criteria for immunogenicity testing and post-

8 authorization risk management including

9 pharmacovigilance.

10 Biosimilars should be uniquely

11 identified and we do not support automatic

12 substitution or interchangeability.

13 Immunoglobulins are highly complex

14 molecules and I would like to focus on

15 immunoglobulins or monoclonals in particular

16 for the remainder of the talk and basically

17 address clinical aspects.

18 Any subtle change in any of these

19 parameters might prompt basically a new

20 biologic or a significant variation in the

21 biosimilar and it continues even with the mode

22 of action for monoclonal antibodies. Mode of


1 actions are complex, not at all understood for

2 all monoclonals. Sometimes they are easy.

3 Sometimes they are more difficult.

4 So, the in vivo net contribution

5 of the mode of action they are often

6 incompletely understood, but as rituximab as

7 been mentioned before, we also need to pay

8 attention that for some monoclonals there's

9 actually more than one mode of action such as

10 apoptosis, such as complement activation or

11 ADCC. For rituximab and each of those three

12 mode of action might contribute differently

13 regarding different disease states.

14 Demonstration of clinical

15 similarities is, of course, a challenge and

16 biomarkers or well established in vitro

17 potency assays might help us. Both correlate

18 with the mechanism of actions. Sometimes

19 quite well with the monoclonal antibodies.

20 But, they are not validated

21 surrogates of clinical benefit. For

22 biosimilars, similarity concerning efficacy


1 and safety with the reference product has to

2 be demonstrated in adequately powered clinical

3 trials.

4 Now, the demonstration of clinical

5 similarity -- the proof of clinical similarity

6 as said before requires in our view a

7 demonstration of equivalence with predefined

8 margins. While the non-inferiority superior

9 efficacy is not acceptable because it might be

10 connected with increased safety risks and

11 there might be actually even consideration be

12 given that within the particular product

13 different safety margins need to be implied

14 for different indications regarding only or

15 relating to the differential benefit a drug

16 has in one indication.

17 The focus of the clinical trials

18 for biosimilars will be to demonstrate

19 similarity to the reference product rather

20 than benefit for patients.

21 Proof of effectiveness. In

22 oncology, these endpoints accepted to be


1 correlated with survival and -- refer here

2 specifically to oncology. Overall survival is

3 usually an accepted endpoint of progression-

4 free survival. There's no justification for

5 an accelerated approval of biosimilars based

6 on nonvalidated surrogate endpoints such as

7 response rate. Of course, if these endpoints

8 have been validated, that's a different story.

9 Which endpoints should be used?

10 Activity endpoints such as biomarkers can

11 often be measured faster, cheaper and with

12 more precision than clinical outcomes.

13 However, these should not be taken as a sole

14 basis for judging similarity.

15 Similarity in effects on a

16 biomarker will not always predict similarity

17 in effects on clinical outcome. This has some

18 regulatory implications. Head-to-head

19 comparisons of effect of biomarkers might be

20 quite powerful tools in identifying or

21 excluding some clinical differences and may

22 prove valuable in supporting extrapolations to


1 other indications.

2 But, the demonstration of similar

3 effects on an easier measured biomarker should

4 be considered necessary, but not usually

5 sufficient to establish equivalence.

6 There's some example in

7 immunology. For example, the impact on

8 circulated levels of cytokines or inflammatory

9 markers is a well-established biomarker that

10 does correlate at least in some instances with

11 clinical outcomes.

12 On the country for B cell

13 diseases, a potential biomarker is the

14 reduction of lymphocytes counts which

15 basically is working for any of the B cell

16 antibodies in development, but does not

17 correlate with the intent of or with the

18 extension of the clinical benefit.

19 Extrapolation of safety across

20 indications may be adversely impacted by any

21 of the following: Concomitant medications,

22 immune competence of the patient's


1 immunogenicity, the approved dose or

2 susceptibility in the populations to specific

3 potential toxicities.

4 Against some regulatory

5 implications this might have, safety in

6 immunogenicity data in all target populations

7 and disease should be, in our view, provided.

8 When an innovator drug has safety

9 concerns and a second indication that are

10 different from or greater in magnitude than

11 those in the first, the biosimilar generally

12 should be assessed for those concerns as well.

13 Again, the example of rituximab

14 had three different modes of action and each

15 contribute in a different way to different

16 indications, different lines of treatments.

17 So, from our review, if we take

18 this example, extrapolation from one disease

19 to another, like rheumatoid arthritis to

20 oncology, likely involves different modes of

21 actions, different effective mechanisms and

22 certainly a different immune status exists in


1 our RA patients as compared to oncology

2 patients. In our view, that should be

3 avoided.

4 Extrapolation from line of

5 treatment, first line versus relapsed versus

6 refractory, might put patients at risk again

7 due to an immune system. It is more affected

8 in later lines of treatment. Affected

9 mechanisms such as NK cells necessary for ADCC

10 might be absent. So, in our view, again, this

11 is not a valid extrapolation mode.

12 Extrapolation from single agent to

13 treatment to combination treatment is in our

14 view also not warranted due to high

15 probability of different net contributions of

16 the mode of actions.

17 What might be a possible way to

18 extrapolate is if one concomitant treatment to

19 another allowing for clinical testing of

20 biosimilar only with one chemotherapy or one

21 additional treatment for the broader approval.

22 So, in summary, for these clinical


1 issues that we address in this talk and we

2 will address more in our written answer, a

3 strong CMC and nonpolitical data limiting the

4 potential differences are critical. For

5 complex molecules, in our view, there will

6 always be differences. It's just a function

7 of how hard you look to detect those.

8 Pre-clinical toxicity studies are

9 essential, but clinical head-to-head trials of

10 the biosimilar product versus an original

11 reference in our view are still essentially

12 required.

13 The goal should be to demonstrate

14 equivalence not just non-inferiority. It's,

15 of course, difficult to do in small trials.

16 For lifesaving drugs, only a small

17 confidence interval may be allowed.

18 Equivalence needs to be also

19 demonstrated for safety and efficacy.

20 Surrogate endpoints are only

21 acceptable if a clear and clinically-validated

22 correlation exists to the desired endpoint.


1 For some of the biosimilar

2 products, maybe an innovator development

3 pathway might be a suitable alternative, but

4 that's, of course, something we leave to the

5 biosimilar companies.

6 Thank you for your attention.



9 Jenkins.

10 DR. JENKINS: I do have two

11 questions. I noted with interest, I don't

12 think your slides are numbered, but your slide

13 where you talked about the demonstration of

14 clinical similarity. You proposed that the

15 endpoints that we would use in oncology would

16 not allow for surrogate endpoints like

17 response rate. I found that curious.

18 Why would it acceptable to approve

19 the innovator on response rate, but not

20 approve a biosimilar on response rate given

21 that there are well-known cases where

22 progression-free survival has not translated


1 into overall survival and yet, you know, those

2 products are out there? So, I'm just curious

3 why would you take that position?

4 DR. WENGER: We actually think the

5 exact same standards should be applied to

6 biosimilars as to innovator products. So, if

7 there is indeed a correlation that is

8 established between say response rate and

9 progression-free survival or progression-free

10 survival to overall survival in the disease

11 for the innovator product, that same pathway

12 should be open also for biosimilars.

13 DR. JENKINS: I would note by the

14 way that you're going to get 12 years of

15 exclusivity. So, you shouldn't have 12 years

16 of still having the surrogate and not having

17 the conversion to the regular approval. So,

18 maybe this is a moot point.

19 DR. BEHRMAN: Yes, but just as --

20 just for clarity. So, you're position is that

21 if a product is under accelerated approval,

22 has not achieved traditional approval, it is


1 not a -- and should 12 years have passed, it

2 should not be a candidate for a biosimilar.

3 Being in a reference pack for biosimilar

4 DR. WENGER: So, if an innovative

5 product has been approved on the basis of the

6 proof that say a surrogate endpoint is

7 actually correlating with the primary

8 endpoint, say progression-free survival, we

9 think this road should be open to biosimilars

10 as well.

11 So, just the same standards and

12 rules should apply to both biosimilars and to

13 innovative products.

14 DR. JENKINS: My second question

15 related to your rituximab example and I wanted

16 to revisit a question I had asked one of the

17 other sponsors earlier. Which is, you know,

18 if you're the innovator for that product,

19 apparently there are now biosimilars approved

20 in other parts of the world. So, what's your

21 experience been in identifying any safety

22 concerns or efficacy concerns that have arisen


1 from those approved biosimilars to rituximab?

2 You made the case that it should

3 be a pretty high bar. So, have you seen

4 evidence of a problem?

5 DR. WENGER: So, we have some

6 experience with India and we can't say that we

7 see a problem, but we also can't see that we

8 or can't say that we have adequate

9 information.

10 Basically, the trial that the

11 colleague was referring to is not published

12 other than in abstract format. So, we don't -

13 - we are not able to confirm the efficacy

14 information that was shown or demonstrated.

15 With regard to this literature

16 comparison as set in our view in a disease

17 that is potentially life threatening like

18 lymphoma or diffused large B cell lymphoma, we

19 would used the agency to consider that the

20 safety bars or the safety standards need to be

21 very high for the comparative product. In

22 regards to the possibility that even if the


1 product is 5 percent less efficacious or has

2 5 percent or 10 percent more side effects, it

3 might have a detrimental outcome if ultimately

4 the goal of the therapy is cure.

5 This might be different from drug

6 to drug and so, we think actually an

7 individualized approach for particular drugs

8 might be warranted with regards to what actual

9 trial needs to be conducted or not.


11 DR. KOZLOWSKI: So, in your

12 presentation, you talk about clinical

13 similarity and talk about the standards for

14 that. So, do you feel that the similarity

15 exercise should be treated separately?

16 There's structural similarity. There's

17 clinical similarity. There's pre-clinical

18 similarity and they don't interact or do you

19 feel, in fact, that, again, information, as

20 has been discussed before, should be leveraged

21 in some way across these different sort of

22 dimensions of similarity?


1 DR. WENGER: Basically, our view

2 is we've looked into new forms, new versions

3 of our own antibodies to basically bring the

4 science forward and while we see that there's

5 very high comparability on the pre-clinical

6 end, it does not necessarily correlate with

7 what we see on the clinical side of things

8 Very subtle modifications would

9 not necessarily would be considered relevant

10 from a pre-clinical end might well translate

11 into greater or smaller clinical benefits.

12 So, in our view, this is a

13 separate issue that should be look at

14 specifically.

15 DR. KOZLOWSKI: I think if any of

16 that isn't public, it should be shared.

17 Because I think that's certainly of interest.

18 And a quick question on

19 extrapolation. So, again, your perspective is

20 really extrapolations are extremely unlikely

21 except for very limited circumstances.

22 So, to throw out an alternative,


1 say you had the two most different indications

2 in a product that had five indications and you

3 explored those two, do you believe you could

4 extrapolate the other three?

5 DR. WENGER: So, if you take this

6 example here where we have two extremely

7 different indications, rheumatoid arthritis

8 and lymphoma oncology, there might be a way to

9 extrapolate within oncology from one disease

10 or from one disease state to another.

11 Again, for us, it depends highly

12 also on the clinical benefit that is

13 achievable with the innovator drug. If this

14 is a marginable benefit or say it's a benefit

15 that can be achieved with relative ease, we

16 would probably be more comfortable with this.

17 While if we're talking about an overall

18 survival benefit, for example, we would

19 propose to redo the trial in each and every

20 disease state.


22 DR. JENKINS: I'd like to go back


1 to your last slide again in your summary. So,

2 for your clinical head-to-head trials, you

3 wanted a demonstration of equivalence and you

4 wanted a small competence interval. You

5 recommend equivalence for safety and efficacy

6 and the surrogate endpoints are not acceptable

7 unless they've been clinically validated.

8 So, is that really an achievable

9 standard? To have a biosimilar approved under

10 that paradigm or is that essentially closing

11 the door to a biosimilar?

12 DR. WENGER: So, we've been asked

13 to comment on the guideline and I think these

14 are our positions. We're not in the position

15 to comment from a biosimilar perspective on

16 these issues.

17 Having said this, I think there --

18 I explain some scenarios where actually there

19 is a feasible way of having a biosimilar being

20 approved in some of these indications.

21 Again, the perspective that we

22 take here is that we shouldn't need to look at


1 the drugs and what they bring to patients on

2 a case-by-case basis. If the additional

3 benefit that a drug gives to patients is

4 really very high, then in our view, the safety

5 margins should be very narrow.

6 In case this is a relatively low

7 benefit or if the benefit can actually be say

8 the drug doesn't work, through a subsequent

9 treatment can be recaptured, that might allow

10 for an easier pathway for biosimilars.


12 your comments. Our next speakers are Charles

13 Ebert and Crawford Brown from Watson

14 Pharmaceuticals.

15 DR. BROWN: Good morning. Watson

16 Pharmaceuticals welcomed the opportunity

17 offered by FDA to participate in the hearing

18 on biosimilars.

19 The focus of our presentation is

20 on two areas. Firstly, biosimilarity and the

21 second on the benefits of global development

22 to progress safe and affordable biosimilar


1 products for the U.S. population.

2 The benefits of global development

3 a reduction in time, a reduction in resource

4 and opportunities to eliminate unnecessary

5 duplication of human and animal testing.

6 In addition to looking to develop

7 local guidance, we believe the Agency can

8 support this global opportunity through

9 regulatory harmonization and indeed FDA has

10 participated actively within ICH that has

11 created a framework for biological products by

12 way of guidance and indeed in the '80s, FDA's

13 pioneering role in evolving guidance for the

14 new technologies based on DNA technology for

15 protein therapeutics formed an excellent basis

16 upon which scientific and regulator experience

17 could then form a guidance under ICH such as

18 ICH Q5E.

19 And we believe that the activities

20 of the European agency, the EMEA, offers a

21 similar opportunity to leverage some of their

22 guidance documents as a basis for scientific


1 dialogue in order to form a common scientific

2 framework.

3 The Agency can also support global

4 development two further ways. Firstly, the

5 FDA should accept non-U.S. trials with non-

6 U.S. source innovative product predicated upon

7 ally to the principles enshrined within ICH

8 Q5E, the demonstration of comparability to

9 that -- to the product available in the United

10 States.

11 And lastly, post-approval safety

12 requirements should align with other new U.S.

13 programs when possible and should not exceed

14 those of the innovator products.

15 In seeking to develop regulation

16 for biosimilars, we believe that there is no

17 one size fits all approach. It will be case-

18 by-case basis and this reflects not only the

19 breathe of complexity of biosimilar products

20 and the range of product types, but also the

21 understanding of the impact of determining

22 there is a different in the relationship to


1 its structure and function and what that

2 difference might mean in a clinical setting.

3 Nevertheless, within the U.S., the

4 use of comparability protocols has, indeed,

5 permitted evaluations pre and post-change of

6 biotech products to permit the introduction of

7 new processes and indeed the stepwise approach

8 starting from a biochemical, physicochemical

9 methodology moving to non-clinical and if

10 necessary, clinical. That cascade in staffing

11 has been an essential cornerstone of European

12 approval of biosimilar products.

13 Similarity should be demonstrated

14 based on comparison of multiple lots of

15 innovator and the biosimilar product.

16 In short, a data-driven process

17 whereby for the biosimilar product plus

18 demonstration of similarity is necessary, is

19 not sufficient and needs to be supported by

20 the same set of scientific tools the

21 application, if you will, of good science from

22 day one in terms of manufacturing design, but


1 has been applied to innovative products, needs

2 to be applied to biosimilar products so that

3 we're able to produce them to predefined

4 specifications within facilities that meet the

5 standards of FDA current manufacturing

6 process.

7 I'll pass you to my colleague Dr.

8 Ebert who will now address issues of non-

9 clinical and clinical testing. Chuck.

10 DR. EBERT: Thank you. First off,

11 we think that significant advances have been

12 made on characterizing biosimilars and in

13 developing processes that allow the

14 development of biosimilar products.

15 That said, non-clinical testing

16 and clinical testing to some extent should be

17 conducted.

18 However, having demonstrated

19 comparability through chemical/biochemical

20 similarity, that program for the non-clinical

21 testing should be reduced appropriately. This

22 is consistent with guidance such as from the


1 EMEA and also the approval of several recent

2 products.

3 Moreover, unnecessary testing in

4 animals is unwarranted and I might add also

5 that certain animal models probably are not

6 appropriate today.

7 Many models exist and are

8 validated, well recognized. They should be

9 utilized as part of the non-clinical program.

10 However, there may be a lack of animal models

11 for certain compounds in which case,

12 conducting non-clinical trials let's say in

13 chimpanzees may not be appropriate.

14 However, in vitro methods can be

15 utilized across essentially drugs and this

16 allows us to demonstrate comparable similarity

17 in pharmacology activity and potency.

18 PK/PD should be demonstrated as

19 part of the non-clinical program. There we

20 would recommend that a single pharmacokinetic

21 trial in a single species should be adequate.

22 Again, in vitro assays can help establish


1 pharmacology equivalence and similarity and PD

2 safety trials should not be required. Again,

3 this is not necessary since these are not new

4 molecular entities.

5 A toxicity study in a single

6 species is appropriate. The duration and the

7 species selection needs to be carefully

8 selected in order to detect relative

9 differences. Immunogenicity being a key

10 component of that.

11 Other routine tox studies such as

12 chronic toxicity, geno tox, reproductive tox,

13 carcinogenicity should not be required since

14 these have already been established for the

15 innovator product.

16 Additional studies may also be

17 appropriate such as local tolerability and

18 need to be assessed on a case-by-case basis.

19 And as the product progresses

20 through development, it is a

21 cumulative evidence-base that you have shown

22 similarity. If you've demonstrated chemical,


1 biochemical and non-clinical similarity, full

2 clin pharm testing should not be required.

3 Which is again consistent with guidances from

4 other regulatory authorities.

5 A single dose bioequivalency may

6 be appropriate for demonstrating

7 pharmacokinetic operability. However, other

8 approaches need to be considered as well have

9 been presented and discussed throughout the

10 last two days.

11 Typically, the standard

12 bioequivalency may be appropriate for most

13 cases. However, the Agency needs to remain

14 open to other approaches as well.

15 Tmax and other pharmacokinetic

16 parameters such as half-life and clearance, of

17 course, need to be considered when appropriate

18 and PD similarity should be assessed if

19 appropriate. There we need to really look at

20 the comparability margins and to have it

21 justified on a case-by-case basis rather than

22 picking an arbitrary number.


1 Some cases PD markers may not be

2 relevant. They may not be appropriate

3 indicators of clinical response. In which

4 case, the Agency should exercise judgment in

5 requiring PD testing.

6 And I see we're blinking red.

7 So, I'm just going to quickly go

8 to we think that a single randomized control

9 clinical trial should be adequate. The

10 efficacy endpoints need to be carefully

11 selected. Surrogate endpoints are

12 appropriate. Safety comparisons need to be

13 assessed as well. The standard safety

14 components specific for that compound should

15 be included as well as immunogenicity.

16 We believe a single trial should

17 support multiple indications when there is a

18 common mechanism action and the size of these

19 studies really needs to be considered in a

20 manner to allow effective development of

21 biosimilars and ICH-type exposures should not

22 be required.


1 The conclusion is that biosimilars

2 are not new molecular entities and having gone

3 through extensive comparability testing plus

4 limited abbreviated non-clinical/clinical

5 testing, there's necessary assurances of

6 quality, safety and efficacy.

7 The FDA has a history of approving

8 biological products based on comparability

9 testing including several biosimilar-type

10 products in the 505 pathway as well as post-

11 manufacturing changes.

12 We would love to see the FDA

13 engage in harmonization through ICH. It think

14 that would allow for the development of global

15 programs.

16 A single clinical trial should

17 support approval for all indications with a

18 common mechanism.

19 The acceptance of U.S. trials with

20 non-U.S. source materials should be encouraged

21 and can be based upon comparability testing

22 and the FDA needs to use scientific discretion


1 in establishing requirements on a case-by-case

2 basis.

3 Thank you.



6 Kozlowski.

7 DR. KOZLOWSKI: In an early slide,

8 you presented that any post-marketing

9 requirements should be no different than the

10 innovator and I guess I ask is that because

11 you think the purpose of post-market studies

12 for biosimilars will always be the same

13 purpose as for innovators?

14 DR. EBERT: Well, I'll address

15 that one. We think that really biosimilars

16 should not be required to have additional

17 post-marketing requirements beyond that of the

18 innovator.

19 I think one of the points there

20 was that there may be post-marketing risk

21 management programs in existence in other

22 territories and that we should try to


1 harmonize with those, but again, the post-

2 marketing requirements should not be any more

3 onerous than that opposed on the innovator.

4 DR. KOZLOWSKI: So, to follow that

5 up, it's conceivable that, for instance, the

6 development program could be, you know,

7 modified in some ways by the ability to use

8 certain post-market studies. So, you know, it

9 may work in a couple of different directions

10 to lock the ability of specific targeted post-

11 market studies.

12 So, I guess I'm wondering again

13 because if -- the reason to keep them the same

14 is if the purpose is the same.

15 DR. BEHRMAN: Could I ask a

16 question because I'm not clear? When you say

17 that they should be the same, do you mean that

18 if there's a REMS program and so forth that it

19 should be the same or do you mean that if the

20 innovator with -- let's say it's been on the

21 market for however many years and had a

22 program of 20,000 patients. Did not have a


1 post-marketing commitment study for any

2 pharmacovigilance. That, therefore, perhaps

3 a biosimilar with an exposure of 5,000

4 patients should also not have such a post-

5 marketing commitment?

6 DR. EBERT: Well, I hope we don't

7 need to expose 5,000 patients in a biosimilar

8 program, but I think our intent here was --

9 and maybe we did not communicate properly. It

10 is that a biosimilar approved in Europe will

11 likely have some sort of post-marketing

12 pharmacovigilance risk management program.

13 We should be able to -- in fact, I

14 think the Agency would want to see that data

15 coming in and that's what we meant by we would

16 couple onto those programs.

17 In addition, I don't think that

18 additional REMS-type program or expanded

19 programs should be required of a biosimilar

20 that was not required of an innovator. It

21 sets the biosimilar up almost as being

22 inferior coming out of the box and it has a


1 higher risk which is not necessarily true.

2 DR. BEHRMAN: But, putting asides

3 REMS for a moment which, of course, is a hot

4 topic, perhaps a registry or other types of

5 safety surveillance, a sentinel study for

6 example, do you feel those would also be

7 appropriate or inappropriate?

8 DR. EBERT: I think it depends on

9 the particular product that needs to be

10 assessed on a case-by-case basis.


12 DR. JENKINS: You mentioned that

13 you think that surrogate endpoints should be

14 okay for the clinical study. The previous

15 speaker suggested that at least in certain

16 indications the surrogate should not be

17 acceptable for the biosimilarity comparison.

18 Can you comment on that a little

19 bit further? Why you think the surrogate

20 endpoint would be okay in the clinical trials?

21 DR. EBERT: Well, I think again

22 it's going to be case-by-case. Let's say


1 you're looking at osteoporosis, then bone

2 mineral density I think is an appropriate

3 surrogate endpoint.

4 If you're looking at MS, I think

5 MRI counting of lesions is appropriate

6 surrogate endpoint.

7 I personally think that overall

8 response, you know, is an appropriate

9 surrogate in oncology, but again, you have to

10 determine that on a case-by-case basis.

11 DR. JENKINS: One other question.

12 You make a lot of reference to ICH and

13 harmonization and you also talk about FDA

14 should be able to use data generated using

15 non-U.S. referenced products.

16 Would you limit that to ICH region

17 countries for the non-U.S. product is

18 registered or would you broaden that?

19 DR. EBERT: I would in general

20 yes, limit it to ICH region countries, but I

21 think you also need to be open to other

22 situations based upon what data is available,


1 the quality of the studies that were conducted

2 and how supportive they are.

3 DR. BEHRMAN: Any other questions?


5 Our next speak is Vijay Tammara

6 from Nuron Biotech.

7 DR. TAMMARA: Thank you. Thanks

8 for the opportunity to come with our opinion

9 from Nuron Biotech. I'm Vijay Tammara.

10 My experience -- my personal

11 history is based upon my prior experience at

12 FDA as well as in this field over the last 18

13 years. I was involved in developing a lot of

14 guidelines at FDA when I was at the Office of

15 Clinical Pharmacology Biopharmacokinetics. We

16 wrote all the FDA guidance inventory and we

17 wrote correlations. I was part of the working

18 groups to develop those guidelines and

19 actually, that intravenously -- worked at

20 Merck and currently at Nuron Biotech.

21 So, I'm going to -- an

22 introduction as to what the biosimilarities


1 and we're going to consider today's

2 presentation only in the biosimilarity factors

3 to consider. We'll leave the comments, the

4 dockets on the other aspects of the open

5 hearing here today and we will touch upon the

6 comparability of PK/PD and economics

7 biosimilars and what biosimilars mean for the

8 future in general outline.

9 So, biosimilars are defined as a

10 product comparable in quality, safety and

11 efficacy to a different product as has been --

12 everybody has been mentioning the last couple

13 of days. Because it's impossible to show two

14 protein products to be identical, the term

15 biosimilar was introduced in the UN following

16 biologics or biogenetics in the United States.

17 Biosimilars as everybody has

18 claimed or at least mentioned are not generic

19 drugs because of the complex science involved.

20 They are new non-innovated products and need

21 be supported by every related clinical data at

22 the time of approval and we have been talking


1 about what's the abbreviated clinical data

2 that's required and how we're going to justify

3 that and I will talk about it a little bit

4 more during my presentation.

5 So, I'm going to talk about the

6 biosimilarity. Particularly the two questions

7 the forum has addressed us to considered.

8 What scientific and technical data

9 should FDA consider in determining whether a

10 valid product is highly similar to the

11 reference product notwithstanding minor

12 differences in clinically inactive components?

13 That is excipients.

14 Current paradigm predominately

15 realize empirical human data with minimal

16 unity of prior knowledge and mechanistic

17 understanding for decision making in most

18 cases. For biosimilars, probably that's not

19 the right case because this are based upon

20 prior knowledge and for biosimilars in general

21 process is the product compared to the small

22 molecules because it's a complex science


1 process.

2 Once you make the process is

3 evolved. Really compare the product in terms

4 of its comparability, in terms of quality and

5 everything else and explain the design space

6 and specifications and now, we have the

7 process and enacted acceptance that's

8 currently the product in a simple -- there is

9 no other excipient used to really make a

10 product other than just making -- a solution.

11 So, if you are interested in the

12 prior knowledge of the product, innovator

13 product, and how that has been used it will

14 play a lot of account for developing a

15 biosimilar.

16 But, the establishment has

17 specifications based upon the originator

18 product through characterization and lot-to-

19 lot variability of the critical

20 characteristics of the drug product to --

21 product profile for the biosimilar product.

22 How you can achieve this not from the product


1 information, but probably obtain the product

2 from the market and testing it and there bring

3 a private profile so that you can make a

4 biosimilar product meet those target profiles.

5 And then designing of the

6 manufacturer's process of a biosimilar product

7 to the label development of the product to

8 meet those specifications and we've been

9 talking about the drift for the last couple of

10 days and drift will occur. Drift will occur

11 for the innovator product. Drift will occur

12 for the biosimilar product. But, as long as

13 the drifts are within the space of those

14 recommended target profile you should be okay.

15 Clinical comparability data should

16 be based on adequacy of design and

17 characterization and uncertainly -- so, for

18 the clinical that are actually locking for

19 these, what uncertainties which we cannot

20 address when we're defining the target profile

21 or the target characteristics of the innovator

22 product or the biosimilar product?


1 What are the uncertainties that we

2 are sure of, but we are not able to address?

3 That's where you need a clinical data to

4 address those uncertainties within a reference

5 product for a biosimilar product.

6 So, what scientific and technical

7 factors should the FDA consider? Analytical

8 and what is the range of structure difference

9 for example? So, we think major structural

10 differences permissible will depend on the

11 totality of the entire item and may vary by

12 product type and from product to product.

13 Data derived to demonstrate

14 comparability utilizing comprehensive

15 techniques to illustrate, for example, a

16 natural sequence or a natural composition of

17 mapping or maspec are two identification

18 steps. Outside exclusions are leading the

19 different quality methods to insure that the

20 analytical tools are matched. Like UV visual

21 or DSC or AUC, analytical certification.

22 The compound is not quality


1 characteristics between the biosimilar and the

2 referenced product. The major differences

3 through the improvement of analytical tools

4 means you may have a different level of

5 impurities, different level of aggregates,

6 something like that. Is because of the

7 technology developed complicate the innovator

8 product which was established and approved say

9 1990s or since 2000 at 2010.

10 So, these improvement of

11 technology, improvement of analytical tools

12 thereby which your biosimilar product may have

13 an enhancement in terms of the added goals,

14 impurities and other things. So, you need to

15 look into that very carefully.

16 And this is based upon the FDA's

17 comparable adjustment which has become as a

18 guidance and which hasn't been applied by all

19 the regions ICH to develop further guidelines

20 to show the comparability.

21 Reasonable pre-clinical and

22 clinical settings are required as per the ICH


1 guideline Q5E which prorates a baseline. It's

2 not very helpful here by the ICH Q5E. But, it

3 develops a baseline. What the minimum studies

4 you're required.

5 Particularly, you must base this

6 in clinical studies. Limited at the time of

7 approval, but followed by post-marketing

8 monitoring, post-approval monitoring. Post-

9 approval follow up is essential including an

10 observation study to collect robust adverse

11 data which can come from the CH of the product

12 once it's approved and is placed into the

13 market. So, to confirm that, I think an

14 observation study in the post-marking area in

15 the pharmacovigilance part is very critical.

16 For example, if you look at the

17 quality differences between biosimilars and

18 different drug products that been approved in

19 the FDA and different products, in terms of

20 the wholesales, there is a difference in

21 wholesales where public data, the biosimilar

22 product is made. For example, Valtropin has


1 made with the East compared to the hemitrope.

2 Different levels of impurities in these

3 products. Zarzio and filgrastim, as it is a

4 different formulation. The change in the

5 excipients and different glycosylation process

6 for some of these compounds.

7 Still, none of these products

8 which have been in the market so far did not

9 lead to any significant adverse events or

10 safety concerns. Indicating that a minor

11 change or deviations in the quality

12 differences between biosimilars and different

13 type products should not really consider a

14 concern, a safety concern. Because none of

15 them are shown to be that to date.

16 So what scientific and technical

17 factors should the FDA consider in determining

18 the analytical and what particularly -- the

19 question I am answering is, what analytical or

20 clinical activities are necessary for a

21 particular biosimilar application? As

22 described earlier, comparability testing for


1 the API, which is a drug substance, and the

2 product, is essential. Analytical and

3 clinical safety activities are necessary but

4 may be abbreviated, notably in the case of PK

5 and the PD. The differences observed in PK

6 profiles but comparable in PD is demonstrated

7 and clinical events could be established,

8 should be considered.

9 I think I'm running out of time.

10 I'll finish in one minute.

11 So, for example, I'm giving you a

12 graphical presentation here. I have a plasma

13 concentration profile for PD. I have a

14 product where you give it at two different

15 dose levels and you can see on the right-hand

16 side the PK profiles are different, but if you

17 look at the PD, they're all lacking more or

18 less in the assay variation. So even though

19 if you see PK differences, if there is no

20 difference in PD, you can still consider that

21 similar and probably you can take it forward

22 with a PD approach.


1 The economics of biosimilars is

2 cost containment, particularly to reduce the

3 output pressure on healthcare, increase

4 affordable access and would help to reduce R&D

5 development costs, particularly gain in

6 production efficiencies, streamline

7 development programs, generate savings and can

8 be offered at prices below the finished

9 product which can be done.

10 In particular, to conclude, what's

11 the future for the biotechnology industry? It

12 offers a pathway because it avoids arbitrary,

13 unnecessary or unethical duplication of pre-

14 approval studies or clinical trials. Testing

15 based on comparable differences or proffered

16 extrapolation between indications based on

17 thorough understanding of mechanism action and

18 other relevant factors, while accommodating

19 scientific progress to allow regulators access

20 to the highest-quality and most important data

21 on which to approve a biosimilar product and

22 sponsors can utilize these. They efficiently


1 use prior knowledge to enhance their efforts.

2 And I appreciate your time and

3 thanks for the opportunity to present and I'll

4 be more than happy to address any comments or

5 questions.



8 Kozlowski.

9 DR. KOZLOWSKI: In your slide on

10 the procedure to go through comparability

11 testing, I think it's before the graphs you

12 show about PK and PD, you state clinical

13 studies to demonstrate efficacy may not always

14 be needed if the PK/PD or PD is sufficient.

15 So I want to ask, do you also mean

16 no safety or immunogenicity studies?

17 DR. TAMMARA: The safety and

18 immunogenicity would be following in the post-

19 approval. Because once you have a PD, as part

20 of the PD study, you can assess immunogenicity

21 in the PD study, and then once you have that

22 information, you can assess the safety


1 immunogenicity problem in the post-approval.

2 DR. KOZLOWSKI: So, to clarify,

3 you would say PK/PD comparison if appropriate

4 plus the structural, you know --

5 DR. TAMMARA: Similarity.

6 DR. KOZLOWSKI: -- yes, similarity

7 would be sufficient pre-market studies and

8 then the rest of the studies would be post-

9 market?

10 DR. TAMMARA: That's right.

11 DR. KOZLOWSKI: So, I would point

12 out that I think you disagree with the

13 previous speaker because you would have a very

14 different post-market plan than the innovator.

15 DR. TAMMARA: That's right. I

16 honestly disagree with that.



19 DR. TAMMARA: Thank you.


21 Terence Ryan from iBio, Inc.

22 DR. RYAN: I'm like to open my


1 statement by thanking the panel and the Food

2 and Drug Administration for holding this

3 hearing to receive public comment on the

4 development of guidances for biosimilar drugs.

5 Because of the complexity of

6 biologics and the various means to

7 manufacturer them, current biotherapeutics are

8 often expensive and their availability to

9 patients may be limited by the resources of

10 the patient or insurance co-payor.

11 The existence of biosimilar

12 versions of these front-line branded biologics

13 is likely to have a dramatic effect on patient

14 access and lessen the financial impact of

15 biologics on patient resources and those of

16 the health care system as a whole. These

17 reasons provide a compelling rationale for the

18 development of biosimilar guidances that will

19 result in the introduction of safe and

20 effective treatments that reach a broader

21 patient population.

22 Because these initial guidances


1 will have a profound influence on the

2 technology and economics of biosimilar

3 development, we'd like to urge the panel to

4 take the broadest possible perspective on how

5 the specification of highly similar should be

6 interpreted. A perspective that emphasizes

7 analytical biochemistry as the benchmark for

8 highly similar would be likely to ensure

9 safety and efficacy of a biosimilar through

10 exact mimicry of the branded biologics primary

11 peptide sequences and various post-


13 However, such an emphasis may

14 restrict the production of a biosimilar to the

15 very specific manufacturing method used to

16 create the branded biologic, ensuring that

17 potentially out of date or costly

18 manufacturing processes will be used and

19 reducing the opportunity for speed or cost

20 savings in bringing these new medicines to

21 patients.

22 For example, a biotherapeutic


1 produced in recombinantly modified Chinese

2 hamster ovary cells grown in stir tank

3 bioreactors may have post-translational

4 glycosylation patterns that include galactose-

5 alpha-1,3-galactose or N-glycolylneuraminic

6 acid residues and these themselves are not

7 produced by humans cells and are not normally

8 seen in human proteins and these are

9 potentially antigenic to patients.

10 Adherence to strict biochemical

11 mimicry to fulfill the highly similar standard

12 might be interpreted to require biosimilar to

13 have identical glycosylation and perforce

14 require the biosimilar to be made in CHO cells

15 rather than by another modality that would

16 provide identical safety and efficacy but at

17 lower cost.

18 Additionally, the strict standard

19 would expose patients to allergic or

20 neutralizing antibody responses which might

21 not otherwise occur if more advanced

22 manufacturing technologies, whether present or


1 future, could be employed.

2 Our interest at iBio, Incorporated

3 is production of protein therapeutics and

4 vaccines in whole plants using a novel method

5 of transient expression. The process is

6 easily scalable and could be semi-automated in

7 a factory setting and modest pilot plant

8 facilities can produce more than half a

9 million vaccine doses per month.

10 Extensive research and development

11 of biotherapeutics using this system has shown

12 similar bioactivity, efficacy and

13 pharmacologic behavior to protein

14 biotherapeutics produced in bacteria, yeast

15 and animal cells.

16 All types of existing

17 biotherapeutics can be manufactured with this

18 whole plant system and, indeed, we've produced

19 some recombinant proteins which could not be

20 produced by more traditional expression

21 systems.

22 Manufacture in plants does not


1 have the risk of endogenous or carryover viral

2 contamination from the use of animal cells or

3 substrates and the resulting proteins are

4 easily characterized due to the homogeneity

5 and reproducibility of post-translational

6 glycosylation and other modifications.

7 Of even greater value from a

8 patient point of view, manufacture of

9 biotherapeutics in whole plants prior to

10 purification steps can result in a decrease in

11 bulk drug material cost of approximately 80 to

12 90 percent when compared with more traditional

13 expression systems, thereby potentially

14 increasing patient access to these medicines.

15 We feel that the term highly

16 similar should emphasize safety and efficacy

17 above all other considerations. Analytical

18 biochemistry analyses should show the same

19 primary sequence as the reference molecule and

20 matches purity and dispersity. The biosimilar

21 molecule should have no significant

22 differences in pharmacokinetics, ADME or


1 toxicology when compared with the reference

2 molecule.

3 Effective characterization of all

4 post-translational modifications of the

5 primary sequence should be required, and where

6 differences occur should be shown to have no

7 significant effect on safety and efficacy as

8 well as on PK, ADME and tox.

9 Such an interpretation of highly

10 similar would allow emerging and currently

11 experimental technologies such as production

12 in new animal or human cell lines, stem cells,

13 engineered plant cells or whole plants to be

14 considered for future biosimilar work and

15 allow for progress to substantially reduce

16 development time and manufacturing cost

17 resulting in an increase in the number of

18 patients receiving life-saving medicines at

19 affordable prices.

20 I'd be happy to answer any

21 questions.




2 Kozlowski.

3 DR. KOZLOWSKI: So, to clarify,

4 the point you're making is that no matter what

5 the manufacturing substrate, as long as the

6 product meets the goalposts, was the term used

7 before, and any impurities, you know, or

8 potential contaminates are adequately

9 controlled and characterized and there's good

10 science behind everything, that source alone

11 should not be a limitation. Is that the --

12 DR. RYAN: Yes, we strongly

13 believe that.

14 DR. KOZLOWSKI: I have another

15 follow-up question.

16 DR. RYAN: Sure.

17 DR. KOZLOWSKI: Which may touch

18 upon one of the statements you're making about

19 the cost of -- I mean, one general question I

20 was asked as we make that point. Are the cost

21 of goods the major driver of the cost for

22 these products?


1 DR. RYAN: There are many drivers

2 for cost of these products, but anything that

3 you can do to lessen the eventual out-the-door

4 cost, we think should be a benefit to the

5 patient. Also, benefit the health care system

6 which has to pay for those products.

7 So cost of goods is one factor and

8 this is the one factor that our technology

9 addresses.


11 DR. JENKINS: So you're taking a

12 fairly different approach from what we've

13 heard from others who have argued that the

14 physicochemical characterization should be the

15 base of the pyramid and one of the earlier

16 presenters had the top of the, the apex of the

17 pyramid was a fairly small segment for the

18 clinical comparison.

19 As I understand it, you're saying

20 that the PK/PD, the pre-clinical studies and

21 the clinical study should be the base of the

22 pyramid, maybe inverted, and that the


1 physicochemical characterization should be

2 more limited so that you don't have to

3 absolutely duplicate the molecule. You want

4 to duplicate the effect of the molecule.

5 DR. RYAN: In broader terms,

6 duplicating the effect of the molecule we feel

7 to be most important. However, that's not to

8 say that we think physical and chemical

9 characterization of the protein is a minor

10 aspect of this.

11 We think that the differences that

12 exist through any manufacturing system,

13 differences between a potential biosimilar and

14 a reference product, those differences should

15 be shown to have no clinical significance.

16 DR. JENKINS: Well, that's where I

17 wanted to go. Because others have built a

18 pyramid from the physicochemical

19 characterization up to argue for a limited

20 clinical comparison.

21 So I'm interested in your model.

22 What would the clinical comparison look like?


1 How rigorous would it be? What size study?

2 What margins? Would it be a feasible study?

3 DR. RYAN: Not being a company

4 that conducts clinical trials or actually

5 develops biologics, but actually holds

6 technologies that are useful to development of

7 biologics, I don't want to comment too

8 extensively.

9 However, my expectation as a

10 scientist would be that on a case-by-case,

11 molecule-by-molecule basis, you could

12 anticipate different levels of requirements

13 and interactions.

14 In a case where a molecule is very

15 simply manufactured with relatively few post-

16 translational modifications, it's easier to

17 establish an identity at a chemical level.

18 However, as the complexity of post-

19 translational modification such as

20 heterogeneous glycoprotein additions are

21 introduced as you go up in a scale of

22 complexity and perhaps activity of a molecule,


1 those post-translational modifications may or

2 may not have clinically significant or

3 relevant activities.

4 They'd be more necessary for

5 proper protein folding. They may not affect

6 serum half-life. They may or may not affect

7 on-rates or molecule receptor. Those should

8 be explored.

9 But, in fact, you know, speaking

10 as a scientist, I believe the differences that

11 do exist that have no clinical significance

12 should not be the subject of, you know, very

13 deep or prolonged discussion. If the molecule

14 itself behaves with the same safety and

15 efficacy which overall are rules number 1 and

16 number 2, every other rule you might make is

17 to ensure those first two.


19 DR. KOZLOWSKI: So, to follow up

20 on Dr. Jenkins' discussion of the approach,

21 even if one uses an unusual source substrate

22 for manufacturing, with genetic engineering,


1 you know, and we've heard examples talked

2 about today, one can alter glycosylation

3 potentially and change things.

4 DR. RYAN: Absolutely.

5 DR. KOZLOWSKI: So, one could use

6 different source material and aim for the

7 pyramid the way it was described earlier which

8 is to try and make the closest material you

9 can. I guess we heard a similar is reasonably

10 achievable and then to work from that. So, is

11 that an area that you're also discussing?

12 DR. RYAN: We're not discussing it

13 specifically, but it's certainly within the

14 realm of possibility and also of current

15 activity.

16 However, we feel that the fact

17 that a production substrate or method is

18 different should not a priori disqualify it

19 from manufacturing a biosimilar. As long as

20 safety and efficacy are fulfilled, we think

21 that should be allowed with appropriate

22 documentation and characterization of the


1 product.

2 DR. BEHRMAN: I thought you went a

3 little farther than that and said that, in

4 fact, if there are modifications, if you will,

5 the molecules that are not necessarily -- or

6 can be shown not to be important to the safety

7 and efficacy profile that there should be no

8 need to make sure, if you will, one tinkers

9 until that degree of similarity is achieved.

10 DR. RYAN: Well, you should

11 understand what the differences are, and if

12 they're inconsequential in terms of your

13 clinical performance, I think we should say

14 that should be good enough at this point.

15 That doesn't rule out somebody

16 aspiring to achieve absolute chemical

17 identity.


19 DR. JENKINS: I just can't get

20 away from, in my mind, thinking that the

21 approach you're describing would lead to a

22 larger, more rigorous clinical program to


1 assure that the differences in the molecule

2 aren't relevant. All the other paradigms I

3 think we've seen have been about making it the

4 same as reasonably possible at the base so

5 that as you get up to the --

6 DR. RYAN: Right.

7 DR. JENKINS: -- top of the

8 pyramid you have do less and less to actually

9 have an abbreviated program. I'm just

10 concerned about your approach. Maybe --

11 DR. RYAN: I am not at all

12 advocating an expanded clinical program. What

13 I am speaking to is directly about the

14 technology that is used to manufacture a

15 biosimilar.

16 With that understanding in hand of

17 what that technology does, we feel it's up to

18 the panel to then establish what they feel are

19 appropriate criteria for the characterization

20 and clinical testing of material made in a

21 different expression system.

22 And we speak only to the


1 technology and I'm not making any suggestions

2 about structure, size or goals of clinical

3 trials. Just to be clear.

4 DR. BEHRMAN: Thanks. Any other

5 questions? Thank you for your comments.

6 Our next speaker is Arthur

7 Tzianabos. Am I close?

8 DR. TZIANABOS: That was really

9 close.

10 DR. BEHRMAN: Thank you.

11 DR. TZIANABOS: Very difficult

12 name. Honored FDA officials, industry

13 colleagues and other interested parties, good

14 morning. My name is Arthur Tzianabos, Vice

15 President, Program Management at Shire Human

16 Genetic Therapies. I'm standing in this

17 morning for Sue Bruhn, Head of Regulatory at

18 our company. She was called away

19 unfortunately, had an unavoidable conflict.

20 I'm testifying today on behalf of

21 Shire and its business unit, Shire Human

22 Genetic Therapies.


1 Shire Human Genetic Therapies has

2 specific experience with all parts of the life

3 cycle of therapeutic biologics which we feel

4 positions us to provide relevant input on the

5 implementation of biosimilars approval

6 pathway.

7 While Shire Human Genetic

8 Therapies is focused on the development of

9 therapeutic biologics for rare diseases, the

10 standards for biosimilars and for

11 interchangeability should be the same across

12 all disease areas, we believe. Our thesis

13 centers on the overriding importance of

14 ensuring patient safety with specific

15 consideration of the unique safety challenges

16 that are faced in the development of biologic

17 products.

18 The first question we will address

19 is the following: What factors should the

20 agency consider in determining whether a

21 proposed biological product can be, quote,

22 "expected to produce the same clinical result


1 as the reference product in any given

2 patient?"

3 What makes biologic products

4 unique is their complexity relative to small-

5 molecule chemical entities. Typically,

6 biologics are developed and manufactured from

7 living organisms, including cell-based

8 systems, that in themselves are a complex

9 environment with potential for impact on

10 product quality.

11 The manufacturing process can

12 impact key attributes of biologic products

13 including stability, impurity, profile, size,

14 shape, glycosylation or other post-


16 Differences in these key

17 attributes may impact pharmacokinetics,

18 pharmacodynamics, biodistribution and,

19 importantly, immunogenicity. This can lead to

20 alterations in purity, potency, efficacy and

21 safety, thereby impacting the benefit/risk

22 profile of the product in patients. It is,


1 therefore, essential that each product be

2 independently evaluated.

3 As a result of these well-

4 characterized differences between biologics

5 and small molecules, biologic innovator

6 companies work to carefully identify and

7 understand the complex relationship between

8 process, product and risk/benefit profile

9 during the development and manufacture of

10 products with all subsequent product

11 improvements, including those derived from

12 alterations in manufacturing processes facing

13 rigorous standards of comparability.

14 These standards are appropriate in

15 the context of the unique challenges that

16 biologics create when used as therapeutics in

17 the human body. They require a demonstration

18 of product comparability and its impact on

19 safety and efficacy.

20 It is important to patients that

21 the same high comparability standards that

22 apply to product improvements of innovative


1 biologics should minimally apply to biosimilar

2 products developed using the 351(k) pathway

3 and the scope of the data required in support

4 of approval should reflect the magnitude of

5 the differences seen in the protein product

6 and their potential impact on the benefit/risk

7 to patients.

8 Any differences in product

9 quality, safety, or efficacy should clearly be

10 outlined in the approved product label.

11 We suggest that biosimilars should

12 undergo comparative clinical assessment at

13 least as stringent as provided by biosimilar

14 guidances published by other health

15 authorities around the globe, including the

16 World Health Organization guidelines on the

17 evaluation of biotherapeutic products in the

18 EMEA.

19 Based on these guidelines, the

20 clinical evidence needed to support

21 interchangeability of a biosimilar product

22 with a reference drug, which we believe should


1 be the innovator drug, should take into

2 consideration the following factors.

3 At least one clinical trial should

4 be comparative in nature, head-to-head with

5 the innovator drug.

6 Clinical study or studies should

7 be designed to demonstrate comparable safety

8 and efficacy of the biosimilar in direct

9 comparison to the innovator product.

10 If any relevant differences

11 between the biosimilar and the innovator

12 product are detected, the reasons need to be

13 explored and justified. If this is not

14 possible, the new product may not qualify as

15 a biosimilar and a full drug application

16 should be considered.

17 In addition to ensuring patient

18 safety, clinical trials should be conducted

19 with established and well-recognized efficacy

20 endpoints for the disease under investigation.

21 The plan for acceptable clinical similarity

22 with regard to efficacy should be proposed and


1 justified, ensuring that a sufficient number

2 of patients are enrolled to demonstrate

3 comparable efficacy.

4 The studies should reflect the

5 original patient population studied with the

6 innovator drug in the same indication.

7 The justification for the choice

8 of the clinical study design such as non-

9 inferiority or equivalence design should also

10 be considered. The design should ensure an

11 adequate study duration that allows the

12 collection of not only the necessary clinical

13 data, but also any long-term immunologic

14 effects such as generation of neutralizing

15 antibodies, anaphylactic responses or cell-

16 mediated immune responses.

17 The biosimilar sponsor should

18 provide a justification for each indication

19 for which approval is sought. Efficacy in one

20 indication should not be extrapolated to

21 efficacy in others, as the characteristics of

22 a product have the potential to affect


1 efficacy and safety in different clinical

2 settings.

3 Because of the potential impact on

4 patient safety, the comparative clinical

5 immunogenicity of biosimilars to innovative

6 products should be specifically addressed in

7 patients. Many factors impact the

8 immunogenicity of biologic products. An

9 assessment strategy should be justified that

10 can adequately characterize and quantify the

11 immunogenic effects in patients.

12 Antibodies which are generated

13 should be fully characterized with a clear

14 understanding of their relationship to and

15 impact on all aspects of safety and efficacy

16 assessed in the study. In particular, the

17 potential for neutralizing the effect or

18 elicitation of anaphylaxis.

19 If differences in immunogenic

20 profiles are observed, further and more

21 detailed characterizations should be required.

22 Because of the complexity of factors related


1 to immunogenicity, each therapeutic indication

2 presents a potentially different clinical

3 environment for the therapeutic that prevents

4 extrapolation from one patient to another.

5 The second question we will

6 address is the following. What factors should

7 the Agency consider in the evaluation of the

8 potential risk related to alternating or

9 switching between use of the proposed

10 interchangeable biologic product and the

11 reference product where among interchangeable

12 biologic products?

13 The safety of the patient should

14 be the most important consideration with

15 regard to interchangeability.

16 Interchangeability, as defined in the

17 legislation, allows two biological products to

18 be switched for patients multiple times at the

19 pharmacy level without consulting a physician

20 provided there is no impact on safety or

21 efficacy in patients.

22 The data required to demonstrated


1 safety in the context of interchangeability is

2 beyond that of market authorization and should

3 require very high standards and careful study

4 for biologics in particular because of the

5 unique challenges associated with the

6 potential for immunogenicity.

7 To ensure patient safety for

8 repeated switching, the sponsor of a

9 biosimilar interchangeable product should be

10 required to conduct clinical trials

11 demonstrating the safety and efficacy of

12 repeated switching between products.

13 The potential risk associated with

14 switching or alternating use between the

15 proposed interchangeable biosimilar and the

16 innovator product or among interchangeable

17 biologic products will need to be addressed

18 using adequately designed and well-executed

19 crossover clinical trials.

20 Particular consideration should be

21 given to the increased risk for immunogenicity

22 in the context of product switches as repeated


1 challenges in the background of existing

2 patient antibodies has the potential to lead

3 to serious hypersensitivity or anaphylactic

4 responses if the two therapeutics have

5 different antigenic profiles.

6 The sponsor of the interchangeable

7 biosimilar should provide justification for

8 the clinical study design. For example, a

9 single crossover design would reflect one

10 switch to a different product, whereas

11 multiple crossover design would reflect

12 alternating use of a product and be more

13 aligned with the true interchangeability.

14 The overall study of the duration

15 will be primarily dependent on the number of

16 cycles of switches needed to ensure no

17 diminished efficacy. Justification for a

18 washout window, if necessary, and the length

19 of the washout window should be provided.

20 Where multiple indications exist

21 for the innovator product, careful

22 consideration should be given for


1 interchangeable safety extrapolation to other

2 indications.

3 So, in summary, the safety and

4 efficacy of highly complex biologic products

5 should be the focus of the approval process

6 for biosimilar therapeutics to be approved via

7 the 351(k) pathway for each product, disease

8 state and labeled population.

9 Clinical immunogenicity needs to

10 be rigorously assessed to ensure the safety of

11 patients. Interchangeability at the pharmacy

12 level should require a higher standard of

13 proof than approval of the innovator product.

14 The specific studies designed to address the

15 unique challenges inherent in the

16 manufacturing of biologics in living systems

17 and the multifactorial impact that biologics

18 can have on different patient populations.

19 We believe the standards for

20 biosimilars and for interchangeability should

21 be the same across the disease areas.

22 Thank you very much.




3 Kozlowski.

4 DR. TZIANABOS: Getting towards

5 lunch. So I'm sure that's impacting energy

6 level.

7 DR. KOZLOWSKI: I'll try and be

8 short. You mention that obviously you need to

9 do immunogenicity studies on these products.

10 So what if you had a product with a very low

11 level of immunogenicity in the innovator, well

12 below 1 percent, no evidence of adverse events

13 from antibody formulation. Would you need

14 potentially a thousand-patient study to, you

15 know, show that that level is the same?

16 And then if you're doing a

17 switching study for such a product, would you

18 need to again have that same level of

19 sensitivity for immunogenicity in the

20 switching study?

21 DR. TZIANABOS: So we're talking

22 about a hypothetical, obviously, to be clear,


1 and then, you know, there's a big difference

2 between doing immunogenicity studies in mice

3 versus rats versus non-human primates versus

4 humans.

5 So, if you're saying that there --

6 if you're demonstrating low immunogenicity in

7 pre-clinical models, I absolutely still think

8 that you need to do that kind of level in

9 humans.

10 So, are you saying humans?

11 DR. KOZLOWSKI: No, the innovator

12 experience. In other words, what you would

13 look in the label as terms of the percent of

14 immunogenicity.

15 DR. TZIANABOS: So we still think

16 that there are a lot of aspects outside of the

17 immunogenicity, just antibodies that could be

18 impacting potential safety for patients.

19 These include cell-mediated responses, T cell

20 responses, anaphylactic reactions. So, there

21 are a lot of other aspects aside from just

22 antibody levels that need to be assess to


1 ensure patient safety.

2 So we still believe that those

3 kind of rigorous studies should be done.

4 DR. KOZLOWSKI: To push the

5 hypothetical, say, in fact, the innovator

6 product didn't have any of those adverse

7 events associated with an immune response and

8 if there was some anaphylaxis or something,

9 you know, it was in the one in 50 or 100,000

10 where literally, you know, you couldn't design

11 a study to compare that.

12 DR. TZIANABOS: I think our

13 position is this. That if we -- what we'd

14 like to see is a standard that's similar to

15 the innovator product. So in the scenario

16 that you're painting, if it's very low

17 immunogenicity, then again you could apply

18 that to the biosimilar.

19 DR. BEHRMAN: Okay. Could I ask

20 you a couple of points of clarification

21 because you gave us a lot of information

22 rapidly?


1 Did you state or imply that the

2 comparison for biosimilarity should only be to

3 the innovator part? Only the innovator part

4 can serve as a reference product?

5 DR. TZIANABOS: Yes, that's our

6 position.

7 DR. BEHRMAN: And was the same

8 true for interchangeability? That the

9 comparison can only be with the innovator

10 product?

11 DR. TZIANABOS: Yes, that's our

12 position.

13 DR. BEHRMAN: And if there were

14 more than one biosimilar then licensed, what

15 do you see as the relationship of those

16 products?

17 DR. TZIANABOS: So, we see -- in

18 the terms of interchangeability is what you're

19 referring to?

20 DR. BEHRMAN: I guess both

21 biosimilarity and interchangeability.

22 DR. TZIANABOS: Well, let me


1 address interchangeability first. I think

2 there we see a higher bar because of the

3 potential for multiple switches back and forth

4 potentially between the innovator branded

5 product and multiple biosimilars and so, what

6 you see there, in our opinion, is a greater

7 potential for immunogenic or anaphylactic

8 response.

9 So I think that is important to

10 assess in a very, very rigorous way.

11 In terms of biosimilarities, I

12 think I stated the same position. I think we

13 need to see the same level of rigorous

14 assessment of the biosimilar compared to the

15 innovator product.


17 You're very kind. I think you get the award

18 for the name I most butcher so far today.

19 Thank you for your time.

20 DR. TZIANABOS: Thank you. It's

21 been an early morning.

22 DR. BEHRMAN: Our last speaker


1 this morning is Joseph P. Miletich from Amgen.

2 How am I doing? I guess I'm getting hungry.

3 DR. MILETICH: That was fine.

4 Thank you. This is Joe Miletich.

5 Dr. Behrman and members of the

6 panel, thank you for the opportunity to

7 testify here today.

8 My name is Dr. Joe Miletich. I'm

9 a physician and molecular biologist. Before

10 joining Amgen, I spent 24 years at Washington

11 University in St. Louis treating patients and

12 using the tools of molecular biology to try to

13 understand human disease.

14 Our message today is really

15 simple: put patients first and sound policy

16 will follow.

17 Amgen does believe that

18 biosimilars have a meaningful role to play in

19 the health care system. However, as we've

20 heard multiple times, biosimilars unlike

21 generic drugs are just simply not identical to

22 the innovator biologic products.


1 So, to keep patients first, we

2 have to acknowledge what it is that we do not

3 yet know and then set a reasoned path forward.

4 My testimony today is intended not

5 to go blank. I'm sorry. Oh, sorry. We were

6 upside down or I was. Something was wrong.

7 Thank you.

8 My testimony today is intended to

9 offer three recommendations. First, use well-

10 designed clinical trials to establish

11 biosimilarity.

12 Second, ensure that the product

13 manufacturer and the lot number are known for

14 each biological and by that I mean that

15 they're traceable from an adverse event report

16 and if possible, from other sources of useful

17 data, to the lot, to the manufacturer and to

18 the lot number.

19 And finally, if interchangeability

20 is deemed feasible, then by all means,

21 consider both scientific and practical

22 criteria for interchangeability.


1 Alongside the Agency's Office of

2 Biotechnology Products, we have learned a lot

3 about the complexity of biologicals and their

4 interactions with the human body and we

5 believe that the biosimilar policy must

6 reflect that knowledge.

7 As we have heard, two biological

8 products are unlikely to ever be identical

9 when they're made inside different living

10 cells that are nourished by raw materials from

11 different sources and then are harvested,

12 purified, formulated, packaged and shipped in

13 different ways.

14 So, the problem is that we have a

15 relatively heterogeneous distribution of

16 closely related molecules in a product. It's

17 important that we characterize these, and

18 Amgen uses all the latest technology to do the

19 best job possible understanding what that

20 variability in the molecules is.

21 It's important as we go forward

22 that we recognize increased characterization


1 is vital. However, that's not the rate-

2 limiting step right at the moment. The

3 problem is that we don't know enough human

4 biology. So we don't know what the

5 distribution of heterogeneity means in every

6 patient, in every clinical setting, in every

7 indication.

8 So when we're trying to compare a

9 biosimilar to the innovator product, we have

10 two different distributions of closely related

11 molecules and it's more complex the more

12 complex the biological is that we're trying to

13 make and we just can't figure out in a mass

14 spec whether or not that makes a difference in

15 the human body.

16 It's important that we understand

17 the differences and that we characterize them,

18 but we don't know what they mean without

19 clinical experience. We have to have clinical

20 evaluations and experience in order to address

21 the questions.

22 So, therefore, the first point.


1 We need to use clinical trials to establish

2 the biosimilarity. In our 30-year history of

3 making biologics, Amgen has achieved

4 remarkable breakthroughs. We've developed

5 complex proteins and we've supplied them to

6 millions of patients.

7 However, in the process, we have

8 been humbled a few times by unexpected

9 outcomes even in the face of encouraging

10 analytical and pre-clinical data.

11 As an example, we planned a major

12 manufacturing change for Epogen. We didn't

13 see any differences analytically or in our

14 non-clinical studies that we thought would

15 have an impact. But, in a clinical study, we

16 found an increasing potency that did exceed

17 our pre-specified endpoint. So we cancelled

18 the process change.

19 An even more important point than

20 that is even with all the analytical tools

21 available to us, I still can't explain to you

22 what the real difference in the distribution


1 of those molecules is that led to the increase

2 in efficacy. I know it's there, but I still

3 can't explain it.

4 We can also look to the biosimilar

5 experience in Europe where 11 distinct

6 products have been submitted for approval,

7 some under multiple trade names. Clinical

8 data provided to the EMA had a significant

9 impact on the regulatory review of at least

10 six of these 11. Three were withdrawn. One

11 was rejected. One was restricted to IV

12 administration and one required a

13 manufacturing change.

14 Amgen has also learned about

15 unintended interactions of a product with its

16 container. We discovered new information

17 through voluntary reporting and we've relied

18 on accurate traceability to conduct recalls,

19 prompt recalls, when necessary.

20 So, as we've heard from many other

21 speakers, products must be distinguishable for

22 correct attribution and reporting of adverse


1 events and it's best if this is as easy as

2 possible for patients and other health care

3 providers.

4 When there's only one manufacturer

5 of a biological, you know who to call. When

6 there's more than one, you need to know who to

7 call.

8 For example, we've heard about

9 PRCA. So, at the time PRCA, this unfortunate,

10 dramatic increase in an uncommon but

11 potentially life-threatening immune reaction

12 against the biological and ultimately against

13 the patient's own erythropoietin. At the time

14 that was detected, there were three ESA

15 manufacturers in Europe.

16 I think we could probably all

17 agree that it was difficult and it took

18 probably too long from a patient's point of

19 view to figure that out.

20 Now, there are six manufacturers

21 distributing ESA products under at least 11

22 brand names. This has being addressed in the


1 EU, but it's being addressed retroactively.

2 We need to get this right for patients from

3 the start.

4 I think next, since I see my

5 yellow light, I think I should turn to


7 Patients need the FDA, not

8 individual states, payors or formulary

9 committees to determine if a biosimilar may be

10 interchangeable. Biosimilars that haven't

11 been determined to be interchangeable by the

12 FDA should clearly be labeled that way and an

13 interchangeability determination, if possible,

14 would be very difficult to make and it

15 requires significant time and experience to

16 address both scientific and public health

17 challenges.

18 Guidance class by class is also

19 going to be necessary to avoid confusion and

20 unnecessary uncertainty in the regulatory

21 pathway.

22 We've heard about some of the


1 practical considerations that need to be

2 considered. This includes differences in

3 approved indications and in use between the

4 products, unintended switching and attribution

5 of the adverse events after switching if it

6 occurs.

7 Safe interchangeability means all

8 patients need to be assured that switching

9 products will not cause harm or differences in

10 their response.

11 The potential for patients to

12 receive their therapies from different

13 pharmacies, hospitals, PBMs or more are all

14 real world concerns. These challenges may not

15 preclude a scientific assessment, but they

16 have to inform the clinical standards and

17 design of studies.

18 So, we want the FDA to be the body

19 to determine if biosimilars are

20 interchangeable for U.S. patients. I think

21 I'll actually conclude there since I see the

22 red light. Thank you very much.



2 remarks and your timeliness. Questions from

3 the panel? Dr. Jenkins. Well, actually, we

4 should let Ms. Esposito go.

5 MS. ESPOSITO: Thank you for your

6 comments. My question relates to your

7 interchangeability discussion.

8 If I heard you right, I thought

9 you were advocating not permitting

10 interchangeability determinations to occur at

11 the time of first approval of the biosimilar.

12 So, are you anticipating or envisioning a

13 second stage of the approval process so that

14 when the product is first approved as a

15 biosimilar, it would only be biosimilarity and

16 then a second submission would be required to

17 establish interchangeability post-marketing?

18 DR. MILETICH: It's very difficult

19 for me to think of an example where it would

20 be prudent to approve interchangeability at

21 the time of approval. I think post-marketing

22 experience and surveillance would definitely


1 be required because of the complexity of

2 interchangeability for all the reasons that

3 have been discussed.

4 MS. ESPOSITO: And to follow up on

5 that, have you put any thought into or have

6 any recommendations regarding either a length

7 of time or number of patients exposed post-

8 approval before enough data would be collected

9 to establish interchangeability?

10 DR. MILETICH: We've heard a

11 number of suggestions from a large number of

12 speakers. I think this testimony, this oral

13 hearing has been extremely helpful in airing

14 some of those.

15 I think that it's impossible to do

16 this by example. I think for every example I

17 can think of I can think of exceptions.

18 That's why I think we need class-by-class

19 guidance. So I think it's dangerous to put

20 out a model that we think would work for

21 interchangeability for all biosimilars. I

22 think we need the guidances and that's the


1 next step, to work on those.


3 DR. JENKINS: I want to ask the

4 question I've asked others who have been

5 innovators who have biosimilar competition

6 around the world. So I'm interested in

7 knowing, has Amgen been able to identify

8 safety, efficacy or immunogenicity problems

9 with the biosimilars of your products that are

10 approved in Europe, India, Asia, wherever in

11 the world they may be approved? Can you point

12 to any places where there have been problems?

13 DR. MILETICH: I wish I could

14 answer that question, but as I and other

15 speakers already told you, I really don't have

16 access to the information that you really need

17 to do that.

18 I'm not aware of problems, but if

19 they haven't been reported or the surveillance

20 programs aren't in place that we think might

21 be the standard, it's impossible to know.



1 MS. ESPOSITO: With respect to

2 your discussion about ensuring ease of

3 identification of the source of the product by

4 manufacturer and lot number, do you have any

5 recommendations regarding whether that should

6 be achieved by different non-proprietary

7 names, a prefix or a suffix? We heard

8 yesterday some discussion about referring to

9 the NDC number and trying to incorporate that

10 somehow.

11 Have you given any thought to how

12 the identification should be achieved?

13 DR. MILETICH: Yes, there were a

14 number of good suggestions made. I think

15 that, from the patient's perspective, having

16 more information and more possible ways to

17 trace any adverse event or even the

18 epidemiology of the use of a product over time

19 is beneficial.

20 So I would certainly be in favor

21 of a unique nonproprietary name. I would also

22 be in favor of a unique brand name and


1 certainly having the lot number information

2 somehow in the system traceable to something

3 that patients and other health caregivers can

4 easily remember and report.

5 DR. BEHRMAN: Ms. Maloney.

6 MS. MALONEY: Just picking up on

7 that, we've had a lot of discussion on the

8 naming, but I'm curious about what are the

9 other issues with regard to, you know,

10 failures for figuring out the adverse events?

11 What other things are we missing? I've heard

12 some people talk about, for instance, more

13 need for education. So are there any other

14 things you might point to?

15 DR. MILETICH: I certainly believe

16 that there is room for improvement in

17 education, in teaching people how they report

18 adverse events and when they should report

19 adverse events.

20 Again, more data for everybody to

21 understand about what the clinical experience

22 is can only be helpful.


1 MS. MALONEY: And just to pick up

2 on that, I think Dr. Siegel talked about, for

3 instance, you know, the electronic medical

4 records there. So what's needed there as

5 we're doing more, you know, Sentinel and

6 active surveillance?

7 DR. MILETICH: Well, there are

8 very large databases, as you're well aware,

9 and if we could connect the use of actual

10 particular products to the clinical experience

11 using those databases, again, I would think

12 that would be beneficial. Our goal here is to

13 understand, really for the benefit of

14 patients, how these products perform and

15 provide them in the safest possible way. So

16 it would have to be beneficial if we could

17 think of a way to do that as well.

18 DR. BEHRMAN: Go ahead.

19 DR. KOZLOWSKI: Just to follow up

20 on the nomenclature in tracking, are there any

21 risks associated with different nonproprietary

22 names like accidentally receiving a medication


1 twice because patient didn't realize they're

2 the same?

3 DR. MILETICH: I suppose when a

4 question is asked in a theoretical sense like

5 that, I guess there's always some risk. I

6 would expect it to be pretty small since the

7 medicines we're talking about at this point

8 are still pretty much injectable medicines and

9 a lot of them are given in settings where

10 there are health care providers in close

11 contact if not in immediate contact.

12 So, I think -- although I can't

13 say there's not a theoretical risk, I think it

14 would be somewhat small at this point.

15 DR. BEHRMAN: Could I ask a point

16 of clarification about the interchangeability?

17 You mentioned labeling. So you believe the

18 biosimilar should be labeled as not

19 interchangeable with the innovator. Should

20 the innovator labeling carry any information?

21 DR. MILETICH: Yes, I think if I'm

22 understanding your question correctly, on the


1 label, I think with the current labels that we

2 have in the U.S. it's possible to include that

3 information for both.

4 If there's non-interchangeability,

5 there shouldn't be interchangeability.

6 Absolutely.

7 DR. BEHRMAN: And then one

8 question about you gave the example where you

9 had made a process change and to your

10 surprise, there was this increase in potency.

11 What made you choose to do a

12 clinical study for that particular process

13 change? If you could --

14 DR. MILETICH: We just deemed that

15 in the best interest of patients. That was

16 not mandated in any way.


18 the process change, you mentioned you don't

19 know the exact biochemical link. Does that

20 mean there were no differences or you just

21 haven't figured out which differences, you

22 know, mattered?


1 DR. MILETICH: Depending on the

2 resolution with which you look, there are

3 always differences.

4 The problem is it's very difficult

5 to know across a wide distribution of

6 molecules exactly which ones might have had

7 the impact. I'm sure you're well aware of

8 this problem. It's just extremely difficult

9 to pinpoint and trace back.


11 Thank you for your comments. Thank all the

12 speakers for the morning. It was a terrific

13 morning.

14 It's now lunch. I just remind you

15 a la carte items are available for purchase.

16 The restrooms are to the left and the right.

17 Don't forget the trash receptacles in the

18 hallways and in the back of the room.

19 And please be back at five to 1:00. Thank you.

20 (Whereupon, the above-entitled

21 matter went off the record at 12:00 p.m. and

22 resumed at 1:02 p.m.)


1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

2 1:01 p.m.

3 DR. BEHRMAN: Welcome back. We're

4 resume with our afternoon session.

5 Our first speaker will be Richard

6 Kingham from Covington & Burling.

7 MR. KINGHAM: Thanks very much.

8 My name is Richard Kingham. I'm a partner

9 with the law firm of Covington & Burling

10 assigned to both the Washington and London

11 offices of the firm. For the last ten years

12 I've been representing research-based

13 manufacturers of biopharmaceutical products in

14 connection with the development of legislative

15 pathways and regulatory implementation for

16 approval of biosimilar products.

17 I was heavily involved in the

18 legislative process and also in the comment

19 and other processes relating to the

20 development of the EU biosimilars regime. I

21 participated in the development of the

22 biosimilars guidance in Canada. And also in


1 proceedings with WHO relating both the

2 international nonproprietary names and to the

3 biosimilar guidance and to the biosimilar

4 guidance that they recently issued.

5 I believe that the European and

6 other non-U.S. experience is particularly

7 relevant here today. Because we find

8 ourselves in the unusual situation of the

9 United States and the FDA being somewhat

10 behind other parts of the world. For 20 years

11 working in the EU I've often been in the

12 reverse situation where I could say, "Well, we

13 thought about that in America." But we hadn't

14 thought about all this yet, and the Europeans

15 have.

16 So, I'd like to talk about a

17 couple of things. First, very briefly, what

18 the biosimilars outside the United States has

19 been. And secondly, with particular reference

20 on the European Union where by far the deepest

21 experience resides, how the procedures have

22 been developed for actually establishing the


1 criteria, the site of the testing

2 requirements, the issuance of guidance with

3 respect to standards for demonstrating

4 similarity.

5 Secondly, the approach to post-

6 marketing measures to detect rare but serious

7 side effects.

8 And finally, how Europe has dealt

9 with the product interchange or substitution

10 issue.

11 Now, Europe has by far the deepest

12 experience in this area. The discussion

13 actually began in earnest in January of 2001

14 when a comparability draft guidance was issued

15 and the question arose whether it should

16 address biosimilars under the heading of

17 comparability as well as changes in the

18 manufacturing process of existing products.

19 Ultimately the decision was no that it was

20 quite with issue and it needed to be addressed

21 in its own body of legislation. That was done

22 in secondary legislation in the annex to


1 Directive 2183 that took effect in October of

2 2003. And at that point there was a pathway

3 in Europe. It was confirmed by primary

4 legislation enacted by the European Parliament

5 and Council taking effect in October of 2005.

6 Since then, the European Union's

7 European Medicines Agency and its Committee

8 for Medicinal Products for Human Use have

9 issued both general umbrella guidance for

10 biosimilars, guidance specifically relating to

11 a common DNA derive therapeutic proteins,

12 other crosscutting advice such as guidance on

13 immunogenicity determinations and product

14 specific guidance for a number of sectors

15 beginning with somatropin and human insulin,

16 GCSF, alpha interferon, erthropoietin, low

17 molecular weight heparin which the Europeans

18 consider to be within their biosimilar regime,

19 and of course now monoclonal antibodies

20 guidance is under development,

21 So, there's a lot of experience

22 there. I'm going to talk about that in more


1 detail in a second.

2 Meanwhile, the WHO has developed

3 guidance who purpose is to assist the national

4 authorities in countries around the world.

5 Canada developed guidance for so called

6 subsequent entry biologics, which is now

7 final. Japan has finalized guidance. And

8 other jurisdictions such as South Africa,

9 Singapore, South Korean, Saudi Arabia now a

10 growing of others have developed guidance.

11 The vast majority, however, have relied

12 heavily on the experience in Europe.

13 So, let's turn to European

14 specific things. First, what's the process

15 for actually establishing the specific testing

16 requirements for particular marketing

17 authorization applications for biosimilar

18 products?

19 The first point that I would make

20 is that the process has been open and

21 transparent. There has been a system under

22 which where appropriate stakeholder meetings,


1 very much like this, have been held. They

2 were held at the beginning of the development

3 of the process and summer before last when a

4 major new departure was undertaken of

5 considering monoclonal antibodies which we

6 believe to present unique and difficult

7 questions.

8 The process is typically begun

9 with the issuance of concept papers that

10 simply identify the issues that should be

11 addressed in guidance, without necessarily

12 taking a position on how they should be

13 addressed. There's then a comment period.

14 That's followed by the issuance on a draft

15 guidance which lays out the CHMP's specific

16 thoughts on what would be in a guidance with

17 another period for comment. And finally,

18 final guidance is issued.

19 Now throughout that process 27

20 member state governments have the right to

21 participate, as do multiple scientific working

22 parties of the CHMP and the full CHMP itself.


1 Despite that, the process has been quite

2 efficient. Guidances have been developed

3 within periods of 18 to 24 months, in most

4 cases. Monoclonal antibodies are taking,

5 perhaps, a bit longer but they are a great

6 deal more complex than, for example,

7 somatropin ones.

8 In the meantime, the possibility

9 of obtaining scientific advice from the

10 European Medicines Agency in dealings directly

11 between sponsors and the agency has not been

12 precluded. But it's been done in parallel

13 with the development of guidance in public,

14 and no product has been approved to date until

15 there was actually guidance in place that has

16 gone through the public guidance development

17 process.

18 Now, it seems to me that this

19 process offers a number of advantages. First

20 of all, the European Medicines Agency benefits

21 from information that is available to all of

22 the relevant stakeholders including the


1 sponsors of the referenced products as well as

2 academics, generic manufacturers, trade

3 associations and so forth.

4 And let me say if you look in the

5 record, and you can do it on the web if you

6 know where to look, you will find that the

7 comments are quite sophisticated. They have

8 been very substantial comments. They've not

9 been political in nature, but they've gotten

10 right down to the scientific issues that have

11 to be addressed. And I believe they've been

12 genuinely helpful to the CHMP in developing

13 its final guidance.

14 So the first point is full

15 information.

16 The second point I think is public

17 confidence in the system. The system is

18 developed openly, transparently and in public

19 and there are documents to point to to show

20 that the standards have been thought through.

21 And finally, there's a roadmap for

22 all concerned companies. Not just the big


1 biosimilar manufacturers, but the smaller ones

2 as well that may not otherwise be able to

3 develop their own roadmaps.

4 Let me move to post-marketing

5 safety assessment. This is a big issue in

6 Europe because of the PRCA experience about

7 which you've probably heard a great deal so

8 far in this hearing, so I won't belabor it.

9 But the fact is that that experience played

10 out when a number of countries outside the

11 U.S., including Canada and elsewhere but

12 particularly in Europe, and as you may know it

13 first came to light through the work of

14 Professor Kasse de Waal in France.

15 As a result of the PRCA experience

16 a great deal of emphasis has been placed on

17 the need to have procedures in place after

18 marketing to find effects that could not be

19 detected in reasonable pre-marketing programs.

20 Now these include routine consideration of

21 risk management plans, routine requirements

22 for detailed pharmacovigilance, and possibly


1 other testing as well. But there's also been

2 a major focus on assuring that adverse events

3 can actually be attributed to specific

4 products. This is done, in part, by requiring

5 some form of distinctness in the name of

6 virtually every product.

7 The EU lacks the authority that

8 FDA has by statute to demand a specific new

9 name for a product if it chooses to do so, and

10 must ordinarily follow the INN and the

11 European pharmacopeia names. But it has de

12 facto achieved this result by either accepting

13 applications with distinct nonproprietary

14 names with a combination of company name and

15 nonproprietary name or with a brand name.

16 Finally, the European Union has

17 proposed and is considering legislation that

18 will require that every adverse event be

19 traceable through the manufacturer's

20 capabilities to the specific product with

21 which it was associated.

22 And finally, let me turn to


1 interchangeability. This is not the EU's job.

2 You've been given the job to consider this

3 issue by Congress, but the European Medicines

4 Agency does not have that job under the

5 European Union legislative system.

6 It has been the position, however,

7 of the CHMP that these products are not

8 generics in the ordinary sense, and the clear

9 signal has been sent that the usual generic

10 substitution arrangements are inappropriate.

11 So far every member state government in the EU

12 within the member states of the European Union

13 that has considered this issue has decided

14 that ordinary rules on substitution and

15 interchange should not apply.

16 So in conclusion, I think there's

17 a great deal for FDA to learn. I'd like to

18 point out to you that the next issue of the

19 Food and Drug Law Journal will have two major

20 articles that you may find interesting, one on

21 the development of international standards and

22 the other a very detailed history of the


1 development of the BPCIA itself.

2 Thanks very much.


4 comments.

5 Questions from the panel? Ms.

6 Esposito?

7 MS. ESPOSITO: Thank you so much

8 for your comments.

9 Can you speak to generally your

10 view of whether the EU process has been

11 overall a positive one, and also any lessons

12 learned in your view either positive or

13 negative that the agency might consider in

14 implementing our BPCI?

15 MR. KINGHAM: Well, I think that

16 you will find that the vast majority of

17 manufacturers and I think also academics and

18 others who have watched the process are pretty

19 satisfied with the quality of the process,

20 with the way in which the interchanges have

21 occurred and the quality of the guidance

22 that's been developed. That doesn't mean


1 everybody's happy with every provision of

2 every guidance, but I think people are happy

3 with the rights of participation and the

4 degree to which attention has been paid.

5 The process has also demonstrated

6 that there are issues associated with some

7 products relating to significantly increased

8 efficacy in the case of one human insulin

9 product, antibody formation in the case of

10 other products and so forth which I do not

11 believe could have been detected without

12 fairly robust programs of pre-market testing.

13 So it seems to have borne out the basic

14 assumption that underlies the European system

15 that fairly substantial comparative clinical

16 trials are key to the process.


18 You mentioned that EU lacks the

19 same authority over naming.

20 MR. KINGHAM: Yes.

21 DR. BEHRMAN: But that they have

22 set things up in a way that most of these


1 products have different nonproprietary names,

2 is that correct?

3 MR. KINGHAM: No. No. Actually,

4 it's very pragmatic and ad hoc, and it's

5 something you don't have to do because you

6 have explicit statutory authority under the

7 federal Food, Drug and Cosmetic Act, which

8 applies to all drugs including biologics to

9 establish legal names if you choose to do so.

10 Of course, you could also work with USAN to

11 ensure that these products get distinct names

12 if that's what you want to do. But that's not

13 how the European legislative system is

14 designed, and normally the EU authorities must

15 defer either to an established WHO INN, or to

16 a name given in the European Pharmacopeia.

17 What's worked out as a practical

18 matter, but it's work out in practice through

19 the cooperation of manufacturers, some

20 products do have distinct nonproprietary

21 names. The manufacturers actually went to the

22 WHO INN process and got new names, epoetin


1 zeta for example.

2 Some products are being marketed,

3 many, with brand names such as Omnitrope for

4 a particular brand of somatropin. And others

5 are marketed where the nonproprietary name is

6 coupled as part of the actual name of the

7 product with the name of the source. For

8 example, epoetin alfa Hexal is one example of

9 that.

10 And I believe that if you look at

11 all of the various European public assessment

12 reports you'll find that to date one or

13 another of those options has been chosen.

14 That's not ideal, but it does increase the

15 chances that an adverse event report will be

16 connected with a particular product source.

17 DR. BEHRMAN: Dr. Jenkins?

18 Could you speak a little bit more

19 about pharmacovigilance? I thought you

20 implied that we might want to consider placing

21 the burden on the biosimilar manufacturer to

22 assure traceability, but basically European


1 experience I'm just curious if you have any

2 other advice, whether they believe they have

3 successfully harnessed what they need to to

4 make sure that they're filing these products

5 appropriately.

6 MR. KINGHAM: I think the candid

7 answer is probably not, and that's one reason

8 why legislation is going through the system

9 now. The mandatory traceability provision

10 that I spoke about, which would apply only to

11 biologics is still a work in progress. It

12 would be an amendment to Article 102 of

13 Directive 2183. It's not there yet. And how

14 it's going to be implemented is unclear. It's

15 simply a mandate from the European Union to

16 the governments of the member states to make

17 sure it gets done somehow. I'm not exactly

18 sure how it's going to be done.

19 It seems to me the distinct names

20 in one way or another are a much better way of

21 assuring that kind of traceability than simply

22 an order to go forth and make things


1 traceable.

2 DR. BEHRMAN: A point Dr.

3 Kozlowski made earlier in the day about

4 perhaps confusion among prescribers if there

5 are several products with different names

6 which were in fact essentially equivalent

7 products, can you comment on that?

8 MR. KINGHAM: Well, the first

9 thing is they're not really essentially

10 equivalent, and that's the reason for having

11 different names. The products almost certainly

12 will have slightly different effects. And the

13 issue is similar to the one that you have now

14 with switching from one manufacturer's source

15 of recombinant DNA human insulin to another

16 where you've re-established the dose and so

17 forth. So it's a question of degree.

18 But, I would echo the answer that

19 a previous speaker made, which is that these

20 are almost all products that are administered

21 in circumstances where the chance of confusing

22 the green pill and the blue pill and so forth


1 is not very likely to occur.

2 DR. KOZLOWSKI: To comment or ask

3 you to clarify on your comments on

4 interchangeability. So, it's been member

5 state decisions?

6 MR. KINGHAM: Right.

7 DR. KOZLOWSKI: Have there been a

8 number of decisions to make things

9 substitutable and related to Dr. Behrman's

10 question, has there been any pharmacovigilance

11 on those decisions?

12 MR. KINGHAM: Okay. Well, first

13 of all, about half the member states have

14 addressed the question as to whether the

15 products should be treated as substitutable in

16 the same way as ordinary generic drugs. Every

17 one of the member states of the EU that has

18 addressed that issue has decided that they

19 should not be.

20 There may be some member states

21 where formal determinations have not yet been

22 made where practices may be going on that are


1 not even known. I have to admit there are

2 some member states that are, frankly, less

3 sophisticated than others in terms of how they

4 manage their pharmacy systems and so on. But

5 the member states that have considered it have

6 decided that substitution is not appropriate.

7 Now, there isn't that much

8 experience with biosimilars actually in the

9 marketplace in Europe. The number of products

10 yet approved, despite the fact that the

11 process begin in 2003, was relatively small

12 and the market penetration is actually

13 relatively small. So, there isn't some vast

14 body of experience.

15 The largest number of products in

16 this category are in the developing countries

17 around the world. And, of course, there

18 they've been admitted to market on conditions

19 that are quite different from what I expect

20 will be required here that they required in

21 Europe and in systems where pharmacovigilance

22 is very difficult to maintain.


1 DR. KOZLOWSKI: So to follow-up,

2 have there been large formularies, you know at

3 a national level that have switched and has

4 there been any follow-up on those?

5 MR. KINGHAM: There are tenders in

6 some countries, in Germany for example. And,

7 yes, there have been. I'm not aware of

8 specific problems. The main problems I'm aware

9 of with respect to products that at least

10 might be called biosimilars are in developing

11 countries. And there have been some

12 significant ones in Thailand and else with

13 erythropietin products.

14 DR. BEHRMAN: Ms. Maloney?

15 MS. MALONEY: I'm just going back

16 to the legislation under consideration with

17 regard to traceability. Have folks identified

18 the key hurdles in the area that need to be

19 addressed?

20 MR. KINGHAM: Well, obviously,

21 there's yet, although there are in theory

22 electronic reporting systems for adverse


1 events in Europe and a variety of other

2 systems have been put into place, they're

3 imperfect as are systems in many other

4 countries. And consequently a lot of data is

5 lost in just the background noise of the

6 system so forth.

7 My personal view is that until we

8 get perfect electronic reporting which links

9 every report to an manufacturer's product and

10 so forth. It would be highly desirable if the

11 name of the product, the name that the

12 physician would recognize from the

13 prescription, the name that the pharmacist

14 would recognize from dispensing were somehow

15 distinctive.

16 DR. BEHRMAN: One last question.

17 You noted there's been quite a lag between

18 legislation and Europe and here. And but you

19 also noted there's been a very small market

20 penetration, so a small experience to date.

21 Can you comment on why you think that is? Is

22 it the difficulty developing the compounds?


1 Is it not an attractive route, or so forth?

2 MR. KINGHAM: I don't think it's

3 an unattractive route. It's clear that the

4 safety oriented requirements that the

5 Europeans have developed make it a pretty

6 substantial enterprise to develop these

7 products. And the traditional generic type

8 manufacturer will have to modify its business

9 practices significantly in order to get into

10 this business.


12 comments.

13 Our next speaker Jeanne Novak.

14 Will you be speaking, or all three of you?

15 DR. RUCKMAN: I'm actually Judy

16 Ruckman.

17 DR. BEHRMAN: Okay. I'm sorry.

18 Well, Judy Ruckman and Michael Strauss from

19 CBR International.

20 DR. RUCKMAN: Thank you. Thank

21 you for the opportunity to speak today. And

22 as I just noted, I'm Judy Ruckman. I'll be


1 presenting on behalf of the co-authors of this

2 presentation, Dr. Jeanne Novak and Mr. Michael

3 Strauss.

4 I'd like to first briefly

5 introduce you to CBR International. We are a

6 biopharmaceutical development consulting firm

7 located in Boulder, Colorado. For over ten

8 years we've assisted our clients on scientific

9 and regulatory issues related to product

10 development with an emphasis on biologic

11 products.

12 Due to the depths of our clients

13 programs we are experienced in the scientific

14 and clinical issues surrounding comparability

15 and immunogenicity testing for biologic

16 products relevant to today's discussions on

17 biosimilar products.

18 First, I'd like to start with a

19 few overarching concepts for consideration.

20 First, the concept of biosimilars includes the

21 principle that biologic products manufactured

22 by similar but non-identical manufacturing


1 processes may exhibit some minor differences

2 in physical chemical attributes. These

3 differences may or may not have impacts on the

4 biological activity of the molecule as

5 measured by in vitro or in vivo biological

6 assays, and further may or may not have

7 significance for the efficacy and safety of

8 the molecule in human patients. The focus

9 should be to identify the differences that are

10 present and the clinical significance of these

11 differences.

12 The EMEA has been engaged in

13 regulating biosimilar products for several

14 years now and has established a worthy

15 precedent to guide the FDA's approach to

16 biosimilars regulation. In particular, the

17 CHMP has shown significant flexibility in its

18 application of guidelines and has allowed

19 scientific considerations to guide its

20 decision making for individual products.

21 We agree with EMEA's stepwise

22 approach to biosimilar assessment building on


1 analytical and non-clinical data to justify

2 comparative clinical trials, However, we

3 strongly recommend that a stepwise approach

4 include flexibility for products or product

5 classes where certain steps may not be

6 necessary, or where steps may be reasonably

7 performed concurrently rather than in

8 succession. Flexibility may be particularly

9 needed for biosimilar products already

10 approved outside the U.S. and for which

11 extensive non-clinical and clinical data are

12 already in hand.

13 We concur with previous speakers

14 that a harmonized approach permitting

15 concurrent development for multiple

16 jurisdictions is desirable.

17 In responding to Question A1, we

18 consider that quality non-clinical and

19 clinical factors are all considerations for

20 the determination of a product as highly

21 similar. We recommend the Agency consider the

22 following with respect to biosimilar product


1 quality.

2 It is widely agreed that a

3 biosimilar product should share the primary

4 amino acid sequence as the referenced product.

5 and in general, secondary and tertiary

6 structure as well as physical chemical

7 characteristics such as pI should also be very

8 similar between the biosimilar product and the

9 referenced products unless it is known or can

10 be demonstrated that any structural or

11 physical chemical differences have no

12 measurable impact on biological activity.

13 Differences in post-translational

14 processing such as differences in the profile,

15 specific glycoforms is not a priori

16 inconsistent with biosimilarity. It depends on

17 whether the differences in the glycan profile

18 impact the biological activity of the protein.

19 We recommend that the focus of comparative

20 physical testing should be on the critical

21 quality attributes of the molecule and where

22 appropriate, orthogonal methods should be used


1 to evaluate CQAs.

2 We recommend that the Agency limit

3 its requirements for any given product to a

4 battery of assays that adequately characterize

5 all key attributes of the molecule without

6 excessive redundancy.

7 FDA should consider that

8 biosimilars are most likely reverse

9 engineered, and as a consequence a biosimilar

10 developer will not know what the design space

11 is of the reference protein. We recommend

12 that FDA primarily judge the similarity of the

13 two proteins by the convergence of their CQAs

14 and not by comparison of release parameters or

15 an unknown design space target.

16 With regard to non-clinical

17 studies, it is our view that these studies

18 should be narrowly targeted since small

19 differences that might be observed in animal

20 studies will ultimately be followed up by

21 human clinical comparisons and are likely to

22 be discounted if the human data detect no


1 differences.

2 We recommend that the primary

3 focus of animal studies should be to ensure

4 the safety of a product not previously tested

5 in humans. A non-comparative toxicity study

6 may be adequate for this purpose.

7 Further, where a relevant animal

8 model exists, pharmacokinetic or

9 pharmacodynamic comparisons might be used to

10 lower the requirements for comparative

11 clinical trials. For example, if no gross

12 differences in pharmacodynamic behavior are

13 found in a well accepted animal model, then it

14 might be appropriate to proceed directly to

15 phase 3 comparative testing of a biosimilar

16 product without the stepwise requirement to

17 evaluate comparative human pharmacokinetics

18 beforehand. However, where a clinical PK/PD

19 study is planned and a non-clinical PK/PD

20 comparison does not add significantly to the

21 overall assessment of biosimilarity, we would

22 ask the Agency to consider whether such a


1 study was needed.

2 We anticipate that clinical data

3 will always be required for initial licensure

4 of a biosimilar product. However, we

5 recommend that the scope of clinical

6 development should be tailored to the product

7 class. Specifically, for relatively simple

8 proteins where physicochemical and

9 bioanalytical data provide a convincing

10 demonstration that the product is similar to

11 the referenced product, a comparative PK/PD

12 study along with an adequate demonstration of

13 safety may be sufficient for licensure. For

14 more complex proteins or products where small

15 differences in structure or activity have been

16 detected by sensitive analytical techniques,

17 a comparative efficacy trial would be

18 expected.

19 Regarding studies to evaluate

20 potential differences in a biosimilar product,

21 the significance of any structural differences

22 depends on whether the differences impact the


1 critical quality attributes of the product in

2 question and therefore have a greater risk of

3 altering the effectiveness of the biosimilar

4 product in clinical use. For one protein the

5 degree of glycosylation may have no impact on

6 biological activity or for another, the

7 identity of the glyco forms may effect

8 receptor binding affinity. CQAs, and

9 therefore the criteria for biosimilarity will

10 differ from protein to protein or between

11 product classes. Even if differences in a

12 known CQA are detected, a biosimilar product

13 may perform comparably to the referenced

14 product in clinical use. So supporting

15 clinical or non-clinical data should be

16 reviewed to assess patient risk.

17 Regarding Question A4 concerning

18 circumstances where non-clinical or clinical

19 studies requirements may be reduced, we

20 consider the non-clinical studies may not be

21 needed in the circumstance where adequate

22 preclinical or clinical safety data exists to


1 support clinical evaluation under a US IND.

2 This scenario may arise when a product is

3 already under investigation or has already

4 been authorized for commercial distribution in

5 a jurisdiction outside the U.S.

6 In addition, as noted previously,

7 we suggest that comparative non-clinical

8 studies should be justified based on the

9 utility of the data to limit the scope of

10 clinical development. And if this

11 justification is lacking, the Agency should

12 consider limiting requests for such studies.

13 We expect clinical testing will be

14 necessary for development of a biosimilar

15 product. And we concur with the EMEA approach

16 describing guidance to permit extrapolation

17 of comparative efficacy data from one

18 indication to other indications where the

19 mechanism of action and safety profile of the

20 reference in biosimilar products are well

21 known.

22 In addition, we recommend that the


1 Agency consider the acceptability of clinical

2 studies preformed in other regulatory

3 jurisdictions using an acceptable, non-U.S.

4 source referenced product to limit

5 inappropriate repetition of clinical studies.

6 Finally, we suggest that the

7 Agency consider scenarios where licensure may

8 be appropriate on the basis of comparative

9 PK/PD only where clinical efficacy data are

10 available from other sources and unwanted

11 immunogenicity risk is deemed to be low.

12 Regarding Question B1, an

13 interchangeable biosimilar product should be

14 labeled for use in all of the indications and

15 patient populations for which the referenced

16 product is labeled.

17 In the case that FDA chose to

18 license a biosimilar product for only a subset

19 of the indications appearing on the referenced

20 product label, that biosimilar product would

21 not meet this criterion for

22 interchangeability. FDA should discuss with


1 sponsors the data necessary to meet this

2 criterion at an early stage of biosimilar

3 product development.

4 Regarding Question B2, the primary

5 theoretical risk associated with switching

6 between referenced product and a biosimilar

7 product is unwanted immunogenicity. Clinical

8 data would be necessary to evaluate this

9 potential risk. This could include cross over

10 studies, pre or post approval safety databases

11 or pharmacovigilance. The preconditions for

12 achieving of similarity versus

13 interchangeability should be agreed upon

14 during prelicensing meetings with the Agency

15 or during application review.

16 Until interchangeability has been

17 established, FDA may wish to consider labeling

18 requirements to indicate that the risk of

19 switching or alternating between products in

20 the same class is unknown.

21 Quickly with regard to guidance

22 development. We recommend that the Agency


1 focus its initial guidance development on

2 overarching guidance for stepwise approach to

3 biosimilar development. And in addition,

4 concrete guidance on expectations for

5 comparative clinical safety and efficacy study

6 design, and a regulatory guidance or

7 information sheet specific for biosimilar

8 products would be beneficial. We've noted

9 additional guidance recommendations for

10 subsequent efforts.

11 And finally in closing, I would

12 like to comment that there may be classes of

13 biosimilar products other than recombinant

14 therapeutic proteins that may be appropriately

15 regulated as biosimilars as the FDA gains

16 experience with this regulatory paradigm. And

17 we list some of those examples here.

18 And, again, thank you for the

19 opportunity today.


21 comments.

22 Questions from panelists? Mr.


1 Schwartz?

2 MR. SCHWARTZ: Thank you.

3 Could you possibly go back to your

4 slide 16. I'm not sure that I understood

5 exactly what you were saying. It has to do

6 with expectations for an interchangeable

7 biosimilar product.

8 DR. RUCKMAN: Yes.

9 MR. SCHWARTZ: Which would be

10 deemed interchangeable if the biosimilar is

11 labeled for us in all of the indications in

12 patient populations for which the referenced

13 product is labeled. Could you just elaborate

14 on that, please?

15 DR. RUCKMAN: Sure. This is our

16 interpretation of the language of the Act that

17 labeled for use in any given patient suggests

18 any given patient for any given indication.

19 In other words, there isn't any subdivision

20 here that any given patient within an

21 indication is not in the language of the Act.

22 So our interpretation is that to meet this


1 criterion for interchangeability the

2 biosimilar product would have also need to

3 have met all of the biosimilarity requirements

4 dictated by the Agency for all of the

5 indications in the referenced product label.

6 DR. BEHRMAN: Can I follow-up. So

7 that if then the innovator gained a new

8 indication, what do you see as happening to

9 the biosimilar product?

10 DR. RUCKMAN: Yes, we've

11 considered that. With this interpretation it

12 certainly it may be the case. But if the

13 referenced product gains a new indication and

14 there would be additional clinical data

15 required for the biosimilar product to obtain

16 that indication, it might lose its

17 interchangeability status. Otherwise, it would

18 be necessary for the Agency to come up with a

19 mechanism to have interchangeability for a

20 subset of the indications.

21 DR. BEHRMAN: Dr. Kozlowski?

22 DR. KOZLOWSKI: So to follow-up in


1 that, so do you think that that covers any

2 given patient that that's basically the

3 explanation of that clause?

4 DR. RUCKMAN: That's our

5 interpretation of the clause, yes.

6 DR. KOZLOWSKI: In another area,

7 you mentioned the importance of critical

8 quality attributes. And clearly, ideally if

9 you knew every critical quality attribute of

10 a product, that's all you'd need to worry

11 about. But there's a lot of uncertainty for

12 complex products in assigning criticality and

13 you have a lot of uncertainty.

14 So, do you have any sense of how a

15 biosimilar manufacturer would go about

16 establish critical quality attributes?

17 DR. RUCKMAN: Critical quality

18 attributes should be defined in part, of

19 course, by what is known about the referenced

20 product and what is in the literature, and

21 based on the information that the biosimilar

22 developer themselves have developed


1 internally.

2 Again, our view is that while

3 these products are derived from very

4 independent processes and the design space

5 around each process is independent, as long as

6 the product remains comparable within its

7 design space, as long as there is appropriate

8 overlap between the critical quality

9 attributes, it should be sufficient.

10 DR. BEHRMAN: Could I go back to

11 do changeability for a moment? How might you

12 see that being implemented? Do you see that

13 as a labeling issue that if a biosimilar is

14 interchangeable, if labeling states that point

15 and if it loses, the labeling change, or do

16 you see another system?

17 DR. RUCKMAN: I think we would see

18 it as a labeling issue that a product that had

19 not achieved interchangeability would

20 appropriately be labeled, that it was not

21 interchangeable. And if that

22 interchangeability status was lost, that might


1 lead to a labeling revision.

2 DR. BEHRMAN: Do you see any

3 information about interchangeability being in

4 the innovative labeling?

5 DR. RUCKMAN: That was brought up

6 previously, and it was an interesting

7 question. It may be appropriate, yes.


9 comments.

10 Our next speakers are Bruce Babbit

11 and Cecil Nick from PAREXEL, or just one.

12 DR. BABBITT: Hi. On behalf of

13 PAREXEL Consulting, part of PAREXEL

14 International, a global biopharmaceutical

15 services provider, we would like to thank the

16 FDA for the opportunity to present our

17 insights regarding the development of

18 biosimilars.

19 My name is Bruce Babbit, and I am

20 accompanied today by my colleague Cecil Nick,

21 who is our European biosimilar expert, and if

22 needed today Cecil can address questions


1 related to the European experience with

2 biosimilars.

3 PAREXEL has participated in the

4 development of many of the biologics approved

5 by the FDA. In addition, to date our experts

6 based in Europe have been involved in

7 supporting approximately 20 biosimilar

8 development programs, including some of the

9 products already approved in the EU.

10 Based on these experiences we

11 understand that there cannot be a one size

12 fits all approach for the development and

13 regulation for biosimilar products. For

14 example, we can envision somewhat different

15 clinical trial requirements depending on the

16 structural and functional complexity of the

17 biologic, as well as the breadth of the

18 approved indications.

19 Patient safety is paramount, and

20 for biosimilars safety can ultimately only be

21 established through clinical trials followed

22 by a post-marketing risk management program.


1 The more complex question is the extent to

2 which comparative efficacy needs to be

3 established through clinical trials. If the

4 preclinical and phase 1 programs already

5 demonstrate biosimilarity, there may be no

6 need to repeat the entire original clinical

7 program performed for the referenced product.

8 A key principle underlying our

9 thinking for streamlining biosimilar

10 development programs is to acknowledge that

11 unlike when a new biological entity is first

12 developed, much is already known about the

13 structure, function, relationships, mechanism

14 of action and safety and efficacy profile of

15 the innovator product in specific patient

16 populations.

17 In addition, there has been a vast

18 improvement in the scope and quality of

19 physical chemical and biological methods used

20 for characterization of therapeutic proteins.

21 Such data will provide the most accurate

22 indication of any structural or functional


1 differences between the product.

2 Another key concept we would like

3 to discuss is what we refer to as the totality

4 of the data. By this we mean that the physical

5 chemical and biologic characterization coupled

6 with clinical pharmacological data already

7 provide a solid basis for establishing

8 biosimilarity. We consider it important to

9 balance the value and relevance of these data

10 against the need for clinical safety and

11 efficacy data, particularly where minor or

12 modest differences between the biosimilar and

13 referenced products are unlikely to translate

14 into any meaningful differences in the clinic.

15 This approach is somewhat similar

16 to how the Agency has reviewed comparability

17 testing data from developers of new biological

18 entities following major changes in

19 manufacturing.

20 Now I'm going to transition to

21 discuss three distinct areas of clinical

22 development: One, extrapolation of


1 indications, two, use of surrogate endpoints,

2 and three, use of non-inferiority trial design

3 that we believe might provide opportunities on

4 a case-by-case basis to streamline biosimilar

5 development.

6 Most biologics have been approved

7 for multiple indications. Clinical trials on

8 new biologic entities were designed to

9 demonstrate efficacy against placebo.

10 However, placebo trials will no longer viable,

11 at least for serious and life threatening

12 diseases for which there exists effective

13 therapies. Therefore, for following biologics

14 it is necessary to perform much larger, non-

15 inferiority or equivalence trials which are

16 not always feasible.

17 It is our position that as long as

18 the mechanism of action if relatively well

19 understood across indications, it should be

20 possible to demonstrate comparable and safety

21 and efficacy of biosimilar and referenced

22 product in one adequately sensitive


1 indication, and then taking into account all

2 prior analytical non-clinical and clinical

3 comparability data, to conclude therapeutic

4 equivalence for all indications. In other

5 words, extrapolate the results across multiple

6 indications.

7 By "adequately sensitive," we mean

8 a patient population where differences between

9 the biosimilar and referenced products if they

10 exist, are most likely to be detected and

11 generate a dataset with a relative low degree

12 of variability.

13 Even in cases where the target

14 indications of how these diverse, for example

15 as is the case with many approve monoclonal

16 antibody products, extrapolation should be

17 considered reasonable. Monoclonals can

18 theoretically exert multiple effect in vivo

19 and the relative contributions of these

20 effects might not be the same across

21 indications. Nevertheless, if all relevant

22 biological effects are understood to be


1 involved in generating a therapeutic effect in

2 the selected target population, then this

3 should be an adequate indicator for general

4 therapeutic equivalence.

5 Selection of clinical trial

6 endpoints represents another potential area

7 for streamlining biosimilar development

8 programs. For those innovative products where

9 there exists a strong and well defined

10 pharmacodynamic effect, for example as with

11 insulin and GCSF, PD markers may trump

12 clinical endpoints in terms of precision and

13 could be equally or more relevant.

14 When using PD endpoints as

15 surrogates for clinical endpoints, the PD

16 effect needs to be dose sensitive and to

17 correlate to the therapeutic effect. If this

18 correlations can be adequately demonstrated

19 from literature, then we would consider a PD

20 marker to be a potentially more sensitive

21 measure of efficacy than a clinical endpoint.

22 The use of surrogate clinical


1 endpoints can also play a key role in the

2 development of biosimilars. For example, in

3 oncology overall survival is considered the

4 gold standard, but this is often not a

5 practical endpoint for non-inferiority trials.

6 Moreover, demonstration of survival becomes

7 extremely challenging as next line therapies

8 become available to treat disease progression.

9 Progression pre-survival is perhaps the next

10 endpoint, but it can also take many years to

11 demonstrate equivalence.

12 Therefore, a more practical

13 approach would be to use response rates as the

14 primary endpoint and to include progression

15 pre survival and where possible overall

16 survival as secondary endpoints. There is

17 already regulatory precedence for this, for

18 example, in the approval of liposomal

19 doxorubicin versus doxorubicin.

20 Finally, we would like to address

21 the issue of whether to perform a non-

22 inferiority or equivalence trial for


1 demonstration of biosimilarity. Where a

2 protein exerts a direct physiological effect

3 and there's a close association between dose

4 and therapeutic effect, as is the case for

5 products such as insulin and GCSF, EPO and

6 somatropin, clearly supra-activity will be a

7 safety concern and equivalence trials are

8 likely essential. However, in the case of

9 monoclonal antibody products, clinical effect

10 and inflammatory disease or oncology is

11 generally measured in terms of the proportion

12 of responders and not as a physiological

13 effect. Under these circumstances it is our

14 view that it is more appropriate to perform

15 non-inferiority trials since an increase in

16 responders, in other words crossing the upper

17 bounds of the selected equivalence margin,

18 should not a priori be a reason to reject the

19 product as biosimilar, especially given that

20 safety would be monitored independently.

21 In this case one would not claim

22 superiority for the biosimilar and there would


1 be a need to provide a rationale for the

2 improved efficacy relative to referenced

3 product, one possibility being the result of

4 reduced immunogenicity.

5 In conclusion, patient safety is

6 paramount and for biosimilars the safety

7 profile can ultimately only be established

8 through clinical trials followed by a post-

9 marketing risk management program. It is our

10 view that certain biosimilar clinical

11 development programs can be streamlined

12 employing some combination of extrapolation of

13 indications, use of surrogate endpoints and

14 non-inferiority trial design. Thus, a single

15 equivalence or non-inferiority therapeutic

16 trial in a sensitive patient population

17 utilizing an appropriate and relevant endpoint

18 should generally be sufficient to confirm

19 biosimilarity even when indications are highly

20 diverse provided that the mechanism of action

21 is reasonably well understood.

22 Finally, we believe that


1 biosimilarity should ultimately judged on the

2 totality of the data taking into account the

3 complex set of head-to-head studies against

4 referenced product. We consider that

5 extensive in vitro physical, chemical and

6 biological characterization followed by

7 comparative PK/PD assessment in humans already

8 provide strong evidence for biosimilarity, and

9 therefore that safety and efficacy trials in

10 patients are intended primarily as final

11 confirmation of therapeutic equivalence.

12 The extent of clinical data

13 required will be driven by any differences

14 detected through the physical, chemical and

15 biological testing, the clinical relevance of

16 any pharmacological data, the therapeutic

17 relevance of the surrogate clinical endpoints

18 and the complexity of the molecule. This

19 approach is somewhat analogous to how the

20 Agency has reviewed comparability testing data

21 submitted by developers of new biological

22 entities in support of major changes in


1 manufacturing.

2 Thank you for your time and

3 attention.


5 comments.

6 Questions from the panel? Dr.

7 Jenkins?

8 DR. JENKINS: As often happens in

9 these meetings, we're getting advice that's

10 pretty diametrically opposite from various

11 speakers. So, an earlier speaker suggested

12 that oncology would be inappropriate to use

13 the earlier endpoint such as response rate as

14 the basis for a biosimilar determination. And

15 they were suggesting overall survival as the

16 ultimate goal, and that should be the

17 endpoint. You articulated reasons why those

18 ultimate endpoints really aren't feasible.

19 So, how should we reconcile those

20 two very different viewpoints on what

21 endpoints to use in the clinical trials?

22 DR. BABBITT: I know that question


1 comes up and you get diametrically opposed

2 responses.

3 My view on it, having seen lots of

4 these different programs come through PAREXEL,

5 is that in this case it's again the totality

6 of the data that's working in favor of using

7 maybe a surrogate endpoint where there might

8 be otherwise for a new biological entity

9 considered some risk.

10 So I think if you built up

11 similarities with very extensive preclinical

12 work, including in vitro work, including some

13 non-clinical testing and then including at

14 least one clinical trial, if more than one if

15 you're developing a monoclonal and you've been

16 both in the rheumatology arena as well as the

17 oncology arena, I just think there's more

18 evidence in it from a risk benefit standpoint,

19 more support for taking the non-inferiority

20 approach and using a surrogate endpoint of

21 needing as a primary endpoint to use

22 progression pre-survival or survival. I think


1 it's a reasonable risk.

2 DR. JENKINS: You mentioned in

3 your talk that in some cases the

4 pharmacodynamic measure might be more

5 sensitive and more useful. So, would you

6 consider response rate and oncology to be

7 closer to a pharmacodynamic measure that's

8 more sensitive than survival? Is that part of

9 the basis for why you look at it that way?

10 DR. BABBITT: Only part. When I

11 was speaking about a pharmacodynamic PD

12 endpoint, I was thinking actually more of the

13 programs that are focused on the GCSF studies

14 and biosimilars where I think there might be

15 stronger evidence that that endpoint

16 correlates with clinical outcome. And I'm

17 aware that some programs including, I think,

18 those that might have been approved in Europe

19 have actually used the pharmacodynamic

20 endpoint in the filgrastim programs as primary

21 endpoint head-to-head against comparators to

22 show biosimilarity, and then they were


1 followed or not depending on their program

2 with a follow-up study in patients.

3 So, I look at those somewhat

4 differently, and I look at them as not having

5 the scientific proof underneath.

6 DR. JENKINS: One other follow-up

7 question, you seem to be inching fairly close

8 to a bio-better standard where you suggested

9 that the biosimilar might in some cases have

10 better efficacy or lower immunogenicity, or

11 better safety and that would still be okay.

12 Can you comment on how you put that together

13 with the statutory language of no clinical

14 meaningful differences? You suggested they

15 wouldn't be able to make a superiority claim,

16 but you also suggested that those products

17 might still be approved as biosimilars?

18 DR. BABBITT: Yes. And let me

19 state first that I've actually dealt at

20 PAREXEL with several bio-better candidates in

21 the last few years, so I'm trying to put this

22 in the right perspective.


1 I guess the point I wanted to make

2 there is that to have some degree of

3 flexibility from the Agency standpoint that if

4 you do see a difference in a controlled trial,

5 a non-inferiority trial is in particular what

6 mentioned in terms of the efficacy, that not

7 to have that mean that you don't have a

8 biosimilar any more if there's sort of data to

9 support a potential understanding of why that

10 difference existed. And all I can think of

11 off the top of my head is that it's possible

12 if you had, as I said, a lower immunogenicity

13 if it came not from lacking in epitope that

14 their referenced product had, but from having

15 a lower degree of aggregation in theory or a

16 greater stability, or something that would not

17 reflect a difference in structure between the

18 molecules, but a difference in those

19 parameters and could that lead to a difference

20 in the efficacy if indeed it's know that

21 there's an antibody response that inhibits

22 efficacy. That's just one example, but I


1 guess I wanted to put it out there that the

2 idea that will it necessarily be the case that

3 you don't have a biosimilar and you're moving

4 towards a bio-better if you are above the

5 upper limit of the efficacy margin?

6 DR. BEHRMAN: So let's say, it's

7 less immunogenetic, which is an advantage to

8 a patient, you believe under 351(k) we have

9 the authority to prove that and label it

10 accordingly?

11 DR. BABBITT: I think I would

12 guess that in most cases unless the sensitive

13 patient population which you did the study

14 had, unlike the B cell malignancies, a

15 relative high degree of immunogenicity it

16 would be actually hard for the developer of

17 the biosimilar what I'm hypothesizing and to

18 have it end up as a label. I mean, to be

19 straightforward about that.

20 DR. KOZLOWSKI: To follow-up on

21 this distinction between products that I guess

22 you described as saturable versus those with


1 a dose response and having need to be treated

2 differently. So, say efficacy is saturable in

3 some way by the product, how do you know that

4 the safety effects are? In other words, there

5 may be some dose response for a safety issue

6 that is different than efficacy, which might

7 be saturable.

8 DR. BABBITT: No. Then I think

9 that's why you need to run randomized

10 controlled trials against comparator and even

11 as a secondary endpoint to follow various --

12 to have safety as a secondary endpoint for

13 whatever period of time that you need to

14 assess safety.

15 DR. KOZLOWSKI: And your comment

16 on the totality of the data. So we certainly

17 heard that description a number of times, and

18 we've also heard examples of where we need to

19 look at each aspect separately. Is there a

20 way of incorporating that totality of the data

21 or prior knowledge to think about what the

22 impact on clinical studies are? Because


1 usually the impact is some big step function;

2 what your endpoint is, you know what's an

3 acceptable surrogate. And the quality of the

4 data may very in terms of the level of

5 characterization and the actual similarity.

6 So, is there a model? And I think we heard a

7 discussion about maybe such models should be

8 developed. But someway of translating

9 totality of the data from some step function

10 in change of how you look at something to an

11 approach, a way of thinking about this study?

12 DR. BABBITT: Well, if I

13 understand your question, I guess what I would

14 say is that all that the biosimilar developer

15 do is do an extremely extensive in vitro and

16 biological in vitro testing of the reference

17 produce product versus the U.S. and typical

18 European source reference product.

19 And I would think that if

20 differences are seen that are qualitative

21 differences, which it might be worrisome you

22 do or you don't have a function, I'm thinking


1 of antibody products for example, versus

2 quantitative differences and then versus small

3 quantitative differences, I think along that

4 spectrum maybe in terms of what you meant by

5 a step function if I see qualitative or non-

6 minor quantitative differences between any of

7 the key parameters that you're measuring, I

8 think I might then do more testing in the

9 clinic. I might even do a little bit more

10 testing if it's relevant in animals.

11 I mean, I guess that's the way I

12 look at it. So, I think that the totality of

13 data to me means that it helps you either

14 further streamline or not further streamline

15 what you're doing next based on the data that

16 you generate.


18 comments.

19 Our next speakers or speaker are

20 from Technology & Business Law Advisors,

21 Robert Bakin and Bernard Rhee.

22 MR. RHEE: Good afternoon. My


1 name is Bernard Rhee. I'm a patent attorney,

2 and I appear before with my colleague Robert

3 Bakin.

4 We're from the law firm of

5 Technology & Business Law Advisors. The

6 majority of our work is for organizations in

7 the pharmaceutical and medical device

8 industries.

9 We want to thank FDA, and

10 specifically each member of the Panel for the

11 opportunity to speak today. We're here to

12 speak on the issue of what factors should be

13 considered when determining what a related

14 entity is for the purposes of the exclusivity

15 provision in the Patient Protection and

16 Affordable Healthcare Act.

17 MR. BAKIN: All right. So thank

18 you, Bernie. Thank you FDA Panel.

19 So as Bernie alluded to, basically

20 our primary goal here is to start a discussion

21 of what actually a related business entity is,

22 and who or who should not be eligible for


1 multiple 12 year extension periods. And the

2 question that we're asking essentially was

3 from the Federal Register. We copied it and

4 pasted it up there. I will read it briefly.

5 That in light of the potential

6 transfer of BLAs from one corporate entity to

7 another and the complexities of corporate and

8 business relationships, what factors should

9 the Agency consider in determining the types

10 of related entitles. And I have that in bold

11 because that's the language in the Act. "That

12 may be ineligible for a period of 12 year

13 exclusivity for a subsequent BLA.

14 And I guess the question is, the

15 broad question we're asking is: Are there any

16 type of favorable evergreening clauses that

17 are good for an admission?

18 And so here's the Act. I'm not

19 going to read it in its entirety. I'm sure

20 you're all somewhat familiar with it. But I

21 will touch on each subject individually.

22 So the first section A, as


1 everybody knows, the intent here is to grant

2 innovators 12 years of market exclusivity

3 against follow-on biological applicants.

4 The second section deals with the

5 four year, the other exclusivity period,

6 follow-on biologic applicants from even

7 submitting the application, similar to the

8 paragraph for ANDAs, which is small molecule

9 generics.

10 And then the third paragraph is

11 kind of where it gets messy and confusing.

12 This is where the anti-evergreen clauses are

13 kind of buried in there. And as you can see,

14 it's kind of large, so I'll just go through it

15 in parts.

16 The first part is essentially to

17 deny additional exclusivity for any company

18 filing non-innovative drugs, a supplemental

19 BLA.

20 The second part, kind of shaded

21 out the superfluous stuff and if you just

22 focus on the bold, essentially starts off the


1 same but then you get the same sponsor

2 language and this other structural language

3 that confuses things a bit. And the intent

4 here is, again, similar. To prevent evergreen

5 by a single related entity. Any related

6 entity that files multiple applications for a

7 new indication market dosage strength will not

8 be rewarded with an additional exclusivity

9 period. But the problem here is that there's,

10 we'll call it the first evergreening loophole,

11 where if the same sponsor or any related

12 entity makes basically any structural, then

13 additional exclusivity is theoretically

14 possible.

15 Now the second part, capital II,

16 again starts off the same. Same sponsor or

17 other related entity and it brings in the

18 structural language. And the intent here is,

19 again, to deny additional exclusivity to a

20 single company or related entity files

21 multiple applications for quote/unquote, we'll

22 call then non-innovator biologics.


1 Again, now there's another problem

2 here. Evergreening loophole, we'll call it

3 number 2, again is basically any structural

4 change will likely presuppose a change in

5 safety and/or potency. And so the same

6 sponsor any other related entity makes

7 structural changes, then it's possible to get

8 another 12 year exclusivity period.

9 And so just to review what we've

10 gone through here so far in the last couple of

11 days, it sounds like, is that some follow=on

12 biologics are going to be biosimilar, not

13 necessarily interchangeable with a notable

14 exception of this recent ANDA, FDA approval of

15 ANDA for Lovenox, which is -- technically it's

16 a small molecule, I guess, but it's somewhat

17 of a pseudo-biologic that may signal the

18 interchangeability are at least possible.

19 Most follow-on biologics, even

20 biologics with minor changes will represent

21 distinct biological drugs.

22 We have number 3, which we're


1 calling it the structural loophole. It's an

2 obvious evergreening loophole.

3 And then the fourth one is the

4 related entity loophole.

5 I think we missed the boat on the

6 legislation part, but this kind of points us

7 in the direction of what we were thinking, or

8 at least our thought process going. So you

9 can just focus on the red bold part of number

10 2 where you would limit, again this is just

11 limiting who gets the extra 12 year

12 exclusivity. And we're thinking along the

13 lines of limiting through any subsequent

14 application for biosimilar interchangeable

15 product filed by the same sponsor or any

16 current entity under the financial control of

17 the same sponsor, the same manufacturer and

18 the same licensure, or any predecessor in

19 interest.

20 And literally, there's nothing

21 here that would prevent an innovator from

22 filing a subsequent application. They just


1 would not get the extra 12 year exclusivity.

2 So, I'll end with that. And leave

3 you off with the related entity loophole that

4 Bernie is going to talk about.

5 MR. RHEE: Thank you, Rob.

6 We know that in some situations a

7 related entity is not eligible for the 12 year

8 exclusivity period. This raises some

9 questions.

10 One question is what happens when

11 a different sponsor or a different

12 manufacturer, a licensee, a successor in

13 interest or other unrelated entity files an

14 application and that entity is subsequently

15 acquired or the marketing rights or license by

16 the referenced product sponsor?

17 Another question is: What are the

18 boundaries of other related entity?

19 We think it would be most helpful

20 to define what an unrelated entity is. Our

21 proposal is the following generally accepted

22 legal concepts and contract language that are


1 commonly used in the industry. An unrelated

2 entity would be an entity that does directly

3 or indirectly control, is not controlled by,

4 or is not under common control with another

5 entity. For the purposes of this law an

6 entity shall be regarded as in control of

7 another entity if:

8 A. It owns directly or indirectly

9 more than 50 percent of the voting stop or

10 other ownership interest of the other entity,

11 or;

12 B. It poses directly or

13 indirectly the power to:

14 (i) Direct the management policies

15 of the other entitles or;

16 (ii) Elect or appoint more than 50

17 percent of the members of the governing body

18 of the other entity.

19 There are two scenarios which can

20 be used to highlight some of the complexity

21 surrounding the issue of related and unrelated

22 entitles. Scenario 1 is a classic situation


1 where you have in January of 2011,

2 hypothetically, Company A filed a BLA for a

3 monoclonal antibody product 1A. In January

4 2015 the BLA is approved. The 12 year

5 exclusivity period is granted. And the

6 exclusivity period extends to January 2027.

7 Sales are great, it becomes a

8 blockbuster product and then the light bulb

9 goes off in Company A's head and says all

10 right, let's do this again. So, in January of

11 2017 Company A files a second BLA for

12 monoclonal antibody product 1B. In January

13 2021 the BLA is approved and they get a second

14 exclusivity period which extends to January

15 2033.

16 Now, scenario 2 is similar to

17 scenario 1, however in scenario 2 a second

18 company comes into the picture. It starts off

19 the same where in January 2011 Company A files

20 a BLA for monoclonal antibody product 1A. In

21 January 2015 the BLA is approved. They get

22 their 12 year exclusivity period. Sales are


1 great, exclusivity period will extend to

2 January 2027.

3 Now in this hypothetical on

4 January 2017 Company B has been working on a

5 similar product for a monoclonal antibody

6 product 1B. And in January 2017 Company B

7 files their BLA. On January 2021 the BLA is

8 approved, a second exclusivity period is

9 granted and extends to the same date, January

10 2023.

11 Now there can be three related

12 situations in this scenario. The first here

13 is that Company A buys Company B one month

14 after Company B's BLA filing, or at any point

15 in time Company A licenses Company B's

16 monoclonal antibody product 1B, or at some

17 point before the second BLA filing Company A

18 establishes an unrelated entity or maybe

19 multiple unrelated entities to develop

20 monoclonal antibody product 1B and file the

21 BLA.

22 And that established unrelated


1 entity can take many forms. That could be a

2 situation where Company A takes a minority

3 ownership interest in Company B, it could be

4 a situation where Company A funds a specific

5 development project within Company B. It could

6 be some type of other complex business

7 relationship.

8 Actually, you can see on the

9 bottom there the equation where conceptually

10 you have Company A with their technology

11 underneath it, Company B with their technology

12 underneath it and it comes the collective

13 Company AB entity with the collective

14 technology. And the exclusivity period will

15 extend to January 2023, which is basically one

16 exclusivity period piggybacking on the other

17 exclusivity period.

18 In all three of these situation we

19 propose maintaining the first and second 12

20 year exclusivity period. We believe that

21 theoretically additional 12 year exclusivity

22 periods will hurt innovation and will act as


1 a barrier to entry for drugs. However, we

2 believe in reality additional 12 year

3 exclusivity periods will actually encourage

4 innovation and result more drugs entering the

5 marketplace.

6 Some of the benefits of multiple

7 12 year exclusivity period were set forth on

8 our final slide here.

9 One benefit is patient safety.

10 More products coming to the marketplace,

11 patients will have more choices so there's

12 greater safety for the public.

13 This technology is complicated and

14 unpredictable. So what is safe for one

15 patient may not be safe for another.

16 Point 2 is better drug products.

17 We create incentive for all companies to

18 develop and commercialize bio-betters.

19 Point 3 is collaboration among the

20 drug companies. An example is creating an

21 incentive for large reference drug companies

22 to help unrelated entities to develop bio-


1 betters.

2 And our final point here is

3 fairness to all drug companies. There's no

4 loss of rightly gained exclusivity rights

5 during intellectual property licensing,

6 business acquisitions, mergers or similar

7 other transactions.

8 Thank you.


10 comments.

11 Questions from the Panel?


13 comments.

14 In terms of, it looks like you're

15 proposing perhaps the adoption of regulatory

16 guidance or regulatory definition of related

17 entity, if something along the lines of the

18 language that you proposed in terms of common

19 control or succession in interest was adopted

20 by the Agency, do you think that is pro or

21 anti evergreening and it would be consistent

22 with the statutory intent?


1 MR. RHEE: To be honest with you,

2 our agenda if we can say we have an agenda is

3 really to bring clarity to everybody. I think

4 it benefits everybody for follow-on biologic

5 companies, innovator companies and everybody

6 in between.

7 We think that without clarity it's

8 going to create a lot of problems. There are

9 going to be companies trying to maneuver left

10 and right to get into the marketplace. And

11 it's going to create a lot of; a lot of people

12 wont' do anything.

13 We think with clarity, whether

14 this proposed language or any language, we

15 think it will benefit everybody. We really

16 don't think it's a pro big company or pro

17 small company or pro innovator or pro follow-

18 on biologic company. But we do feel strongly

19 that there should be some clarity with regard

20 to this because the majority of the people

21 that talk today and yesterday talked about the

22 scientific issues. We think once we take a


1 step pass that, there are very, very real

2 business issues and we need to deal with those

3 issues now to keep technology innovation

4 going.

5 DR. KOZLOWSKI: Do you think some

6 of your concerns about this will depend on how

7 we interpret or how it's interpreted that a

8 structural change that impacts safety, purity

9 and potency is interpreted?

10 MR. BAKIN: Yes. I mean, to be

11 honest with you, the whole structural issue I

12 find very confusing. I don't really know what

13 that means. Any changes is going to change

14 the structure, so by definition any change is

15 going to be a new rug. I'm not sure I

16 answered your question.

17 DR. KOZLOWSKI: Again, depending

18 on how you define the change in safety, purity

19 and potency, that creates a very different

20 standard for what could be evergreened and

21 what couldn't. So, I think there is a sort of

22 a scientific component to interpreting this


1 too that may deal with some of your concerns.

2 MR. RHEE: Yes. Our position is

3 that at this moment in time with the

4 technology that we have today basically any

5 structural change will be a change in

6 efficacy, potency and safety. That's really

7 our position. That's not say, I mean

8 hopefully down the road it's not going to be

9 like that.

10 DR. BEHRMAN: I just have one

11 question, which is yesterday we heard from a

12 number of speakers that the 12 year period of

13 exclusivity had drawbacks from the point of

14 view of patient safety, innovation, perhaps

15 encouraging unnecessary or unethical

16 duplicative testing. And your last slide is

17 entitled Benefits of Multiple 2-4 Year

18 Exclusivity Periods. Do you have any comments

19 on that?

20 It sounds like from what you just

21 said you're here primarily to help provide

22 clarity, yet you seem to be, in fact, taking


1 a position somewhat opposite from what we

2 heard yesterday.

3 MR. RHEE: Yes. There's some irony

4 here where it's analogous to maybe a patent

5 situation where on the surface having patent

6 rights one argument is that it blocks

7 innovation, blocks drugs from coming to the

8 marketplace. But in reality I think we'll

9 agree that there's a strong incentive there to

10 bring products to the marketplace and to be

11 innovative.

12 That's analogous to this slide

13 where multiple 12 year exclusivity periods

14 will actually in reality bring more drug

15 products to the marketplace, encourage

16 collaboration among drug companies and

17 ultimately, hopefully, result in greater

18 patient safety.

19 I think we all wished that we all

20 lived in a world where drugs were 100 percent

21 safe, 100 percent effective and a 100 percent

22 free. But there are just certain economic


1 realities that don't make it such a place.


3 comments.

4 MR. RHEE: Thank you.


6 Mary Gustafson from Plasma Protein

7 Therapeutics Association.

8 MS. GUSTAFSON: I would like to

9 thank the organizers of the Part 15 Hearing

10 for providing the opportunity to comment on

11 FDA's implementation of this milestone

12 legislation.

13 PPTA is an international trade and

14 standard setting organization. We represent

15 the collectives of source plasma, which is a

16 human plasma that is used in the manufacture

17 of plasma drug therapies. And we represent the

18 manufacturers of plasma drug therapies and

19 their recombinant analog products, which are

20 referred to as plasma protein therapies

21 collectively.

22 Plasma protein therapies are used


1 in the treatment of a number of rare diseases.

2 These diseases are often genetic, chronic,

3 life threatening conditions. They require

4 patients to receive regular infusions or

5 injections of plasma protein therapies for the

6 rest of their lives. Some of these conditions

7 are hemophilia A and B, and other clotting

8 factor deficiencies primary immune deficiency

9 disorders and alpha 1-antitrypsin deficiency.

10 PPTA appreciates FDA's efforts to

11 create a forum to obtain input on specific

12 issues and challenges associated with

13 implementation of the Biologics, Price

14 Competition and Innovation Act. We do not

15 doubt that FDA, specifically the Center for

16 Biologics, Evaluation and Research that

17 reviews our products, recognizes the

18 uniqueness of plasma protein therapies and

19 their vital role for patients with a number of

20 rare diseases. We welcome the opportunity to

21 discuss our therapies in this public forum,

22 and my comments will be limited to the effect


1 of the law on our therapies.

2 As has been mentioned previously,

3 the consideration of biosimilars has not

4 unique to the U.S. FDA. PPTA member companies

5 market globally. On a practical level

6 harmonization between U.S. and EU requirements

7 will prevent the necessity of different

8 clinical development plans in the U.S. and EU.

9 It helps that we also consider

10 that both the European Medicine Agency and the

11 World Health Organization to have adopted the

12 right approach. And PPTA supports an FDA

13 approach similar to EMEA and WHO for plasma

14 drugs and recombinant analog therapies. Both

15 positions are addressed in published

16 guidelines.

17 It is important to note that the

18 BPCI Act does not allow the Agency to be as

19 far-reaching as either the EMEA or the WHO

20 with respect to recombinant proteins.

21 Subsection 351(k)(8)(a) allows guidance to be

22 developed that is either general or specific.


1 For recombinant proteins that are analogs to

2 native plasma drug proteins, PPTA support

3 specific FDA guidance with strict criteria for

4 approval of an abbreviated BLA.

5 For plasma drugs therapies the

6 EMEA states in its guidance that, and I quote,

7 in view of complex and variable

8 physiochemicals, biological and functional

9 characteristics it will not be acceptable to

10 submit reduced clinical dossier when claiming

11 similarity to referenced medicinal product.

12 Applications for such similar products will

13 certainly dissatisfy safety and efficacy

14 requirements for new product.

15 New subsection 351(k)(8)(e)(i) of

16 the PHS Act allows FDA to indicate in a

17 guidance document that the science and

18 experience with respect to a product or a

19 product class, not including recombinant

20 proteins, does not allow approval of an

21 application for a license as provided under

22 this subsection for such product or product


1 class.

2 PPTA supports the development of

3 such guidance documents for plasma derived

4 therapies. While much is known about these

5 proteins, much is not known. For these

6 products the process truly defines the

7 product. Similarly, small differences in

8 manufacturing methodologies can result in

9 unexpected differences in the plasma drug

10 product.

11 In the short amount of time

12 allotted for the presentation, we have chosen

13 to focus on the general aspects and

14 harmonization as just noted, and the topics of

15 biosimilarity and interchangeability as they

16 relate to plasma protein therapies.

17 The first question asked what

18 scientific and technical factors should be the

19 agency consider. As just stated, while much

20 is known there are potentially relevant

21 scientific and technical factors in plasma

22 protein therapies that are numerous and are


1 not known. Testing alone cannot guarantee

2 that the biosimilar is highly similar to the

3 relevant product.

4 What scientific and technical

5 factors should the agency consider in

6 determining the appropriate analytical studies

7 and other studies to assess differences

8 between the proposed biosimilar product and

9 the referenced product?

10 For plasma protein therapies, the

11 agency must consider that these therapies are

12 used to treat small patient population on a

13 continuing life long basis. At present it is

14 impractical, if not impossible, to identify

15 all the differences between the proposed

16 biosimilar product and the referenced product

17 as the products are process dependent.

18 Also, it would be impossible to

19 anticipate how much product difference may

20 effect the outcomes and adverse event profiles

21 in patients with different patient

22 characteristics.


1 That range of structural

2 differences between a proposal biosimilar

3 product and the referenced product is

4 consistent with the term highly similar, we

5 would contend for plasma protein therapies

6 that no range of structural differences is

7 consistent with standard, highly similar, or

8 acceptable in a 351(k) application. Small

9 differences in manufacturing methods and the

10 fractionation of purification, stabilization

11 and viral inactivation can produce structural

12 differences. Such structural differences, for

13 example, heterogeneity and the chemical

14 structure of the molecule or antibody content

15 and structure and/or impurities can interact

16 with particular patient characteristics in

17 ways that are clinically meaningful, but

18 impossible detect, measure or recognize

19 without efficacy and safety data for human

20 clinical studies.

21 In terms of clinical studies,

22 while we support the need for studies, it must


1 be recognized that the patient populations

2 that receive plasma protein therapies are

3 small, novel approaches as are currently

4 employed by the reviewers in CBER must be

5 considered and are supported by PPTA.

6 As part of novel approaches to

7 studies for therapies that treat small patient

8 populations there are some circumstances that

9 the Agency should consider in determining the

10 necessity of certain animal and human studies.

11 These circumstances include whether the

12 product is manufactured by a similar process,

13 and if the product has a similar analytical

14 profile, and if the referenced product has a

15 history, a long history of safety and

16 efficacy.

17 In terms of interchangeability,

18 what factors should the Agency consider?

19 Since we know that small differences in

20 manufacturing can result in significant

21 differences in products, we do not believe

22 that plasma protein therapies are


1 interchangeable with respect to the product

2 classes. The interactions of these changes

3 with patient characteristics are numerous and

4 highly variable.

5 What factors should the Agency

6 consider in evaluating the potential risk

7 related to alternating or switching? While

8 plasma protein therapies generally have a good

9 adverse event profile, we know that real but

10 serious adverse events can occur. The adverse

11 events often result from interaction between

12 product and patient characteristics. Some

13 events are the formation of inhibitors caused

14 by immunogenicity, particularly in patients

15 receiving clotting factors.

16 The differences in the

17 manufacturing methods of immune globulins can

18 result in different adverse event profiles in

19 patients due to excipients and/or contaminates

20 in the product. Also thrombosis is a rare but

21 serious adverse event in patients with certain

22 characteristics.


1 The Federal Register notice asked

2 for comments in other areas. As the time

3 allotted today is short, we cannot cover all

4 the areas today, but we will address them in

5 written comments to the docket.

6 PPTA thanks FDA for holding this

7 public hearing. And I will end now.

8 Thank you.

9 DR. BEHRMAN: Thank you for

10 comments.

11 Questions from the Panel? No.


13 MS. GUSTAFSON: Thank you.


15 from the European Generic Medicines

16 Association. And instead of butchering your

17 name, I will ask you to introduce yourself.

18 DR. WINDISCH: So my name is Jeorg

19 Windisch, and I represent the European Generic

20 Medicines Association.

21 I would like to thank FDA for the

22 opportunity to share our thoughts on the new


1 pathway in the U.S. today.

2 EGA represent all license holders

3 of biosimilars in the European Union with one

4 exception, and that is a company that has

5 licensed this project from one of our members.

6 So there's enormous experience we can draw

7 from, up to 15 years without our companies and

8 much longer even for biologics in general as

9 some of our members also work on biologics.

10 EGA members have pioneered

11 biosimilars in Europe, but also in Japan,

12 Canada, Australia and if one may count growth

13 hormone as an FD&C Act product which is not

14 formally a biosimilar to a degree also in the

15 U.S.

16 Biosimilars are in fact gaining

17 significant market share in these markets, and

18 they have been used safely without any safety

19 and potency issues for more than four years

20 now.

21 Now going into the topics raised

22 by FDA, starting out with the biosimilarity.


1 We believe that a degree of similarity is key,

2 and it is in fact the basis for a number of

3 things. It's the basis to justify abbreviated

4 non-clinical and clinical programs. It is the

5 basis to extrapolate between indications. It

6 is the basis to allow interchangeability. And

7 I'm not saying the basis doesn't mean that

8 that is all that we have to do, but it's the

9 basis. And it is also, and that's not

10 unimportant, the basis to gain acceptance by

11 health care providers and by patients.

12 While we acknowledge that there is

13 still some debate about the terminology, we

14 are convinced that the scientific principles

15 that underlie the demonstration of

16 biosimilarity and that underlie the

17 demonstration of comparability of a product

18 pre and post manufacturing change are the

19 same. And provocatively speaking it is not

20 the process that is being injected into a

21 patient, it is the product. And that product

22 carries certain product attributes, which can


1 be critical or not critical and these

2 similarities or differences are what matters

3 and what needs to be evaluated very closely.

4 Now, today we do have the

5 technology in place to get very close to the

6 original product. And defining the original

7 product is actually the first thing one needs

8 to do. Defining the target range, we've heard

9 that several times before, actually comes from

10 buying the original product over a number of

11 years, multiple batches and also from

12 different geographies, and then defining the

13 variability both from batch-to-batch and also

14 historically. And if we buy from different

15 geographies, that also gives us a lot of

16 information about the reference products from

17 different geographies and how they differ or

18 how they are the same.

19 And then we've already heard about

20 the interactive process that we have to go

21 through to get our product as close as

22 possible to the original product. And today


1 the science is in place to actually get this

2 accomplished.

3 Now what does it mean? How close

4 does one have to close to get or how close is

5 close enough or what factors need to be taken

6 into account to access differences?

7 First of all, the differences

8 should be very minor. And the nature of all

9 the differences should be fully elucidated

10 analytically, and then the individual

11 differences should be assessed based on

12 existing knowledge and also based on

13 specifically conducted investigations.

14 One needs to look at the extent of

15 the difference, how much is there and how

16 different is it. The information from the

17 literature, and there's a lot that can be

18 found, the presence and products other than

19 the referenced product, and that is

20 fortunately also included in the statute and

21 can be very helpful. And then the

22 characterization of these products in


1 bioassays, immunologic assays and if

2 necessary, also animal studies. And in most

3 cases the above studies should clarify the

4 relevance of these differences. That doesn't

5 that then one doesn't have to do a clinical

6 study.

7 We do not think there's any

8 general range or rule of which differences

9 would still be consistent with the standard of

10 highly biosimilar. We believe that FDA has

11 years and years of experience in this area and

12 should be given the discretion to make that

13 decision on a case-by-case basis.

14 Now when it comes to

15 pharmacovigilance, we think there's no need to

16 reinvent the wheel. The U.S. already has a

17 functioning REMS system in place, and this

18 system will work just fine for biosimilars as

19 well.

20 We think that it would be very

21 beneficial to have a close collaboration

22 between FDA and EMEA when it comes to


1 pharmacovigilance, but also when it comes to

2 biosimilars in general.

3 With respect to naming, we don't

4 believe that different non-proprietary names

5 prefixes or suffixes will be necessary since

6 we can already clearly identify biologics

7 today based on the product name, the

8 manufacturer, the NBC number and a lot number.

9 Now coming again to what we call

10 global development, which is the use of

11 reported data or the use of data generated

12 against a foreign reference product. And when

13 we talk about foreign reference product, then

14 we only talk about reference products coming

15 from highly regulated markets such as the EU.

16 And we know that while these products are

17 often the same, legally they are different

18 products. And if we do not introduce some

19 flexibility here, this would mandate the

20 performance of separate full development

21 programs for each country. And this is

22 unnecessary. It's also unethical because it


1 leads to the duplication of animal and human

2 studies. And it would also be uneconomical.

3 And I think if we keep in mind

4 what the BPCI Act actually has in mind as it's

5 main objective, that's the affordability, and

6 that is access to patients, then we shouldn't

7 lose track of this.

8 Now, if we have clear

9 demonstration that the reference products are

10 coming from different regions are physically

11 the same or if we can show a very high level

12 of comparability, then we do not think it

13 should be required to duplicate preclinical or

14 clinical studies for each country or region.

15 Now there may be cases where, for

16 example, there are slight differences in

17 formulation. And, of course, those need to be

18 looked at specifically again. A rigor

19 physical, chemical and functional comparison

20 needs to be demonstrated. But in those cases,

21 it may also be necessary to provide more proof

22 in the form of comparative animal studies or


1 rigorous clinical phase 1 PK/PD studies.

2 And in summary, EGA welcomes the

3 establishment of a pathway in the U.S. and the

4 opportunity to work with FDA. Biosimilars

5 have been used for many years already safely

6 in the EU. The science and the technology to

7 develop these products exists already today.

8 And global development must be allowed in my

9 view, if we want to achieve the objectives of

10 the BPCI Act, that being affordability and

11 patient access.

12 Thank you.


14 comments.

15 Questions from the Panel? Dr.

16 Jenkins?

17 DR. JENKINS: The question I've

18 asked of the innovators yesterday and today

19 who have biosimilars to their innovative

20 products marked in other countries is whether

21 they've been able to identify any problems

22 with those biosimilars. And I don't think


1 anyone has said they've identified any

2 problems. You said the same, that there have

3 been no problems in Europe without four years

4 in marketing.

5 Have there been any challenges in

6 Europe from the innovators claiming that the

7 biosimilars that have been approved or less

8 effective, less safe, more immunogenetic, or

9 have they been pretty well accepted by the

10 public as well as the innovator companies?

11 DR. WINDISCH: The acceptance, I

12 think, correlates very strongly with knowledge

13 and education. So, initially when we talk to

14 people, we often see a reaction oh well, we're

15 not sure about this. And then when you

16 explain how these products are developed and

17 how they're brought close to the original

18 product and how extensive the development

19 program is for these products, then their

20 reaction typically changes totally. But we

21 still do see quite a significant need for

22 education in Europe as well. But of course, as


1 these products are becoming more common and as

2 they've been around for a longer period of

3 time, they are gaining a lot more acceptance

4 now.

5 And as to the originators, I'll

6 let them comment. But, of course, they're

7 doing their job as we are doing ours.

8 DR. JENKINS: Just to probe it a

9 little further: Have the innovators

10 challenged the biosimilar approvals in Europe?

11 Have they tried any legal challenges to say

12 these products are not equally safe or

13 effective or --

14 DR. WINDISCH: Not to my

15 knowledge.

16 DR. JENKINS: Okay.

17 DR. BEHRMAN: Dr. Marchand?

18 DR. MARCHAND: Thank you very much

19 for your presentation.

20 I'd like to refer to your slide 7,

21 and your second bullet point there you

22 indicate that given that the U.S. already has


1 a REMS system, for example, you would

2 recommend that there would be no need for a

3 separate system for biosimilars. And if we

4 reflect on some of the elements to assure safe

5 use under REMS programs, in some instances

6 there's some significant post-marketing

7 studies that might be required. So, are you

8 also advocating a position for biosimilar you

9 would recommend a similar type of a post-

10 marketing study that would be required?

11 DR. WINDISCH: I think that will

12 very much depend on the product. And also now

13 in Europe for certain products we do have such

14 programs in place post-approval, in the form

15 of post-approval safety studies. I think that

16 will be necessary for some products and not be

17 necessary for others. And where it is

18 necessary, of course it would be ideal if it

19 could be harmonized between the different

20 countries and regions.

21 DR. BEHRMAN: Dr. Kozlowski?

22 DR. KOZLOWSKI: Sir, you discussed


1 use of ex-U.S. manufactured material or

2 foreign material in the clinical trials in

3 place of U.S. material. So, you talk about

4 structural, functional comparisons and then

5 potentially a bridging study.

6 DR. WINDISCH: Right. Correct.

7 DR. KOZLOWSKI: So you feel that

8 in some cases even a bridging study would not

9 be necessary?

10 DR. WINDISCH: I think that if

11 there is evidence that the product is really

12 physically the same, coming out of the same

13 factory and if we can also show that

14 analytically that would not be the case.

15 And if I could just to the power

16 of the analytics. We've been following these

17 products for more than ten years now. And we

18 can tell batch from batch. So, you know,

19 products coming out of one facility we can

20 tell when a new batch comes to the market.

21 So, it is possible to show a high degree of

22 comparability here.


1 DR. KOZLOWSKI: I think though we

2 can show this high degree of structural

3 similarity for a biosimilar versus an

4 innovator, we still worry about uncertainty.

5 So the question is are you adding a second

6 layer of uncertainty if you're entirely

7 relying on the structural similarity?

8 And then sort of as a follow-up

9 for that you have a lot of experience with

10 these products in the EU, but the EU doesn't

11 use non-EU approved references, not that I'm

12 aware of. And so there is anywhere where there

13 is experience about using reference standards

14 that are not marketed within the approving

15 country?

16 DR. WINDISCH: The whole effort of

17 biosimilars, of course, started in Europe. So

18 most companies actually did use EU source

19 products.

20 And, yes, it is correct that the

21 same discussion actually currently is going on

22 with EU regulators and lawmakers. I think


1 what we would really appreciate here is a

2 dialogue between European and American

3 regulators, how this conundrum can be solved.

4 I think it can only be solved in a joint

5 effort.


7 about your last bullet on the slide. Again,

8 thinking about Centennial and our efforts to

9 make use of data or what's secondary use and

10 similar efforts in Europe. How easily

11 traceable are these products if they don't

12 have a different name, well in our country of

13 claims databases?

14 DR. WINDISCH: I think the key

15 thing is to establish the systems that capture

16 all of the information to make them traceable.

17 I agree that today improvements may be needed

18 and the systems may be imperfect, but if that

19 can be fixed, that is possible.

20 I also think that it is

21 inconsistent with the whole concept of

22 biosimilarity and interchangeability to start


1 off with non-proprietary names. I think that

2 that would actually make the administration

3 of, for example, interchangeability very

4 different. And we've already seen cases in

5 Europe, and we think that's unfortunate, and

6 also Australia where either companies have

7 gone ahead and voluntarily selected different

8 names or where different names have been

9 allocated. So the products leading to a

10 situation are one in the same product may have

11 different non-proprietary names in different

12 countries around the world. We think that

13 that might actually cause more confusion.


15 your comments.

16 We've reached our break time.

17 We'll take a 15 minute break and then we'll

18 resume at a quarter to 3:00.

19 Thank you.

20 (Whereupon, the above-entitled

21 matter went off the record at 2:34 p.m. and

22 resumed at 2:48 p.m.)


1 DR. BEHRMAN: Okay. Our next

2 speaker will be Marie Vodicka. Oh, good.

3 From PhRMA. Welcome.

4 DR. VODICKA: Good afternoon. I

5 mean Marie Vodicka, Associate Vice President

6 of Scientific and Regulatory Affairs at the

7 Pharmaceutical Research and Manufacturers of

8 America or PhRMA. And I am a biologist by

9 training.

10 PhRMA represents the country's

11 leading pharmaceutical research and

12 biotechnology companies which are devoted to

13 inventing medicines that allow patients to

14 live longer, healthier and more productive

15 lives.

16 We thank FDA for the opportunity

17 to provide PhRMA's views. Given the brief time

18 allotted, my comments will address some of the

19 key issues raised by the FDA in the Federal

20 Register notice. PhRMA plans to submit to the

21 docket more detailed answers.

22 We hope this will be the first of


1 many opportunities for public comment and

2 dialogue as FDA establishes policies in the

3 form of regulation and guidance for the

4 implementation of a biosimilar pathway.

5 First, I will present a set of key

6 principles that should guide FDA's

7 implementation of the new approval pathway for

8 biosimilars, later I will provide PhRMA's

9 views on several specific items identified in

10 the FDA's hearing notice.

11 The FDA should be guided by the

12 following principles as it implements the

13 pathway passed by Congress. Ensure patient

14 access to safe and effective biosimilars,

15 create a science-based pathway through an open

16 transparent process and encourage innovation

17 and enable additional competition.

18 In the interest of transparency,

19 predictability, sound science and the public

20 health the PhRMA stresses the importance for

21 FDA to issue implementing guidances and

22 regulation. Regulations and guidance would


1 provide certainty and transparency to sponsors

2 in order to help them design effective

3 development strategies to meet FDA regulatory

4 expectations and help ensure consistency

5 amongst and between biosimilars and referenced

6 product.

7 We urge FDA to look to the

8 European Medicines Agency processes that

9 enabled safe and effective biosimilars to

10 reach European patients.

11 As FDA implements a biosimilar

12 pathway in the U.S., PhRMA urges the FDA

13 especially to consider how it implements the

14 following topics addressed in the Federal

15 Register notice: Biosimilarity,

16 interchangeability, pharmacovigilance, naming

17 and labeling and exclusivity.

18 In the interest of patient safety

19 FDA should require that companies seeking to

20 demonstrate biosimilarity to an existing

21 licensed biologic should use a stepwise

22 process requiring high quality, well designed


1 comparative studies beginning with molecular

2 evaluation and ending in safety and efficacy

3 trials in patients.

4 BPCIA requires a biosimilar to use

5 a biologic project licensed in the U.S. under

6 a full application as a reference product for

7 a showing of biosimilarity. Data generated

8 using the biosimilar and the U.S. licensed

9 referenced product should be sufficient to

10 support the biosimilar product's claims and

11 for FDA evaluation and licensing of the

12 biosimilar product.

13 Demonstration of the likely

14 similarity is a prerequisite for using the

15 abbreviated preclinical and clinical pathway

16 for biosimilars. Analytical methods to

17 demonstrate molecular similarities should be

18 orthogonal and sensitive enough to detect

19 relevant differences if they exist.

20 Structure that can be controlled,

21 such as amino acid sequence, should be

22 conversed between the biosimilar and the


1 referenced biologic, and any other structural

2 features such as post-translational

3 modifications including glycosylation should

4 be conserved if they are known to be essential

5 for function.

6 Given that it is difficult to link

7 differences in molecular structure to function

8 and clinical outcomes, comparative clinical

9 trials for safety and efficacy and relevant

10 patient populations should be required for

11 biosimilars including an immunogenicity

12 assessment.

13 For safe and effective medicines

14 for patients clinical data with the biosimilar

15 should be required for each indication.

16 Allowing approval of indications without

17 clinical data would be waiving the clinical

18 data requirement under the statute. This

19 should only be done if justified

20 scientifically. FDA should at a minimum

21 consider the following factors before deciding

22 to waive the clinical requirement for any


1 indication:

2 Molecular mechanism of action;

3 Diseased mechanism of action, and;

4 Diseased state of the patients.

5 Congress intended the scientific

6 and regulatory standard for interchangeable

7 biologics to be above and beyond that for

8 biosimilars. Given current science we do not

9 think it would be safe for patients if FDA

10 were to approve interchangeable biologics now.

11 Unlike a generic drug, which is the same as

12 the reference drug, a biosimilar will be

13 similar to and not the same as the reference

14 biologic. There's currently no scientific

15 regulatory or medical consensus on how the

16 statutory requirement, the same clinical

17 effect in any given patient, would be

18 demonstrated. However, the statute authorizes

19 FDA to make such determination and we

20 therefore suggest that FDA consider additional

21 factors, including those outlined below, when

22 considering how to implement the statutory


1 provisions on interchangeability.

2 Only FDA should make

3 interchangeability decisions. In making an

4 interchangeability determination, FDA should

5 require clinical data for all indications of

6 the referenced product. Because once it is on

7 the market it will be used interchangeably for

8 all indications by physicians and pharmacists.

9 Beyond the issues of what evidence

10 should be required for approval of an

11 interchangeable biologic, FDA should consider

12 the potential impact of the following on

13 public health and safety of interchangeable

14 biologics in the market:

15 Divergence of products post-

16 approval;

17 The many potential

18 interchangeability relationships with multiple

19 biosimilar products, interchangeable products

20 and the referenced products in class;

21 The potential for increased

22 immunogenicity from switching between


1 products, and;

2 Especially the implications this

3 would have for pharmacovigilance including

4 determining whether an adverse event was

5 caused by a single products or by switching

6 between one or more products.

7 Pharmacovigilance for biologics

8 will be especially challenging in an

9 environment in which patients may receive

10 multiple similar products that are not the

11 same and may or may not be distinguishable by

12 name. FDA should apply post-marketing

13 commitments to biosimilars using the same

14 scientific criteria as for any new products,

15 using what is currently known about the

16 product class and individual product.

17 In order to assure that patients

18 who take biosimilar medicines are protected to

19 the same extent as those taking a license

20 referenced biologic, any REMS for a biosimilar

21 should be at least as rigorous as for the

22 referenced product.


1 In the interest of patient safety

2 to help ensure clear prescribing and

3 dispensing and for pharmacovigilance purposes

4 each biologic product should have a unique

5 non-proprietary name. In the interests of

6 transparency and patient safety each

7 biosimilar and interchangeable biologic should

8 have it's own labeling which clearly states

9 relevant regulatory information such that the

10 product is a biosimilar to a specific

11 referenced product, the approved indications

12 and whether the product is deemed

13 interchangeable.

14 For each indication the biosimilar

15 labeling should state whether there are

16 supporting data for the biosimilar or only for

17 the referenced product. Moreover, if FDA has

18 not determined that a biosimilar is

19 interchangeable, then labeling should state

20 this to help prevent substitution without an

21 interchangeability determination by FDA.

22 Congress thought to balance the


1 desire for increased competition with the need

2 to preserve incentives for R&D investment to

3 develop tomorrow's new treatments and cures.

4 In determining which products are eligible for

5 the 12 year data production period, refer to

6 as the exclusivity period in the Federal

7 Register notice, FDA should adhere to the

8 wording of the statute. Any difference in

9 structure of the product accompanied by data

10 demonstrating differences in safety, purity or

11 potency from a previous product warrant a

12 product receiving its own 12 year exclusivity

13 period.

14 We know that notwithstanding the

15 phrasing of the question in the Federal

16 Register notice, this is not a second period.

17 Under the statute the original biological

18 product receives a 12 year exclusivity period

19 and a next generation product that meets the

20 criteria receives a separate and independent

21 period. After the data exclusivity period

22 ends for the first generation product, an


1 approved biosimilar of that product could

2 enter the market.

3 Qualifying structural differences

4 in a subsequent product would include, but are

5 not limited to: Differences in amino acid

6 sequence and post-translational modifications

7 such as peglylation. FDA should apply the

8 provisions to encourage, not discourage,

9 innovation that expands treatment options for

10 patients.

11 In conclusion, as the discussion

12 over the past two days has demonstrated, the

13 science and complexities of biologics are

14 many. These complexities underscore the need

15 for the FDA to engage in ongoing dialogue

16 through an open and transparent process with

17 key stakeholders.

18 And I'm happy to take your

19 questions.


21 comments.

22 Questions from the panel? No.



2 Our next speaker is Rasmus

3 Rojkjaer. He's correct me. From Generic

4 Pharmaceutical Association.

5 DR. ROJKJAER: Yes. Rojkjaer.

6 Not even close, I'm afraid.

7 Well anyway, good afternoon and

8 thank you for the opportunity to provide

9 Generic Pharmaceutical Association's view on

10 the Biologics, Price Competition and

11 Innovation Act of 2009.

12 My name is Rasmus Rojkjaer, again.

13 In real life I'm head of R&D for Biologics for

14 Mylan, the biggest global generics company

15 headquartered in the U.S. and one of the GPhA

16 member companies.

17 GPhA represent more than 100

18 generic manufacturers and distributors, and

19 their products is usually nearly two billion

20 prescriptions every year.

21 The GPhA mandate to improve the

22 lives of consumers by providing timely access


1 to safe and effective, yet affordable

2 pharmaceuticals. With health care costs

3 rising to unsustainable levels, nowhere will

4 the GPhA mandate be more important that the

5 area of biologic medicines.

6 In the eyes of the GPhA the

7 Biologics, Price Competition and Innovation

8 Act was a cautious first step. However, it

9 will take much more to create price

10 competition for the more than $30 billion

11 worth of biologics scheduled to expire their

12 date of exclusivity on or before 2018.

13 Fortunately, the FDA has the scientific

14 expertise and experience of approving complex

15 biologic products and the GPhA members is

16 blazing a trail towards of approval of high

17 quality biogeneric medicines at prices that's

18 within the grasp of the American patients.

19 Collectively we think that we have the tool to

20 make this work, just as a quarter of a century

21 ago for small molecules under the Hatch-Waxman

22 Act.


1 So, biogenerics has the key to

2 lowering pharmaceutical costs over the next

3 several decades while increasing patient

4 access. Yet as we see the new pathway is full

5 of land mines that will hamper the true

6 intention of the law, namely bringing low cost

7 high quality biogenerics to the American

8 public. FDA's immediate support for this new

9 pathway is crucial, and this includes the

10 Agency's timely advice to sponsors allowing a

11 reduced biosimilarity data burden, always

12 preserving the safety, purity and potency of

13 all FDA licensed biologics.

14 So, I'm here today to discuss ways

15 to achieve this. Due to the time constraints,

16 we have focused in on four of the issues

17 raised in the FDA notice. Namely:

18 biosimilarity, naming, interchangeability and

19 the use of referenced products.

20 I've also show the cover and

21 approach to user fees at the end.

22 So the first one, biosimilarity.


1 I think to some extent it has been covered

2 extensively. I think it's worthwhile to say

3 at the end, though, that this is the

4 cornerstone of the new pathway, and that we

5 feel that it's possible that the FDA already

6 has extensive experience here. The FDA has

7 been evaluating products for biosimilarity for

8 years. Anytime a brand new biologic

9 manufacturer has changed his manufacturing

10 process, added new facilities, substituted an

11 ingredient or changed the cell line, the FDA

12 has used the same time honored data driven

13 scientific standard: Comparability to analyze

14 these changes.

15 As the FDA is well aware,

16 comparability between biologic products is

17 defined as highly similar quality attributes.

18 Rarely are clinical studies required. FDA's

19 work in developing its approach to

20 comparability lead to the creation and the

21 international comparability standard, the ICH

22 Q5E now in use all over the world. And really


1 the basis for the already approved European

2 biosimilars.

3 So we think that the ultimate goal

4 of the comparability exercise is to ensure

5 that the safety, purity and potency of the

6 biologic are the same before and after this

7 manufacturing change, and this same approach

8 can and should be applied to biogenerics.

9 Again, step one, as we heard many

10 times today, is to compare physical chemical

11 attributes and truly promoting between the

12 potential biogeneric medicine and the

13 reference product. For this a series of

14 overlapping analytical tests should be

15 employed. The science necessary for this

16 sophisticated analytical comparability

17 exercise is already in use for multiple

18 biologics today.

19 The second step is to conduct long

20 standing studies, compare functions using

21 appropriate animal or tissue modeling

22 necessary. The aim of these studies is to


1 verify comparability.

2 Finally, step 3, chemical testing

3 for biogenerics should not be required to the

4 same extent as for new active substances given

5 that the patient response to a biogeneric will

6 be vastly more predictable. Thus, biogeneric

7 sponsors using state of the art and analytical

8 validation tools that are confirmed that the

9 proposed product is highly similar to the

10 referenced product should be subjected to

11 clinical study requirements only to the same

12 degree as expected for the originator products

13 making manufacturing changes.

14 Accordingly, any clinical -- must

15 be need based and data driven taking into

16 account the degree of similarity demonstrated

17 earlier in developments. If the biogeneric

18 has been demonstrated to be highly similar to

19 the referenced product, the established safety

20 approach and potency profile of the referenced

21 product can be relied upon without mandating

22 unnecessary duplicative testing.


1 Naming. In our view, one of the

2 most unfortunate features of the abbreviated

3 biogenerics pathway study does not dictate

4 that biogeneric has the same name as the

5 referenced product. Both the EU and WHO gives

6 them the same name. This process to us is

7 sensible the actual degree has been shown to

8 be highly similar. It's the GPhA's position

9 that biogenerics should be given the same

10 generic name as the referenced product,

11 otherwise a finding of interchangeability or

12 biosimilarity for that matter will come for a

13 review among health care providers diminishing

14 meaningful opportunities for market access.

15 Interchangeability. Confidence in

16 the FDA and the Agency's determination in

17 interchangeability is what drives generic

18 competition. It is the reason why generic

19 drugs has generated savings in excess of $800

20 billion U.S. dollars over the last decade.

21 The way that FDA deals with this

22 topic interchangeability will be directly


1 responsible for the market dynamics generated

2 for biogeneric pathway. Thus, FDA must be

3 exceedingly cautious in elevating the

4 interchangeability status to a level that is

5 unattainable. The standard imposed for their

6 own products is the correct standard for

7 generics also, otherwise products that have

8 been driven monopoly pricing for the last 25

9 years often costing tens of thousands of

10 dollars for a single patient will burden

11 patients and payers for the next 25 years

12 also.

13 Finally, use of data on foreign

14 reference products. One of the most immediate

15 ways for FDA to be proactive is to permit

16 biogeneric applicants to use the work they

17 have already done to establish biosimilarity

18 against referenced products marketed in all

19 the highly regulated markets in support of

20 their application in the United States.

21 All the first high approval

22 agencies such as Canada, Japan as well, has


1 supported this scientific sound way of

2 thinking. Permitting the use of testing --

3 that are highly similar to U.S. referenced

4 product will maximum the availability of high

5 quality, safe and effective biogenerics by

6 minimizing unnecessary and unethical

7 questionable studies. This is essentially the

8 case where the foreign referenced product is

9 the same the U.S. referenced product in all

10 ways except the label.

11 More generally, we encourage the

12 FDA to take the leadership role in developing

13 a framework for appropriate use of foreign

14 referenced product data that recognizes

15 genuine science while at the same time

16 preserving FDA's authority on the ultimate

17 question of safety and efficacy.

18 Lastly, on the user fees. The

19 GPhA look forward to working with the FDA to

20 create a user fee program for biogenerics to

21 emphasize safety, access and transparency.

22 This program should also include a program


1 metrics to help expedite the availability of

2 biogeneric medicines and user fees should not

3 be used to create a barrier to entry for

4 biogenerics. A proactive and safety driven

5 approach will expedite the availability of

6 competitively priced biogenerics while at the

7 same time ensuring the FDA is able to

8 appropriately manage their development and

9 manufacturing. Then when the patient is faced

10 with a choice brand or biogeneric, they will

11 rest assured that the product is safe and

12 effective according to FDA standards.

13 So, at the end, we would like to

14 thank the FDA for its time and interest and

15 GPhA hopes that this public hearing is the

16 start of a dialogue between the FDA,

17 stakeholders on these important issues.

18 I'll be glad to at least try to

19 answer any questions you might have.


21 comments.

22 Questions from the panel? Dr.


1 Kozlowski?

2 DR. KOZLOWSKI: We've heard from

3 prior speakers that in a development of

4 biosimilars in Europe there were examples

5 where the clinical studies were important,

6 that they yielded information that changed the

7 development path. So, I guess I want your

8 view on the importance of the clinical

9 development part of the O program and how that

10 would reflect on what the Agency should think

11 about?

12 DR. ROJKJAER: No. I think that

13 there is no doubt that in some cases clinical

14 programs is -- I think our point here is that

15 it should be evaluated on a case-by-case

16 basis. That this extensive program of

17 biosimilars should be leveraged toward

18 clinical trials. Not sort of a package

19 solution that everybody has to do the same

20 thing, but in every single what makes sense.

21 So, I'm very much aware of the

22 experience from Europe, and I think clinical


1 trials has its role to play. But forcing the

2 industry to fit into a one fits all kind of

3 approach I think will seriously keep the

4 development of these biogeneric compounds

5 back.

6 DR. BEHRMAN: Other questions from

7 the Panel?

8 All right. Thank you for your

9 comments.

10 DR. ROJKJAER: Thank you.


12 Sara Radcliffe from BIO.

13 MS. RADCLIFFE: Good afternoon and

14 thank you for the opportunity to present

15 today. I am Sara Radcliffe, Executive Vice

16 President for Health at the Biotechnology

17 Industry Organization, BIO.

18 BIO supported the passage of

19 legislation to enable FDA to approve

20 biosimilars so that patients living with unmet

21 medical needs with have expanded access to

22 safe and effective medical therapies at lower


1 cost.

2 I will address only four broad

3 topics this afternoon, but we have appended 21

4 slides to our presentation that provide more

5 information and we look forward to submitting

6 written comments to the docket. My testimony

7 today is grounded by the specific hands-on

8 experience of bio-member companies.

9 Experience that is crucial to understanding

10 biological products.

11 First, I would like to address

12 biosimilarity. The demonstration of

13 biosimilarity should begin with the side-by-

14 side analytical comparison of the biosimilar

15 against the reference product. This

16 comparison should be made with regard to the

17 active protein molecule as well as the

18 formulated drug product.

19 While analytical techniques are

20 increasingly capable of discerning differences

21 between biologics, at present, they have

22 limited predictive value with respect to


1 establishing that no clinically meaningful

2 differences exist. Therefore, comparative

3 non-clinical and clinical studies should also

4 be performed.

5 Clinical data should be provided

6 for all indications for which the biosimilar

7 applicant seeks approval except in cases where

8 extrapolation can be scientifically justified

9 and where the mechanism of action is not only

10 known, but well understood.

11 Extrapolation of data among

12 indications must be handled extraordinarily

13 carefully because it is well known that

14 products behave quite differently when used to

15 treat different disease states and patient

16 populations.

17 In particular, immunogenicity

18 should be assessed in clinical studies. The

19 present limitations of analytical and non-

20 clinical testing are particularly apparently

21 when predicting immunogenicity is concerned

22 and especially across indications.


1 Second, I'd like to address

2 interchangeability. The standard for

3 interchangeability in the law states in part

4 that an interchangeable product can be

5 expected to produce the same clinical result

6 as the reference product in any given patient.

7 This is an appropriately high standard

8 directed toward protecting patient safety.

9 We believe this standard requires

10 that there be no divergence in safety or

11 efficacy profiles when an interchangeable

12 product is substituted or alternated by any

13 individual in any relevant patient population.

14 We think that FDA guidance will be

15 needed for each product type to establish

16 acceptable confidence intervals for analysis.

17 Further, for interchangeable

18 biosimilars, we urge that efficacy and safety

19 be studied in clinical trials for each

20 indication. If an interchangeable biosimilar

21 is approved, it is likely to be used

22 interchangeably for all indications by


1 pharmacists and physicians. There must be

2 assured that patients would not be deprived of

3 therapeutic actions as a result of alternating

4 or switching.

5 For example, the patients would

6 develop a reaction that would render use of

7 the reference product ineffective or unsafe.

8 Moving to my third topic, patient

9 safety and pharmacovigilance. Current systems

10 for naming and labeling generic medicines were

11 not designed to address biosimilars which are

12 not identical with the innovative product. To

13 avoid inappropriate assumptions about product

14 sameness and interchangeability, facilitate

15 clinical vigilance and traceability and

16 protect patient safety, each biologic should

17 have a distinct international non-proprietary

18 name, INN.

19 Ideally a standardized naming

20 system would be developed and utilized

21 globally. For example, a distinct INN could

22 consist of the same stem name as the innovator


1 plus a unique suffix.

2 We are aware that some suggest

3 national drug codes. NDC numbers and lot

4 numbers could be used in place of unique non-

5 proprietary name. However, while lot numbers

6 are always provided by the manufacturer,

7 experience has shown that they are not always

8 recorded by the end user. In addition,

9 neither NDC codes nor lot numbers are very

10 useful to patients and prescribers and they

11 are not used globally.

12 Finally, I'd like to address

13 several issues related to maintaining

14 incentives for innovation. First, use of the

15 351(a) versus the 351(k) pathway where

16 submitted BLA meets the statutory definition

17 of a biosimilar.

18 FDA should not accept such

19 applications under Subsection A. To do so

20 would result in the biosimilar applicant

21 receiving the benefits of the new pathway

22 without having to bear the concomitant


1 burdens. For example, waiting for the expiry

2 of exclusivity or complying with other

3 provisions designed to protect innovator

4 rights.

5 Protection of innovator rights to

6 notice and comment to biosimilar applications.

7 Biomembers believe that FDA has an important

8 role in the implementation of the Act's patent

9 resolution and information exchange process.

10 For example, we ask FDA to obtain binding

11 assurance from the Subsection (k) applicant

12 that the applicant has or will provide the

13 reference product's sponsor with sufficient

14 notice and information to allow the resolution

15 process to begin. Otherwise, innovators will

16 not be able to exercise their rights as set

17 forth in the statute.

18 Additionally, we ask that FDA

19 clarify other procedures necessary to insure

20 that the careful statutory balance of

21 innovator and biosimilar rights is preserved.

22 FDA reliance on reference BLA and


1 protection of confidential information. In

2 the Hatch-Waxman context, FDA does not review

3 or rely upon information or data contained in

4 the reference NDA. Rather the Agency relies

5 upon its previous finding of safety and

6 effectiveness. Likewise, in the biosimilars

7 context, the statute makes clear that the

8 Agency may rely only on the information

9 submitted by the Subsection (k) applicant.

10 Therefore, we ask the FDA to make

11 clear implementing regulations. That when

12 evaluating a Subsection (k) application,

13 reviews are not permitted to rely upon

14 proprietary or confidential information and

15 data contained in the reference product BLA.

16 Significant product modifications.

17 We believe it is important for FDA to make

18 several clarifications regarding the proper

19 interpretation of the statute exclusivity-

20 related provisions. Three of these are the

21 following.

22 First, FDA's Federal Register


1 notice states that the date of first licensure

2 does not apply to approval of a supplement or

3 subsequent BLA meeting certain criteria for

4 the same product. We note that the proper

5 interpretation of this provision is that a

6 subsequent BLA or supplement that falls within

7 the statutory criteria in Subsection(k)(7)(c)

8 is protected by the remaining period of

9 exclusivity that applies to the first license

10 BLA.

11 Second, the notice states that in

12 certain circumstances a subsequent BLA may be

13 eligible for a second 12-year period of

14 exclusivity. This is inaccurate and the only

15 product has been modified structurally so that

16 it is different from the reference product in

17 terms of safety, purity or potency can obtain

18 a 12-year period of exclusivity. In such a

19 case, the exclusivity period attaching to the

20 original product is not extended in anyway.

21 We suggest that relevant

22 modifications to structure include but are not


1 limited to changes in amino acid sequence,

2 critical post-translational features of the

3 active ingredient or biological components

4 that result in a product with a change in

5 safety, purity or potency as compared to the

6 reference product.

7 Third, we ask that FDA prepare,

8 publish and periodically update a list of

9 approved biologics identifying first licensure

10 dates and establishing associated dispute

11 resolution process. Also, we ask that FDA

12 establish a process by which a company can

13 obtain advanced determination of whether first

14 licensure restrictions would limit exclusivity

15 for proposed R&D targets.

16 Finally, I'd like to say a word

17 about user fees. BIO recognized that

18 application for approval of biosimilar

19 products will raise novel and complex

20 questions of science and law.

21 We ask FDA to insure that workload

22 associated with these new applications does


1 not harm the Agency's ability to efficiently

2 review new drugs and biologics.

3 We also note that under PDUFA 4

4 innovator user fees were extended to support

5 post-market safety evaluation by FDA.

6 Biosimilar user fees should also support post-

7 market safety evaluation.

8 Again, thank you for the

9 opportunity to present today and I'd be happy

10 to take your questions.


12 comments. Mr. Schwartz.

13 MR. SCHWARTZ: Yes, thank you for

14 your comments.

15 Can we go back to slide number 7

16 for a moment please? I was hoping you could

17 elaborate on the first bullet point and

18 whether you think that the statute actually

19 requires that the products go under the 351(k)

20 pathway or whether you are urging that the

21 Agency use discretion which you might believe

22 is in the statute to require that the product


1 go through the 351(k) pathway.

2 MS. RADCLIFFE: We believe that

3 the statute is not clear in its language.

4 However, in constructing the statute, Congress

5 went through a very careful process of

6 balancing innovator and biosimilar rights and,

7 therefore, we think it can be understood from

8 the statute that it would not make sense for

9 FDA to establish a process wherein the

10 biosimilar applicants were able to evade the

11 rights that are extended to the innovator

12 manufacturer.



15 that, we've heard today a variety of different

16 clinical programs described. Some of which

17 were actually much larger than it would take

18 to approve an innovator product.

19 So, I think it's an interesting

20 challenge if one has to be (k) and that (k)

21 pathway is actually rather larger in terms of

22 effort and resources than an innovator


1 product.

2 MS. RADCLIFFE: I think we should

3 separate two different things. One is

4 biosimilarity and the other is


6 Clearly, the purpose of the

7 statute is to permit an abbreviation in the

8 data that would be necessary to submit to get

9 a biosimilar application onto the market. The

10 amount of abbreviation in that data package

11 will depend very heavily on what data the

12 biosimilar applicant is able to bring forward

13 from analytical and non-clinical testing. We

14 think that that would be very different for

15 different products.

16 And that is one reason why

17 touching on a product that I was -- I'm sorry.

18 Touching on a topic that I wasn't able to

19 bring up this morning, we think it would be

20 very useful for the Agency to provide product

21 specific guidance.

22 In the realm of


1 interchangeability, I think it does become

2 much more complicated. Our company has not

3 said that interchangeability is impossible.

4 That being said, I think it is widely

5 understood that the size of the clinical

6 trials that would be necessary to show

7 interchangeability for many if not all complex

8 biologics would be very big and that that

9 exercise at this point in time seems to be

10 infeasible.

11 DR. KOZLOWSKI: One of the earlier

12 speakers, I think from Amgen, had mentioned

13 the possibility of post-market data being

14 useful in establishing interchangeability.

15 Does BIO have a perspective on

16 that?

17 MS. RADCLIFFE: I think that for

18 every product, for every applicant who submits

19 an application to FDA, it is clear that the

20 clinical -- that the data package including

21 most importantly the clinical data does not

22 remove all risk. It is always the case that


1 there is some risks that remain to be

2 addressed by pharmacovigilance and adverse

3 collection post-market.

4 That being said, it is incumbent

5 upon us to provide as much information as

6 possible in our application to FDA because to

7 do otherwise is necessarily to expose the

8 general population to some risk and,

9 therefore, I think it is possible to address

10 some risk post-market.

11 But, certainly the intent and the

12 default should be to try and get that

13 information into the application prior to

14 marketing.

15 DR. KOZLOWSKI: I think actually

16 the thought was almost a two-stage process

17 where that would be pre-market for the

18 interchangeability determination. It would be

19 post-market for the biosimilarity. At least

20 to clarify what the question was.

21 MS. RADCLIFFE: Okay. Yes. The

22 other way.


1 DR. KOZLOWSKI: Oh, right. So,

2 post-market for biosimilarity, pre-market for


4 MS. RADCLIFFE: Yes. Now, that I

5 understand --

6 DR. KOZLOWSKI: So, that --

7 MS. RADCLIFFE: I think I

8 understand what you're saying.

9 DR. KOZLOWSKI: So -- well, no,

10 what I meant is that the post-market data

11 would effectively become pre-market before an

12 interchangeability determination and I have

13 one last question. You mentioned --

14 MS. RADCLIFFE: If I could just

15 address that though. Yes, I do understand

16 your question better now and if, in fact, it

17 is that perhaps a determination of

18 interchangeability would not be possible at

19 the time of marketing and that it would be

20 better to gain some market experience before

21 that exercise was undertaken, yes, I think

22 that view is shared by the majority of our


1 company.

2 DR. KOZLOWSKI: And then one last

3 comment. You mentioned active ingredients.

4 So, obviously obtaining purified active

5 ingredients can be a challenge depending on

6 the nature of the product formulation.

7 So, does BIO have any plans to

8 help make such material available?

9 MS. RADCLIFFE: You know, we

10 cannot make promises of that kind on behalf of

11 our company. I did hear a number of

12 presenters earlier today talk about the ways

13 in which they would undertake the

14 biosimilarity exercise. They obtain product

15 over a number of years from different

16 geographic locations and that is the way they

17 approach that.


19 on naming. So, you're in favor of unique

20 names. We heard over the course of the two

21 days a number of speakers who suggested that,

22 in fact, such an approach might be burdensome


1 to patients and to prescribers, that it might

2 be confusing, that it could lead inadvertently

3 to a patient being prescribed what are

4 essentially highly similar or identical

5 medications at the same time.

6 Do you have any comments on those

7 concerns?

8 MS. RADCLIFFE: It has been BIO's

9 long-standing position that international non-

10 proprietary names are essential. There is

11 really no other system that permits -- that

12 could be extended internationally to allow

13 pharmacovigilance and tracking.

14 It is also important as I very

15 briefly said in my testimony to avert

16 inappropriate assumptions about


18 The alternatives that have been

19 discussed, NDC codes and lot numbers and so

20 forth, I think are not really recognized by

21 patients or physicians and, therefore, don't

22 provide wise alternatives to a unique non-


1 proprietary name.


3 Ms. Esposito.


5 comments. With respect to the comment that

6 you made about FDA being permitted to rely

7 only on publicly available information about

8 the reference product, can you elaborate a

9 little bit more on that in terms of how you

10 and your member companies view FDA's ability

11 to approve a biosimilar based on certain

12 knowledge that it already has of an approved

13 reference product and how you would

14 distinguish between what the Agency knows

15 from, you know, having dealt with the company

16 over the years versus what is actually

17 publicly available in terms of clinical and

18 non-clinical data?

19 MS. RADCLIFFE: As in the Hatch-

20 Waxman context, we think it is inappropriate

21 for reviewers to rely on proprietary

22 information and data contained in an


1 application.

2 We understand that there are

3 circumstances in which reviewers do look at

4 another application in order to determine, for

5 example, whether the two products are similar,

6 whether they are identical and so forth and

7 various characteristics. We understand that.

8 Nevertheless, it is different

9 conceptually for the reviewer to be relying on

10 information in the application that is, in

11 fact, a proprietary property of the innovator.

12 MS. ESPOSITO: One follow-up

13 question. When you talk about the

14 acknowledgment that the reviewer would, by

15 definition, kind of need to look -- to make

16 similarity determinations, need to look at the

17 comparator product --

18 MS. RADCLIFFE: Yes.

19 MS. ESPOSITO: When you're

20 referring to confidential proprietary

21 information, are you focused more on the

22 clinical and non-clinical data rather than the


1 CMC or are you speaking of both and if both,

2 then how can you make the comparison?

3 MS. RADCLIFFE: I am speaking

4 about any trade secret or proprietary

5 information that is contained in the

6 application whether it is the CMC information,

7 the pre-clinical information or the clinical

8 information. To the extent that that is the

9 proprietary information of the innovator, it

10 cannot be relied upon for -- that information

11 as opposed to the finding of safety and

12 efficacy cannot be relied upon for the

13 approval of the biosimilar application just as

14 it cannot be relied upon for the approval of

15 a generic application.


17 comments.

18 We've now reach the open public

19 comment period. The first commenter is Dr.

20 Lehrman from Lehrman Consulting.

21 Please limit your comments to five

22 minutes. Thank you.


1 DR. LEHRMAN: Good afternoon.

2 Okay. So, since I believe you're not familiar

3 with me, I'll give you a brief induction.

4 My name is Dr. Russ Lehrman. I've

5 been a pharmaceutical sciences consultant with

6 over 25 years of experience supporting

7 pharmaceutical and biotech companies in the

8 development of large and small molecular

9 therapeutics. That means that I've been a

10 director and senior director of analytical R&D

11 formulation, R&D late stage API refinement

12 prior to development.

13 I greatly appreciate this

14 opportunity to speak to the Committee on the

15 topic of biological product definitions and

16 will describe one specific situation that I

17 hope will help clarify the way that the Agency

18 characterizes chemically synthesized

19 polypeptides.

20 This is a point that's been raised

21 during the course of the two days, but I don't

22 think anybody has really focused in on that


1 and that's why I'm speaking.

2 The FDA defines biologics as

3 proteins otherwise known as polypeptides that

4 are produced by biological media. Earlier

5 comments at this hearing have clearly

6 highlighted the heterogeneity that can arise

7 in proteins that are generated by

8 fermentation.

9 In contrast, peptides that are

10 chemically synthesized using a process that

11 adds one amino acid at a time from one end of

12 the molecule and proceeds in an orderly

13 fashion to the other end in a highly-

14 controlled, high-yield process that produces

15 following purification obviously a very

16 purified material.

17 For this reason, peptides are

18 typically regulated much as small molecules

19 are not as biologics, but please consider the

20 case of glatiramer acetate, an amino acid

21 copolymer also known as Copaxone.

22 This peptide is one of the primary


1 treatments for multiple sclerosis. Something

2 that I'm sure you're aware of.

3 Glatiramer is produced by a

4 process in which four amino acids modified to

5 readily form peptide bonds are mixed together

6 and generate a gamish of peptides that contain

7 peptide chains that both differ in length and

8 in the ordering of the four component amino

9 acids.

10 The length of the chains and the

11 order of the amino acids is highly dependent

12 on reaction conditions, amino acid ratios and

13 other factors too numerous to name in the time

14 I have.

15 This polypeptide cannot be

16 chemically characterized in the same detail,

17 in anywhere close to the same detail as other

18 synthetic peptides and is absolutely defined

19 by the process. No question about that.

20 In addition, a recent publication

21 has clearly shown that altering the length and

22 composition of this peptide mixture -- the


1 peptide mixture that constitutes this drug can

2 result in increased safety risk and for

3 technical details, I refer members of the

4 Committee to published reports and if you

5 would like references from me to help you in

6 that end, I'll be happy to do that.

7 For these reasons, the glatiramer

8 needs to be classified as a biologic agent and

9 any follow-on products based on this drug

10 should be reviewed as biosimilars not as small

11 molecules, not as generics and should,

12 therefore, be chemically characterized as well

13 as current technologies permit and clinically

14 using clinically-driven endpoints such as

15 relapse remission.

16 In addition, any new peptide

17 product candidate utilizing synthetic

18 approaches such as the one used in the

19 manufacture of glatiramer will clearly be a

20 distinct chemical entity. They cannot match

21 it and should be given a distinct non-

22 proprietary name.


1 And more broadly, I fully expect

2 that there will be additional peptide

3 therapeutic drug candidates that will be

4 reviewed by the Agency in years to come and

5 that are manufactured using alternate

6 technologies that generate heterogeneous

7 mixtures or that include distinct chemical

8 features that will require that they be

9 classified as biologics.

10 I thank you very much for your

11 time and attention and I'll welcome questions.


13 comments. Are there any questions from the

14 panel? No. Thank you.

15 DR. LEHRMAN: Thank you.

16 DR. BEHRMAN: The next presenter

17 is Eric Katz from Katz and Company and again,

18 please limit your remarks to five minutes.

19 Thank you.

20 MR. KATZ: Thank you. Good

21 afternoon. My name is Eric Katz and I'm here

22 on behalf of decision.org which is the


1 American Center for Patient Decision Marking,

2 a nonprofit group that helps connect to the

3 health care they need.

4 I'm attending today with just one

5 brief comment, I hope brief, on the issue of

6 accepting non-U.S. data in regulating and

7 approving biosimilars.

8 I'll start out by saying that this

9 is part of a larger context that includes

10 patients in this because just a very small

11 degree of variation in the amount of data that

12 you might take from a non-U.S. source product

13 or a non-U.S. based clinical trial could have

14 an amazing difference in terms of the cost of

15 development, the speed of development and then

16 ultimately even the number of products that

17 patients might be able to access.

18 I know this goes into the context

19 of a larger discussion of international

20 harmonization. I myself was the delegate of

21 the Surgeon General back to the first pair of

22 ICH conferences back in the dinosaur age and


1 I think that one of the lessons from those

2 early chapters was that different kinds of

3 international drug regulation can stem from

4 different kinds of international policy

5 concerns and so, you don't need to take a one

6 size fits all kind of model to the question of

7 whether data from other nations would be fully

8 accepted, fully rejected or something in

9 between.

10 I will fast forward here to three

11 specific points in that then. I know it's the

12 end of the day.

13 The first is that non-U.S. data

14 whether from a clinical trial or in vitro

15 studies or even in the inspection of

16 manufacturing plants when it comes from a non-

17 U.S. source innovator product should and must

18 be acceptable essentially when these come from

19 states in the ICH space.

20 Exceptions to that ought to be

21 rare and keep in mind that it's the patients

22 who are paying with their cost in copays and


1 with the unavailability of more cost-effective

2 products.

3 The second piece, this same sort

4 of faith in credit in the clinical trials

5 should be given to the other aspects of the

6 submission whether it be, as I said, the

7 inspection of the manufacturing facility or

8 the animal testing or the other aspects that

9 lead into the dossier, the approval and even

10 into the post-marketing surveillance.

11 The third point is that in this

12 area vague guidelines could cause a lot of

13 damage. So, that as clear as you folks can be

14 as early on in the process will have an impact

15 on whether or not companies keep or drop

16 opportunities and the kind of patient

17 availability that there might be a few years

18 down the road.

19 In sort of looking at the signals

20 that might be coming out of the agency

21 recently in looking, for example, at a

22 citizen's petition on Lovenox, we see that


1 there are very clear guidelines on what needs

2 to be met or doesn't need to be met in the

3 small molecule area that might be applicable

4 in a large molecule area including the extent

5 to which the data will need to be reproduced

6 or whether it can be sort of incorporated by

7 reference in a U.S. FDA submission.

8 It's the end of the day. I'll

9 just close by saying that there's such a large

10 pipeline out there. There are patients who

11 are hurting under just the copays alone and

12 under the lack of availability of treatment

13 options and we're hoping that you'll keep in

14 mind that the patient has an equal place at

15 the table here along with the regulators, the

16 scientists and the industry.

17 Thank you.


19 comments. Are there any questions from the

20 panel?

21 Okay. Before we conclude I wanted

22 to ask the panel if there are any speakers


1 they would like to recall and, in fact, I

2 already have a note.

3 Could the three speakers from the

4 last panel please either come up one by one or

5 come up together and Ms. Esposito has two

6 questions for each of you.

7 MS. ESPOSITO: And just to clarify

8 so it helps you determine whether you all want

9 to stand up, I thought since we had all three

10 organizations from a bio and GPA here today,

11 I'd like to ask two questions of each of you.

12 One is with respect to guidance

13 documents that the Agency might issue, do you

14 have any input regarding priorities and what

15 would be most useful to your member companies?

16 And then the second is whether you

17 have any input on biosimilar user fees and if

18 you do, to share at a high level what you

19 think about levels and structure of user fees

20 for biosimilars.

21 DR. VODICKA: So, on the first

22 question about guidances, we think that it


1 would be helpful for the Agency to issue an

2 overall guidance that kind of lays out the

3 structure of the pathway and kind of what's

4 expected generally.

5 You could follow the model in

6 Europe. You don't have to follow it exactly,

7 but that's one model that seemed to be pretty

8 successful. They had an overview general

9 guidance and then more specific guidances on

10 CMC and pre-clinical and clinical and then

11 finally product class specific guidances.

12 You know, notwithstanding -- not

13 letting the lack of guidance get in the way of

14 approval, at the same time, a lack of clarity

15 that may be provided and that may exist in the

16 absence of guidance may be just as stifling

17 as, you know, waiting for guidance to come out

18 to clarify.

19 With regard to user's fees, that's

20 something that our members are still

21 discussing and I'm not prepared to talk about

22 today, but we will address it in our docket


1 comments.

2 DR. ROJKJAER: Yes, generally on

3 the first question, we are I guess against

4 those from two points of view. We feel that

5 each of the product's applicants should be

6 looked at on a case-by-case basis. That there

7 are so many differences between these products

8 that those kinds of ready-made guidances kind

9 of hold some development back in terms of time

10 and also effort.

11 On the user fee, I touched upon

12 that a little bit. It's in our paper and a

13 more expanded version of that will be in the

14 docket at the end of the year for you all.

15 Your review.

16 MS. RADCLIFFE: In terms of

17 guidance, our members are not really to

18 provide conclusions about specific topics that

19 would be helpful to address first. I agree

20 with what Marie Vodicka has said about

21 starting out by providing broader guidance and

22 then moving on to specific product areas as


1 was done in the European Union.

2 I would say we recognize that

3 there is no requirement for guidance prior to

4 approval of biosimilars and that requests for

5 guidance should not be used to obstruct the

6 approval of biosimilars.

7 That being said, we think there

8 are many reasons why issuing guidance would be

9 very helpful. It will improve the

10 transparency of the process. It will allow

11 our members innovative companies to provide

12 their input on the standard that would be

13 necessary in specific product areas as well as

14 the general public and we think that will, in

15 fact, facilitate the entrance of biosimilar

16 products to the market.

17 With respect to users fees, in

18 addition to the two points I made in my

19 presentation regarding the fact that

20 biosimilar user fees -- biosimilar workload

21 should not negatively affect the review of new

22 products and that we think user fees should be


1 directed toward post-market safety evaluation

2 as they are for PDUFA products.

3 We will also make some more

4 extensive comments in our written submission

5 to the docket about the best ways for a user

6 fee program to function including technical

7 discussions with regulated industry including

8 a regular sunset so that the characteristics

9 of the program can be revisited and so forth.

10 But, we'll be laying that out in

11 more detail in our written submission.

12 DR. BEHRMAN: Are there any other

13 speakers? Okay.

14 On behalf of the FDA panel, I

15 would like to thank the speakers for their

16 presentations and all in the audience whether

17 in person or by webcast for your attention to

18 the issues discussed today in the meeting.

19 I would also like to thank the

20 staff in the CDER's Office of Medical Policy

21 for supporting the meeting and in particular

22 Sandy Benton for a really superb and flawless


1 organization of this meeting.

2 The public hearing was extremely

3 productive and informative. We will carefully

4 consider all comments both from the hearing

5 and from the docket as we move forward in our

6 implementation of the BPCI Act.

7 Please remember the docket will

8 stay open until December 31st and we strongly

9 encourage all interested parties to submit

10 comments.

11 As I mentioned, we take these very

12 seriously. This will not be obviously your

13 last opportunity to present your views to the

14 agency, but it is a particularly critical time

15 period. So, please take advantage of that and

16 please see the Federal Register notice for

17 details.

18 Today's meeting is concluded.

19 Thank you for your participation.

20 (Whereupon, the hearing was

21 concluded at 3:42 p.m.)

22



AAB 285:13abbreviated 7:1

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abbreviation 351:7351:10

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26:22 27:3 61:13

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7:7 8:6 34:1536:5 75:1,6 77:1230:7 251:16,21275:16 276:11,18285:22 293:14294:18 295:16302:13 308:4309:10 328:11329:8,22 374:6

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145:4 244:20added 161:13

331:10adding 314:5addition 141:6

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252:14 277:17278:8,13,19285:21 286:2318:17 322:20364:2

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additions 177:20address 12:18

25:21 88:4,1898:6 105:5 124:17131:1,2 144:8150:14 159:20160:2,4 166:4183:18 190:6193:14 198:1202:20 206:16219:16 255:22262:20 301:4317:18 340:2,11342:1 343:11344:12 353:9354:15 370:22371:19

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affordable 6:19140:22 165:4173:19 275:16329:1

afraid 328:6Africa 221:8afternoon 6:5

217:4 274:22317:4 328:7339:13 340:3360:1 364:21

age 365:22agencies 69:9 78:20

110:10 335:22agency 27:10 29:2

35:18 36:15 37:143:6 45:19 122:15135:19 141:7,20142:3 147:13148:4 152:14183:20 190:7220:7 223:10,11223:20 227:4228:13 241:21243:2 244:22247:11 248:1,7249:14,22 252:4252:18 258:16265:20 270:3

276:9 287:20294:10,18 296:19297:5,11 299:9,18300:5 319:8338:10 346:4,8349:21 351:20357:14 360:17364:4 367:20369:13 370:1374:14

Agency's 6:17 7:8,98:1 35:11 36:4201:1 330:10334:16 349:1

agenda 9:13,13,1610:20 12:4 288:2288:2

agent 130:12 363:8aggregates 161:5aggregation 270:15aggressive 70:9ago 329:21agree 43:6 96:3

205:17 240:21291:9 315:17371:19

agreed 242:2249:13

ahead 213:18 316:7aim 179:6 332:22airing 209:13al 34:4alfa 68:4 231:8align 142:12aligned 192:13allergic 170:19allocated 316:9allot 11:13allotted 10:21 11:2

12:6 296:12 301:3317:18

allow 21:8 30:1635:18 36:5 37:151:18 52:9 55:1797:15 113:1116:16 132:16140:9 144:13

148:20 149:14165:19 173:10,15294:18 295:20303:6 317:13345:14 356:12372:10

allowance 114:11allowed 10:1 62:22

116:19 131:17179:21 240:18309:8

allowing 15:13130:19 321:16330:10

allows 10:3 55:20145:16 188:11190:17 294:21295:16

alluded 24:10123:15 275:19

ally 142:7Alongside 201:1alpha 220:16 293:9alpha-1,3-galact...

34:2 170:5alter 179:2alterations 184:20

185:12altering 35:1 246:3

362:21alternate 364:5alternated 342:12alternating 54:18

63:1 190:8 191:14192:12 249:19300:7 343:3

alternative 132:3137:22

alternatives 356:18356:22

alters 107:14amazing 69:18

365:14amendment 232:12amends 6:21America 68:3

218:13 317:8

American 315:2329:18 330:7365:1

Amgen 3:23 199:1199:10,17 201:18203:3 204:14210:7 352:12

amino 71:20 242:4320:21 327:5348:1 361:11,20362:4,8,11,12

amount 15:11 27:538:22 296:11351:10 365:11

analog 292:19294:14

analogous 40:4265:19 291:4,12

analogs 295:1analyses 118:14

172:18analysis 59:22

60:11,13,19 112:1112:6 117:14342:16

analytic 13:2analytical 32:5,21

33:17 36:13 39:1844:7 48:5,2170:18 90:13 92:293:1,22 96:14,1897:14,15 99:2101:5 112:4 160:7160:20,21 161:3161:11 163:18,19164:2 169:7172:17 203:10,20241:1 245:16260:2 297:6299:13 320:16332:14,16 333:7340:14,19 341:19351:13 360:10

analytically 203:13305:10 313:14

analytics 90:18110:16 112:21


313:16analyze 331:13analyzed 117:11,19anaphylactic

188:15 192:3195:20 198:7

anaphylaxis 189:18196:8

ancillary 65:9ANDA 279:14,15ANDAs 277:8and/or 38:3 42:7

279:5 298:15300:19

animal 34:21 48:2273:1,3,15 74:2141:5 145:5,10171:15 172:2173:12 243:19244:3,7,13 299:10306:2 308:1,22332:21 367:8

animals 85:5 145:4274:10

ankylosing 88:22annex 219:22announcements

5:15Anshuman 2:4 3:9

66:20 67:1answer 43:10 101:8

122:21 131:2173:20 210:14232:7 233:18337:19

answered 289:16answering 163:19answers 15:22

317:21anti 287:21antibodies 14:22

15:3 18:10 29:1029:13 107:22108:1 124:22125:19 128:16137:3 188:15189:12 192:2

195:17 220:19222:5 223:4

antibody 56:161:20 83:4 107:1108:2 170:20194:13 195:22229:9 260:16263:9 270:21274:1 283:3,12,20284:5,16,20298:14

anticipate 99:10109:21 177:12245:2 297:19

anticipates 62:7anticipating 208:12antigenic 170:9

192:5Antigens 34:2anti-evergreen

277:12anti-TNF 89:4anybody 360:22Anytime 331:8anyway 328:7

347:20apart 30:2,3,5apex 175:16API 104:9 106:2,9

164:1 360:11apoptosis 125:10apparently 134:19

341:20appear 40:19 275:2appearing 248:19appended 340:3applicable 22:21

90:9 368:3applicant 341:7

344:20 345:11,12346:9 351:12352:18

applicants 277:3,6335:16 350:10371:5

application 35:6143:21 163:21

187:15 240:18249:15 277:7280:14,22 281:14295:21 298:8320:6 335:20346:12 348:18351:9 352:19353:6,13 358:1,4358:10 359:6,13359:15

applications 35:1490:7 221:17226:13 278:6,21295:12 344:19345:6 348:22

applied 13:1633:20 41:15 46:889:18 133:5 144:1144:2 161:18332:8

applies 50:10 90:7230:8 347:9

apply 9:20 32:844:7 50:6 54:266:3 87:4 89:1289:13 134:12185:22 186:1196:17 227:15232:10 324:12327:7 347:2

applying 33:16appoint 282:16appreciate 109:2

166:2 315:1360:13

appreciates 293:10approach 33:4 40:1

45:1 49:21 71:491:7 94:12,2195:6,13 96:13101:6 107:8 110:2136:7 142:17143:7 164:22175:12 178:20180:21 181:10219:5 240:15,22241:3,14 247:15

250:2 256:12258:15 262:13265:19 267:20273:11 294:12,13330:21 331:19332:7 333:20337:5 339:3355:17,22

approaches 35:635:15 147:8,14299:3,6 363:18

appropriate 20:425:7 34:19 37:739:20 51:14 107:5145:6,13 146:6,17147:6,12,17,19148:2,12 153:7154:2,5,8 167:3179:21 181:19185:14 221:22235:6 242:22244:14 248:8254:7 255:7263:14 264:17297:6 332:21336:13

appropriately13:17 27:21 41:14144:21 232:5250:14 254:20337:8 342:7

approval 1:6 5:77:1 23:4 35:2036:2,9,17 39:1350:13 52:22 65:2068:8 70:1 71:272:2,7 75:9 76:2277:12 82:6 90:199:8 109:3 113:20116:13,17 117:10118:17 123:19127:5 130:21133:17,21,22143:12 145:1149:17 156:22162:7,9 165:14166:19 183:5

186:4 188:19193:5,13 204:6208:11,13,21209:8 217:16249:10 262:18279:14 295:4,20318:7 321:16323:10,16 329:16335:21 341:7347:2 348:18359:13,14 367:9370:14 372:4,6

approvals 21:1622:20 66:12311:10

approve 23:14 87:6132:18,20 165:21208:20 260:15322:10 339:19350:18 357:11

approved 21:2122:3 23:2,5 24:1,724:12,19,20 46:2248:16 49:15 65:1766:8 74:11 111:5114:7,14 129:1134:5,19 135:1139:9,20 152:10161:8 162:12,18186:10 193:6207:3 208:14210:10,11 223:14235:10 241:10256:4,9,18 259:6268:18 269:17283:4,13,21 284:8310:7 314:11325:11 327:1332:1 342:21348:9 357:12

approving 149:7314:14 329:14365:7

approximately10:17 172:11256:7

Arabia 221:9


arbiter 49:9arbitrary 57:19

147:22 165:12area 18:11 28:4,19

101:2 162:14179:11 219:12236:18 253:6261:6 306:11329:5 367:12368:3,4

areas 18:12 102:9140:20 183:12193:21 258:21301:2,4 371:22372:13

arena 267:16,17arguably 42:6argue 176:19argued 175:13arguing 41:18argument 291:6arguments 48:19arisen 24:22

134:22arm 70:3 78:13

81:8 106:20arms 57:18 58:10

65:3arose 219:15arrangements

227:10arrive 18:17arrow 93:17art 333:7arthritis 59:1

129:19 138:7Arthur 2:10 3:22

182:6,14Article 232:12articles 79:17

227:20articulated 39:9

266:17Asia 68:2 210:10aside 195:21asides 153:2asked 12:19 14:2

60:4 73:1 74:1079:8 134:16139:12 174:20210:4 214:4296:17 301:1309:18

asking 276:2,15asks 71:10aspect 96:22

176:10 272:19aspects 22:13 89:8

124:17 156:4189:15 195:16,21296:13 367:5,8

aspiring 180:16assay 83:4,6,10,13

83:15 164:18assays 75:13

125:17 145:22240:6 243:4 306:1

assert 17:9assess 38:2 94:22

166:20,22 195:22198:10 246:16272:14 297:7

assessed 129:12146:18 147:18148:13 153:10189:16 193:10305:11 341:18

assessment 55:564:3 110:8 186:12189:9 198:14207:15 225:5231:11 240:22244:21 265:7321:12

assigned 95:17217:10

assigning 253:12assist 28:16 221:3assisted 239:8Associate 5:10 8:21

9:6,8 317:5associated 93:10,15

191:5,13 196:7213:21 226:21

229:6 249:5293:12 348:10,22

association 4:8,94:13 263:3 292:7301:16,20 328:4

associations 224:3Association's 328:9assume 63:7 93:10assumed 54:12

60:13assumes 45:3assuming 10:3 71:1

119:19assumption 229:14assumptions 53:13

343:13 356:16assurance 32:18

39:17 118:9345:11

assurances 149:5assure 122:15

181:1 231:22312:4 324:17

assured 207:8337:11 343:2

assuring 28:1637:5 226:2 232:21

attaching 347:19attendees 5:4,18attending 365:4attention 30:6

61:22 125:8 132:6229:4 266:3364:11 373:17

attorney 275:1attractive 238:1attribute 253:9attributed 226:3attributes 21:4

36:14 39:2 40:1145:18 72:1 90:2191:11 92:10,1594:14 96:18 97:1198:2,4 100:5,13102:6,11 111:18112:12,14 114:6184:12,17 240:2

242:21 243:5246:1 253:8,16,18254:9 303:22331:17 332:11

attribution 19:7,18204:22 207:4

AUC 160:21audience 373:16audio 5:17Australia 302:12

316:6authorities 96:3

147:4 186:15221:4 230:14

authority 226:7229:19 230:6271:9 336:16

authorization124:8 191:2221:17

authorized 247:4authorizes 322:18automatic 76:8

124:11availability 168:8

336:4 337:1,5367:17 368:12

available 8:3 10:443:3 58:15 105:2105:14 142:9154:22 203:21216:15 223:21248:10 262:8355:8 357:7,17

Avenue 1:14avert 356:15avoid 26:6 27:1

206:19 343:13avoidable 13:22avoided 19:20 27:6

27:7 34:22 130:3avoids 165:12award 198:17aware 24:5,21

88:20 210:18213:8 216:7 236:7236:8 268:17

314:12 331:15338:21 344:2362:2

awareness 121:14121:15

A's 283:9A-F-T-E-R-N-O-...

217:1a.m 1:12 5:2,20

108:16,18A1 241:17A3 71:10A4 73:1 246:17

BB 30:9,10,14 58:7,8

87:11 128:12,15135:18 271:14282:12 284:4,6,13285:3,5,11 293:7

Babbit 4:4 255:10255:19

BABBITT 2:14255:12 266:22268:10 269:18271:11 272:8273:12

back 6:7 11:1054:18 56:11 77:11117:7 122:13138:22 198:3216:9,18,19 217:3236:15 251:3254:10 339:5349:15 365:21,22371:9

background 192:1237:5

backyard 69:16bacteria 171:14bad 29:12Bakin 2:15 4:6

274:21 275:3,17289:10

balance 43:2 108:4119:14 258:9325:22 345:20


balancing 350:6banks 91:19bar 47:18 51:10

119:2,8,9 135:3198:2

barrier 74:18286:1 337:3

bars 135:20base 61:15 90:15

101:5 162:5175:15,21 181:4

based 26:1 39:1649:7,10,19 69:1070:2 71:3 75:1175:16 83:20 87:790:13 96:18 99:15106:9 110:18113:22 114:14116:9 123:20127:5 141:14143:14 149:8,21154:22 155:11157:19 158:17159:16 161:16165:15,16 186:19247:8 253:21256:6,10 274:15305:11,12 307:7333:15 357:11363:9 365:13

baseline 162:1,3basic 229:13basically 62:14

63:9 77:20 78:979:13 106:18124:16,19 128:15135:10 137:1,3231:22 253:2275:19 278:12279:3 285:15290:4

basis 16:2 23:1535:21 37:3 44:448:2 70:1 72:1197:22 111:6127:14 134:5140:2 141:15,22

142:18 146:18147:21 150:2153:10 154:10177:11 248:8258:7 259:4266:14 268:9297:13 303:2,3,5303:6,7,9,10306:13 332:1338:16 371:6

batch 104:3 111:16313:18,18,20

batches 105:11304:11

batch-to 111:15batch-to-batch

93:3,8,13 101:14304:13

battery 243:4Bayesian 64:6bear 69:3 344:22becoming 311:1began 219:13beginning 5:21

72:6 220:15 222:2320:1

begun 222:8behalf 108:22

182:20 239:1255:12 355:10364:22 373:14

behave 341:14behaves 178:14behavior 171:13

244:12Behrman 1:14,18

3:2 4:22 5:3,109:12 21:11 25:229:18 31:16,2043:11 47:1 51:2052:12,15 62:1,663:4 64:13 66:1666:19 77:8 79:1881:16 82:2,8,1182:14,20 85:987:14 98:11 99:22102:17 104:5

106:14 108:12,19117:2 120:20121:20 122:12,22123:6 132:7133:19 136:10138:21 140:11150:4 151:15153:2,11 155:3166:6 167:17,20173:22 175:10178:18 180:2,18182:4,10 194:1196:19 197:7,13197:20 198:16,22199:5 208:1 210:2210:22 212:5213:18 214:15215:7 216:10217:3 228:3229:17,21 231:17233:2 236:14237:16 238:11,17250:20 252:6,21254:10 255:2,8266:4 271:6274:17 287:9290:10 292:2,5301:9,14 309:13311:17 312:21315:6 316:14317:1 327:20337:20 339:6,11349:11 350:13355:18 357:2359:16 364:12,16368:18 373:12

Behrman's 234:9belabor 225:8believe 13:4 14:5

20:22 27:14 28:1432:20 33:7,1339:8 51:22 52:471:14 72:2 73:673:22 110:6 112:3113:2,9 116:11117:20,21,22119:7 121:10,13

138:3 141:7,19142:16 148:16174:13 178:10183:12 186:22193:19 196:2199:17 201:5212:15 214:17218:5 222:6224:11 229:11231:10 232:2259:3 264:22271:8 285:20286:2 299:21303:1 306:10307:4 342:9 345:7346:17 349:21350:2 360:2

belongs 32:4benchmark 169:7beneficial 211:19

213:12,16 250:8306:21

benefit 21:6 34:1136:4 41:16 48:658:17 61:4 71:580:18,21 81:6125:21 126:15,20128:18 138:12,14138:14,18 140:3,7140:7 175:4,5213:13 267:18286:9 288:15

benefits 34:1668:22 70:21 75:576:10 81:13121:19 137:11140:21 141:2223:20 286:6288:4 290:17344:21

benefitting 42:5benefit/risk 184:21

186:6Benton 11:10

373:22Bernard 2:17 4:6

274:21 275:1

Bernie 275:18,19281:4

best 69:15 201:19205:1 215:15373:5

better 29:12,1377:14 232:20269:10,11 286:16354:16,20

betters 287:1beverages 6:12beyond 28:11

33:10 50:14 85:398:1 113:3 150:17191:2 322:7 323:9

big 195:1 224:22225:5 273:1288:16 352:8

bigger 66:11biggest 328:14billion 328:19

329:10 334:20billions 69:20binding 28:3 246:8

345:10bio 32:4 286:22

339:12,17,18348:17 352:15355:7 369:10

bioactivity 85:3171:12

bioanalytical 86:8245:9

bioassays 85:1306:1

biocharacterizati...48:5,22

biochemical 63:884:5 143:8 147:1170:10 215:19

biochemistry 169:7172:18

biodistribution184:18

bioequivalence113:8

bioequivalency


147:5,12bioequivalents

49:19biogeneric 329:17

332:12 333:5,6,17334:4 335:2,16337:2,10 339:4

biogenerics 330:1,7332:8 333:3 334:3334:9 336:5,20337:4,6

biogenetics 156:16biologic 33:15

34:20 39:10 54:354:10 57:11 89:490:17 97:15109:11 124:20169:16 183:16184:3,12 185:5189:8 190:10,12191:17 193:4199:22 239:10,15239:21 256:17258:5 259:8 277:6288:4,18 319:21320:5 321:1322:14 323:11324:20 325:4,7329:5,15 331:8,16332:6 343:16363:8

biological 1:7 5:86:19 7:2,4,18,198:8 38:11,12 53:153:8 141:11 149:8183:21 190:17200:14 201:7202:12 205:5,12240:4,5 242:12,18246:6 257:11,19258:17 260:22265:6,15,21 267:8273:16 277:3279:21 295:8326:17 340:10348:3 360:15361:4

biologicals 201:3biologics 9:6,9

16:13 29:7 32:2233:1 34:5,18 36:838:19 40:19 67:1168:1 73:8 76:4,876:18 77:3 88:789:13 97:16 109:6110:3,9 111:15156:16 168:6,12168:15 169:10177:5,7 183:3,9184:6 185:4,16186:1 191:4193:16,17 203:3221:6 230:8232:11 256:4259:6,13 278:22279:12,19,20293:13,16 302:8,9307:6 322:7,10323:14 324:7327:13 328:10,13329:7,11 330:13332:18 340:21348:9 349:2 352:8361:2,19 364:9

biologist 199:9317:8

biology 199:12202:4

biomarker 85:4127:16 128:3,9,13

biomarkers 125:16127:10,19

Biomembers 345:7biopharmaceutical

217:13 239:6255:14

Biopharmacokin...155:15

biophysical 114:22bioreactors 170:3biosimilar 1:6 5:7

7:2,17 8:7 13:5,915:2 17:21,2220:13 30:9 31:9

32:11 33:2 37:1938:3 39:13 40:3,843:16 44:9 45:2046:16,21 47:14,2152:22 53:7,10,1858:7,12,16 60:1560:16 71:18 72:1272:15,16,19 73:1774:18 76:22 84:1084:16,20 85:2186:15 89:9 90:692:15 93:19,2194:3 95:18,2299:4,10,11 101:3101:4 104:10,18104:22 105:18108:5 109:22111:10 112:13,15113:5,10 114:9,17114:19 115:13116:14 118:3,10119:22 124:21129:11 130:20131:10 132:1,5,20134:2,3 139:9,11139:15,19 140:22142:19 143:12,15143:17 144:2,14152:3,7,10,19,21156:15 158:15,21159:4,6,12,22160:5 161:1,12162:21 163:21165:21 168:4,11168:18 169:2,9,14170:12,14 172:20173:14 176:13179:19 181:15186:1,13,21 187:8187:11,15 188:17191:9,15 192:7193:6 196:18197:14 198:14201:5 202:9 204:4206:9 208:11,15210:5 214:18217:16 218:3,3

220:18 221:17225:1 231:21239:17 240:13,22241:9,22 242:3,8243:9 244:15245:4,20 246:3,12247:14,20 248:13248:18,20 249:2,6250:3,7,13 251:7251:10 252:2,9,15253:15,21 254:13255:21 256:7,13257:9 258:12259:4,21 260:9261:7 263:19,22264:10 266:14269:9 270:8 271:3271:17 273:14279:12 280:14297:2,8,16 298:2302:14 306:10311:10 312:8314:3 318:4319:11 320:4,8,10320:12,22 321:14322:12 323:19324:18,20 325:7325:10,14,16,18327:1 340:14341:6 342:20344:17,20 345:6345:21 348:18349:6 350:6,10351:9,12 357:11359:13 369:17372:15,20,20

biosimilarities 98:6155:22 198:11

biosimilarity 7:137:15 13:2 23:2244:1 54:4 60:1461:1 64:4,1665:11 66:14 88:199:12 100:7102:15 140:20153:17 156:2157:6 197:2,21

200:11 203:2208:15 242:16244:21 246:9252:3 257:5 258:8263:1 264:19265:1,8 268:22296:15 302:22303:16 315:22319:15,20 320:7330:11,18,22331:7 334:12335:17 340:12,13351:4 353:19354:2 355:14

biosimilars 8:199:10 17:14,2121:5,22 22:1623:5 24:7 27:1528:17 29:17 34:934:14 36:7 46:950:6 53:3 55:1155:13 56:1 61:1863:22 65:15 67:667:12,14,22 70:1971:2 73:11 74:1587:21 88:11,1589:13 92:14 97:1098:2 109:4,19,20110:3,9,12 111:2111:5,21 112:7116:4,8 123:18,19124:10 125:22126:18 127:5133:6,12 134:9,12134:19 135:1140:10,18 142:16144:12 148:21149:1 150:12,15156:7,7,9,17157:18,20 162:17163:12 165:1183:5,10 186:11189:5 193:20198:5 199:18,20206:10 207:19209:21 210:9217:20,22 218:18


235:8 236:10239:20 240:16243:8 250:15255:18 256:2,20262:2 264:6268:14 269:17294:3 302:3,11,16306:18 307:2309:4,19,22 310:7312:3 314:17318:8,14 319:5,9320:16 321:11322:8 324:13332:2 338:4,17339:20 342:18343:11 346:6363:10 365:7369:20 372:4,6

biosimilar's 58:15biosimilar-type

149:9biotech 3:18 143:6

155:6,9,20 360:7biotechnology 4:14

8:13 32:3 33:2240:15 41:10165:11 201:2317:12 339:16

biotherapeutic169:22 186:17

biotherapeutics168:7 171:11,14171:17 172:9

BIO's 356:8bio-better 269:8,20

271:4bio-betters 286:18bio-member 340:8bit 41:12 62:12

85:18 98:17153:19 157:3223:5 231:18274:9 278:3 357:9371:12

bites 42:10BLA 36:12 91:7

276:13 277:19

283:2,4,11,13,20283:21 284:7,7,14284:17,21 295:4344:16 345:22346:15 347:3,6,10347:12

blank 200:5BLAs 276:6blazing 329:16blinking 148:6bloc 68:3blockbuster 283:8blocks 291:6,7blood 56:5blue 77:22 79:14

233:22boat 280:5Bob 9:7body 185:17 201:4

202:15 207:18219:21 235:14282:17

bold 45:6 276:10277:22 280:9

bonds 362:5bone 154:1borne 229:13borrow 42:19Bosques 34:3bottom 285:9Boulder 239:7boundaries 281:18bounds 263:17box 79:14,21

152:22boxes 78:3 79:15

79:22BPCI 6:21 7:7 8:6

34:15 36:5 43:875:1,6 77:1228:14 294:18308:4 309:10374:6

BPCIA 228:1 320:4brand 40:13 68:18

78:21 82:17 87:13205:22 211:22

226:15 231:3,4331:8 337:10

branded 33:137:20 38:4 46:1047:15 81:2 83:16168:12 169:10,16198:4

breadth 256:17break 6:3,4,10

11:14 77:4 108:14316:16,17

breakthroughs203:4

breathe 142:19Brian 34:3bridging 114:18

313:5,8brief 317:17 360:3

365:5,5briefly 218:17

239:4 276:4356:15

bring 31:12 34:845:9 66:3 137:3140:1 159:2 288:3291:10,14 351:12351:19

bringing 169:20330:6

brings 278:17broad 12:17 35:18

75:2 109:5 276:15340:2

broaden 154:18broader 130:21

168:20 176:5371:21

broadest 169:4broadly 15:14

364:1brought 75:6 255:5

310:17Brown 2:6 3:16

140:13,15Bruce 2:14 4:4

255:10,19Bruhn 182:17

building 1:13240:22

built 176:17 267:10bulb 283:8bulk 172:11bullet 311:21 315:7

349:17burden 40:6 48:18

67:18 69:3 74:16231:21 330:11335:10

burdens 345:1burdensome 35:5

119:4 355:22buried 277:13Burling 3:25 217:6

217:9business 4:5 67:11

67:13 109:17182:21 238:8,10274:20 275:5,21276:8 285:6 287:6289:2

butcher 198:18butchering 301:16buy 304:14buying 304:10buys 284:13by-case 142:18B's 284:14,15B1 248:12B2 249:4

CC 1:21calculation 63:6call 91:21 205:5,7

278:10,22 279:2307:9

called 19:15 182:18221:5 236:10

calling 280:1Campus 1:13Canada 217:22

221:5 225:11302:12 335:22

cancelled 203:17

cancer 68:14candid 232:6candidate 134:2

363:17candidates 269:20

364:3capabilities 226:20capability 106:13

112:15capable 115:14

340:20capital 278:15capture 33:8

315:15captures 79:21carcinogenicity

146:13care 6:19 62:9 67:9

67:19 70:21 75:575:19,22 76:5,1177:5 79:2 89:2168:16 175:5199:19 205:2214:10 303:11329:2 334:13365:3

careful 25:14 191:3192:21 345:20350:5

carefully 43:4146:7 148:10161:15 185:6341:13 374:3

caregivers 212:3Carlos 34:3carries 303:22carry 214:20carryover 172:1carte 216:15cascade 143:10case 14:21 15:18

18:9 67:17,1968:16 70:14 73:874:5 75:8 109:15114:15 135:2140:6 142:17145:11 148:4


157:19 164:4177:14 229:8,9248:17 252:12260:15 263:4,8,21267:5 271:2313:14 336:8347:19 352:22361:20

cases 19:19 24:1626:20 55:15113:19 132:21147:13 148:1157:18 223:4260:13 268:3269:9 271:12306:3 308:15,20313:8 316:4338:13 341:7

case-by-case 35:2039:12 48:2 140:2146:18 147:21150:1 153:10,22154:10 177:10259:4 306:13338:15 371:6

category 235:16cause 77:2 207:9

316:13 367:12caused 300:13

324:5causing 38:11cautious 329:8

335:3CBER 8:21 299:4CBER's 9:10CBR 4:2 238:19

239:5CDER 8:13,15,18

8:18CDER's 373:20Cecil 255:11,20,22cell 16:12 91:18,19

110:15 128:12,15135:18 173:12188:15 195:19271:14 331:11

cells 34:1 130:9

170:2,7,14 171:15172:2 173:12,13201:10

cell-based 184:7cell-mediated

195:19Centennial 315:8center 5:4,11 9:9

293:15 365:1centers 183:13century 329:20certain 8:4 10:10

23:13 26:22 36:238:5 39:4 44:9,1247:13 49:18 145:5145:11 151:8153:15 241:5264:10 291:22299:10 300:21303:22 312:13347:3,12 357:11

certainly 14:1637:7 38:18 44:446:8 48:21 52:562:8 97:19 116:7118:6,8 120:13121:13 129:22137:17 179:13211:20 212:1,15233:11 252:12272:16 295:13353:11

certainty 319:1certification

160:21cetera 100:21CH 162:11chains 362:7,10Chair 8:18 9:10challenge 111:10

125:15 350:20355:5

challenged 311:10challenges 42:15

183:15 185:15191:5 192:1193:15 206:17

207:14 293:12310:5 311:11

challenging 102:11122:20 262:7324:8

chance 11:16 67:5233:21

chances 231:15change 14:11 30:18

30:19 31:9 40:643:22 58:20 60:562:22 90:19 93:494:5 101:9,10103:5 104:2110:14,18 111:18124:18 163:4,11179:3 203:12,18204:13 215:9,13215:18 254:15273:10 279:4,4289:8,13,14,18290:5,5 303:18332:7 348:4

changeability254:11

changed 103:20331:9,11 338:6

changes 14:8 15:816:12 18:15 19:1726:6 31:10 90:391:16 93:11,15100:16 102:22103:12 104:8,19105:12 106:9111:19 113:2149:11 219:17258:18 265:22279:7,20 289:13300:2 310:20331:14 333:13348:1

chapters 366:2characteristics

158:20 159:21161:1 188:21242:7 295:9297:22 298:16

300:3,12,22 358:7373:8

characterization32:7 63:15 84:590:13,17 93:194:1 96:15,1997:16 98:1 105:10158:18 159:17173:3 175:14176:1,9,19 179:22181:19 201:22257:20 258:5265:6 273:5305:22

characterizations189:21

characterize 26:833:14 45:3 189:10201:17 202:17243:4

characterized29:13 40:2 55:1456:2 172:4 174:9185:4 189:13362:16 363:12

characterizes360:18

characterizing33:4 144:12

charge 33:5Charles 2:6 3:17

140:12cheaper 127:11chemical 90:16

146:22 176:8177:17 180:16184:5 240:2 242:6242:11 257:19258:5 265:5,14298:13 308:19332:10 333:2363:20 364:7

chemically 360:18361:10 362:16363:12

chemical/bioche...144:19

chemotherapy95:16 130:20

Chief 7:11 9:6 32:142:20

chimpanzees145:13

Chinese 33:22170:1

CHMP 222:22,22224:12 227:7240:17

CHMP's 222:15CHO 170:14choice 188:7

337:10choices 286:11choose 215:11

230:9chooses 226:9chose 62:13 248:17chosen 71:8 231:13

296:12Chow 55:9Chow's 56:12chronic 59:10

146:12 293:2Chuck 144:9circulated 128:8circumstance

246:21circumstances 38:6

137:21 233:21246:18 263:13299:8,11 347:12358:3

CIS 68:3citizen's 367:22claim 20:9 263:21

269:15claimed 156:18claiming 93:18

295:10 310:6claims 315:13

320:10clarification 98:16

196:20 214:16clarifications


346:18clarify 83:3 167:2

174:3 234:3 306:3345:19 353:20360:17 369:7370:18

clarity 133:20288:3,7,13,19290:22 370:14

class 8:2 16:1,117:16 90:18206:18,18 245:7249:20 295:19296:1 323:20324:16 370:11

classes 26:15 29:1241:5 246:11250:12 300:2

classic 282:22classified 363:8

364:9class-by-class

209:18clause 253:3,5clauses 276:16

277:12clear 51:12 59:2

75:11 87:10 111:5116:9 131:21151:16 182:3189:13 194:22227:8 238:3 308:8325:2 346:7,11350:3 352:19367:13 368:1

clearance 147:16clearly 37:5 48:18

80:21 186:9206:12 253:8263:6 307:6 325:8351:6 361:5362:21 363:19

clients 53:4 61:4239:8,12

clin 147:2clinic 258:14 274:9clinical 13:15 14:3

14:4,5,9,13,17,2015:16 16:4,1617:2,5,17 25:1227:5 28:10 36:1136:16 37:4,8,1237:20 39:20 40:1342:1 43:5 47:4,547:15,18 49:1,1350:1 51:2 52:154:19 56:16,20,2257:2,15 61:7,9,1063:17 66:6 70:371:15 72:5,6 73:573:7,16,19 74:174:13,16 77:1478:21 81:20 85:1386:3,5,6,10,14,1988:3 89:16 91:591:10,13,13 94:1095:9 97:13 98:6111:4 112:9 113:7114:14 115:2116:9,12,20 117:9117:18 124:1,5,17125:14,21 126:2,4126:5,17 127:12127:17,21 128:11128:18 130:19,22131:9 132:14136:12,17 137:7137:11 138:12139:2 143:2,10144:9,9,16 148:3148:9 149:16153:14,20 155:15156:21 157:1159:15,18 160:3161:22 162:6163:20 164:3,7165:14 166:12175:18,21 176:15176:20,22 177:4178:11 180:13,22181:12,20 182:2183:22 186:12,20187:3,6,18,21188:8,12 189:1,4

190:2 191:10,19192:8 193:9200:10 202:6,19202:19 203:1,15204:7 207:16212:21 213:10215:12 229:15239:14 240:10241:2,11,19243:21 244:11,18245:2,5 246:4,14246:15,18,22247:1,10,13 248:1248:5,9 249:7250:5 252:14256:15,21 257:3,6258:6,10,21 259:7260:2 261:5,12,15261:21,22 263:9264:8,10 265:12265:15,17 266:21267:14 268:16269:13 272:22294:8 295:10298:20,21 303:4306:5 308:14309:1 313:2320:15 321:8,8,14321:17,17,22322:16 323:5331:18 333:11,14338:5,8,13,18,22341:3,5,18,20342:5,19 343:15350:16 352:5,20352:21 357:17358:22 359:7365:13 366:14367:4 370:10

clinically 14:716:20 25:20 26:1747:20 53:20 58:1171:12 72:21118:18 119:3139:7 157:12178:2 298:17341:1 363:13

clinically-driven363:14

clinically-validat...131:21

clinician 103:21close 21:22 30:6

70:5 182:7,9214:10 263:3269:7 304:5,21305:3,4,4,5306:21 310:17328:6 362:17368:9

closely 9:17 11:20201:16 202:10304:3

closer 268:7closest 179:8closing 4:21 139:10

250:11clotting 293:7

300:15CMC 113:3 114:21

131:3 359:1,6370:10

code 65:7codes 121:16 344:3

344:9 356:19collaboration 97:1

286:19 291:16306:21

colleague 135:11144:7 255:20275:2

colleagues 182:13collect 162:10collected 209:8collection 15:15

188:12 353:3collective 48:20

49:8 285:12,13collectively 292:21

329:19collectives 292:15Collins 34:3Colorado 239:7combination 76:15

130:13 226:14264:12

come 23:4 46:460:1 62:17,1979:4 86:17 155:8162:11 252:18267:4 334:12364:4 366:18369:4,5 370:17

comes 119:10267:1 283:18285:12 304:9306:14,22 307:1313:20 366:16

comfort 102:14comfortable 49:4

138:16coming 56:1

152:15,22 286:10291:7 307:9,14308:10 313:12,19367:20

comment 11:7,1611:18 28:1 43:2052:21 65:13 85:14100:2 105:9 109:3121:9 139:13,15153:18 168:3177:7 217:18222:13,17 233:7234:2 237:21250:12 269:12272:15 292:10311:6 318:1 345:6355:3 357:5359:19 365:5

commentary 22:9commenter 359:19comments 4:17

11:6,19 18:2020:1 21:12 27:2029:20 31:17 43:743:12 47:3,1152:13 57:9 62:266:17 77:9 85:1187:15 98:12108:13 117:3


123:1 132:8140:12 150:5155:4 156:3 166:4166:7 167:18174:1 182:5 194:2208:6 216:11224:7,8 228:4,8234:3 238:12250:21 255:9266:5 274:18287:10,13 290:18292:3 293:22301:2,5,10,12309:14 316:15317:18 327:21328:1 337:21339:9 340:6349:12,14 356:6357:5 359:17,21361:5 364:13368:19 371:1373:4 374:4,10

commercial 247:4commercialization

87:21 94:8 109:19commercialize

116:8 286:18commercialized

40:16Commissioner 9:4commitment 152:1

152:5commitments

324:13Committee 8:19

9:11 220:7 360:14363:4

committees 206:9common 54:19

71:4 114:2,17142:1 148:18149:18 220:11282:4 287:18311:1

commonly 282:1communicate

28:14 152:9

communicated103:20

compact 55:21companies 29:17

36:9 40:15,1841:11 87:19 132:5185:6 224:22286:17,20,21287:3 288:5,5,9291:16 294:4302:7 310:10314:18 316:6317:12 319:19328:16 340:8357:10 360:7367:15 369:15372:11

company 3:12 4:1927:18 30:4 32:383:16 109:1 177:3182:18 226:14277:17 278:20283:2,9,11,18,19284:4,6,13,13,14284:15,15,17285:2,3,4,5,10,11285:13 288:16,17288:18 302:4328:14 348:12352:2 355:1,11357:15 364:17

company's 103:2comparability 30:7

30:8,16 37:1638:20 39:10,15,1839:22 43:16 47:1051:19 56:19,2257:2,5 61:7 90:493:19 96:19 97:997:20 100:18104:15 110:19111:9 112:18113:3 114:21115:3 137:5 142:8143:4 144:19147:20 149:3,8,21156:6 158:4

159:15 160:14161:20 163:22166:10 185:13,18185:21 219:14,17239:14 258:16260:3 265:20303:17 308:12313:22 331:13,16331:20,21 332:4332:16 333:1

comparable 30:1130:12 46:21 92:192:7,11 145:16156:10 161:17164:6 165:15187:7 188:3 254:6259:20

comparably 246:13comparative 82:11

135:21 186:12187:4 189:4229:15 241:2242:19 244:10,15244:17 245:11,17247:7,17 248:8250:5 257:2 265:7308:22 320:1321:8 341:2

comparator 113:18115:7 272:10358:17

comparators268:21

compare 57:760:15 63:10 95:1996:16 104:11105:22 158:3196:11 202:8332:10,20

compared 19:254:9 106:10 130:1157:21 163:1172:12 173:1198:14 348:5

comparing 113:10comparison 40:2,5

60:14 83:15 89:21

105:15 123:21135:16 143:14153:17 167:3175:18 176:20,22187:9 197:2,9243:14 244:20308:19 340:14,16359:2

comparisons 60:20127:19 148:12243:21 244:9313:4

compatible 88:12compelling 168:17competence 128:22

139:4competing 88:11competition 6:20

68:22 69:11 74:2276:7 77:2 210:5293:14 318:17326:1 328:10329:7,10 334:18

competition-frie...71:3

competitively337:6

complement125:10

complete 25:1258:20 93:18

completely 14:1188:12

complex 15:21 32:941:6 68:1 97:16115:17 124:13125:1 131:5156:19 157:22184:8 185:7 193:4202:11,12 203:5223:6 245:14253:12 257:1265:3 285:6 295:7329:14 348:19352:7

complexities 276:7327:13,14

complexity 26:933:8 112:20142:19 168:5177:18,22 184:4189:22 201:3209:1 256:16265:18 282:20

compliance 75:16complicate 161:7complicated 29:6

286:13 352:2complying 345:2component 146:10

289:22 362:8components 53:21

148:14 157:12348:3

composition160:16 362:22

compound 55:2,557:11 58:1,4,1258:19 59:16 61:1365:12 148:14160:22

compounds 45:10145:11 163:6237:22 339:4

comprehensive40:10 41:22160:14

conceivable 151:5conceive 15:13concentration

164:13concept 38:15

41:19 45:16 50:950:9 84:20 123:20222:9 239:20258:2 315:21

concepts 239:19281:22

conceptually 285:9358:9

concern 41:20 42:4123:16 163:14,14263:7

concerned 62:9


181:10 224:22341:21

concerning 6:14125:22 246:17

concerns 22:1,224:9 65:14 117:13129:9,12 134:22134:22 163:10207:14 289:6290:1 356:7 366:5

conclude 41:776:20 165:10207:21 260:3368:21

concluded 374:18374:21

conclusion 11:841:22 42:18 116:6149:1 227:16264:5 327:11

conclusions 371:18concombinant 18:7concomitant

128:21 130:18344:22

concrete 250:4concur 123:16

241:13 247:15concurrent 241:15concurrently 241:7condition 72:2conditions 235:18

293:3,6 362:12conduct 37:18

119:5 191:10204:18 332:19

conducted 42:148:9 55:19 75:15136:9 144:17155:1 187:18305:13

conducting 42:5145:12

conducts 177:4conference 5:4 6:8conferences 365:22confidence 59:20

80:3,6,6 96:4106:13 131:17224:17 334:15342:16

confidential 346:1346:14 358:20

confirm 135:13162:13 264:18

confirmation265:11

confirmed 220:3333:8

conflict 182:19confused 64:17confuses 278:3confusing 233:21

277:11 289:12356:2

confusion 206:19233:4 316:13

Congress 227:3318:13 322:5325:22 350:4

conjunction 49:1450:12

connect 213:9365:2

connected 126:10231:16

connection 217:14consensus 322:15consequence 243:9consequently 114:1

237:4conserved 321:4consider 37:1 91:8

135:19 156:1,3157:9 160:7163:13,17 164:20183:20 190:7200:21 220:18227:2 228:13231:20 241:18,21243:7 244:22246:20 247:12248:1,7 249:17258:8 261:19

265:4 268:6 276:9294:9 296:19297:5,11 299:9,18300:6 319:13321:21 322:20323:11 361:19374:4

considerable 38:22considerably 36:20consideration 25:7

25:14 31:5 101:22102:2 126:11183:15 187:2190:14 191:20192:22 225:20236:16 239:19294:3

considerations39:16 72:11172:17 207:1240:19 241:19

considered 17:1322:10 39:5 73:274:12 128:4 137:9147:8,17 148:19157:7 164:8173:14 187:16188:10 207:2227:13 235:5252:11 260:17262:3 267:9275:13 299:5

considering 222:5226:17 322:22

consist 343:22consisted 77:15consistency 89:18

319:4consistent 70:10

84:20 110:4,6144:22 147:3287:21 298:4,7306:9

consistently 45:18constituents 116:1constitute 112:6constitutes 363:1

constraints 330:15constructing 350:4consultant 360:5consulting 4:4,18

190:19 239:6255:13 359:20

consumers 328:22contact 214:11,11contain 362:6contained 346:3,15

357:22 359:5container 204:16containment 165:2contaminates

174:8 300:19contamination

172:2contend 298:5content 298:14CONTENTS 3:1

4:1context 37:11 47:6

185:15 191:1,22346:2,7 357:20365:9,18

continue 36:2165:6 70:13 109:6

CONTINUED 4:1continues 124:21continuing 297:13contract 88:8

281:22contrast 95:19

361:9contribute 53:5

125:12 129:15contribution 125:4contributions

130:15 260:19control 32:17 55:20

116:12,20 117:22118:15,19 148:8280:16 282:3,4,6287:19

controlled 13:1715:16 117:8 174:9270:4 272:10

282:3 320:20361:14

controls 83:9110:17

conundrum 315:3convened 1:12convergence

243:13conversed 320:22conversion 133:17convince 119:12convinced 303:14convincing 245:9cooperation 230:19Copaxone 361:21copays 366:22

368:11copied 276:3copies 10:15copolymer 361:21core 94:14cornerstone 143:11

331:4corporate 276:6,7Corporation 4:2correct 79:19 82:1

82:4 99:21,21107:15 123:8204:22 230:2313:6 314:20328:3 335:6

correctly 214:22correlate 125:17

128:10,17 137:6261:17

correlated 127:1correlates 268:16

310:12correlating 134:7correlation 131:22

133:7correlations 155:17

261:18Cosmetic 230:7cost 34:6 69:4

70:21 74:15 77:489:4 108:7 165:2


169:19 170:17172:11 173:16174:19,20,21175:2,4,7 330:6340:1 365:14366:22

costing 335:9costly 169:17costs 74:13 76:5

165:5 329:2 330:2cost-effective 367:1Council 220:5Counsel 9:6count 16:12 302:12counting 154:5countries 68:11

69:1 75:20 154:17154:20 221:4225:10 235:16236:6,11 237:4309:20 312:20316:12

country 62:1078:19 128:12307:21 308:14314:15 315:12

country's 317:10counts 128:14couple 24:16 104:6

151:9 152:16156:12 159:9196:20 218:17279:10

coupled 231:6258:5

course 27:19 40:656:15 79:3 125:15127:7 131:15132:4 147:17153:3 220:19230:10 235:17253:19 308:17310:22 311:6312:18 314:17355:20 360:21

cover 301:3 330:20coverage 10:7 89:2

covered 331:1covers 253:1covigilance 18:22Covington 3:25

217:6,9co-authors 239:1co-payor 168:10CQA 246:12CQAs 243:1,13

246:8Crawford 2:6 3:16

140:13create 6:15 7:1

13:22 27:3 69:974:22 99:1 102:5169:16 185:16286:17 288:8,11293:11 318:15329:9 336:20337:3

created 141:11creates 289:19creating 77:2

286:20creation 331:20credit 113:1 367:4criteria 42:6 54:6

56:14 124:7181:19 200:22219:1 246:9 295:3324:14 326:20347:3,7

criterion 248:21249:2 252:1

critical 17:11 21:472:1 92:19 115:11131:4 158:19162:15 242:20246:1 253:7,9,16253:17 254:8304:1,1 348:2374:14

criticality 253:12critically 35:17CRO 53:2cross 15:1 67:18

249:9

crosscutting220:12

crossing 263:16crossover 57:18,19

101:10 191:19192:9,11

cross-over 55:17crucial 330:9 340:9cumulative 38:13

146:21cure 136:4cures 326:3curious 53:9

132:17 133:2212:8 232:1

current 76:1 97:14112:22 144:5157:14 168:7179:14 215:1280:16 322:8343:9 363:13

currently 67:12109:20 155:20158:8 173:10299:3 314:21322:14 324:15

cycle 183:3cycles 95:15 192:16cytokines 128:8

DD 2:6 74:10damage 367:13dangerous 209:19Daniela 42:20darbepoetin 68:4data 14:3,4,9,13,17

15:11,15 17:2,622:19 23:3 33:1835:20 36:13 37:1037:12 39:11,2147:4,7 48:22,2249:1,8,13,14 52:152:11 57:3 65:1966:6 70:13 73:2179:15 83:12 96:996:10,20 98:1,7,8

99:7,15 105:13,14105:14 111:7113:18 114:18116:16 129:6131:3 152:14154:14,22 156:21157:1,8,15 159:15160:3,13 162:11162:21 165:20186:3 188:13190:22 200:17203:10 204:8209:8 212:20237:4 241:1,11243:22 245:2,9246:15,22 247:9247:17 248:9249:1,8 252:14257:21 258:4,6,9258:11,17 260:3265:2,12,16,20267:6 270:8272:16,20 273:4,9274:13,15 298:19307:11,11 315:9320:7 321:14,17321:18 323:5325:16 326:5,9,21330:11 331:12333:15 335:13336:14 341:5,11346:3,15 351:8,10351:11 352:13,20352:21 354:10357:18,22 358:22365:6,11 366:7,13368:5

database 77:15105:21

databases 20:9,15213:8,11 249:10315:13

dataset 260:11data-driven 143:16date 100:20 163:15

169:17 223:14231:12 237:20

256:5 284:9329:12 347:1

dates 348:10day 5:9 49:3 75:3

143:22 233:3366:12 368:8

days 5:19 10:17147:10 156:13159:10 279:11327:12 355:21360:21

de 50:18 225:14226:11

deal 88:20 108:11223:6 225:7,16227:17 289:2290:1

dealing 89:8dealings 223:10deals 277:4 334:21dealt 219:8 269:19

357:15debate 42:10

303:13decade 36:21

334:20decades 330:3December 11:17

374:8decided 227:13

234:18 235:6deciding 36:15

321:21decision 62:3 82:3

92:14 122:18157:17 219:19240:20 306:13365:1

decisions 234:5,8234:11 323:3

decision.org364:22

deck 92:19decrease 54:7

88:21 172:10decreased 106:19deemed 17:22


23:19 92:6 200:20215:14 248:11251:10 325:12

deep 178:13deepest 218:20

219:11default 353:12defer 230:15deficiencies 293:8deficiency 293:8,9define 32:13 51:16

75:4 281:20289:18

defined 29:1238:20 40:10 67:15156:9 190:16253:18 261:9331:17 362:18

defines 296:6 361:2defining 159:20

304:6,8,12definitely 86:2

208:22definition 7:19

53:19 287:16289:14 344:16358:15

definitions 53:16360:15

deformulate 106:7deformulation

106:4,11degree 36:13 45:10

46:10 57:1 90:590:12 180:9 229:4233:17 246:5260:11 270:2,15271:15 302:14303:1 313:21314:2 333:12,16334:7 365:11

delaying 27:22delegate 365:20delineated 72:10deliver 45:17 64:10delivered 62:10deluxe 60:17

delve 33:11demand 29:16 34:7

226:8demonstrable 13:9demonstrate 38:17

40:7 89:14 94:17104:15 107:8115:4 126:18131:13 145:16160:13 166:13187:7 188:2 257:5259:9,20 262:11319:20 320:17

demonstrated 61:663:9 69:18 73:12113:8 126:2131:19 135:14143:13 144:18145:18 146:22164:6 190:22229:5 242:10261:18 308:20322:18 327:12333:16,18

demonstrating147:6 191:11195:6 219:3326:10

demonstration75:11 111:9 113:4125:14 126:4,7128:2 132:13139:3 142:8143:18 185:17245:10,12 262:6263:1 303:15,17308:9 320:13340:12

Denise 1:19 8:14density 154:2deny 277:17 278:19DEPARTMENT

1:1departure 222:4depend 18:8 23:9

160:10 289:6312:12 351:11

dependent 120:9192:15 297:17362:11

depending 15:1230:15 48:10 60:11100:20 103:11,14216:1 256:15269:1 289:17355:5

depends 138:11153:8 242:16245:22

depicted 93:17deprived 343:2depths 239:12derive 220:11derived 160:13

185:11 254:3296:3

describe 77:12360:16

described 163:22179:7 271:22350:16

describing 180:21247:16

description 272:17design 45:13 51:7

53:10 56:9 57:1457:17 63:16 70:1895:1,12 143:22158:5 159:16188:8,9,10 192:8192:9,11 196:10207:17 243:10,15250:6 254:4,7259:2 264:14319:2

designed 37:1438:16 47:8 71:1786:4,11,20 117:11117:18 187:7191:18 193:14200:10 230:14259:8 319:22343:11 345:3

designing 159:5

designs 53:6 55:1855:21

desirable 237:10241:16

desire 43:2 326:1desired 15:19

131:22despite 223:1

235:10detail 221:1 362:16

362:17 373:11detailed 33:11

72:17 121:8189:21 225:22227:22 317:21

details 11:22 363:3374:17

detect 14:7 131:7146:8 219:6243:22 298:18320:18

detected 187:12205:14 225:19229:11 245:16246:12 260:10265:14

detection 19:7determination 7:12

7:15 13:1 17:1119:4 23:11 31:237:9 97:3 100:17113:3 206:13241:20 266:14322:19 323:4325:21 334:16348:13 353:18354:12,17

determinations17:12 35:19 39:1597:22 208:10220:13 234:21358:16

determine 14:2219:16 38:10 49:18154:10 206:9207:19 358:4369:8

determined 25:1122:16 206:11325:18

determining 39:1147:18 142:21157:9 163:17183:20 275:13276:9 297:6 299:9324:4 326:4

detrimental 136:3develop 32:5,8,11

48:4 94:3 99:10105:19 108:6110:2 141:6142:15 155:18161:19 225:3238:6 284:19286:18,22 309:7326:3 343:6

developed 41:1164:15 67:20 161:7184:6 186:2 203:4218:22 221:2,5,10223:2 224:18228:22 238:5253:22 257:12273:8 294:22310:16 343:20

developer 243:10253:22 271:16273:14

developers 258:17265:21

developing 22:7,1088:9 99:11 108:4111:20 144:13155:13 158:14224:12 235:16236:10 237:22267:15 331:19336:12

development 7:167:20 20:20 29:1032:18 35:9,1636:6 41:14 44:846:9 52:19 53:363:21 66:10,14


71:17 74:15 86:986:11 87:20 88:388:7 90:19 93:2294:10 96:12 97:697:13 99:3 105:17105:19 109:8,14109:18,21,22110:8 111:2,10112:7 123:10,17128:16 132:2140:21 141:2142:4 144:14146:20 148:20149:14 151:6159:7 165:5,7168:4,18 169:3171:10 173:16177:6 183:8,16185:9 217:14,20217:21 220:20222:2 223:13,16227:21 228:1239:6,10 241:15245:6 247:10,14249:3,22 250:1,3255:17 256:4,8,12257:10 258:22259:5 261:7 262:2264:11 285:5294:8 296:2307:10,20 309:8310:18 319:3337:8 338:3,7,9339:4 360:8,12365:15,15 371:9

developments 53:7333:17

develops 28:10162:3 177:5

deviate 91:11deviations 163:11device 275:7devices 5:16devoted 317:12diagnostics 88:9dialogue 142:1

315:2 318:2

327:15 337:16diametrically

266:10 267:1Diane 1:21 8:20dictate 334:3dictated 252:4differ 246:10

304:17 362:7difference 47:20

59:20 96:8 101:18101:19 103:22118:2 143:2 160:8162:20 164:20195:1 202:14203:22 270:4,10270:17,18,19297:19 305:15326:8 365:14

differences 13:2,1413:21,22 14:7,1016:16,19 17:1818:3 20:13 25:1626:17 27:1,243:21,21 44:5,1953:20,22 71:11,1371:16 72:3,9,1872:20,21 84:685:2,6 86:12,1386:17 87:10112:19 114:7119:22 127:21131:4,6 146:9157:12 160:10161:2 162:17163:12 164:5,19165:15 172:22173:6 176:11,13176:14 178:10180:11 181:1184:16 185:4186:5,8 187:10189:19 202:17203:13 207:2,9215:20,21 216:3240:1,3,9,11242:11,13,14,17243:19 244:1,12

245:15,20,21,22246:11 258:1,12258:14 260:8265:13 269:14273:20,21 274:2,3274:6 296:7,9297:7,15 298:2,6298:9,12,12299:19,21 300:16304:2 305:6,7,9305:11 306:4,8308:16 320:19321:7 326:10327:3,5 340:20341:2 371:7

different 15:4 18:418:6,16,18,1926:11,11 30:443:19 69:13 81:591:19,20 99:4101:12 104:10113:20 118:17,18119:3 120:4,4,6122:10 125:13126:13,14 127:8129:10,14,15,15129:16,20,21,22130:15 136:5,21138:1,7 142:22150:9 151:9156:11 160:19161:4,5 162:18,19163:2,4,5,12164:14,16 167:14175:12 177:12179:6,18 181:21189:1 190:2 192:5192:10 193:18201:9,11,13202:10 207:12211:6 213:21230:1 233:5,11,12235:19 256:14266:20 267:4272:6 281:11,11289:19 294:7297:21 300:18

304:12,14,17305:16 307:4,17308:10 312:19315:12 316:4,7,8316:11,11 341:15347:16 350:15351:3,14,15355:15 358:8366:2,4

differential 126:15differentiate 74:3

122:7differently 22:14

125:12 269:4272:2 341:14

differs 17:20 18:14difficult 19:16

38:10,14 102:10119:11 125:3131:15 182:11205:17 206:14208:18 216:4,8222:6 235:22321:6

difficulty 237:22diffused 135:18diligence 87:7dimensions 136:22diminished 192:17diminishing 334:13dinosaur 365:22direct 187:8 263:2

282:14directed 35:8 342:8

373:1direction 280:7directions 151:9Directive 220:1

232:13directly 181:13

223:10 244:14282:2,8,12 334:22

director 5:11 8:128:17,21 9:1,8360:10,10

Dirk 2:3 3:8 52:1652:18

disagree 167:12,16disappointing

58:17discerning 340:20discounted 243:22discourage 19:21

327:8discovered 204:16discretion 35:12,19

149:22 306:12349:21

discuss 55:7 248:22258:3,21 293:21330:14

discussed 18:2154:12,21 64:1136:20 147:9209:3 312:22356:19 373:18

discussing 179:11179:12 370:21

discussion 16:2253:6 54:16 61:1493:5 178:13,20208:7 211:2,8212:7 219:12273:7 275:20314:21 327:11365:19

discussions 29:9,20239:16 373:7

disease 109:7125:13 129:7,18133:10 135:16138:9,10,20183:12 187:20193:7,21 199:13262:8 263:10341:15

Diseased 322:3,4diseases 18:16

128:13 183:9259:12 293:1,2,20

disincentive 117:16disorders 293:9disparity 69:2dispensing 237:14


325:3dispersity 172:20disproportionate

67:18dispute 348:10disqualify 179:18dissatisfy 295:13distinct 204:5

226:13 230:11,20232:19 258:21279:21 343:17,21363:20,21 364:7

distinction 271:21distinctive 237:15distinctness 226:5distinguish 357:14distinguishable

204:21 324:11distributing 205:21distribution 98:3

201:15 202:5203:22 216:5247:4

distributions202:10

distributors 328:18divergence 114:5

323:15 342:10diverse 260:14

264:20diversified 67:8Division 42:21DNA 141:14

220:11 233:15docket 10:16 11:16

301:5 317:21340:6 370:22371:14 373:5374:5,7

dockets 156:4document 88:5

295:17documentation

179:22documents 141:22

224:19 296:3369:13

doing 28:20 43:1664:19 81:22 82:982:15 88:13 92:1106:15 194:16195:2 199:2 213:5274:15 311:7,7

dollars 69:20334:20 335:10

door 139:11doors 5:20dosage 278:7dose 17:19 55:16

55:16 57:6 59:17120:11 129:1147:5 164:15233:16 261:16263:3 272:1,5

doses 171:9dossier 295:10

367:9dotted 80:2dotted-line 79:21double 30:11,13doubt 293:15

338:13doxorubicin

262:19,19Dr 3:9 5:3 8:11,16

8:22 9:7,12 12:1421:11,13,14 22:422:17 23:7 24:524:10 25:2,2,3,325:10 26:2,1327:8,17 29:3,1830:1 31:16,18,2031:22 42:20 43:1143:13,14,14 44:245:2,5,11,13,1445:15 46:5 47:1,147:2 48:1 49:1649:22 50:1,7,2151:9,20 52:3,1252:14,15,17 55:956:11 62:1,5,6,1463:4,4,5,6,1864:13,13,14,2165:13 66:2,16,18

66:19,21 67:2,867:11 76:6 77:8,977:11,20 79:13,1779:18,19,20 80:280:14,17 81:16,1781:18 82:1,2,5,882:10,11,13,14,1582:20,20,22 83:683:8,13,17,19,2083:22 84:1,8 85:985:9,10 86:187:14,17 98:11,2299:21,22,22 100:1100:3,4,10 101:7102:1,17 103:8104:5,5,6 105:4106:14,15,17107:6 108:12,19108:21 111:11117:2,3,5,20118:11 119:6,17120:7,16,19,20121:10,20,20,21122:8,12,19,22123:5,6,8 132:7,8132:10 133:4,13133:19 134:4,14135:5 136:10,10136:11 137:1,15138:5,21,21,22139:12 140:11,15144:7,10 150:4,5150:7,14 151:4,15152:6 153:2,8,11153:11,12,21154:11,19 155:3,7166:6,7,9,17167:2,5,6,10,11167:15,17,19,20167:22 173:22174:1,3,12,14,16174:17 175:1,10175:10,11 176:5176:16 177:3178:18,18,19,20179:4,5,12 180:2180:10,18,19

181:6,7,11 182:4182:8,10,11 194:1194:2,4,7,21195:11,15 196:4196:12,19 197:5,7197:11,13,17,20197:22 198:16,20198:22 199:3,5,8208:1,3,18 209:10210:2,2,3,13,22211:13 212:5,15213:2,7,18,19214:3,15,21 215:7215:14,17 216:1216:10 217:3228:3 229:17,21231:17,17 233:2,2234:2,7,9 236:1236:14 237:16238:11,15,17,20239:2 250:20251:8,15 252:6,10252:21,21,22253:4,6,17 254:10254:17 255:2,5,8255:12 266:4,6,8266:22 268:2,10269:6,18 271:6,11271:20 272:8,15273:12 274:17287:9 289:5,17290:10 292:2,5301:9,14,18309:13,15,17310:11 311:8,14311:16,17,17,18312:11,21,21,22313:6,7,10 314:1314:16 315:6,14316:14 317:1,4327:20 328:5337:20,22 338:2338:12 339:6,10339:11 349:11350:13,13,14352:11 353:15354:1,6,9 355:2

355:18 357:2359:16,19 360:1,4364:12,15,16368:18 369:21371:2 373:12

draft 219:14222:14

dramatic 76:9168:13 205:10

draw 49:10 302:6drawbacks 290:13drift 29:21 30:2,3,5

46:3,11,20 87:593:6,7 111:19122:13 159:9,10159:10,11

drifting 46:14drifts 30:19 46:17

98:8 159:13drive 65:17,22driven 265:13

331:12 333:15335:8 337:4

driver 174:21drivers 175:1drives 334:17drop 60:9 367:15drug 1:4,13 5:11

17:15 18:8 35:1541:13 44:12,16,1757:7,8 59:3 66:797:4,5 106:2,9114:2 126:15129:8 136:5,6138:13 140:3,8158:20 162:18164:1 168:2172:11 186:22187:1,5,15 188:6227:19 230:7286:16,20,21287:3 291:14,16292:17,18 295:2296:9 322:11,12340:18 344:3363:1,9 364:3366:3


drugs 8:17 9:649:17 69:6 131:16136:7 140:1145:15 156:19168:4 199:21230:8 234:16277:18 279:21286:1,4 291:7,20294:14 295:5334:19 349:2

DSC 160:21due 87:7 89:4

111:18 112:19130:7,14 172:4239:12 300:19330:15

duplicate 176:3,4308:13

duplicating 176:6duplication 34:21

141:5 165:13308:1

duplicative 290:16333:22

duration 146:6188:11 192:14

dynamics 335:1

EE 2:9eager 61:20earlier 61:18 65:14

121:22 134:17163:22 175:15179:7 233:3266:11,13 333:17352:11 355:12361:4

early 27:9,16 29:146:6 59:2,10,12150:7 198:21249:2 366:2367:14

earnest 219:13ease 63:1 138:15

211:2easier 128:3 140:10

177:16easily 171:6 172:4

212:4 315:10East 68:3 163:1easy 15:6 26:8

102:4 125:2 205:1Ebert 2:6 3:17

140:13 144:8,10150:14 152:6153:8,21 154:19

echo 233:18economic 291:22economically

117:16economics 156:6

165:1 169:2education 115:20

212:13,17 310:13310:22

educational 116:2effect 18:5 20:13

38:17 47:15 84:985:6 107:13118:21 127:19168:13 173:7176:4,6 189:17220:1,5 246:7260:18 261:1,10261:16,17 263:2,4263:9,13 293:22297:20 322:17

effective 13:1934:13 49:8 118:16129:21 148:20168:20 173:3259:12 291:21310:8 311:13318:14 319:2,9321:13 329:1336:5 337:12339:22

effectively 40:21354:11

effectiveness126:21 246:3346:6

effects 15:20 17:17

18:8 127:15,17128:3 136:2188:14 189:11219:7 225:18233:12 260:20,22272:4

efficacious 108:5136:1

efficacy 15:20 22:124:8 37:6,15 38:238:12 43:5 47:956:19 73:20 76:1695:8,10,20 106:19107:14,20 113:5120:6 124:4125:22 126:9131:19 134:22135:13 139:5148:10 149:6156:11 166:13169:9 170:16171:12 172:16173:7 178:15179:20 180:7184:20 185:19186:9 187:8,19,22188:3,19,21 189:1189:15 190:21191:11 192:17193:4 204:2 210:8229:8 240:7245:17 247:17248:9 250:5 257:2257:14 258:11259:9,21 261:21264:2 265:9269:10 270:6,20270:22 271:5272:2,6 290:6295:13 298:19299:16 320:2321:9 336:17342:11,18 359:12

efficiencies 31:12165:6

efficiency 69:18efficient 108:5

223:2efficiently 165:22

349:1effort 116:4 314:16

315:5 350:22371:10

efforts 112:17116:7 166:1250:10 293:10315:8,10

EGA 302:2,10309:2

eight 51:21eight-minute 10:20

11:1either 19:2 21:17

49:20 67:16103:10 209:6226:12 228:12230:15 274:13294:19,22 316:6369:4

elaborate 98:17251:13 349:17357:8

Elect 282:16electronic 10:7,9

20:8 213:3 236:22237:8

elements 312:4elevating 335:3elicitation 189:18eligible 275:22

281:7 326:4347:13

eliminate 141:4Elonva 109:16elucidated 305:9EMA 97:1 204:8embark 116:4embrace 46:13EMEA 141:20

145:1 186:18240:12 247:15294:13,19 295:6306:22

EMEA's 240:21

emerge 17:18 18:319:9

emerging 67:17173:10

emphasis 34:10169:13 225:16239:10

emphasize 34:735:4 48:17 172:16336:21

emphasizes 169:6emphatically 41:6empirical 157:15employ 76:22employed 171:1

299:4 332:15employing 264:12enable 20:15

318:17 339:19enabled 319:9enables 42:12enacted 35:12

158:7 220:4enactment 8:5encompass 91:18encourage 6:9

11:17 69:11 88:13286:3 291:15318:16 327:8336:11 374:9

encouraged 149:20encouraging 203:9

290:15endogenous 172:1endpoint 59:6 65:2

127:3 131:22134:6,8 153:20154:3,6 203:17261:21 262:5,10262:14 264:17266:13,17 267:7267:20,21 268:12268:15,20,21272:11,12 273:2

endpoints 16:5,816:17 59:9 81:11126:22 127:6,7,9


127:10 131:20132:15,16 139:6148:10,11 153:13187:20 259:1261:6,12,14,15262:1,16 264:13265:17 266:18,21363:14

ends 326:22energy 194:5engage 149:13

327:15engaged 240:12engineered 173:13

243:9engineering 178:22enhance 35:10

166:1enhanced 32:14enhancement

36:19 161:13enormous 302:6enoxaparin 32:10

41:1 90:2enrolled 85:17

188:2enshrined 142:7ensure 13:18 20:3

42:2 46:9,14169:8 178:17188:10 191:7192:16 193:10196:1 200:12230:11 244:3318:13 319:4325:2 332:4

ensures 34:12ensuring 169:16

183:14 187:17188:1 211:2 337:7

enter 327:2entering 286:4enterprise 238:6entire 12:15 33:15

49:14 69:3 100:5101:2 112:3160:11 257:6

entirely 314:6entirety 276:19entities 146:4 149:2

184:5 258:18259:8 265:22284:19 286:22

entitled 33:22290:17

entitles 276:10282:15,22

entity 257:11 267:8275:14,21 276:6278:5,6,12,17,20279:6 280:4,16281:3,7,13,14,18281:20 282:2,2,5282:6,7,10,18284:18 285:1,13287:17 363:20

entrance 124:6372:15

entry 74:18 221:6286:1 337:3

environment 184:9190:3 324:9

envision 26:1038:15 48:11 51:7256:14

envisioned 75:6envisioning 81:7

208:12envisions 26:14epidemiology

211:18epitope 270:13epitopes 15:4EPO 17:21 95:14

263:5epoetin 230:22

231:8Epogen 203:12equal 34:10 368:14equally 89:13

261:13 311:12equation 285:9equivalence 37:19

48:13 51:4,13,16

59:15 60:8 117:14118:5,7 126:7128:5 131:14,18139:3,5 146:1188:9 259:15260:4 261:4262:11,22 263:7263:17 264:15265:11

equivalent 233:6233:10

equivalents 90:1Eric 4:19 364:17,21erthropoietin

220:16erythropietin

236:13erythropoietin

24:11 205:13erythropoietins

19:12ESA 205:14,21escalation 57:6especially 69:1

73:17 113:21263:19 319:13324:2,8 341:22

Esposito 1:19 8:148:14 27:8 28:21208:4,5 209:4211:1 228:6,7287:12 357:3,4358:12,19 369:5,7

ESQ 2:17essential 14:6 37:5

118:4 131:9143:11 162:9164:2 185:1 263:8321:4 356:10

essentially 118:1131:11 139:10145:15 233:6,9276:2 277:16,22336:7 356:4366:18

establish 35:537:15 39:21 47:9

94:7 96:1 118:15128:5 145:22177:17 181:18200:10 203:1208:17 209:9230:9 253:16315:15 335:17342:15 348:12350:9

established 52:154:5 125:16 133:8146:14 161:8164:7 187:19230:15 240:14249:17 256:21257:3 264:7284:22 333:19

establishes 284:18318:2

establishing 37:1847:19 89:22 150:1218:22 221:15258:7 341:1348:10 352:14

establishment 8:648:12 111:3158:16 309:3

estimated 118:21et 34:4 100:21ethically 74:7EU 113:22 206:1

217:20 218:11226:7 227:11228:10 229:18230:14 234:17256:9 294:6,8307:15 309:6314:10,10,18,22334:5

Europe 16:2217:15,21 21:1622:20 23:6,16,1729:8,9 89:3103:15 152:10204:5 205:15210:10 219:8,11220:3 221:12

225:6,12 235:9,21237:1,18 256:6268:18 302:11310:3,6,22 311:10312:13 314:17315:10 316:5338:4,22 370:6

European 4:921:20 22:6 23:2124:7 141:20143:11 218:5,20220:4,6,7 221:13223:10,20 226:11226:16 227:3,5,12229:14 230:13,16231:11,22 232:15255:21 256:1273:18 294:10301:15,19 302:3315:2 319:8,10332:1 372:1

Europeans 218:14220:17 238:5

EU's 227:1evade 350:10evaluate 43:4 44:3

97:9 243:1 244:17245:19 249:8

evaluated 91:1797:19 102:3 185:2304:3 338:15

evaluating 33:5300:6 331:7346:12

evaluation 5:12 9:943:17 44:1 83:2124:2 186:17190:7 247:1293:16 320:2,11349:5,7 373:1

evaluations 143:5202:20

event 20:3,8 200:15211:17 226:18231:15 297:20300:9,18,21 324:4

events 83:5 115:14


120:4 163:9 164:7194:12 196:7205:1 207:5212:10,18,19226:2 237:1300:10,11,13

eventual 175:3evergreen 278:4evergreened

289:20evergreening

276:16 278:10279:2 280:2287:21

everybody 45:1949:4 156:12,17212:20 277:1288:3,4,5,15338:19

everybody's 229:1evidence 9:20

39:19 51:19 68:21116:10,20 135:4186:20 194:12265:8 267:18268:15 313:11323:9

evidence-base146:21

evolved 36:20158:3

evolves 52:5evolving 44:21

141:13ex 114:6exact 119:7 133:5

169:10 215:19exacting 99:19exactly 60:2 77:18

84:18 86:16 216:6232:17 251:5370:6

example 17:19 18:533:19 38:16 51:1551:19 64:22 69:1572:8 74:5 80:2093:12 128:6,7

129:13,18 134:15138:6,18 153:6160:9,15 162:16162:22 164:11169:22 192:8203:11 205:8208:19 209:16,16215:8 223:6 231:1231:8,8 236:6244:11 256:14260:14 261:10262:2,18 270:22274:1 286:20298:13 308:16312:1 316:3 343:5343:21 345:1,10358:5 367:21

examples 179:1250:17 272:18338:4

exceed 142:13203:16

exceedingly 335:3excellent 76:16

89:20 141:15exception 279:14

302:4exceptions 209:17

366:20excess 334:19excessive 243:6exchange 345:9excipient 158:9excipients 157:13

163:5 300:19exclude 14:6 16:19excluding 26:17

127:21exclusions 160:18exclusive 70:22exclusivity 7:22

133:15 275:14276:13 277:2,5,17278:8,13,19 279:8280:12 281:1,8283:5,6,14,22284:1,8 285:14,16

285:17,20,21286:3,7 287:4290:13,18 291:13319:17 326:6,12326:18,21 329:12345:2 346:19347:9,14,18,19348:14

Executive 339:15exercise 54:16

56:11,15 59:1262:15 63:3 110:19136:15 148:4332:4,17 345:16352:9 354:21355:14

exercises 97:9,20exert 260:18exerts 263:2exhibit 38:22 240:1exist 15:9 25:11

33:14 73:9 145:7176:12 178:11192:20 260:10320:19 341:2370:15

existed 270:10existence 61:18

150:21 168:11existing 34:20

37:12 38:21 47:749:14 64:1 171:16192:1 219:18305:12 319:20

exists 52:8 74:2129:22 131:22244:8 246:22259:12 261:9309:7

expanded 152:18181:12 339:21371:13

expands 327:9expansion 76:13expect 40:12 84:13

84:17 214:6235:19 247:13

364:1expectation 29:4

70:3 79:9 86:2187:8 102:12 177:9

expectations 250:4251:6 319:4

expected 70:2291:6 183:22245:18 333:12342:5 370:4

expedite 337:1,5expensive 168:8experience 17:14

19:11 21:21 28:728:8,9 62:18 76:778:11 87:20 88:789:20 93:7 97:8109:14 110:10118:6 134:21135:6 141:16155:10,11 183:2195:12 202:19,20204:5 206:15208:22 212:21213:10 218:6,21219:12 220:21221:12 225:6,9,15232:1 235:8,14237:20 250:16256:1 295:18302:6 306:11314:9,13 329:14331:6 338:22340:8,9 344:7354:20 360:6

experienced 239:13experiences 256:10experimental

173:11expert 255:21expertise 329:14experts 256:5expire 329:11expiry 100:20

103:11 345:1explain 62:12

139:18 158:5

203:21 204:3310:16

explanation 72:17253:3

explicit 230:6explore 55:15explored 138:3

178:8 187:13expose 152:7

170:19 353:7exposed 95:21

100:12,14 101:1101:12 103:16209:7

exposing 101:18exposure 38:9,14

55:2,4 57:21112:10 152:3

exposures 148:21express 123:12expression 171:5

171:20 172:13181:21

extend 34:16 284:1285:15

extended 347:20349:4 350:11356:12

extends 283:6,14284:9

extension 86:22128:18 276:1

extensive 70:476:18 79:10 84:485:16 110:14149:3 171:10241:11 265:5267:11 273:15310:18 331:6338:16 373:4

extensively 177:8331:2

extent 144:16257:1 265:12305:14 324:19331:1 333:4 359:8368:4


extra 280:11 281:1extraordinarily

341:12extrapolate 25:5

130:18 138:4,9260:5 303:5

extrapolated 25:9188:20

extrapolation 17:425:22 64:5 102:15111:6 113:13116:18 124:3128:19 129:18130:4,11,12137:19 165:16190:4 193:1247:16 258:22260:16 264:12341:8,11

extrapolations127:22 137:20

extreme 76:4extremely 16:18

19:16 137:20138:6 209:13216:8 262:7273:15 374:2

ex-U.S 61:15 111:7113:18 114:11,13114:19 116:16313:1

eye 80:18 81:5eyes 329:6

Fface 203:9faced 183:16 337:9facilitate 19:22

27:14 343:14372:15

facilities 30:4 91:20110:16 144:4171:8 331:10

facility 313:19367:7

facing 185:12fact 42:11 44:17

62:11 69:15 78:2279:1 81:8 86:294:2 121:7 136:19152:13 178:9179:16 180:4196:5 225:9 233:6235:10 290:22302:16 303:2354:16 355:22358:11 369:1372:15,19

facto 226:12factor 89:5 110:13

175:7,8 293:8factors 7:12,21 8:1

25:6,8,11 66:392:13 156:2 160:7163:17 165:18183:19 187:2189:7,22 190:6241:19 275:12276:8 296:18,21297:5 299:18300:5,15 305:5321:21 322:21362:13

factory 171:7313:13

failures 212:10fairly 55:21 59:2

75:2 89:19 106:3175:12,17 229:12229:15 269:7

fairness 287:3faith 367:4falling 80:8,12falls 39:3 40:9

347:6familiar 50:4,8,15

91:15 276:20360:2

families 88:19far 24:16 47:17

61:13 74:14 163:8198:18 218:20219:11 225:8227:11 279:10

farther 180:3far-reaching

294:19fashion 86:20

361:13fast 366:10faster 127:11favor 211:20,22

267:6 355:19favorable 276:16FDA 1:4 7:3,5 8:9

9:22 10:2,6,7,1110:21 12:15 20:2028:15,16 42:2249:6 52:20 67:572:10 74:12,2175:3,11,16 76:2181:9 87:1 89:1997:8 123:11140:17 141:9142:5 144:5 149:7149:12,22 154:13155:12,14,16157:9 160:7162:19 163:17182:12 206:7,12207:18 218:9226:8 227:17243:7,12 248:17248:22 249:17250:15 255:16256:5 275:9,18279:14 293:15294:4,12 295:3,16301:6,21 302:22306:10,22 309:4317:16,19 318:2318:11,21 319:3,7319:11,12,19320:11 321:20322:9,19,20 323:2323:4,11 324:12325:17,21 326:7327:7,15 329:13330:13,17 331:5,6331:11,15 334:16334:21 335:2,15

336:12,19 337:7337:12,14,16339:19 342:14344:18 345:7,10345:18,22 346:2346:10,17 348:7348:11,21 349:5350:9 352:19353:6 357:6 361:2368:7 373:14

FDA's 27:22 69:17141:12 161:16240:15 292:11293:10 318:6,10330:8 331:18336:16 346:22357:10

FD&C 302:13feasibility 62:15feasible 20:5 36:6

37:17 38:4 53:653:12 55:18 56:760:7 95:2 117:16117:21 139:19177:2 200:20259:16 266:18

feasibly 107:10features 321:2

334:2 348:2 364:8federal 11:21 12:2

12:20 230:7 276:3301:1 317:19319:14 326:6,15346:22 374:16

fee 8:6 336:20371:11 373:6

feel 25:7 88:11 89:791:3 93:16 94:1696:20 101:2136:14,19 153:6172:15 176:6179:16 181:17,18183:3 288:18313:7 331:5 371:4

fees 330:21 336:18337:2 348:17349:4,6 369:17,19

370:19 372:17,20372:22

felt 58:19fermentation 361:8field 155:12figure 70:7 77:17

77:21 202:13205:19

figured 215:21figuring 212:10file 96:21 284:20filed 280:15 283:2files 278:6,20

281:13 283:11,19284:7

filgrastim 122:6163:3 268:20

filing 232:4 277:18280:22 284:14,17

film 10:11final 86:15 221:7

222:18 224:13265:10 286:8287:2

finalized 221:7finally 72:16 97:7

115:5,12 116:1,18200:19 219:8222:17 224:21226:16,22 248:6250:11 262:20264:22 333:2335:13 344:12348:16 370:11

financial 168:14280:16

find 22:12 41:353:12 218:7 224:6225:18 227:20228:16 231:12289:12

finding 17:2 334:11346:5 359:11

finds 43:7fine 199:3 306:18fingerprints 44:13finish 164:10


finished 165:8firm 124:6 217:9

217:11 239:6275:4

firmly 13:4first 9:19 12:12

23:8 29:14 45:1248:16 53:18 54:1155:2,13 56:1657:22 58:3 60:1461:5,11 68:772:14 103:18104:7 105:5,5106:1 108:19129:11 130:5144:10 178:17183:18 198:1199:15 200:1,9202:22 208:11,14217:5 218:17221:14,19 223:19224:14 225:13233:8 234:12239:4,18,20257:11 269:19276:22 277:16278:10 284:12285:19 296:17304:7 305:7317:22 318:5326:22 329:8330:22 335:21340:11 344:14346:22 347:1,9348:9,13 349:17359:19 365:21366:13 369:21371:3,19

Firstly 140:20142:4

first-hand 76:6fit 105:1 339:2fits 142:17 256:12

339:2 366:6five 109:21 138:2

216:19 359:21364:18

fixed 315:19flawless 373:22flexibility 240:17

241:4,8 270:3307:19

flexible 36:2252:10

fly 81:9focus 20:6 110:21

124:14 126:17140:19 193:5226:2 240:8242:19 244:3250:1 277:22280:9 296:13

focused 56:1467:12 183:8268:13 330:16358:21 360:22

focuses 109:18fold 76:13folding 178:5folks 236:17 367:13Follistim 109:13follow 22:18 45:2

45:11 47:2 50:2181:16 93:2 94:7100:2 101:7 105:8119:17 121:21151:4 162:9178:19 199:16209:4 213:19215:17 226:10272:11 288:17350:14 370:5,6

followed 162:7222:14 243:20256:21 264:8265:6 269:1

following 8:5 35:4128:21 156:15166:18 183:19187:2 190:6241:22 258:18259:13 281:21313:16 318:12319:14 321:21

323:12 346:21361:15

follow-on 277:3,6279:19 288:4363:9

follow-up 28:21174:15 236:1,4252:6,22 269:2,6271:20 314:8358:12

follow=on 279:11Food 1:4,13 168:1

227:19 230:7forcing 339:1forego 21:7foregone 41:21foreign 307:12,13

313:2 335:13336:8,13

foremost 56:17foreseeable 14:15forget 216:17form 6:16 70:9

141:17 142:1226:5 308:22312:14 318:3362:5

formal 96:18234:21

formally 302:14format 135:12formation 229:9

300:13formed 90:16

141:15forms 137:2 246:7

285:1formularies 236:2formulary 206:8formulated 201:12

340:18formulation 106:6

163:4 194:13308:17 355:6360:11

forth 19:19 50:1954:18 151:18

198:3 224:3229:10 232:22233:17,22 237:6237:10 238:1286:7 345:17356:20 358:6373:9

fortunately 305:20329:13

forum 33:11 157:7293:11,21

forward 12:9 42:1043:8 67:5 89:1094:19 96:5,1199:17 102:7 107:9108:4 137:4164:21 200:3201:21 336:19340:5 351:12366:10 374:5

found 19:12 74:6132:17 203:16244:13 305:18

foundational 90:1197:10

four 57:17 58:2123:2,3 277:5302:19 310:3330:16 340:2362:4,8

fourth 280:3fractionation

298:10framework 7:16

71:2 123:18141:11 142:2336:13

frameworks 69:10France 225:14frankly 48:10

235:2free 127:4 291:22front 18:22 86:9front-line 168:12fulfill 170:11fulfilled 179:20full 12:4 25:12

57:21 147:1187:15 222:22224:14 307:20320:6 330:4

fully 74:20 76:21189:13 305:9364:1 366:7,8

function 32:16101:9 131:6 143:1257:13 273:1,9,22274:5 321:5,7373:6

functional 75:1384:22 85:1 256:16257:22 295:8308:19 313:4

functioning 88:8306:17

functions 332:20fundamental 88:18

90:8funds 285:4further 32:13 35:8

53:4 87:2 111:17142:4 153:19161:19 189:20240:6 244:7274:14,14 311:9342:17

furthermore114:18

future 14:16 156:8165:11 171:1173:14

F.A.A.P.S 2:7

Ggain 165:5 303:10

354:20gained 68:8 252:7

287:4gaining 302:16

311:3gains 250:15

252:13galactose 34:1

170:4


gamish 362:6gathered 73:19GCPs 75:17GCSF 68:1,12,15

76:14 95:14220:16 261:11263:5 268:13

Genentech 123:7123:10

general 16:2 22:522:14 29:4 154:19156:8 157:20174:19 220:9242:5 261:3294:22 296:13302:8 306:8 307:2353:8 365:21370:8 372:14

generally 30:1633:7 41:3 66:7129:11 228:9263:11 264:18281:21 300:8336:11 370:4371:2

generate 105:15,22112:2,5 165:7260:11 274:16362:6 364:6

generated 154:14189:12 307:11320:7 334:19335:1 361:7

generating 261:1generation 55:13

109:15 188:14326:19,22

generic 4:9,13 32:949:17 89:22156:18 199:21224:2 227:9234:16 238:7301:15,19 322:11328:3,9,18 334:10334:17,18 343:10359:15

generics 13:7 227:8

277:9 328:14335:7 363:11

genetic 3:21 178:22182:16,22 183:1,7293:2

geno 146:12genuine 336:15genuinely 224:12geographic 355:16geographies 304:12

304:15,17Germany 236:6getting 48:7 194:4

199:2 266:9give 15:3 23:6 96:4

102:14 106:12164:14 360:3

given 10:20 12:418:1 25:15 27:1231:5 42:19 119:1126:12 132:20184:1 191:21192:22 211:11214:9 227:2230:16 243:3251:17,18,18,20253:2 263:19306:12 311:22317:17 321:6322:8,17 333:4334:9 342:6363:21 367:5

gives 59:4 140:3304:15 334:5

giving 67:5 123:11164:11

glad 337:18glatiramer 32:10

361:20 362:3363:7,19

global 52:19 53:267:9 96:12 140:21141:2,8 142:3149:14 255:14307:10 309:8328:14

globally 294:5

343:21 344:11globe 186:15globulins 300:17GLPs 75:17glycan 242:17glyco 246:7glycoforms 84:6,10

85:2,6 242:15glycoprotein 33:9

177:20glycosignature

71:21glycosylation 33:6

163:5 170:4,13172:6 179:2184:14 246:5321:3

GMPs 75:17go 9:17 26:18 28:11

54:17 57:4 59:1760:12 72:22 77:1178:8 120:22138:22 148:7166:10 176:17177:21 200:5201:21 208:4213:18 232:22251:3 253:15254:10 277:14304:20 349:15,19350:1

goal 33:2 71:1477:1 131:13 136:4213:12 266:16275:20 332:3

goalpost 92:16,2193:20

goalposts 100:2174:6

goals 35:7 161:13182:2

goes 11:1 58:461:14 283:9365:18

going 29:18 55:256:10 58:7 85:486:17 94:18 102:7

105:16 107:9108:14 118:7,9121:11 133:14148:7 153:22155:21 156:1157:2,5 206:19220:22 232:8,14232:18 234:22236:15 258:20276:19 279:12280:8 281:4 288:8288:9,11 289:4,13289:15 290:8302:21 314:21

gold 262:4good 5:3 22:15

31:22 52:17 61:566:21 89:2 105:4108:21 114:16140:15 143:21174:9 180:14182:13 211:14274:22 276:17300:8 317:2,4328:7 339:13360:1 364:20

goods 174:21 175:7gotten 78:5 224:9governing 282:17government 227:11governments

222:20 232:16GPA 369:10GPhA 32:4 328:15

328:17,21 329:4,6329:15 336:19337:15

GPhA's 334:8grant 277:1granted 283:5

284:9graph 70:12 75:19

93:11,17graphical 164:12graphs 166:11grasp 329:18great 44:2 107:7

223:5 225:7,16227:17 283:7284:1

greater 32:1848:14 118:9129:10 137:11172:7 198:6 246:2270:16 286:12291:17

greatly 21:3 360:13green 233:22gross 244:11ground 9:18grounded 340:7group 87:18 365:2groups 47:12

155:18growing 34:6

221:10grown 170:2growth 302:12growths 97:4guarantee 297:1guaranteed 74:17guess 5:19 45:22

46:4 50:14 51:651:12 52:3 78:280:11 101:20107:2 150:10151:12 179:9197:20 199:2214:5 270:1 271:1271:12,21 273:13274:11 276:14279:16 338:7371:3

guidance 7:2020:21 21:6 27:1027:16,21 28:2,2,629:2,15 39:9,1453:14 61:5 141:7141:12,13,17,22144:22 155:16161:18 206:18209:19 217:22218:3,4 219:2,14220:9,10,12,14,20


221:3,5,7,10222:11,15,16,18223:13,15,16224:13 228:21229:2 247:16249:21 250:1,2,4250:6,9 287:16294:21 295:3,6,17296:3 318:3,22342:14 351:21369:12 370:2,9,13370:16,17 371:17371:21 372:3,5,8

guidances 36:161:5 147:3 168:4168:18,22 186:14209:22 223:2318:21 369:22370:9,11 371:8

guide 240:15,19318:6

guided 318:11guideline 123:13

139:13 162:1guidelines 61:17,19

75:4 76:22 155:14155:18 161:19186:16,19 240:18294:16 367:12368:1

Gustafson 2:18 4:8292:6,8 301:13

Hhalf 55:14 59:19

171:8 234:13half-life 56:3

147:16 178:6hallways 6:2,8

216:18hamper 330:5Hampshire 1:14hamster 34:1 170:2hand 11:11 55:22

181:16 241:12handled 341:12hands-on 340:7

happen 18:14 53:958:13 69:8

happened 29:8happening 252:8happens 46:16

266:8 281:10happy 43:10 166:4

173:20 229:1,2327:18 349:9363:6

hard 15:13 131:7271:16

harm 207:9 349:1harmonization

141:9 149:13154:13 294:6296:14 365:20

harmonize 151:1harmonized 241:14

312:19harnessed 232:3harvested 201:11Hatch 357:19Hatch-Waxman

34:17 69:17329:21 346:2

head 60:6 124:1182:17 270:11283:9 328:13

heading 219:16headquartered

328:15heads 58:22head-to 123:22head-to-head 14:20

127:18 131:9139:2 187:4 265:3268:21

health 1:1 6:22 9:19:3 62:9 67:9,1970:20 75:5,19,2276:5,7 77:2,488:14 89:2 168:16175:5 186:14,16199:19 205:2206:16 212:3214:10 294:11

303:11 318:20323:13 329:2334:13 339:16365:3

healthcare 165:3275:16

healthier 317:14healthy 69:11hear 355:11heard 21:15 22:18

47:11 65:13117:12 121:3,6175:13 179:1,9199:20 201:7204:20 205:8206:22 208:8209:10 211:7212:11 225:7272:17,18 273:6290:11 291:2304:8,19 332:9338:2 350:15355:20

hearing 1:6 5:5,65:13 6:14,15 7:6,810:18 11:8,1512:3,10,16 21:19140:17 156:5168:3 209:13225:8 292:9 301:7318:10 337:15361:5 374:2,4,20

hearings 10:5heavily 217:17

221:12 351:11Heidi 1:21 8:22held 222:1,2help 21:3 36:15

125:17 145:22165:4 286:22290:21 319:2,4325:2,20 337:1355:8 360:17363:5

helpful 52:12 97:5162:2 209:13212:22 224:12

281:19 305:21370:1 371:19372:9

helps 274:13 294:9365:2 369:8

hemitrope 163:1hemophilia 293:7heparin 220:17heterogeneity

202:5 298:13361:6

heterogeneous177:20 201:15364:6

Hexal 231:8HHS 1:1Hi 8:11 255:12high 33:17 34:6

62:20 75:12 84:1386:6,7 89:12,1490:5 92:2 99:17110:4,6 130:14135:3,21 137:5140:4 185:21191:3 271:15308:11 313:21314:2 319:22329:16 330:7335:21 336:4342:7 369:18

higher 24:17 46:1098:19 99:6,8,1299:19 110:20153:1 193:12198:2

highest-quality165:20

highlight 282:20highlighted 361:6highly 13:12,13

17:16 47:14 53:1970:10 71:20 73:1274:4 90:20 91:991:17 93:20 102:8124:13 138:11157:10 169:5,8170:11 172:15

173:9 193:4237:10 241:20264:19 297:2298:4,7 300:4306:10 307:15331:17 333:9,18334:8 335:19336:3 356:4361:13 362:11

high-yield 361:14historical 79:16

80:13historically 33:3

80:8 304:14history 73:14 149:7

155:11 203:2227:22 299:15,15

hoc 230:4Hodgkin's 70:10Hoffman-La 3:14

123:6hold 31:6 371:9holders 302:2holding 12:16

168:2 301:6holds 177:5homogeneity 172:4honest 288:1

289:11honestly 167:16honored 182:12

331:12hope 42:9 43:6 53:5

63:20 152:6317:22 360:17365:5

hopefully 290:8291:17

hopes 337:15hoping 349:16

368:13hormone 302:13hospitals 207:13host 71:19hot 153:3housekeeping 5:15huge 102:7


human 1:1 3:2115:5 34:21 73:14141:5 157:15170:8 173:12182:15,21 183:1,7185:17 199:13201:4 202:3,15220:8,15 229:8233:15 240:8243:21,22 244:17292:16 298:19299:10 308:1

humans 170:7195:4,9,10 244:5265:7

humbled 203:8Humira 59:3,21

65:20hundreds 69:20hungry 199:2hurdle 72:4hurdles 236:18hurt 285:22hurting 368:11hypersensitivity

192:3hypothesizing

271:17hypothetical

194:22 196:5284:3

hypothetically283:2

IiBio 3:19 167:21

171:2ICH 39:9 113:21

141:10,17,18142:7 149:13154:12,16,20161:19,22 162:2331:21 365:22366:19

ICH-type 148:21idea 29:12 119:18

271:2

ideal 231:14 312:18ideally 253:8

343:19identical 71:19,19

78:10 90:6 106:6156:14 170:13,16199:21 201:8343:12 356:4358:6

identification160:17 211:3,12

identified 24:6124:11 236:17310:1 318:9

identifiers 115:20122:2,4

identify 185:6210:7 222:10240:9 297:14307:6 309:21

identifying 127:20134:21 348:9

identity 33:5177:17 180:17246:7

ignore 29:18ii 278:15 282:16illustrate 160:15illustrated 100:11immediate 214:11

330:8 335:14immune 128:22

129:22 130:7188:16 196:7205:11 293:8300:17

immune-related83:5

immunocompetent25:18

immunogenetic271:7 310:8

immunogenic 38:770:14 189:11,19198:7

immunogenicity14:14,18,21 15:17

19:1 22:2 24:825:19 38:2 54:959:11 73:21 76:1783:2 95:3,9,1096:6,8 106:18107:4,11,12,14,17115:2 124:7 129:1129:6 146:9148:15 166:16,18166:20 167:1184:19 189:5,8190:1 191:6,21193:9 194:9,11,19195:2,6,14,17196:17 210:8220:13 239:15248:11 249:7264:4 269:10270:12 271:15300:14 321:11323:22 341:17,21

immunogenicity's95:5

immunoglobulins124:13,15

immunologic188:13 306:1

immunology 42:21128:7

immunosuppress...18:6 25:17

impact 57:9 68:1085:2 107:19 111:1113:1 128:7142:21 168:14184:9,12,17185:18 186:6189:3,7,15 190:20193:17 203:15204:9 216:7242:12,18 245:22246:5 272:22273:1 323:12367:14

impacted 94:1895:10 128:20

impacting 184:21

194:5 195:18impacts 240:3

289:8impair 19:6imperfect 237:3

315:18implement 27:22

35:21 43:8 85:21322:22

implementation6:17 7:7,10 16:2220:5 36:5 69:17183:5 217:15292:11 293:13318:4,7 345:8374:6

implemented 37:1140:21 232:14254:12

implementing22:15 34:12228:14 318:21346:11

implements 318:12319:11,13

implications104:14 127:18129:5 324:2

implied 126:13231:20

imply 25:11 51:22197:1

importance 45:4183:13 253:7318:20 338:8

important 12:1614:18,21 15:616:7,10 21:130:21,22 35:1738:21 113:19115:5,18 165:20176:7 180:6185:20 190:14198:9 201:17,21202:16 203:19258:8 294:17329:4 337:17

338:5 345:7346:17 356:14

importantly 42:17184:19 352:21

imposed 335:5impossible 40:19

41:1,7 80:22156:13 209:15210:21 297:14,18298:18 352:3

impractical 37:21297:14

improve 32:22328:21 372:9

improved 13:1990:14 264:2

improvement161:3,10,11212:16 257:18

improvements185:11,22 315:17

impurities 161:5161:14 163:2174:7 298:15

impurity 184:13inaccurate 347:14inactivation 298:11inactive 53:21

157:12inadvertent 19:21

115:21 121:12inadvertently

356:2inappropriate 51:5

153:7 227:10248:5 266:12343:13 356:16357:20

incentive 286:17,21291:9

incentives 326:2344:14

inching 269:7incidence 24:17include 58:20

109:12,16 114:21170:4 195:19


215:2 225:20241:4 249:9262:14 299:11327:4 336:22347:22 364:7

included 20:321:16 148:15305:20

includes 110:14111:15 207:2239:20 330:9365:9

including 10:1248:20 65:10 88:889:10 90:21 96:21109:8 116:15,20124:8 149:9 162:9184:7,13 185:11186:15 223:22225:11 230:8256:8 267:12,12267:13 268:17295:19 321:3,11322:21 324:3352:20 368:4373:6,7

income 69:2incompletely 125:6inconsequential

180:12inconsistent 242:16

315:21incorporate 211:9incorporated 171:2

368:6incorporating 64:3

272:20increase 13:10 19:1

54:8 59:18 76:9165:3 173:17204:1 205:10215:10 231:14263:15

increased 32:1535:2 68:15 79:5126:10 191:21201:22 229:7

323:21 326:1363:2

increasing 172:14203:16 330:3

increasingly 20:834:6 340:20

increment 30:19incumbent 353:4IND 72:2 247:1independent 254:4

254:5 326:20independently

185:2 263:20India 68:5,12,16,20

69:1,13 70:276:14 77:13 78:178:15,16,17,1979:1 80:20 82:682:16 135:6210:10

indicate 249:18295:16 311:22

indicated 27:9Indicating 163:10indication 17:5,6

17:18,19 18:10,1125:16 74:3 78:6113:12 115:9116:12,21 119:19119:20,20 120:2,8120:9,14 126:16129:9 188:6,18,20190:1 202:7247:18 251:18,21252:8,13,16257:22 260:1278:7 321:15322:1 325:14342:20

indications 17:424:21 25:5,937:22 56:3 61:2111:6 113:13,15114:8 116:19,22124:4 126:14128:1,20 129:16138:1,2,7 139:20

148:17 149:17153:16 165:16192:20 193:2207:3 247:18248:14,19 251:11252:5,20 256:18259:1,7,19 260:4260:6,14,21264:13,19 303:5321:16 323:5,8325:11 341:6,12341:22 342:22

indicator 261:3indicators 148:3indirectly 23:19

282:3,8,13indisputable 68:21indistinguishable

70:20individual 22:13

66:11 115:15206:8 240:20305:10 324:16342:13

individualized136:7

individually 276:21individuals 69:2induction 360:3industrial 110:10industries 45:21

275:8industry 4:14

27:11 32:22 33:341:4 165:11182:12 282:1339:2,17 368:16373:7

ineffective 343:7ineligible 276:12infeasible 119:5

352:10inferior 152:22inferiority 37:19

96:2 118:1 188:9259:15 262:22

inflammation 59:7

inflammatory128:8 263:10

influence 169:1influenced 44:14influences 57:2inform 8:1 36:15

207:16informal 9:19information 7:5,14

19:17 20:10 28:1537:15 47:9 64:1,9105:3 135:9,14136:19 159:1166:22 196:21204:16 210:16211:16 212:1214:20 215:3223:21 224:15250:7 253:21255:3 304:16305:16 315:16325:9 338:6 340:5345:9,14 346:1,3346:8,14 353:5,13357:7,22 358:10358:21 359:5,6,7359:8,9,10

informative 38:5374:3

informed 92:9infusions 293:4ingredient 331:11

348:3ingredients 355:3,5inherent 111:14

193:15inhibitors 300:13inhibits 270:21initial 38:9 93:12

114:15 117:10168:22 245:3250:1

initially 310:13injectable 214:8injected 303:20injections 293:5INN 226:10 230:15

230:22 343:18,21innovation 32:20

41:5 88:13 285:22286:4 289:3290:14 291:7293:14 318:16327:9 328:11329:7 344:14

Innovations 6:20innovative 20:12

41:13 109:11110:3,9 123:22134:4,13 142:6144:1 185:22189:5 255:4 261:8291:11 309:19343:12 372:11

innovator 14:915:2 21:2 24:1848:15 65:17 83:11104:8,11,20 114:1120:1 129:8 132:2132:19 133:6,11134:18 138:13142:14 143:15146:15 150:10,18151:3,20 152:20158:12 159:11,21161:7 167:14185:5 187:1,5,9187:11 188:6191:16 192:21193:13 194:11195:11 196:5,15197:3,3,9 198:4198:15 199:22202:9 214:19,20252:7 257:15280:21 288:5,17310:10 314:4343:22 345:3,5,21349:4 350:6,11,18350:22 358:11359:9 366:17

innovators 40:1745:20 150:13210:5 277:2


309:18 310:6311:9 345:15

innovator's 17:3input 6:17 12:17

21:2 22:9 183:4293:11 369:14,17372:12

inside 201:9insights 28:10

255:17inspection 366:15

367:7instance 83:11

151:5 212:12213:3

instances 40:4 48:9128:10 312:5

insufficient 39:21insulin 220:15

229:8 233:15261:11 263:5

insurance 20:9168:10

insure 69:5 112:18114:12 160:19345:19 348:21

insures 114:16integration 33:18integrity 110:7intellectual 287:5intended 15:20

35:9 200:4,8265:10 322:5

intent 128:17 152:8277:1 278:3,18287:22 353:11

intention 330:6intentional 13:21

26:6interact 136:18

298:15interaction 300:11interactions 96:2

177:13 201:4204:15 300:2

interactive 304:20interchange 219:9

227:15interchangeability

7:13,16 18:2219:5 29:22 31:1,251:22 53:11 56:1357:14 59:9 61:864:4,16 65:1187:12 88:1 94:1198:7,19 99:5,1399:16 100:9101:22 102:16103:7,9 115:22124:12 183:11186:21 190:15,16191:1 192:13193:11,20 197:8197:18,21 198:1200:19,22 206:6206:13 207:7208:7,10,17,20209:2,9,21 214:16215:5 227:1 234:4248:22 249:13,16252:1,17,19254:19,22 255:3279:18 296:15299:17 303:6315:22 316:3319:16 323:1,3,4323:18 325:21330:18 334:11,15334:17,22 335:4342:2,3 343:14351:5 352:1,3,7352:14 353:18354:3,12,18356:17

interchangeable1:6 5:8 7:3,18 8:730:10,14 31:432:12 36:7 39:640:9 53:1,8,1792:7 101:4 103:3104:2 109:4122:17,20 190:10190:11 191:9,15191:16 192:6

193:1 206:10,11207:20 214:19248:13 251:6,10254:14,21 279:13280:14 300:1322:6,10 323:11323:13,19 325:7325:13,19 342:4342:11,17,20

interchangeables87:6

interchangeably101:1 323:7342:22

interchanges228:20

interest 12:8 28:2041:11 53:4 132:11137:17 171:2215:15 280:19281:13 282:10285:3 287:19318:18 319:18325:1 337:14

interested 6:16 7:811:18 21:19 31:1347:16 64:8 158:11176:21 182:13210:6 374:9

interesting 41:363:19 227:20255:6 350:19

interests 325:5interfere 5:16interferon 220:16intermediates

43:19internally 254:1international 4:2

218:2 227:21238:19 239:5255:14 292:13331:21 343:17356:9 365:19366:3,4

internationally356:12

interpret 289:7interpretation 8:2

173:9 251:16,22252:11 253:5346:19 347:5

interpreted 169:6170:12 289:7,9

interpreting289:22

interrupt 9:21interval 59:20 80:3

80:6,7 131:17139:4

intervals 342:16intravenous 24:12intravenously

155:19intrinsic 13:14introduce 8:10

116:4 239:5301:17 307:18

introduced 84:12156:15 177:21

introduction 34:1372:13 143:6155:22 168:19

Intron 109:12,16inventing 317:13inventory 155:16inverted 175:22investigation 72:17

187:20 247:3investigations

305:13investment 35:8

326:2involved 42:17

53:3 155:13156:19 217:17256:6 261:1

involves 129:20irony 291:3irrelevant 71:16irrespective 89:19isoform 72:14

84:18isoforms 72:12

84:4,12,14,15issuance 219:2

222:9,14issue 15:19,21

16:21 23:9 29:1530:22,22 88:18,2089:6 98:18 99:1100:10 121:2137:13 219:10,20225:5 227:3,13,18233:13 234:18254:13,18 262:21272:5 275:12282:21 289:11318:21 365:5369:13 370:1

issued 218:4219:14 220:9222:18

issues 7:10 9:312:19 18:1,2121:1 23:14 38:843:18 46:20 55:1088:4 89:4 97:1897:19 107:17108:10 110:22131:1 139:16144:8 212:9222:10 224:10229:6 239:9,14288:22 289:2,3293:12 302:19317:19 323:9330:16 337:17344:13 373:18

issuing 27:16 36:1372:8

item 160:11items 87:22 216:15

318:9iterate 93:21iterations 94:4iterative 90:14IV 17:22 204:11i.e 114:2 123:22

J


James 2:2 3:631:21 34:3

January 219:13283:1,3,6,10,12283:14,19,21284:2,4,6,7,9285:15

Japan 221:7302:11 335:22

Jay 2:2 3:4 12:12Jeanne 238:13

239:2Jenkins 1:19 8:16

8:16 21:13,1422:17 24:5 47:1,249:16 50:1 63:564:13,14 65:1377:10,11 79:13,2080:14 81:17 104:5104:6 117:4,5118:11 121:20,21132:9,10 133:13134:14 138:21,22153:11,12 154:11175:10,11 176:16178:20 180:19181:7 208:3 210:2210:3 231:17266:7,8 268:2269:6 309:16,17311:8,16

Jeorg 301:18Jim 32:1job 22:15 74:21,21

201:19 227:1,2,4311:7

Joe 199:4,8Joerg 2:19 4:10John 1:19 8:16Johnson 3:4,4

12:13,13 27:12,12joining 199:10joint 59:7 315:4Joseph 2:11 3:23

199:1Journal 227:19judge 243:12

judged 265:1judging 127:14judgment 25:14

90:3 91:21 92:592:11 148:4

Judy 2:13 4:2238:15,18,22

jump 122:13jumps 93:9,9jurisdiction 247:5jurisdictions 73:18

74:11 75:10,15221:8 241:16248:3

justification 72:2079:7 99:16 127:4188:7,18 192:7,17247:11

justified 73:8 74:1147:21 187:13188:1 189:9 247:8321:19 341:8

justify 92:17 98:5114:10 157:2241:1 303:3

J&J 21:17J.D 1:19,21,22

Kk 1:19 345:11 346:9

346:12 350:20,20Kasse 225:14Katz 4:19,19

364:17,17,20,21keep 9:16 12:5,6

82:22 110:13114:4 151:13200:1 289:3 308:3339:3 366:21367:15 368:13

keeping 112:14kept 81:12key 21:8 53:16 71:7

71:22 72:11 89:1796:10,11 110:22113:11 116:12119:18,19 120:1,8

146:9 184:12,16229:16 236:18243:5 257:8 258:2262:1 274:7 303:1315:14 317:19318:5 327:17330:1

kind 44:22 46:1350:18 52:11 86:12195:8 196:3198:17 232:21277:11,13,14,20280:6 339:2355:10 358:15366:6 367:16370:2,3 371:8

kinds 366:2,4 371:8Kingham 2:12 3:25

217:6,7,8 228:15229:20 230:3232:6 233:8 234:6234:12 236:5,20238:2

knew 253:9know 5:19 13:8

20:15 22:12 23:825:16 26:4 27:227:17,20 28:2,428:17 30:9,1345:5,20 47:1948:20 50:10,1551:9 61:12 63:1464:9 65:19 68:673:3 74:13 75:175:21 84:2,3 87:7101:13 104:3,18104:20 105:1118:13 120:5133:1 134:17151:6,8 154:8167:4 174:7 178:9178:12 179:1194:15 195:1196:9,10 200:3202:3,4,18 204:2205:5,6 210:21212:9 213:3,5

215:19,22 216:5224:6 225:12236:2 243:10266:22 270:20272:3 273:2 281:6289:12 299:19300:9 307:16313:18 326:14355:9 357:15365:18 366:11370:12,17

knowing 210:7knowledge 32:7,15

36:14 37:12 41:1248:4 63:13 157:16157:20 158:12166:1 201:6272:21 305:12310:12 311:15357:12

known 34:19 65:8200:13 235:1242:9 246:12247:21 253:19257:12 296:4,5,20297:1 321:4324:15 341:10,13361:3,21

knows 277:1357:14

Korean 221:9Kozlowski 1:20

8:11,12 25:2,326:2 43:13,1445:2,11,15 50:2163:4,6 81:1882:21,22 83:8,1783:20 84:1 99:22100:1,4 101:7106:15,17 119:17120:16 136:10,11137:15 150:6,7151:4 166:8,9167:2,6,11 174:2174:3,14,17178:18,19 179:5194:3,7 195:11

196:4 213:19215:17 233:3234:2,7 236:1252:21,22 253:6271:20 272:15289:5,17 312:21312:22 313:7314:1 338:1,2350:13,14 352:11353:15 354:1,6,9355:2

Lla 123:10,17 216:15lab 16:11label 159:7 186:10

195:13 215:1248:20 252:5271:9,18 336:10

labeled 193:8206:12 214:18248:14,16 251:11251:13,17 254:20

labeling 103:18,19214:17,20 249:17254:13,14,15,18255:1,4 319:17325:8,15,19343:10

labels 215:1Laboratories 3:9

67:3Laboratory 42:20lack 43:21 145:10

368:12 370:13,14lacking 164:17

247:11 270:13lacks 226:7 229:18lag 237:17land 330:5language 251:16,21

269:13 276:11278:2,2,18 281:22287:18 288:14,14350:3

large 15:14 16:1820:11 55:13 65:22


106:21 135:18209:11 213:8236:2 277:14286:21 360:8368:4,9

larger 65:16101:19 118:8180:22 259:14350:17,21 365:9365:19

largest 67:10 74:14235:15

lastly 142:11336:18

late 360:11latest 201:18late-stage 123:9Latin 68:2launch 67:14 68:17

76:14 78:14launched 68:4,12

78:14 79:4,6law 4:5 26:14 27:21

69:18 217:9227:19 274:20275:4,5 282:5294:1 330:6 342:3348:20

lawmakers 74:21314:22

layer 314:6laying 373:10lays 222:15 370:2lead 32:15 65:15

68:22 72:21 163:9180:21 184:19192:2 255:1270:19 331:20356:2 367:9

leader 109:7leadership 336:12leading 117:15

160:18 316:9317:11

leads 308:1learn 44:9 227:17learned 38:19

201:2 204:14228:12

learnings 44:16learns 27:1leave 69:22 132:4

156:3 281:2led 204:1left 6:2 70:7 77:17

77:21 216:16288:9

legal 13:10 230:9281:22 311:11

legally 307:17legislation 34:17

35:7 90:4 190:17219:21,22 220:4226:17 232:8236:16 237:18280:6 292:12339:19

legislative 217:14217:18 227:5230:13

legitimate 100:7,9Lehrman 4:18,18

359:20,20 360:1,4364:15

lend 64:6length 81:11

192:18 209:6362:7,10,21

lesions 154:5lessen 168:14 175:3lessons 38:18

228:11 366:1letting 370:13let's 145:12 151:20

153:22 221:13271:6 283:10

level 57:7,22 59:1563:14,15 84:1386:14 92:2,3101:13 107:3115:15 161:4,5177:17 190:19193:12 194:6,11194:15,18 195:8

198:13 236:3273:4 294:5308:11 335:4369:18

levels 56:5 128:8163:2 164:15177:12 195:22329:3 369:19

leverage 141:21leveraged 136:20

338:17Liaison 9:2license 248:18

281:15 295:21302:2 324:19347:9

licensed 7:3 88:296:11,15,16 102:8115:6 197:14302:5 319:21320:5,8 330:13

licensee 281:12licenses 284:15licensing 287:5

320:11licensure 245:3,13

248:7 280:18347:1 348:9,14

life 34:22 55:15135:17 183:2259:11 293:3297:13 328:13

lifesaving 35:167:16 68:19 69:6131:16

lifetime 103:13life-saving 173:18life-threatening

205:11light 20:17 29:19

206:5 207:22225:13 276:5283:8

Likewise 346:6limit 59:19 154:16

154:20 243:2247:9 248:4 271:5

280:10 348:14359:21 364:18

limitation 174:11limitations 10:10

35:5 341:19limited 33:7 34:6

49:1,13 50:1767:16 70:2 137:21149:4 162:6 168:9176:2,19 293:22327:5 340:22348:1

limiting 97:6 131:3202:2 247:12280:11,13

line 49:10 80:3104:7 130:4,5262:7 331:11

lines 91:19 110:15129:16 130:8173:12 280:13287:17

link 215:19 321:6links 237:8liposomal 262:18list 74:10 250:17

348:8listed 12:1 25:6

109:9literally 69:19

196:10 280:20literature 78:3

90:11 135:15253:20 261:19305:17

little 43:20 62:1285:18 98:17153:18 157:3180:3 231:18274:9 311:9 357:9371:12

live 5:5 317:14lived 291:20lives 293:6 317:15

328:22living 184:7 193:16

201:9 339:20

LLC 4:5LLP 3:25lobby 6:2,13local 141:7 146:17located 1:13 6:1,7

239:7locations 355:16lock 151:10locking 31:14

159:18London 217:10long 16:18 39:3

56:2 73:13 94:2159:12 174:5179:19 205:18254:5,7 259:17297:13 299:15332:19

longer 30:13 70:22103:5 223:5259:10 302:8311:2 317:14

long-standing356:9

long-term 38:13188:13

look 12:9 20:1129:15 65:6 66:584:5 93:13 95:1696:6 97:1 106:8120:11 131:7137:13 139:22147:19 161:15162:16 164:17176:22 195:13204:4 216:2 224:4224:6 231:10268:9 269:3,4272:19 273:10274:12 305:14319:7 336:19340:5 358:3,15,16

looked 59:12 97:18137:2 308:18371:6

looking 51:8 83:489:22 90:2,5


94:13 95:3 100:14106:2 141:6 154:1154:4 367:19,21

looks 287:14loophole 278:10

279:2 280:1,2,4281:3

lose 252:16 308:7loses 254:15loss 54:8 287:4lost 237:5 254:22lot 20:2 39:3 47:11

61:14 93:5 154:12155:13 158:14,19195:16,21 196:21200:13,17,18201:2 211:4 212:1212:7 214:9220:21 237:4253:11,13 288:8288:11,11 304:15305:17 307:8311:3 314:9 344:3344:5,9 356:19367:12

lots 112:2 115:15143:14 267:3

lot-to 158:18lot-to-lot 39:1

44:19Louis 199:11love 149:12Lovenox 279:15

367:22low 119:9 140:6

194:10 195:6196:16 220:16248:11 260:11330:6

lower 59:19 86:799:11,20 119:10170:17 244:10269:10 270:12,15339:22

lowering 330:2lower-cost 88:15lunch 6:10 11:14

194:5 216:14lymphocytes

128:14lymphoma 70:10

135:18,18 138:8

MMabThera 78:10

78:16magnitude 129:10

186:4main 44:6 52:8

98:22 236:8 308:5maintain 235:22maintaining

285:19 344:13major 14:8,12

74:17,17 84:14,1586:12,13 107:19111:1 160:9 161:2174:21 203:11222:4 226:2227:19 258:18265:22

majority 11:2274:18 221:11228:16 275:6288:20 354:22

making 28:7 38:1038:14 84:3 90:3157:17 158:10174:4,18 181:3182:1 203:3240:20 323:3333:13

malignancies271:14

Maloney 1:21 8:208:20 102:18,19120:21,22 212:5,6213:1 236:14,15

manage 116:2235:4 337:8

managed 13:1827:4

management 9:8124:8 150:21

152:12 182:15225:21 256:22264:9 282:14

mandate 36:178:20 97:12232:15 307:19328:21 329:4

mandated 215:16mandating 333:21mandatory 232:9maneuver 288:9manifest 38:8manner 148:20manufacture

171:22 172:8181:14 185:9292:16 363:19

manufactured 30:397:2 171:17177:15 184:6239:21 299:12313:1 364:5

manufacturer14:11 39:17 43:1543:22 46:12 88:9103:12 168:7200:13,17 205:4211:4 231:21238:8 253:15280:17 281:12307:8 331:9 344:6350:12

manufacturers21:5 28:17 74:19115:13 205:15,20217:13 224:2225:1 228:17230:19,21 292:18317:7 328:18

manufacturer's159:6 226:19233:14 237:9

manufactures21:18

manufacturing14:8 45:17,2256:22 61:9 90:3

91:16,19 93:10,1597:4 100:16 101:9102:22 105:11110:15,16 111:19112:15 143:22144:5 149:11169:15,18 170:22173:16 174:5176:12 178:22179:19 184:11185:12 193:16203:12 204:13219:18 239:22258:19 266:1296:8 298:9299:20 300:17303:18 331:9332:7 333:13337:9 366:16367:7

mapping 160:17Marchand 1:21

8:22,22 85:9,10311:17,18

margin 30:1751:17,18 59:1596:2 118:1 263:17271:5

marginable 138:14marginal 73:16margins 118:12

126:8,13 140:5147:20 177:2

Marie 2:20 4:12317:2,5 371:20

Mark 1:22 2:4 3:119:5 87:15

marked 309:20marker 261:20markers 85:7

128:9 148:1261:11

market 19:1031:10 34:9 46:1748:8 67:10,1568:14 69:19 74:1776:8 92:8 100:6

100:19 101:17103:6 151:11,21159:2 162:13163:8 167:9 191:2235:12,18 237:19277:2 278:7 294:5302:17 313:20323:7,14 327:2334:14 335:1349:7 351:9354:20 372:16

marketable 23:19marketed 15:14

23:16,17 68:273:18 82:7 231:2231:5 314:14335:18

marketing 151:2152:5 219:6221:16 225:18264:9 281:15310:4 312:10353:14 354:19

marketplace 34:1469:12 74:22 235:9286:5,10 288:10291:8,10,15

markets 21:1767:17,20 68:7302:17 307:15335:19

Marking 365:1Mary 2:18 4:8

292:6Maryland 1:14maspec 160:17mass 202:13master 91:18match 363:20matched 160:20matches 172:20material 172:11

179:6,8 181:20313:1,2,3 355:8361:16

materials 149:20201:10


matter 12:17 25:13108:17 174:4216:21 230:18316:21 334:12

mattered 215:22matters 28:12

304:2maximum 336:4McCAMISH 2:4

3:11 87:15,1798:22 99:21 100:3100:10 102:1103:8 105:4 107:6111:11

Meador 34:3mean 25:10 49:9

78:22 87:6 143:2151:17,19 156:7166:15 174:19200:14 202:18215:20 228:22258:4 260:7 270:7271:18 274:11289:10 290:7303:7 305:3 317:5

meaning 30:9103:9

meaningful 14:716:5,6,20 19:1726:17 47:20 53:2271:12 72:21199:18 258:14269:14 298:17334:14 341:1

meaningfully118:18 119:3

means 53:18 56:8161:4 168:6200:20 202:5207:7 274:13289:13 360:9

meant 54:13152:15 274:4354:10

measurable 13:9242:12

measure 15:6 16:7

59:7 65:3 80:1185:1 261:21 268:4268:7 298:18

measured 15:1016:13,14 127:11128:3 240:5263:11

measures 16:11,1565:9,10 219:6

measuring 274:7mechanism 17:7,10

25:4 26:1 54:1,2113:15 120:17125:18 148:18149:18 165:17247:19 252:19257:13 259:18264:20 322:2,3341:9

mechanisms 72:15120:6 129:21130:9

mechanistic 157:16media 10:7,9 361:4mediated 188:16mediations 69:7medical 5:11 20:9

32:1 89:9 213:3275:7 322:15339:21,22 373:20

medication 213:22medications 18:7

35:1 67:17 128:21356:5

medicinal 220:8295:11

medicine 294:10332:12

medicines 4:9169:20 172:14173:18 214:7,8220:7 223:10,20227:3 301:15,20317:13 319:8321:13 324:18329:5,17 337:2343:10

meet 26:16 89:9124:6 144:4 159:4159:8 248:21249:1 251:22319:3

meeting 9:19 10:1452:21 57:9 347:3373:18,21 374:1374:18

meetings 221:22249:14 266:9

meets 174:6 326:19344:16

Mehta 2:5 3:13108:20,21,22117:20 119:6120:7,19 121:10122:8,19

member 222:20227:11,12 232:16234:4,13,17,20235:2,5 275:10294:4 328:16357:10 369:15

members 1:17 8:109:22 10:22 199:5282:17 302:5,9,10329:15 363:3370:20 371:17372:11

mention 51:1 85:15194:8

mentioned 25:426:3 43:17 63:1484:2 105:7 107:10118:13 125:7153:12 156:18214:17 215:18229:18 253:7268:2 270:6 294:2352:12 354:13355:3 374:11

mentioning 156:12Merck 3:12 109:1,5

109:17 118:11155:20

Merck's 117:17

mergers 287:6message 199:14messy 277:11met 42:8 252:3

368:2,2method 169:15

171:4 179:17methodologies

296:8methodology 143:9methods 32:5,8,21

33:6,17 145:14160:19 242:22257:19 298:9300:17 320:16

metrics 337:1mice 195:2Michael 2:5 3:14

123:3,9 238:18239:2

micro 111:16Middle 68:3migrate 26:21milestone 292:11Miletich 2:11 3:23

199:1,3,4,8208:18 209:10210:13 211:13212:15 213:7214:3,21 215:14216:1

million 108:6,9171:9

millions 203:6mimicry 169:10

170:11mind 35:3 104:14

110:13 112:14114:4,9 119:15180:20 308:3,4366:21 368:14

mineral 154:2mines 330:5minimal 56:4 57:22

157:15minimally 186:1minimizing 336:6

minimum 162:3321:20

ministrations 56:7minor 53:20 72:3

84:17 85:2,686:17 157:11163:10 176:9240:1 258:11274:6 279:20305:8

minority 285:2minute 164:10

316:17minutes 10:21

359:22 364:18misread 121:22missed 280:5missing 212:11mitigate 115:21mitigating 66:3mixed 362:5mixture 362:22

363:1mixtures 364:7mobile 5:16modality 170:15mode 124:21,22

125:5,9,12 130:11130:16

model 49:16 50:4,850:9,16 58:2259:2 64:15 74:2,6176:21 209:20244:8,13 273:6366:6 370:5,7

modeling 62:1864:10 332:21

models 145:5,7,10195:7 273:7

modes 129:14,20modest 18:14 171:7

258:12modification

177:19modifications 72:4

72:10 84:7 90:2291:2 137:8 169:12


172:6 173:4177:16 178:1180:4 184:15321:3 327:6346:16 347:22

modified 151:7170:1 347:15362:4

modify 91:1 106:11238:8

molecular 146:4149:2 199:9,12220:17 320:1,17321:7 322:2 360:8

molecule 18:9,15172:19,21 173:2176:3,4,6 177:14177:22 178:7,13181:1 184:5 240:4240:8 242:21243:5 265:18277:8 279:16298:14 340:17361:12 368:3,4

molecules 49:1974:4 124:14 131:5157:22 180:5185:5 201:16,20202:11 204:1216:6 270:18329:21 361:18363:11

molecule-by-mol...177:11

moment 153:3202:2 254:11290:3 349:16

Momenta 3:531:21 32:1,3 90:2

monitored 107:21263:20

monitoring 30:6121:2 162:8,8

monoclonal 55:2261:19 124:22125:19 220:19222:5 223:4

260:15 263:9267:15 283:3,12283:20 284:5,16284:20

monoclonals124:15 125:2,8260:17

monopolies 69:5monopoly 76:2

77:3 335:8month 171:9

284:13months 223:3moot 133:18morning 5:3 6:4

31:22 52:17 61:1764:2 66:21 108:21140:15 182:14,17198:21 199:1216:12,13 351:19

mouse 74:6move 43:7 69:21

225:4 374:5moves 42:10moving 74:9 89:10

96:5,11 99:17108:4 143:9 271:3343:8 371:22

MRI 154:5multifactorial

193:17multiple 18:8 95:15

95:20 112:1143:14 148:17190:18 192:11,20198:3,5 199:20204:7 222:21241:15 259:7260:5,18 276:1278:6,21 284:19286:6 290:17291:13 304:11323:18 324:10332:17 362:1

multiplicity 60:19mutually 70:22Mylan 328:14

M.B.A 2:4M.D 1:18,19,20 2:2

2:2,3,4,5,11,21M.P.H 1:18

Nn 85:14name 19:15 52:18

67:1 108:21 121:4121:11 122:7,11123:9 182:12,14198:18 199:8211:21,22 217:8226:5,9,14,15,15230:16 231:5,6,7237:11,11,13255:19 275:1301:17,18 307:7315:12 324:12325:5 328:12334:4,6,10 343:18343:22 344:5357:1 360:4362:13 363:22364:21

names 121:18122:6,10 204:7205:22 211:7213:22 218:2226:11,14 230:1,9230:11,21,22231:3 232:19233:5,11 307:4316:1,8,8,11355:20 356:10

naming 19:21,22121:2 212:8229:19 307:3319:16 330:18334:1 343:10,19355:19

narrow 94:7 140:5narrowly 243:18Nasr's 45:13national 221:3

236:3 344:3nations 366:7

native 295:2natural 160:16,16nature 30:15 33:22

36:16 66:13110:14 116:3187:4 224:9 305:8355:6

NBC 307:8NCE 50:20 51:18NDA 346:4NDC 121:7,16

211:9 344:3,9356:19

NDCs 20:2near 20:18nearly 328:19necessarily 26:14

50:18 51:14 137:6137:9 153:1 180:5222:11 271:2279:13 353:7

necessary 17:1018:17 73:2 87:298:1,9 99:7 113:8128:4 130:9143:10,18 146:3149:5 163:20164:3 178:4188:12 192:18204:19 206:19241:6 247:14249:1,8 252:18259:14 306:2307:5 308:21312:16,17,18313:9 332:15,22345:19 351:8352:6 372:13

necessity 294:7299:10

need 15:22 17:1320:6 25:12 28:1734:18 36:22 43:453:14 54:22 55:755:8,12 56:4 57:559:16 61:10,1263:10 72:4 88:15

111:4 121:3 125:7126:13 135:20139:22 146:18147:8,17,19148:10,12 152:7154:21 156:20160:3 161:14180:8 187:12191:17 194:8,13194:18 195:8,22198:13 203:1205:6 206:2,7207:1,8 209:18,22210:16 212:13225:17 232:3236:18 252:2253:10 257:6258:10 264:1272:1,9,13,18289:2 298:22305:5 306:15308:17 310:21312:2 326:1327:14 333:15358:15,16 365:3366:5 368:2,5

needed 14:9,1415:11 25:20 35:1948:15 166:14186:20 192:16213:4 219:20241:9 245:1246:21 255:22315:17 342:15

needing 267:21needs 25:14 31:5

49:4 56:16 61:689:9 119:13131:18 136:9143:19 144:1146:7 147:13148:19 149:22153:9 193:9 257:2261:16 304:3,7305:14 308:20339:21 363:8368:1


negative 228:13negatively 372:21neither 13:8 38:4

344:9net 125:4 130:15neutralizing

106:22 107:4108:1 170:20188:14 189:17

never 89:3Nevertheless 143:3

260:21 358:8new 1:14 8:17

17:19 18:4,1119:18 31:11,1235:6,14 72:1481:12 84:12 90:491:18,19 93:14100:21 104:4118:16 124:19137:2,2 141:14142:12 143:7146:3 149:2156:20 169:20173:12 187:14204:16 222:4226:8 230:22252:7,13 257:11258:17 259:8265:21 267:8278:7 289:15295:14,15 301:22313:20 318:7324:14 326:3330:4,8 331:4,8331:10 333:4344:21 348:22349:2 363:16372:21

Nick 255:11,20Nikhil 2:5 3:13

108:20,22NK 130:9noise 237:5nomenclature

213:20non 37:18 56:21

61:8 70:9 73:2296:1 117:22 142:5144:8 188:8259:14 262:21274:5 341:19344:4 356:9,22363:21 366:16

noncomparative80:15

nonpolitical 131:3nonprofit 365:2nonproprietary

122:4,6 211:21213:21 218:2226:13,15 230:1230:20 231:5

nonvalidated 127:6non-clinical 39:19

41:22 124:1 143:9144:15,20 145:9145:12,19 147:1203:14 241:1,11241:18 243:16244:19 246:15,18246:20 247:7260:2 267:13303:4 341:3351:13 357:18358:22

non-clinical/clini...149:4

non-comparative244:5

non-EU 314:11non-human 195:3non-identical

239:22non-inferiority

48:12 51:3,13,1660:8 95:6,12113:9 117:14118:14 126:8131:14 259:2262:5 263:15264:14,15 267:19270:5

non-innovated

156:20non-innovative

277:18non-innovator

278:22non-interchange...

215:4non-proprietary

211:6 307:4 316:1316:11 325:5343:17

non-U.S 23:2 88:296:10,15 115:6142:5 149:20154:15,17 218:6248:3 365:6,12,13366:13

normally 170:7230:14

notable 279:13notably 113:21

164:4note 6:6 20:6 45:12

113:19 133:13294:17 347:4349:3 369:2

noted 17:6 132:11237:17,19 238:22247:6 250:8296:14

notice 11:22 12:212:20 301:1317:20 318:10319:15 326:7,16330:17 345:6,14347:1,11 374:16

notwithstanding157:11 326:14370:12

nourished 201:10Novak 238:13

239:2Novartis 3:10

87:16,18 88:689:7 97:7

novel 37:6 38:1943:3 73:8 88:10

89:8 94:4 171:4299:3,6 348:19

NOVEMBER 1:10novo 50:19number 39:1 62:17

68:14,18 78:16,1781:1 106:20 107:3119:7,15 121:7147:22 173:17178:15,16 188:1192:15 200:13,18209:7,11,11 211:4211:9,14 212:1220:14 223:19225:10 234:8235:9,15 272:17279:3,22 280:9290:12 293:1,19303:2 304:10307:8,8 349:15355:11,15,21365:16

numbered 132:12numbers 15:14

20:2,2,11 53:1260:12 62:20,21344:3,4,5,9356:19

numerous 296:22300:3 362:13

Nuron 3:18 155:6,9155:20

N-glycolylneura...170:5

OO 338:9Oak 1:13objective 70:8

77:22 78:4,9 80:480:7,12 308:5

objectives 309:9objectivity 42:12OBP 42:22observation 162:10

162:14observed 44:19

80:9 112:19 164:5189:20 243:19

observing 44:5obstacles 35:22obstruct 372:5obtain 159:1

252:15 293:11345:10 347:17348:13 355:14

obtained 7:6obtaining 223:9

355:4obvious 280:2obviously 11:19

44:21 50:19 53:1764:5 66:9 194:8194:22 236:20355:4 361:15374:12

occur 16:12 30:19159:10,10,11170:21 173:6208:10 234:1300:10

occurred 104:20228:21

occurs 207:6October 220:1,5offer 35:14 36:3

200:9offered 140:17

165:8offers 32:21 34:15

141:20 165:12223:19

Office 8:12,15,179:2,3 49:17155:14 201:1373:20

officer 1:14,18 3:25:13 32:1

offices 217:11officials 182:12oh 123:3 200:5

310:14 317:2354:1

okay 31:16 80:14


82:14 83:8 106:14108:12 117:7122:22 123:3140:11 153:14,20159:14 196:19234:12 238:17269:11 311:16316:14 317:1353:21 360:2368:21 373:13

old 31:14 100:21103:5

Omnitrope 231:3once 31:9 54:4,6,17

58:14 91:8 94:6101:20 158:2162:12 166:19,21288:22 323:6

oncology 38:1695:13 126:22127:2 129:20130:1 132:15138:8,9 154:9262:3 263:10266:12 267:17268:6

onerous 151:3ones 16:5,6 56:14

71:16 216:6 223:7225:1 236:12

ongoing 37:2 92:22105:7 327:15

on-rates 178:7open 4:17 11:7,16

20:22 22:7 28:15113:14 133:12134:9 147:14154:21 156:4167:22 221:20318:15 327:16359:18 374:8

opened 5:20Opening 3:2openly 224:18open-label 116:21operability 147:7opinion 49:7 73:16

84:19 86:3 103:1155:8 198:6

opportunities141:4 259:3 318:1334:14 367:16

opportunity 32:2234:16 42:16 109:2123:12 140:16141:8,21 155:8166:3 169:19199:6 238:21250:19 255:16275:11 292:10293:20 301:22309:4 317:16328:8 339:14349:9 360:14374:13

opposed 81:14151:3 267:1359:11

opposite 266:10291:1

optimal 7:17options 231:13

327:9 368:13oral 11:5 209:12orange 78:2order 9:16 13:10

16:18 21:8 61:9104:1 142:1 146:8202:20 232:22238:9 319:2324:17 358:4362:11

ordered 10:15ordering 362:8orderly 361:12ordinarily 226:10ordinary 227:8,14

234:16organisms 184:7organization 4:14

67:9 186:16292:14 294:11339:17 374:1

organizations 9:14

275:6 369:10organizers 292:9oriented 238:4origin 97:11original 59:21

65:20 70:1 114:2131:10 188:5257:6 304:6,6,10304:22 310:17326:17 347:20

originating 111:17originator 66:12

68:9 70:11 78:492:20 93:12,14100:16 106:7,12108:7 112:8113:20 158:17333:12

originators 311:5orthogonal 33:17

242:22 320:18osteoporosis 154:1ought 366:20outcome 16:4 59:3

127:17 136:3268:16

outcomes 16:17127:12 128:11203:9 297:20321:8

outline 93:11 94:20156:8

outlined 94:13186:10 322:21

outlines 57:1392:19

output 165:3outside 102:8

109:13 160:18195:16 218:18225:10 241:10247:5

out-the-door 175:3ovary 34:1 170:2overall 78:17 127:2

133:1,10 138:17154:7 178:15

192:14 228:11244:21 262:3,15266:15 370:2

overarching239:19 250:2

overlap 254:8overlapping 96:17

332:14overnight 105:19overriding 183:13overview 67:21

370:8ownership 282:10

285:3owns 282:8

PP 2:2,11 199:1pack 134:3package 48:20 49:6

49:11,15 50:1351:11 52:11338:18 351:10352:20

packaged 201:12packets 23:3paid 229:4painting 196:16pair 365:21panel 1:12,17 8:10

9:22 10:22 12:1521:12 43:12 52:2162:2 77:9 98:12117:3 132:8 150:5166:7 168:1 169:3174:1 181:18194:2 199:6 208:3228:5 266:6275:10,18 287:11301:11 309:15327:22 337:22339:7 364:14368:20,22 369:4373:14

panelists 250:22paper 33:21 371:12papers 222:9

paradigm 35:16139:10 157:14250:16

paradigms 181:2paragraph 277:8

277:10parallel 57:17

223:12parameters 14:19

30:18 124:19147:16 243:14270:19 274:7

paramount 41:2042:4 116:7 256:19264:6

paraphrase 12:21PAREXEL 4:4

255:11,13,13256:3 267:4269:20

Parliament 220:4part 1:6 5:6 10:5

19:4 23:8 24:329:15 145:9,19155:17 162:15166:19 197:3,3226:4 231:6253:18 255:13268:8,10 277:16277:20 278:15280:6,9 292:9299:6 338:9 342:3365:9

participant 9:21,22participate 140:17

222:21participated

141:10 217:21256:3

participation 12:9229:3 374:19

particular 28:19,22124:15 126:12136:7 153:9163:21 165:10189:16 191:4,20213:10 215:12


218:19 221:16231:4,16 240:16270:5 298:16341:17 373:21

particularly 15:1638:5 52:20 55:1957:4 157:6 162:5163:18 165:2,5218:6 225:12241:8 258:11300:14 341:20374:14

parties 11:18182:13 222:22374:9

partner 217:8parts 18:8 134:20

183:2 218:10277:15

pass 144:7 289:1passage 339:18passed 134:1

318:13passes 119:11pasted 276:4patent 275:1 291:4

291:5 345:8path 200:3 338:7pathway 1:6 5:7

7:1 27:15 34:1235:22 36:10,1240:22 42:13,1443:8 52:22 65:1866:1 67:7 77:1392:17 109:3 132:3133:11 140:10149:10 165:12183:6 186:2 193:7206:21 220:2302:1 309:3 318:4318:7,13,15319:12 320:15330:4,9 331:4334:3 335:2344:15,21 349:20350:1,21 370:3

pathways 8:3

217:15patient 6:18 20:16

34:5 41:19 42:2,347:12 54:13,1655:1 58:3,6 60:1267:16 68:10,2270:15,21 71:575:5,22 76:1,3,1076:13 79:5 100:12100:15 101:11107:21 112:10114:8 115:15116:6 168:10,13168:15,21 172:8172:14 175:5183:14 184:2187:17 188:5189:4 190:4,13191:7 192:2193:18 196:1202:6 214:1246:16 248:15251:12,17,18,20253:2 256:19257:15 260:8264:5,16 271:8,13275:15 286:9,15290:14 291:18297:12,21 298:16299:1,7 300:3,12303:21 309:11318:13 319:18321:10 322:17325:1,6 330:3333:5 335:10337:9 341:15342:6,8,13 343:8343:16 356:3365:1 367:16368:14

patients 15:1419:13,22 20:1234:8,11,18 36:441:17 42:5,1748:7 58:15 60:3,960:21 68:14,1870:6,9 78:1,17,17

79:12 80:21 81:281:13,19 82:1785:5,17 92:995:15,21 96:7101:2 106:20,22121:14 126:20130:1,2,6 140:1,3151:22 152:4,7168:9 169:21170:9,19 173:18184:22 185:20186:7 188:2 189:7189:11 190:18,21193:11 195:18199:11,15 200:1203:6 205:2 206:2206:7 207:8,11,20209:7 212:3213:14 215:15240:8 265:10269:2 286:11293:4,19 297:21300:14,19,21303:11 308:6317:13 319:10320:3 321:14322:4,9 324:9,17327:10 329:18335:11 339:20343:2,5 344:10356:1,21 365:10365:17 366:21368:10

patient's 128:22205:13,18 211:15

patterns 170:4Patwardhan 2:4

3:9 66:20,21 67:177:20 79:17,1980:2,17 82:1,5,1082:13,15 83:6,1383:19,22 84:886:1

pause 23:6 88:17pay 30:5 125:7

175:6payer 103:21

payers 92:8 335:11paying 366:22payors 206:8pays 75:22PBMs 207:13PD 61:6 85:7 91:5

115:2 146:1147:18 148:1,5164:5,6,13,17,20164:22 166:12,14166:19,20,21261:11,14,15,19268:11

PDUFA 349:3373:2

PEG 109:16peglylation 327:7penetration 18:13

235:12 237:20people 11:12 40:22

45:8 65:17 121:6212:12,17 229:2288:11,20 310:14

peptide 169:11361:22 362:5,7,22363:1,16 364:2

peptides 361:9,17362:6,18

percent 30:1759:14,14,18,2080:6,9 95:5107:18 118:21,22136:1,2,2 172:12194:12 195:13282:9,17 291:20291:21,21

percentage 106:22percent/90 118:22perfect 237:8perfectly 56:8perforce 170:13perform 213:14

246:13 259:14262:21 263:14

performance180:13 307:20

performed 115:7

241:7 257:7 341:4period 8:5 11:7

56:6 101:11103:10 222:13,17272:13 276:12277:5 278:9 279:8281:8 283:5,6,14283:22 284:1,8285:14,16,17,20286:7 290:12311:2 326:5,6,13326:16,18,21,21347:8,13,18,19359:19 374:15

periodically 348:8periods 223:3

276:1 285:22286:3 290:18291:13

permissible 160:10permit 143:6

247:16 335:15351:7 363:13

permits 11:8356:11

permitted 10:914:1 143:5 346:13357:6

permitting 34:18208:9 241:14336:2

person 373:17personal 89:6

155:10 237:7personally 154:7perspective 21:20

81:12 89:7 99:2101:3 110:22111:3,20 120:12137:19 139:15,21169:4,6 211:15269:22 352:15

petition 94:9367:22

pharm 147:2pharmaceutical

4:13 45:16 69:4


275:7 317:7,11328:4,9 330:2360:5,7

pharmaceuticals3:5,15 31:21 32:2140:14,16 329:2

pharmacies 207:13pharmacist 104:3

237:13pharmacists 92:8

323:8 343:1pharmacodynamic

16:8 55:11 56:18244:9,12 261:10268:4,7,11,19

pharmacodynam...49:21 55:17184:18

pharmacokinetic55:10 56:18145:20 147:7,15244:8

pharmacokinetics15:5 49:20 55:16172:22 184:17244:17

pharmacologic171:13

pharmacological258:6 265:16

pharmacology145:17 146:1155:15

pharmacopeia226:11 230:16

pharmacovigilan...7:17 20:7 27:6116:3 121:4,17,19124:9 152:2,12162:15 225:22231:19 234:10235:21 249:11306:15 307:1319:16 324:3,7325:3 343:9 353:2356:13

pharmacovigilant

19:8pharmacy 190:19

193:11 235:4Pharm.D 1:21phase 87:9 244:15

257:4 309:1phased 95:1phases 105:17phenomenon 69:16phrase 41:20phrasing 326:15PhRMA 4:11 317:3

317:8,10,20318:20 319:12

PhRMA's 317:17318:8

PHS 295:16physical 90:16

176:8 240:2 242:6242:11,20 257:19258:4 265:5,14308:19 332:10

physically 308:10313:12

physician 190:19199:9 237:12

physicians 92:8121:15 323:8343:1 356:21

physician/pharm...115:20

physicochemical114:22 143:8175:14 176:1,18245:8

physiochemicals295:8

physiological 263:2263:12

Ph.D 1:22 2:4,4,5,62:6,7,9,10,11,132:14,15,19,20,21

pI 242:7pick 59:10 95:11

97:17,17 107:16107:19 120:14213:1

picked 63:3 65:2picking 147:22

212:6picture 283:18piece 367:3piggybacking

285:16pill 233:22,22pilot 171:7pinpoint 216:9pioneered 302:10pioneering 141:13pipeline 67:22

368:10pivotal 66:9,10,11

96:21PK 15:17 30:18

61:6 91:5 115:2164:4,5,16,19166:12 173:8

PK/PD 65:10145:18 156:6166:14 167:3175:20 244:18,19245:11 248:9265:7 309:1

PK20 30:17place 48:16 61:11

68:13 210:20223:15 225:17237:2 292:1 304:5305:1 306:17312:14 313:3344:4 368:14

placebo 59:21259:9,10

placed 34:11162:12 225:16

places 29:15210:12

placing 231:20plan 67:14 167:14

187:21planned 203:11

244:19planning 6:3plans 225:21 294:8

317:20 355:7plant 171:7,18

173:13plants 171:4,22

172:9 173:13366:16

plasma 4:8 164:12292:6,15,16,17,18292:20,22 293:5293:18 294:13295:2,5 296:3,9296:16,21 297:10298:5 299:2,22300:8

platform 45:8platforms 41:10,14plausible 94:22play 16:9 37:8

120:18 158:14199:18 262:1339:1

played 225:9please 5:15 6:6,9

11:21 216:19251:14 349:16359:21 361:19364:18 369:4374:7,15,16

plus 143:17 149:3167:4 344:1

point 11:9 31:344:6 46:6 52:6,954:11,21 55:157:18,19 58:5,859:4 70:16 78:778:12 90:6 121:5133:18 167:11172:8 174:4,20180:14 202:22203:19 205:18210:11 212:14214:7,14,15 220:2221:19 224:14,16224:19 227:18233:2 254:14270:1 284:14,17286:16,19 287:2

290:13 311:21338:14 349:17352:9 360:20367:11

pointed 55:9points 16:2 21:8

35:4 44:8 63:2150:19 196:20280:6 366:11371:4 372:18

policies 282:14318:2

policy 5:11 8:15,2110:6 29:5,1036:22 40:20 52:9199:15 201:5366:4 373:20

political 224:9polypeptide 362:15polypeptides

360:19 361:3population 18:4

25:17,18 101:11101:19 115:8,8120:18 141:1168:21 188:5193:8 260:8 261:2264:16 271:13297:12 342:13353:8

populations 100:13100:15 114:8120:5 129:2,6193:18 248:15251:12 257:16299:1,8 321:10341:16

portfolio 109:5portion 118:2posed 87:5poses 111:9 282:12position 27:18

46:15 52:2,3 71:775:9 84:9,21121:3 133:3,20139:14 196:13197:6,12 198:12


222:12 227:6259:17 290:2,7291:1 312:8 334:8356:9

positioned 37:1341:21 47:6

positions 69:21139:14 183:4294:15

positive 22:6 108:2116:11 117:8,18228:11,12

possibility 52:8135:22 179:14223:8 264:3352:13

possible 9:17 25:2226:4,7,16 49:1252:5 56:9 66:270:18 78:22 82:19116:15 130:17142:13 169:4181:4 187:14200:16 201:19205:2 206:13211:16 213:15215:2 259:20262:15 270:11278:14 279:7,18304:22 313:21315:19 331:5353:6,9 354:18

possibly 225:22251:3

post 40:5 84:690:21 104:1 124:7149:10 151:1,10152:4 162:8166:18 167:8169:11 177:15,18184:14 209:7219:5 249:10264:8 303:18312:9 323:15349:6

post-approval142:11 162:8

167:1 312:14,15post-change 91:22

92:6 143:5post-market 81:20

150:11 151:8167:14 349:5352:13 353:3,10353:19 354:2,10373:1

post-marketing70:4,12 73:2076:18 79:10 85:1586:18,22 87:9150:8,17,20 152:1152:11 162:7208:17,21 225:4256:22 312:6324:12 367:10

post-marking162:14

post-product103:14

post-translation91:2

post-translational72:3,9 170:3172:5 173:4 178:1242:13 321:2327:6 348:2

potency 32:19 54:194:17 125:17145:17 184:20203:16 215:10279:5 289:9,19290:6 302:19326:11 330:12332:5 333:20347:17 348:5

potential 25:6,1534:7,11 36:3 38:241:15 43:4 46:1973:9 103:16 118:3119:22 120:17128:13 129:3131:4 174:8176:13 184:9186:6 188:22

189:3,17 190:8191:6,13 192:2195:18 198:3,7207:11 245:20249:9 261:6 270:9276:5 300:6323:12,17,21332:12

potentially 24:1432:11 34:22 36:737:8 40:8 135:17169:17 170:9172:13 179:3190:2 194:14198:4 205:11261:20 296:20313:5

power 59:13 60:1874:8 81:1 82:1695:4 282:13313:15

powered 73:478:20 96:7 107:11107:12,12 126:2

powerful 20:10127:20

PPD 3:7 52:16,1953:2

PPTA 292:13293:10 294:4,12295:2 296:2 299:5301:6

practical 36:6200:21 207:1230:17 262:5,12294:5

practically 69:3practice 58:14

81:15,21 230:18practices 234:22

238:9pragmatic 23:13

69:10 71:4 86:20107:8 230:4

PRCA 24:16 205:9205:9 225:6,15

pre 72:1 91:12 92:6

103:13 104:1143:5 165:13249:10 262:15303:18

preamble 71:6precedence 262:17precedent 240:15precisely 16:13

35:13precision 127:12

261:12preclinical 246:22

257:4 267:11308:13 320:15

preclude 207:15precluded 223:12precludes 27:21preconditions

249:11predecessor 280:18predefined 39:4

126:7 144:3predicated 142:6predict 73:5 85:5

127:16predictability

318:19predictable 333:6predicted 14:17predicting 341:21predictive 340:22predominately

157:14preferred 49:21prefix 211:7prefixes 307:5preformed 248:2prelicensing

249:14prepare 348:7prepared 370:21prerequisite 73:7

73:15 320:14prescribed 356:3prescribers 47:12

119:12 233:4344:10 356:1

prescribing 325:2prescription

237:13prescriptions

328:20presence 67:9

72:12,15 305:18present 1:17 11:6

18:18 71:7,1872:13 84:10,11166:3 170:22222:6 240:10255:16 297:13318:5 339:14340:21 341:19349:9 374:13

presentation 9:159:21 10:13 11:521:15 27:9 33:1242:19 43:18 77:784:2 98:15 136:12140:19 156:2157:4 164:12239:2 296:12311:19 340:4372:19

presentations12:12 373:16

presented 147:9150:8

presenter 10:1,2,4364:16

presenters 2:1175:16 355:12

presenting 49:6239:1

presents 42:14,16190:2

preserve 326:2preserved 345:21preserves 118:1preserving 330:12

336:16President 52:18

182:15 317:5339:16

presiding 1:14,15


1:18 3:2 5:13pressure 165:3presumably 35:12Presuming 71:17presuppose 279:4pretty 135:3 214:6

214:8 228:18238:5 266:10310:9 370:7

prevent 121:12278:4 280:21294:7 325:20

prevention 109:7prevents 190:3previous 43:17

111:11 153:14167:13 233:19241:13 326:11346:5

previously 244:4247:6 255:6 294:2

pre-change 40:591:22

pre-clinical 36:1036:16 37:4,7 91:591:10 98:5 131:8136:17 137:5,10161:21 175:20195:7 203:10359:7 370:10

pre-market 24:22167:7 229:12353:17 354:2,11

pre-marketing225:19

pre-specified203:17

pre-survival 262:9267:22

price 6:19 78:15293:13 328:10329:7,9

priced 337:6prices 79:4 165:8

173:19 329:17pricing 76:2 77:3

335:8

prided 41:4primarily 192:15

243:12 265:10290:21

primary 65:3 89:5123:15 134:7169:10 172:19173:5 220:3 242:3244:2 249:4262:14 267:21268:20 275:20293:8 361:22

primates 195:3prime 30:11,12,12

30:13 87:7,11principle 90:12

97:10 239:21257:8

principles 39:8142:7 303:14318:6,12

prior 63:13 81:14155:11 157:16,20158:12 166:1172:9 260:2272:21 338:3353:13 360:12372:3

priori 179:18242:15 263:18

priorities 7:20 61:4369:14

private 111:8 112:6159:3

privilege 87:18pro 287:20 288:16

288:16,17,17proactive 335:15

337:4probability 130:15probably 29:14

58:13 59:16 65:681:9 87:3 92:18138:16 145:5157:18 159:1164:21 205:16,18225:7 232:7

probe 311:8problem 46:18

115:18 135:4,7167:1 201:14202:3 216:4,8278:9 279:1

problems 23:4 24:624:8,8,21 41:6210:8,12,18 236:8236:8 288:8309:21 310:2,3

procedure 166:10procedures 10:6

218:21 225:17345:19

proceed 12:11244:14

proceedings 10:810:12 218:1

proceeds 361:12process 22:7 28:15

32:7,17,18 40:1843:1 44:8,10,1470:17 90:19,2091:1,16 93:4,2294:5 100:17102:22 106:11110:17 111:13,19112:16,20 123:19143:16 144:6157:21 158:1,2,7159:6 163:5 171:5184:11 185:8193:5 203:7,18208:13 215:9,12215:18 217:18219:18 221:14,20222:3,8,19 223:1223:17,19 228:10228:18,19 229:5229:16 230:22235:11 254:5280:8 296:6297:17 299:12303:20 304:20318:16 319:22327:16 331:10

334:6 345:9,15348:11,12 350:5,9353:16 361:10,14362:4,19 367:14372:10

processes 90:1491:21 110:15143:7 144:13169:18 185:12217:19 240:1254:4 319:8

processing 242:14produce 34:1 71:19

144:3 171:8183:22 273:17298:11 342:5

produced 170:1,7171:14,18,20361:4 362:3

produces 361:14product 7:4,20,22

8:2 15:13,22 16:116:1,1 18:17 19:220:12,16,22 21:423:10,10,14,15,1723:21 24:18 26:828:5,8,9,13,2232:6,13,14,1735:10 36:14,1937:12,16,20 38:438:10 39:1,13,1540:3,6,9,11,12,1440:18 41:12 44:444:4,11,12,16,1744:18,20 46:11,1446:17,20,22 47:1047:15,22 48:4,1649:15 51:17 52:1954:3,10 57:1063:11 68:9 70:1171:18 72:7 77:1378:4 80:22 81:2183:21 89:15,2190:21 91:4,11,1291:22 92:10,15,1692:21 93:21 94:394:4,8,14 95:18

95:22 96:16,17,1797:4,11,12 98:2,398:4 99:1,3,9,1399:17 100:6,13102:5,11 103:2,5103:13,14 104:1,4104:9,12,18105:16 106:5,6,7106:8 108:8111:14,16,17112:18 113:20114:2,3,7,13,16118:9,16 119:12120:15 122:21123:22 126:1,12126:19 131:10133:11,21 134:5134:18 135:21136:1 138:2 142:6142:9,20 143:15143:17 146:15,19153:9 154:17156:10,11 157:10157:11,21 158:3,8158:10,12,13,18158:20,21,21,22159:1,4,6,7,11,12159:22,22 160:5,5160:12,12,12161:2,8,12 162:11162:22 164:2,14165:9,21 174:6176:14 180:1183:21 184:1,10184:22 185:1,8,10185:18,22 186:5,8186:10,21 187:9187:12,14 188:22190:10,11 191:9191:16,22 192:10192:12,21 193:7193:13 194:10,17196:6,15 197:4,10198:5,15 200:12201:16 202:9204:15 208:14211:3,18 219:9


220:13 223:14226:6,9,20 229:9231:7,16 237:9,11239:9 241:4,20,22242:3,4,8 243:3244:4,16 245:4,6245:10,11,20246:1,4,11,12,14247:2,15 248:4,13248:16,18,20,20249:3,6,7 251:7251:13 252:2,5,9252:13,15 253:10253:20 254:6,18257:7,15 258:1259:22 263:19264:3 265:4270:14 272:3273:17,18 280:15281:16 283:3,8,12283:20 284:5,6,16284:20 295:11,14295:18,19,22,22296:7,10 297:3,8297:9,16,16,19298:3,3 299:12,13299:14 300:1,12300:20 302:13303:17,21,21,22304:6,7,10,21,22305:19 307:7,12307:13 310:18312:12 313:11316:10 319:6320:6,9,12 323:6324:16,16,22325:4,10,11,12,17326:9,11,12,18,19326:22 327:1,4332:13 333:9,10333:19,21 334:5334:10 336:4,8,9336:14 337:11340:15,18 342:4,6342:12,15 343:7343:12,13 346:15346:16 347:4,15

347:16,20 348:4,6349:22 350:18351:1,17,20352:18 355:6,14357:8,13 358:17360:15 363:17365:12 366:17370:11 371:22372:13

production 165:6169:14 171:3173:11 179:17326:5

productive 12:10317:14 374:3

products 1:7 5:87:2,18 8:4,8,1313:15,20 15:1,917:15,17 19:10,1419:15 21:3,1722:2 23:2 26:1229:13 30:1,2,331:9,11,15 32:932:12 33:9 37:637:21 38:22 39:1040:16 46:10 48:750:3 51:14 52:753:1,8 63:8 85:2188:2,10 89:9,2292:6 93:2 95:1496:11 97:2 100:11100:18,19 101:12101:15,16,20102:8 103:11,17105:10 109:4,6,12109:15 112:2,4,20113:11 115:16118:4 122:16132:2 133:2,6134:13 141:1,11142:14,19 143:6143:12 144:1,2,14145:2 149:8,10154:15 156:14,20162:18,19 163:3,7163:13 174:22175:2,6 183:17

184:3,12 185:10186:2,17 189:6,8190:12,17 191:12191:17 193:4194:9 197:16199:22 201:2,8204:6,21 205:21207:4,9 210:9213:10,14 217:13217:16 219:18220:8 221:18224:1 226:4 227:7229:7,10 230:1,11230:20 231:2232:4 233:5,7,11233:20 234:15235:9,15 236:9,13238:7 239:11,16239:17,21 240:13240:20 241:4,9242:9 245:14247:20 249:19250:8,13 253:12254:3 256:9,13258:13 260:9,16261:8 263:5,9269:16 271:21274:1 286:10,16291:10,15 292:19293:17 295:12296:6 297:17299:21 304:16305:18,22 307:14307:16,18 308:9309:7,20 310:16310:19 311:1,12312:13,16 313:17313:19 314:10,19315:11 316:9323:15,19,19,20324:1,5,6,10,14326:4 328:19329:15 330:19331:7,16 333:12335:6,7,14,18340:10 341:14348:19 349:19

351:15 358:5363:9 365:16367:2 371:7372:16,22 373:2

product's 103:19320:10 345:13371:5

Professional 9:1Professor 225:14proffered 165:15profile 19:18 33:6

76:17 113:5158:21 159:3,14159:20 164:13180:7 184:13,22185:8 242:14,17247:19 257:14264:7 299:14300:9 333:20

profiles 55:11159:4 164:6,16189:20 192:5297:20 300:18342:11

profound 169:1program 8:7 9:2

22:16 65:15 66:1389:16 91:10 93:194:10 96:12,2197:13 98:6 105:8105:20 144:20145:9,19 151:6,18151:22 152:8,12152:18 180:22181:9,12 182:15256:22 257:7264:9 269:1310:19 336:20,22336:22 338:9,16373:6,9

programs 88:3109:22 115:21142:13 149:15150:21 152:16,19165:7 210:20225:19 229:12239:13 256:8

257:4,10 261:8264:11 267:4268:13,17,20303:4 307:21312:5,14 338:14350:16

progress 140:22165:19 173:15232:11

progresses 146:19progression 127:3

262:8,9,14 267:22progression-free

132:22 133:9,9134:8

prohibited 81:2282:9

project 285:5 302:5320:5

prolonged 178:13promises 355:10promoting 332:11prompt 124:19

204:19promptly 5:21proof 86:15 126:5

126:21 134:6193:13 269:5308:21

proper 178:5346:18 347:4

properly 13:16152:9

property 287:5358:11

proportion 74:14263:11

proposal 117:10,17281:21 298:2

proposals 117:12propose 50:11

138:19 285:19proposed 31:8 95:7

132:14 183:21187:22 190:9191:15 226:17287:18 288:14


297:8,15 333:9348:15

proposing 287:15propositions 71:1proprietary 115:19

122:1,11 344:5346:14 356:10357:1,21 358:11358:20 359:4,9363:22

prorates 162:1prospectively

40:10protect 343:16

345:3protected 324:18

347:8protecting 342:8protection 6:18

275:15 345:5346:1

protein 4:8 8:4141:15 156:14171:3,13 176:9178:5 186:5242:18 243:11246:4,10,10 263:2292:6,20,22 293:5293:18 296:16,22297:10 298:5299:2,22 300:8340:17

proteins 33:4 34:242:22 170:8171:19 172:3203:5 220:11243:13 245:8,14250:14 257:20294:20 295:1,2,20296:5 361:3,7

protocols 143:4prove 127:22 271:9provide 5:14 6:16

37:14 39:17 47:849:13 51:19168:17 170:16183:4 188:18

192:7 213:15245:9 257:21258:7 259:3 264:1265:8 290:21308:21 317:17318:8 319:1 328:8340:4 345:12351:20 353:5356:22 371:18372:11

provided 34:17114:20 115:16129:7 186:13190:20 192:19204:8 264:20295:21 341:5344:6 370:15

provider 255:15providers 205:3

214:10 303:11334:13

provides 118:8121:18

providing 292:10328:22 371:21

provision 229:1232:9 275:15347:5

provisions 323:1327:8 345:3346:20

provocatively303:19

prudent 208:20pseudo-biologic

279:17public 1:6 4:17

6:21 7:6 10:5,7,1110:17 12:10,1721:1,2 22:9 52:2188:14 105:21137:16 162:21168:3 206:16223:13,16 224:16224:18 231:11286:12 293:21301:7 310:10

318:1,19 323:13330:8 337:15359:18 372:14374:2

publication 362:20publications 56:12publicly 62:8 105:2

105:14 357:7,17publish 348:8published 28:11

33:21 79:18 90:11135:11 186:14294:15 363:4

pulled 59:22purchase 6:12

108:8 216:15purification 91:20

172:10 298:10361:15

purified 201:12355:4 361:16

purity 32:19 53:2294:17 172:20184:20 289:8,18326:10 330:12332:5 347:17348:5

purpose 6:15 35:1354:15 150:11,13151:14 221:3244:6 351:6

purposes 26:559:11 275:14282:5 325:3

pursue 33:2 36:9push 196:4put 67:5 106:5

130:6 199:15209:5,19 237:2269:12,21 271:1

putting 50:19153:2

PVG 115:14pyramid 90:10,16

91:4 175:15,17,22176:18 179:7181:8

P-R-O-C-E-E-D-...5:1

p.m 5:22 216:21,22217:2 316:21,22374:21

Qqualified 89:3

112:8qualify 187:14Qualifying 327:3qualitative 273:20

274:5quality 28:13 33:1

36:14 39:2,16,2040:11 45:13 46:1072:1 75:14 76:1191:11 92:15,2093:12,14,18 94:1499:17 104:4 110:4111:3,8,18 112:12112:14 114:6124:1 149:6 155:1156:10 158:4160:19,22 162:17163:11 184:10186:9 228:19,21241:18 242:1,21246:1 253:8,9,16253:17 254:8257:18 273:3319:22 329:17330:7 331:17336:5

quantify 189:10quantitative 72:18

274:2,3,6quantitativeness

84:15quarter 316:18

329:20question 10:1 14:2

23:8 24:1,4 26:328:22 29:19 44:346:2,12 51:2163:19 71:10 72:2273:1 74:9,10

81:17 85:12 106:1107:7 108:3122:12,20 134:14134:16 137:18151:16 154:11163:19 174:15,19183:18 190:5208:6 210:4,14214:4,22 215:8219:15 233:17234:10,14 237:16241:17 246:2,17248:12 249:4255:7 257:1266:22 269:7273:13 276:2,14276:15 281:10,17289:16 290:11296:17 309:17314:5 315:6326:15 336:17353:20 354:13,16355:18 358:13362:19 366:6369:22 371:3

questionable 336:7questioning 21:9questions 10:3,22

11:2 12:1,19,2221:12 43:10,1262:2 66:16 71:877:9 87:4 98:12102:17 104:7105:4 106:16117:3 120:20132:8,11 150:5155:3 157:6 166:5166:7 167:17173:21 174:1180:18 182:5194:2 198:16202:21 208:2210:22 216:10222:7 228:5229:17 250:22255:22 266:6281:9 287:11


301:11 309:15327:19,22 337:19337:22 339:6348:20 349:10357:2 364:11,13368:19 369:6,11

quick 41:6 51:2098:15 137:18

quickly 20:19 34:8148:7 249:21

quite 14:12 23:2048:10 62:7 67:13125:19 127:20219:20 223:1224:7 235:19237:17 310:21341:14

quote 39:14 42:19183:21 295:6

quote/unquote278:21

Q5E 39:9 141:18142:8 162:1,2331:22

RRA 130:1Rachel 1:14,18 3:2

4:22 5:10Radcliffe 2:22 4:15

339:12,13,15350:2 351:2352:17 353:21354:4,7,14 355:9356:8 357:19358:18 359:3371:16

raise 23:13 348:19raised 12:19

302:21 317:19330:17 360:20

raises 281:8randomized 81:22

148:8 272:9range 71:11 76:2

80:8,13 92:2093:18 100:5

101:18 102:6,7,12104:21,21 105:6112:2,4,12 142:20160:8 298:1,6304:8 306:8

ranges 104:19105:2

rapidly 16:14 43:3196:22

rare 183:9 219:6293:1,20 300:20366:21

Rarely 331:18Rasmus 2:21 4:13

328:2,12rate 70:8 77:22

78:5,9 127:7132:17,19,20133:8 202:1266:13 268:6

rates 262:13ratio 81:5rationale 168:17

264:1ratios 362:12rats 195:3raw 201:10reach 168:20

319:10 359:18reached 65:1

316:16react 15:1reaction 205:11

310:14,20 343:6362:12

reactions 195:20read 276:4,19readily 362:5ready-made 371:8real 203:22 207:14

289:1 300:9328:13

realities 292:1reality 65:5 75:7

286:2 291:8,14realize 74:20 77:1

115:17 157:15

214:1really 20:5 28:12

46:1 60:17 69:586:3,11 99:7137:20 139:8140:4 147:19148:19 150:15158:3,9 163:13182:8 199:14210:15,16 213:13233:9 266:18288:3,15 289:12290:6 313:11315:1 331:22356:11,20 360:22371:17 373:22

realm 179:14351:22

real-time 37:2reason 69:5 151:13

232:7 233:10263:18 334:18351:16 361:17

reasonable 29:4119:2,14 161:21225:19 260:17268:1

reasonably 13:626:4,7,16 40:12179:9 181:4 241:6264:21

reasoned 200:3reasons 168:17

187:12 209:2266:17 363:7372:8

recall 10:2 369:1recalls 204:18,19recaptured 140:9receive 61:20 116:2

168:3 207:12293:4 299:2 324:9

received 20:16receives 58:6

326:18,20receiving 20:12

54:13 68:15,19

78:18 80:22173:18 213:22300:15 326:12344:21

receptacles 6:7216:17

receptor 178:7246:8

recognize 38:21201:22 237:12,14298:18 372:2

recognized 107:9145:8 299:1348:17 356:20

recognizes 293:17336:14

recombinant171:19 233:15250:13 292:19294:14,20 295:1295:19

recombinantly170:1

recommend 139:5145:20 241:3,21242:19 243:2,11244:2 245:5247:22 249:22312:2,9

recommendations122:14 200:9209:6 211:5 250:9

recommended159:14

recommending117:9

reconcile 47:16266:19

record 10:11108:17 216:21224:5 316:21

recorded 344:8records 20:9 213:4recreate 85:8red 29:19 148:6

207:22 280:9Reddy's 3:9 67:2,8

67:12 76:6Reditux 68:18 70:1

70:8 78:15 83:7redo 138:19reduce 165:2,4

173:15reduced 11:2 36:11

144:21 246:19264:4 295:10330:11

reducing 169:19reduction 77:3

128:14 141:3,3redundancy 243:6redundant 42:5refer 33:20 56:11

80:1 94:15 127:1258:3 311:20326:5 363:3

reference 7:4,2223:2,9 37:16 40:344:18,20 46:17,2247:22 54:9 57:1158:4,12,19 60:1560:16 61:13 91:391:12 93:2 95:1895:22 98:4,18111:17 112:2,4113:10 114:3,13114:16,17,20123:21 126:1,19131:11 134:3154:12 157:11160:4 172:19173:1 176:14184:1 186:22190:11 197:4218:19 243:11247:20 273:16,18286:21 304:16307:12,13,14308:9 314:13320:6 322:12,13332:13 335:14340:15 342:6343:7 345:13,22346:4,15 347:16


348:6 357:8,13368:7

referenced 47:1054:3 57:8 61:1789:15 92:16 118:3154:15 161:2224:1 242:4,9245:11 246:13248:4,15,19 249:6251:12 252:5,13253:19 257:7258:13 259:21260:9 264:2 265:4270:14 281:16295:11 297:9,16298:3 299:14305:19 319:5320:9 321:1 323:6323:20 324:20,22325:11,17 330:19333:10,19,20334:5,10 335:18336:3,8,9,14

references 314:11363:5

referred 40:17 99:7292:20

referring 135:11197:19 211:8358:20

refinement 360:11reflect 31:10,11

186:4 188:4 192:9192:11 201:6270:17 312:4338:10

reflects 142:18refractory 130:6regard 16:3 20:1

23:7 28:6 69:1485:13 135:15187:22 190:15212:9 236:17243:16 249:21288:19 340:16370:19

regarded 282:6

regarding 6:17 7:928:1 29:10 78:1284:21 87:5 107:17113:17 125:13126:14 209:6211:5 245:19246:17 248:12249:4 255:17346:18 369:14372:19

regards 22:5135:22 136:8

regime 217:20220:18

region 97:6 154:16154:20 308:14

regions 102:9113:21,21 161:19308:10 312:20

register 11:5,2112:2,20 276:3301:1 317:20319:15 326:7,16346:22 374:16

registered 10:19154:18

registration 80:16registry 85:19

153:4regular 133:17

293:4 373:8regulated 102:9

250:15 307:15335:19 361:18373:7

regulating 240:13365:6

regulation 142:15240:16 256:13318:3,22 366:3

regulations 116:8318:22 346:11

regulator 141:16regulators 42:15

165:19 314:22315:3 368:15

regulatory 8:3,15

43:1 69:9,10 71:178:20 89:18 96:397:21 123:18127:18 129:4141:9 147:4182:17 204:9206:20 217:15239:9 248:2 250:6250:16 262:17287:15,16 317:6319:3 322:6,15325:9

reinvent 306:16reiterate 72:6

76:12 90:18reiterating 21:7Reitsma 2:3 3:8

52:16,17,18 62:562:14 63:18 64:2166:2,18

reject 263:18rejected 204:11

366:8relapse 363:15relapsed 130:5relate 296:16related 7:12,21

134:15 156:21189:22 190:8201:16 202:10234:9 239:9 256:1275:13,21 276:10278:5,5,11,17,20279:6 280:4 281:3281:7,18 282:21284:11 287:16300:7 344:13346:20

relates 8:3 46:2112:10 208:6

relating 126:15217:19 218:1220:10 229:7

relationship 142:22185:7 189:14197:15 285:7

relationships 32:17

257:13 276:8323:18

relative 36:1137:20 38:3 51:1151:17 63:19138:15 146:8184:4 260:11,19264:2 271:15

relatively 15:6,857:16 140:6177:15 201:15235:11,13 245:7259:18

release 94:7 243:14relevance 86:5

258:9 265:15,17306:4

relevant 39:1158:11 71:15 74:274:6 137:9 148:2165:18 178:3181:2 183:4187:10 218:7223:22 239:16244:7 260:21261:13 264:17274:10 296:20297:3 320:19321:9 325:9342:13 347:21

reliance 34:19345:22

relied 16:6 204:17221:11 333:21359:10,12,14

relies 346:4rely 18:10 346:3,8

346:13 357:6,21relying 106:19

314:7 358:9remain 147:13

353:1remainder 124:16remained 122:18remaining 88:4

347:8remains 10:4 254:6

remarkable 203:4remarks 3:2 208:2

364:18Remarks/Adjour...

4:21remember 212:4

374:7Remicade 109:12remind 11:13

216:14remission 363:15remove 352:22REMS 151:18

153:3 306:17312:1,5 324:20

REMS-type 152:18render 40:21 43:2

343:6repeat 74:16 257:6repeated 56:6

62:11 97:6 191:8191:12,22

repetition 248:5replaced 42:11replicate 48:8replicating 40:19

41:1report 200:15

212:4,17,18231:15 237:9

reported 210:19307:11

reporting 204:17204:22 236:22237:8

reports 20:3,8231:12 363:4

represent 74:1476:4 79:16 87:18279:20 292:14,17301:19 302:2328:17

Representatives10:8

representing 67:2217:12

represents 261:6


317:10reproduced 368:5reproducibility

172:5reproductive

146:12request 12:5requesting 81:6requests 247:12

372:4require 16:17

18:12 91:5 170:12170:14 185:17191:3 193:12226:18 293:3319:19 323:5349:22 364:8

required 18:1835:20 36:17 39:1265:20 91:14 99:15113:6,11 114:10116:13 131:12146:2,13 147:2148:22 150:16152:19,20 157:2161:22 162:4173:5 186:3189:21 190:22191:10 204:12208:16 209:1235:20,20 245:3252:15 265:13308:13 312:7,10321:10,15 323:10331:18 333:3

requirement 14:419:3 37:10 82:6244:16 321:18,22322:16 372:3

requirements 36:236:10 40:20142:12 150:1,9,17151:2 177:12219:2 221:16225:21 238:4243:3 244:10246:19 249:18

252:3 256:15294:6 295:14333:11

requires 31:2 47:2192:3 126:6 206:15320:4 342:9349:19

requiring 48:1273:14 148:5 226:4319:22

research 5:12 9:10171:10 293:16317:7,11

research-based217:12

resides 218:21residues 170:6resolution 33:17

45:10 75:12 86:486:6,8 216:2345:9,14 348:11

resource 141:3resources 168:9,15

350:22respect 36:19 211:1

219:3 236:9241:22 294:20295:18 300:1307:3 340:22357:5 369:12372:17

respectively 76:15respond 52:10responders 263:12

263:16responding 241:17response 38:11

59:8 65:7 70:8,1477:22 78:5,9 80:480:7 102:2 120:9120:11 127:7132:17,19,20133:8 148:3 154:8196:7 198:8207:10 262:13266:13 268:6270:21 272:1,5

333:5responses 38:7

80:12 170:20188:15,16 192:4195:19,20 267:2

responsible 42:13335:1

rest 167:8 293:6337:11

restrict 169:14restricted 204:11restrictions 348:14restrooms 6:1

216:16restudy 95:1result 38:13 58:17

76:9 168:19172:10 183:22185:3 225:15226:12 264:3286:4 291:17296:8 299:20300:11,18 342:5343:3 344:20348:4 363:2

resulting 172:3173:17

results 112:3 260:5resume 108:15

217:4 316:18resumed 216:22

316:22retaining 118:21retroactively 206:1reverse 218:12

243:8review 8:19 9:8

129:17 204:9249:15 279:9334:13 346:2349:2 371:15372:21

reviewed 49:6246:16 258:16265:20 363:10364:4

reviewer 358:9,14

reviewers 299:4357:21 358:3

reviews 293:17346:13

revised 7:19revision 255:1revisit 134:16revisited 373:9rewarded 278:8re-established

233:16Rhee 2:17 4:6

274:21,22 275:1281:5 288:1 290:2291:3 292:4

rhetoric 42:11rheumatoid 59:1

129:19 138:7rheumatology

267:16Richard 2:12 3:25

217:5,8right 6:2 25:8 48:7

69:16 70:12 83:183:19 157:19167:10,15 181:6202:2 206:2 208:8216:16 222:20224:10 234:6269:22 275:17283:10 288:10294:12 313:6339:8 354:1

rightly 287:4rights 229:3 281:15

287:4 291:6 345:4345:5,16,21 350:6350:11

right-hand 164:15rigor 110:19

308:18rigorous 123:22

177:1 180:22185:13 196:3198:10,13 309:1324:21

rigorously 193:10

ripe 29:1rise 15:3rising 329:3risk 13:14,17 19:1

27:3,4 71:4 80:1994:22 114:5 124:8130:6 150:20152:12 153:1172:1 190:8191:13,21 214:5214:13 225:21246:2,16 248:11249:5,9,18 256:22264:9 267:9,18268:1 300:6352:22 353:8,10363:2

risks 14:1 34:7 43:573:9 120:17126:10 213:21353:1

risk-based 25:8risk/benefit 81:4

185:8Rituxan 78:10,16

78:18rituxima 76:15rituximab 68:2,16

77:13 125:6,11129:13 134:15135:1

RMP 70:20 72:1373:13,13 74:1175:9 84:11,1686:14

RMPs 75:14Roach 2:2 3:6

31:21,22 32:143:14 44:2 45:545:14 46:5 48:149:22 50:7 51:952:3,14

road 134:9 290:8367:18

roadmap 224:21roadmaps 225:3Rob 281:5


Robert 1:22 2:154:6 274:21 275:2

robust 57:16 97:15113:9 115:13162:10 229:12

Roche 3:14 123:6123:10,17

Rojkjaer 2:21 4:13328:3,5,5,12338:12 339:10371:2

role 16:10 37:5,847:3,18 120:18141:13 199:18262:1 293:19336:12 339:1345:8

room 1:13 5:17 6:811:11 212:16216:18

route 17:20,22 18:224:12,14,15 238:1238:3

routine 146:11225:20,21

routinely 76:2Ruckman 2:13 4:2

238:15,16,18,20238:22 251:8,15252:10 253:4,17254:17 255:5

rug 289:15rule 178:16 180:15

306:8rules 9:18,20 35:4

134:12 178:15227:14

run 48:13 117:21272:9

runaway 77:4running 164:9rush 34:8Russ 4:18 360:4Ryan 2:9 3:20

167:21,22 174:12174:16 175:1176:5 177:3 179:4

179:12 180:10181:6,11

R&D 165:4 326:2328:13 348:15360:10,11

R.Ph 2:17

Ssafe 13:19 31:4

34:13 49:8 73:14118:16 140:22168:19 207:7286:14,15 291:21310:8 311:12312:4 318:14319:9 321:13322:9 329:1 336:5337:11 339:22

safely 302:18 309:5safest 213:15safety 15:11,15

18:1 19:8 20:1322:1 24:7 35:1037:6,14 38:341:19 42:2 43:447:8 53:22 54:856:15,16 59:1073:20 76:16 94:17113:4,14 115:12116:6,10,22120:17 121:1123:15 124:3126:1,10,13128:19 129:5,8131:19 134:21135:20,20 139:5140:4 142:11146:2 148:12,13149:6 153:5156:10 163:10,14164:3 166:16,17166:22 169:9170:16 172:16173:7 178:14179:20 180:6183:14,15 184:21185:19 186:9

187:7,18 189:1,4189:15 190:13,20191:1,7,11 193:1193:3,10 195:18196:1 210:8 225:5238:4 240:7 244:4245:13 246:22247:19 249:10250:5 256:19,20257:14 258:10259:20 263:7,20264:5,6 265:9269:11 272:4,5,12272:14 279:5286:9,12 289:8,18290:6,14 291:18295:13 298:19299:15 302:18312:15 319:18320:2 321:9323:13 325:1,6326:10 330:12332:5 333:19336:17,21 337:4342:8,10,18 343:9343:16 346:5347:17 348:5349:5,7 359:11363:2 373:1

safety-related 38:8salads 6:12Sales 283:7,22sameness 13:7

32:19 42:7 343:14sample 60:2,9

64:12 117:15Sandoz 90:2sandwiches 6:12Sandy 11:10

373:22Sara 2:22 4:15

339:12,15satisfactory 56:8satisfied 228:19saturable 271:22

272:2,7Saudi 221:9

save 64:11saved 69:19savings 70:21 75:5

165:7 169:20334:19

saying 76:20 80:5104:21 118:17175:19 195:5,10251:5 303:7 354:8365:8 368:9

says 103:19 122:1283:9

scalable 171:6scale 177:21scenario 48:11

196:15 247:2282:22 283:16,17283:17 284:12

scenarios 139:18248:7 282:19

schedule 12:7scheduled 5:21

6:10 9:15 329:11Schwartz 1:22 9:5

9:5 98:13,1499:18 251:1,2,9349:12,13

science 32:6 36:1842:12 44:22 52:569:9 71:3 77:190:7,8 97:21112:22 137:4143:21 156:19157:22 174:10295:17 305:1309:6 318:19322:8 327:13332:15 336:15348:20

sciences 70:18360:5

science-based318:15

science-driven 22:8scientific 7:11,21

7:22 17:12 20:2225:13 35:6,11,15

35:18 37:1 89:1792:12 94:12 107:8110:5,7 116:9141:16,22 142:1143:20 149:22157:8 160:6163:16 165:19200:21 206:16207:15 222:21223:9 224:10239:8,13 240:19269:5 288:22289:22 296:18,21297:4 303:14317:6 322:5,14324:14 329:13331:13 336:1

scientifically 94:2295:2 321:20 341:8

scientist 177:10178:10

scientists 368:16sclerosis 362:1scope 7:18 33:10

36:16 186:3 245:5247:9 257:18

screening 105:7107:22 108:1

se 62:22 99:9second 5:9 24:3

55:3,4 58:6 105:5109:15 129:9134:14 140:21190:5 200:12208:13,16 221:1224:16 277:4,20278:15 283:11,13283:17 284:8,17285:19 311:21314:5 326:16332:19 342:1347:11,13 367:3369:16

secondary 219:22242:5 262:16272:11,12 315:9

secondly 103:22


104:16 218:19219:5

secret 359:4section 12:2 276:22

277:4sectors 88:12

220:14see 11:9,21 20:17

44:12 63:20 64:1070:13 86:12 90:1593:7,7,8,14 135:7135:7 137:4,7148:6 149:12152:14 164:15,19196:14 197:15,17198:2,6,13 203:13206:4 207:21252:8 254:12,12254:16,17 255:2270:4 274:5277:13 285:8310:14,21 330:4367:22 374:16

seeing 28:8 29:1661:1 77:19

seek 32:13seeking 12:17

98:15 142:15319:19

seeks 341:7seen 17:20 23:5

135:3 170:8 181:3186:5 267:3273:20 316:4

segment 175:17select 12:18selected 57:17,20

59:1,3,6 146:8148:11 261:2263:17 316:7

selection 57:10120:7 146:7 261:5

semi-automated171:6

senior 360:10sense 11:12 26:21

36:8 50:12 71:4

101:21 214:4227:8 253:14338:20 350:8

sensible 334:7sensitive 15:8

16:15 106:21113:12 114:21119:18,19,21120:2,8,10 245:16259:22 260:7261:16,20 264:16268:5,8 271:12320:18

sensitivity 83:10,21107:4 194:19

sent 227:9sentinel 153:5

213:5separate 71:15

86:4,11 137:13307:20 312:3326:20 351:3

separately 136:15272:19

sequence 71:20160:16 172:19173:5 242:4320:21 327:6348:1

sequences 58:2,3169:11

sequential 60:13series 332:13serious 192:3 219:6

259:11 300:10,21seriously 11:19

339:3 374:12serum 178:6serve 5:12 55:20

72:4 197:4Service 6:22services 1:1 255:15session 6:5 217:4set 13:11 36:22

37:12 40:10 47:747:17 48:10 49:249:8,13 51:10

61:9 113:22114:14 118:12119:2,8,9 135:16143:20 200:3229:22 265:3286:7 318:5345:16

sets 45:17 92:2193:16 152:21

setting 15:12,1616:8 60:9 63:281:20 111:8118:15 143:2171:7 202:6292:14

settings 19:13 50:2161:22 189:2214:9

seven 10:21 105:18shaded 277:20shape 184:14share 242:3 301:22

302:17 369:18shared 111:11

137:16 354:22sharing 87:19sheet 250:7shift 92:9shipped 201:12Shire 3:21 182:15

182:21,21 183:1,7shop 83:14short 55:14 101:10

143:16 194:8296:11 301:3

show 23:21 53:1168:11 87:10 96:8156:13 161:20166:12 172:18194:15 224:19268:22 308:11313:13,21 314:2330:20 352:6

showing 77:21 78:3110:21 320:7

shown 7:2 17:1670:11 72:8 135:14

146:21 163:15171:11 173:6176:15 180:6240:17 334:7344:7 362:21

shows 67:21 70:770:12 75:19 90:11

side 136:2 137:7164:16 219:7340:14

side-by 340:13Siegel 2:2 3:4 12:13

12:14 22:4 23:724:10 25:3,1026:13 27:8,1729:3 30:1 31:18213:2

sign 5:18signal 227:9 279:17signals 19:8,8 20:1

367:19significance 13:16

59:15 176:15178:11 240:7,10245:21

significant 34:1668:10 73:9,1995:9 107:13109:14 110:18124:20 144:11163:9 172:21173:7 178:2 204:8206:15 236:12240:17 299:20302:17 310:21312:6 346:16

significantly 35:264:11 86:7 110:20229:7 238:9244:20

Silver 1:14similar 13:5,12,13

17:16,17 23:9,1523:20 26:4,6,1530:14 39:6 44:1847:14 53:19 68:871:20 73:12 74:4

75:14 76:14,1783:10 85:22 90:2091:3,9,17 92:1292:14 93:21101:14 111:12124:6 128:2141:21 157:10164:21 169:5,8170:11 171:12172:16 173:10179:9 196:14233:13 239:22241:21 242:8245:10 258:15277:7 278:4283:16 284:5287:6 294:13295:12 297:2298:4,7 299:12,13312:9 315:10322:13 324:10331:17 333:9,18334:8 336:3 356:4358:5

similarities 125:15267:11 304:2320:17

similarity 17:318:11,12 37:938:20 42:7 63:863:15 71:22 84:1389:14 90:5,1292:2 110:8 113:4116:10 123:21125:22 126:5,5,19127:14,15,16132:14 136:13,14136:16,17,18,22143:13,18 144:20145:16 146:1,22147:1,18 167:5,6180:9 187:21219:4 243:12249:12 273:5295:11 303:1314:3,7 320:14333:16 358:16


similarly 38:1268:16 296:7

simple 57:16 67:13158:8 199:15245:7

simpler 29:6simply 26:1 78:22

81:3 95:12 103:8177:15 199:21222:10 232:15,21

Simponi 109:16sincerely 42:9Singapore 221:9single 31:3 55:16

55:16 62:4,1370:2,14 78:1281:7 130:12145:20,21 146:5147:5 148:8,16149:16 192:9264:14 278:5,20324:5 335:10338:20

single-arm 77:1678:2,8 79:7,1582:3,7 85:13

sir 98:22 312:22site 97:4 219:1sites 18:13situation 46:19

54:20 218:8,12282:22 285:2,4,18291:5 316:10360:16

situations 49:18154:22 281:6284:12

six 204:10 205:20sixfold 68:20 76:13

79:5size 33:5 48:14 60:2

60:10,22 64:1266:4,13 81:10117:15 118:22142:17 148:18177:1 182:2184:13 256:11

352:5 366:6slide 45:12 51:21

64:15 67:21 68:1177:7,12 78:779:14 83:1,192:18,19 94:20102:19 104:17,18117:6 121:1,22132:12 139:1150:7 166:9 251:4286:8 290:16291:12 311:20315:7 349:15

slides 33:12 132:12340:4

slight 308:16slightly 233:12slot 10:20 11:1slots 9:15small 49:19 107:17

131:15,16 139:4157:21 175:17184:4 185:5 214:6214:14 235:11,13237:19,20 243:18245:14 274:2277:8 279:16288:17 296:7297:12 298:8299:3,7,19 329:21360:8 361:18363:10 365:10368:3

smaller 29:6 66:1579:22 137:11225:1

snapshots 69:22sold 23:10sole 127:13solely 39:16solid 42:12 97:21

258:7solution 31:7

158:10 338:19solutions 35:14

115:16solve 41:5

solved 315:3,4somatropin 220:15

223:7 231:4 263:6somebody 180:15someway 273:8somewhat 57:19

214:14 218:9256:14 258:15265:19 269:3276:20 279:16291:1

soon 52:7,8sophisticated 92:22

106:4 224:7 235:3332:16

sorry 200:5,5238:17 351:17

sort 45:13 57:683:9 136:21152:11 270:8289:21 314:8338:18 367:3,19368:6

sorting 77:18sought 188:19sound 42:10 199:15

318:19 336:1soundness 122:17sounds 279:11

290:20source 142:6

149:20 174:10178:21 179:6211:3 231:7,16233:14 248:4273:18 292:15314:18 365:12366:17

sources 20:10200:16 201:11248:10

South 221:8,9space 33:15 109:7

109:11 158:5159:13 243:10,15254:4,7 366:19

speak 11:7,12 71:8

121:6 155:5181:22 228:9231:18 238:21275:11,12 360:14

speaker 10:19,2212:5,12 31:8,2043:17 52:15 66:1987:15 108:19111:11 153:15167:13,20 182:6198:22 217:5233:19 238:13266:11 274:19292:5 301:14317:2 328:2339:11

speakers 9:13,1410:13 11:22 123:2123:14 140:12204:21 209:12210:15 216:12241:13 255:10266:11 274:19290:12 338:3352:12 355:21368:22 369:3373:13,15

speaking 178:9181:13 238:14268:11 303:19359:1,3 361:1

speaks 88:6spec 202:14Special 9:2specialize 67:22species 71:19

145:21 146:6,7specific 28:6 129:2

148:14 151:10169:15 183:2,14193:14 220:14221:14,15 222:15226:3,8,20 236:8242:15 250:7257:15 285:4293:11 294:22295:3 318:9

325:10 340:7351:21 360:16366:11 370:9,11371:18,22 372:13

specifically 61:1675:8 127:2 137:14179:13 189:6220:10 245:7275:10 293:15305:13 308:18

specification 169:5specifications

28:12 39:4 144:4158:6,17 159:8

specifics 50:16specs 94:7spectrum 76:5

274:4speed 169:19

365:15spend 33:12spending 75:20spent 199:10spirit 66:14spite 112:17spoke 232:10spondylitis 89:1sponsor 28:14 40:7

48:9,18 50:1172:19 75:12 87:989:19 114:10,11188:17 191:8192:6 278:1,11,16279:6 280:15,17281:11,16 345:13

sponsors 21:242:15 49:5 66:1134:17 165:22223:11 224:1249:1 319:1330:10 333:7

Spring 1:14St 199:11stability 184:13

270:16stabilization

298:10


staff 373:20staffing 143:10stage 65:1 208:13

249:2 360:11stakeholder 221:22stakeholders 6:16

7:9 223:22 327:17337:17

stand 369:9standard 13:4,6,10

13:13 26:3,16,2043:15 79:2 98:1999:6,9,11,12,1999:20 119:2 139:9147:11 148:13170:11,18 193:12196:14 210:21262:4 269:8289:20 292:14298:7 306:9 322:6331:13,21 335:5,6342:2,7,9 372:12

standardized343:19

standards 26:1165:14 89:12,12110:4,5,7 111:4,8133:5 134:11135:20 136:13144:5 183:10185:13,14,21191:3 193:19207:16 219:3224:20 227:21314:13 337:12

standing 11:10182:16 332:20

standpoint 267:18270:3

start 12:20 29:1258:16 206:3239:18 275:20315:22 337:16365:8

started 62:16314:17

starting 143:8

302:22 371:21starts 111:21

277:22 278:16283:18

state 36:18 40:1857:20 59:5 112:22138:10,20 166:12193:8 197:1222:20 227:11234:5 269:19322:4 325:15,19333:7

stated 26:5 40:22198:12 296:19

statement 45:6168:1

statements 174:18states 22:22 53:20

67:7,10 69:12125:13 142:10156:16 206:8218:9,18 227:12232:16 234:13,17234:20 235:2,5254:14 295:6325:8 335:20341:15 342:3347:1,11 366:19

statistical 37:18statistically 73:4status 129:22

252:17 254:22335:4

statute 7:10 47:2162:7 94:15 98:2099:15 226:8305:20 321:18322:18 326:8,17345:17 346:7,19349:18,22 350:3,4350:8 351:7

statutes 6:22statutory 35:11

230:6 269:13287:22 322:16,22344:16 345:20347:7

stay 11:16 374:8Staying 64:14stays 58:4steady 57:20 59:5

65:1stem 173:12 343:22

366:3step 101:9 202:2

210:1 273:1,9274:5 289:1 329:8332:9,19 333:2

steps 160:18172:10 241:5,6

stepwise 143:7240:21 241:3244:16 250:2319:21

Steven 1:20 8:11sticking 81:14stifling 370:16stimulus 88:19stir 170:2stop 56:5 282:9story 127:8straightforward

271:19strategies 106:4

319:3strategy 67:13

189:9Strauss 238:18

239:3streamline 165:6

259:4 274:14,14streamlined 91:10

264:11streamlining 257:9

261:7strength 278:7stresses 318:20strict 117:14

170:10,18 295:3stringent 111:5

186:13strong 131:3 261:9

265:8 291:9stronger 268:15

strongly 11:1720:20 113:2174:12 241:3288:18 310:12374:8

structural 33:1544:12 71:11,1672:18 75:13119:21 136:16160:9 167:4242:10 245:21256:16 257:22278:2,12,18 279:3279:7 280:1 289:8289:11 290:5298:1,6,11,12313:4 314:2,7321:1 327:3

structurally 347:15structure 15:7 29:7

32:14,16 143:1160:8 182:2 242:6245:15 257:13270:17 289:14298:14,15 320:20321:7 326:9347:22 369:19370:3

studied 188:5342:19

studies 15:17 36:1137:21 38:1,1639:18,20 49:162:19 66:8 73:2,473:15 74:1,1075:9,15 85:4,886:18,20 87:1091:13 94:16112:10 113:14,18115:6 116:22131:8 146:11,16148:19 150:11151:8,11 155:1162:3,6 165:14166:13,16 167:7,8175:20 187:6188:4 193:14

194:9 195:2 196:3203:14 207:17243:17,17,20244:3 245:19246:19,20 247:8247:12 248:2,5249:10 265:3268:13 272:22297:6,7 298:20,21298:22 299:7,10306:2,3 308:2,14308:22 309:1312:7,15 320:1331:18 332:20,22336:7 338:5 341:3341:18 366:15

study 11:20 50:1150:18 64:18,1866:9,10,11 95:496:4 106:18107:10,17 113:10119:5 146:5 152:1153:5,14 162:10162:14 166:20,21175:21 177:1,2187:6 188:8,11189:16 191:3192:8,14 194:14194:17,20 196:11203:15 215:12244:5,19 245:1,12250:5 269:2271:13 273:11306:6 312:10313:5,8 333:11334:3

stuff 277:21subcutaneous 18:2

24:14,15subdivision 251:19subject 10:6,10

55:19 115:12178:12 276:21

subjected 333:10subjects 95:17submission 98:21

208:16 367:6


368:7 373:4,11submit 41:9 42:3

51:11 295:10317:20 351:8374:9

submits 352:18submitted 204:6

265:21 344:16346:9

submitting 277:7340:5

subsection 294:21295:15,22 344:19345:11 346:9,12

Subsection(k)(7)(...347:7

subsequent 140:8185:10 221:6250:10 276:13280:13,22 327:4347:3,6,12

subsequently 24:13281:14

subset 12:18112:13 248:18252:20

substance 97:5106:3,10 164:1

substances 333:4substantial 22:9

41:16 118:2120:15 224:8229:15 238:6

substantially 118:8173:15

substitutable 234:9234:15

substituted 331:10342:12

substitution 76:9115:22 121:12124:12 219:9227:10,14 235:6325:20

substrate 174:5178:21 179:17

substrates 172:3

subtitle 6:18subtle 124:18 137:8successful 370:8successfully 40:16

232:3succession 241:8

287:19successor 281:12sudden 93:9Sue 182:17sufficient 17:11

25:5 55:4 74:7121:8 128:5143:19 166:14167:7 188:1245:13 254:9264:18 320:9345:13

sufficiently 39:6suffix 211:7 344:1suffixes 307:5suggest 51:3 92:12

94:21 186:11247:7 248:6322:20 344:2347:21

suggested 116:15153:15 266:11269:8,14,16355:21

suggesting 51:13122:5 266:15

suggestion 100:5suggestions 22:18

182:1 209:11211:14

suggests 251:17suitable 132:3summary 41:18

75:18 97:7 130:22139:1 193:3 309:2

summer 222:3sunset 373:8superb 373:22superfluous 277:21superior 126:8superiority 263:22

269:15supplement 347:2

347:6supplemental

277:18supplemented

116:21supplied 203:5support 7:14 20:20

22:20 24:14 28:136:17 39:12 40:141:21 49:1 50:1365:10 76:21 88:288:4 95:16 96:20116:13,17 124:11141:8 142:3148:17 149:17186:3,20 247:1265:22 267:19270:9 295:2298:22 320:10330:8 335:19349:4,6

supported 41:1590:17 113:14124:5 143:19156:21 299:5336:1 339:18

supporting 17:2111:7 113:17127:22 246:14256:7 325:16360:6 373:21

supportive 37:1347:7 51:2,7 95:1396:9 98:7 155:2

supports 123:17294:12 296:2

suppose 23:11214:3

supra-activity263:6

sure 20:5 44:2 45:862:16,21 65:783:9 84:3,8102:20 103:6107:6 121:2

122:21 160:2174:16 180:8194:5 216:7 232:4232:17,18 251:4251:15 276:19289:15 310:15362:2

surface 291:5Surgeon 365:21surprise 215:10surprised 66:4surrogate 95:8

127:6 131:20132:16 133:16134:6 139:6148:11 153:13,16153:19 154:3,6,9259:1 261:22264:13 265:17267:7,20 273:3

surrogates 16:9125:21 261:15

surrounding239:14 282:21

surveillance 70:470:13 76:19 79:1186:22 153:5208:22 210:19213:6 367:10

survival 38:17127:1,2,4 132:22133:1,9,10,10134:8 138:18262:3,6,15,16266:15 267:22268:8

susceptibility 18:5129:2

sustain 56:4switch 54:12,17,22

54:22 55:6 58:958:11 60:15,1662:4,13 64:19,2064:21 192:10

switched 19:1454:7,14 58:18190:18 236:3

switches 95:20191:22 192:16198:3

switching 18:2119:1,4,6,21 31:438:1,15 51:4 58:558:8 59:4 62:1063:2,10 94:15,1895:1,19,21 106:18190:9 191:8,12,14194:17,20 207:4,5207:8 233:14249:5,19 300:7323:22 324:5343:4

synthesized 360:18361:10

synthetic 362:18363:17

system 22:3,6,8,1167:19 69:19 85:22115:14 116:5130:7 168:16171:11,18 175:5176:12 181:21199:19 212:2221:21 224:17,17227:5 229:14230:13 232:8237:6 254:16306:17,18 312:1,3343:20 356:11

systems 171:21172:13 184:8193:16 235:4,21236:22 237:2,3315:15,18 343:9

S-E-S-S-I-O-N217:1

TT 195:19table 3:1 4:1

368:15tackling 68:1tailored 245:6take 7:5 11:18


55:12 56:21 59:1463:22 64:9 65:987:1 96:13 98:18108:14 118:5121:3 129:17133:3 138:5139:22 164:21169:4 187:1262:10 285:1288:22 316:17324:18 327:18329:9 336:12349:10 350:17365:12 366:5374:11,15

taken 33:4 61:1587:12 90:10127:13 305:5

takes 94:2 105:18108:6 285:2

talk 20:18 83:285:18 102:21124:16 131:1136:12,13 154:13157:3,5 212:12218:16 220:22268:3 281:4288:21 307:13,14310:13 313:3355:12 358:13370:21

talked 28:5 132:13179:1 213:2288:21

talking 30:17 102:3118:20 122:3138:17 156:22159:9 194:21214:7

Tammara 2:7 3:18155:5,7,9 166:17167:5,10,15,19

tank 170:2target 18:4 100:7,9

104:22 129:6159:4,14,20,21243:15 260:13

261:2 304:8targeted 45:17 46:1

111:22 112:17151:10 243:18

targets 348:15teaching 212:17technical 7:11,21

8:1 33:11 92:13157:8 160:6163:16 296:18,21297:4 363:3 373:6

technically 279:15techniques 33:18

48:5 64:6 86:8160:15 245:16340:19

technologies 31:1131:14 35:9 44:746:7,13 97:14141:14 170:22173:11 177:6363:13 364:6

technology 4:533:20 41:9 45:8141:14 161:7,11169:2 175:8181:14,17 182:1201:18 274:20275:5 285:10,11285:14 286:13289:3 290:4 304:5309:6

tell 313:18,20ten 217:11 239:7

313:17tend 56:2tenders 236:5tens 335:9ten-plus 68:13ten-year 8:4Terence 2:9 3:20

167:21term 122:13 156:14

172:15 174:6298:4

terminology303:13

terms 15:21 27:1528:13 29:16,2162:9 88:20 90:1994:11,13 95:6100:16 102:15103:22 105:6106:1,2 107:19122:15 143:22158:3,4 161:13162:19 176:5180:12 195:13197:18 198:11235:3 261:12263:11 270:6273:4 274:4287:14,18 298:21299:17 347:17350:21 357:9,17365:14 371:9,16

terrific 216:12territories 150:22tertiary 242:5test 14:18 19:3

108:2tested 24:13 244:4testify 199:7testifying 182:20testimony 200:4,8

209:12 340:6356:15

testing 13:3 14:624:22 27:5 28:1030:8 34:21 71:1572:5,7 115:1124:7 130:19141:5 144:9,15,16144:21 145:3147:2 148:5 149:3149:5,9,21 159:2163:22 165:14166:11 181:20219:1 221:15226:1 229:12239:15 242:20244:15 247:13258:17 265:15,20267:13 273:16

274:8,10 290:16297:1 333:2,22336:2 341:20351:13 367:8

tests 14:19 16:11332:14

Thailand 19:12236:12

thank 12:8,14,1521:10,11 31:16,1943:9,11 52:13,1452:20 61:22 62:166:17,18 77:7,882:20 85:10 87:1487:17 98:11,14108:12,15 117:1,2122:22 123:1,11132:6,7 140:11144:10 150:3,4155:4,7 166:6167:18,19 173:22182:5,10 193:22194:1 198:19,20199:4,6 200:7207:22 208:1,5216:11,11,19228:3,7 238:11,20238:20 250:18,20251:2 255:8,15266:2,4 274:17275:9,17,18 281:5287:8,9,12 292:2292:4,9 301:8,9301:12,13,21309:12,13 311:18316:14,19 317:16327:20 328:1,8337:14,20 339:8339:10,14 349:8349:11,13 357:4359:16,22 364:10364:12,14,15,19364:20 368:17,18373:15,19 374:19

thanking 67:4168:1

thanks 21:14 82:14

98:10 155:7 166:3182:4 217:7 228:2301:6

theme 89:11theoretical 214:4

214:13 249:5theoretically

260:18 278:13285:21

theory 236:21270:15

therapeutic 42:21183:3,9 190:1,3220:11 250:14257:20 260:3261:1,4,17 263:4264:15 265:11,16343:3 364:3

therapeutically70:19

therapeutics 4:843:3 141:15 171:3185:16 192:4193:6 292:7 360:9

therapies 3:21182:16,22 183:1,8207:12 259:13262:7 292:17,18292:20,22 293:5293:18,21 294:1294:14 295:5296:4,16,22297:10,11 298:5299:2,7,22 300:8339:22

therapy 68:19 69:4136:4

thesis 183:12They'd 178:4thing 87:3 102:4

233:9 304:7315:15 338:20

things 28:5 44:1081:12 137:7161:14 179:3212:11,14 218:17221:14 229:22


232:22 234:8278:3 303:3 351:3

think 14:15 21:1721:21 22:14 24:224:3 25:13,1426:14,19 27:2028:6 29:3,1130:21,22 31:5,744:3,6,13 45:1545:18 46:2,6,6,1248:1,3 49:3,9,1250:9,12 51:1054:19 59:4 61:362:4 63:12,18,2066:12 69:12 77:1581:8 83:14 94:21103:1 104:16105:3 106:19107:5 115:18119:6,13,14 120:7120:10 121:11,18122:8,19 132:12133:4 134:9 136:6137:15,17 139:13139:17 144:11148:8 149:13150:11,15,19152:8,14,17 153:8153:13,19,21154:2,4,7,21160:9 162:13164:9 166:11167:12 175:4176:8,11 179:20180:13 181:3195:7,15 196:12198:1,9,12,12,17205:16 206:4,5207:20 208:19,21209:12,15,16,17209:17,18,19,20209:22 210:20211:14 213:2,11213:17 214:12,13214:21 215:1224:16 227:16228:15,17 229:2

232:6 237:21238:2 253:1254:17 267:10,17267:22 268:14,17270:10 271:11272:8,21 273:6,19274:3,8,12 280:5281:19 287:20288:3,7,13,15,16288:22 289:5,21291:8,19 306:7,15306:20 308:3,12309:22 310:12312:11,15 313:10314:1,22 315:4,14315:20 316:1,5,12322:9 329:19331:1,2 332:3338:10,12,14,22339:3 342:14349:18 350:7,19351:2,14,19 352:1352:4,12,17 353:9353:15 354:7,21356:20 357:20360:22 366:1369:19,22 372:7372:14,22

thinking 64:1765:21 111:12180:20 257:9268:12 273:11,22280:7,12 315:8336:2

third 277:10 343:8348:7 367:11

thorough 32:6112:1 165:17

thoroughly 33:1440:2

thought 27:13 40:458:10,14 111:12119:1 180:2203:14 208:8209:5 211:11218:13,14 224:20231:19 280:8

325:22 353:16369:9

thoughts 50:557:13 67:6 118:12222:16 301:22

thousand 70:578:18 79:11 82:1785:16

thousands 335:9thousand-patient

194:14threatening 135:17

259:11 293:3three 68:17 71:7

87:22 95:5 110:22125:11 129:14138:4 200:9204:10 205:14238:14 258:21259:2 284:11285:18 346:20366:10 369:3,9

thrombosis 300:20throw 137:22tight 12:7 57:5tighter 32:17time 10:3,20 11:1,1

11:8,13 12:6,721:8 26:21 30:2031:3,6 33:12 44:844:11,15 52:4,665:6 72:14 73:2279:2,6 82:16 87:193:2 95:22 98:10100:20 101:11,13101:17 103:10105:8,20 111:18114:5 122:16141:3 156:22162:6 164:9 166:2173:16 198:19205:9,13 206:15208:11,21 209:7211:18 266:2272:13 284:15290:3 296:11301:2 311:3

316:16 317:17330:15 331:12336:15 337:7,14352:9 354:19356:5 361:11362:13 364:11370:14 371:9374:14

timeliness 208:2timely 20:21

328:22 330:10times 60:22 100:19

190:18 199:20203:8 272:17304:9 332:10

timing 55:6tinkers 180:8tissue 18:13 332:21tissues 18:19Tmax 147:15today 5:22 6:15

9:14 10:13 45:746:4 68:13 71:975:2 85:11 88:193:6 110:21117:13 145:6156:5 179:2182:20 198:18199:7,14 200:4,8218:7 238:21250:19 255:20,22275:11 288:21290:4 301:3,4302:1 304:4,22307:7 309:7,18315:17 330:14332:10,18 339:15340:7 349:9350:15 355:12365:4 369:10370:22 373:18

today's 6:10 70:17156:1 239:16374:18

told 210:15tolerability 146:17tomorrow's 326:3

tool 329:19tools 32:5,21

127:20 143:20160:20 161:3,11199:12 203:20333:8

top 84:18 175:16181:7 270:11

topic 153:4 334:22343:8 351:18360:15

topical 50:2topics 27:13,14

296:14 302:21319:14 340:3371:18

total 66:13totality 160:11

258:3 265:2 267:5272:16,20 273:9274:12

totally 310:20touch 156:5 174:17

276:21touched 371:11touching 351:17,18tox 73:3,15 74:1

146:11,12,12173:8

toxicities 74:4129:3

toxicity 73:5 131:8146:5,12 244:5

toxicology 73:1173:1

trace 211:17 216:9traceability 204:18

231:22 232:9,21236:17 343:15

traceable 200:15212:2 226:19233:1 315:11,16

tracing 115:14track 121:17 308:7tracking 20:1,4

213:20 356:13trade 122:7 204:7


224:2 292:13359:4

traditional 35:1536:12 41:13 91:695:11 133:22171:20 172:12238:7

trail 329:16training 317:9transactions 287:7transcribed 10:14transcript 10:15transfer 276:6transient 171:5transition 8:5

258:20transitive 30:8translate 41:16

137:10 258:13translated 132:22translating 273:8translational 84:7

90:22 169:12177:16,19 184:15

transparency318:18 319:1325:6 336:21372:10

transparent 20:2127:10 221:21318:16 327:16

transparently224:18

trash 6:6 216:17treat 262:8 297:12

299:7 341:15treated 39:7 56:4

103:2 136:15234:15 272:1

treating 199:11treatment 54:14

58:18 130:5,8,13130:13,18,21140:9 293:1 327:9368:12

treatments 129:16168:20 326:3

362:1tremendous 42:16trends 19:18trial 48:14 51:3,4,4

51:8 53:6,11 56:856:16 57:3,14,1557:17 58:21 59:1360:18,20 63:1765:5,22 66:4 70:377:15,16 78:1,2,878:13 79:7,1580:15 81:1,8,1081:11,22 82:3,782:12,16 85:13,1585:19,20 116:12116:20 117:9,18117:22 118:3,5,7119:10,18 135:10136:9 138:19145:21 148:9,16149:16 187:3245:17 256:15259:2 261:5262:22 264:14,16267:14 270:4,5365:13 366:14

trials 14:20 16:1825:12 36:17 37:437:8,13,17 42:1,647:5,19 48:8 50:251:2 59:22 60:660:22 61:10 73:773:16 74:16 78:2179:16 81:7 86:3,586:6 91:6 111:4112:9 113:7,22114:15 118:15124:5 126:3,17131:9,15 139:2142:5 145:12146:2 149:19153:20 165:14177:4 182:3187:18 191:10,19200:10 203:1229:16 241:2244:11 256:21

257:3 259:7,10,15262:5 263:7,15264:8 265:9266:21 272:10313:2 320:3 321:9338:18 339:1342:19 352:6367:4

tried 53:10 311:11trouble 77:18trough 57:22true 153:1 192:13

197:8 330:5truly 76:4 296:6

332:11trump 261:11try 46:15 60:5

77:14 150:22179:8 194:7199:12 337:18353:12

trying 70:16 78:14104:10 107:7117:5 202:8,12211:9 269:21288:9

turn 5:15 206:5221:13 226:22

Turning 9:12twice 94:2 214:1two 17:16 30:4

33:22 47:16 57:1858:3,9 74:4 75:1395:5 101:16132:10 138:1,3,6140:20 142:4147:10 156:13157:6 160:17164:14 178:17190:17 192:4201:7 202:10227:19 243:13259:1 266:20282:19 327:12328:19 351:3355:20 358:5360:21 369:5,11

371:4 372:18two-sided 51:3two-stage 353:16type 7:13 26:7

39:11 57:2,360:11 61:10 85:22160:12 163:13238:7 276:16285:6 312:9342:15

types 14:10,1326:22 142:20153:4 171:16276:9

typical 273:17typically 147:11

184:5 222:8310:20 361:18

Tzianabos 2:103:22 182:7,8,11182:14 194:4,21195:15 196:12197:5,11,17,22198:20

Uultimate 49:9

266:16,18 332:3336:16

ultimately 136:3205:12 219:19243:20 256:20264:7 265:1291:17 365:16

umbrella 220:9UN 156:15unattainable 335:5unattractive 238:3unavailability

367:1unavoidable

182:19uncertainly 159:17uncertainties

159:19 160:1,4uncertainty 206:20

253:11,13 314:4,6

unclear 232:14uncommon 205:10underestimate 48:6undergo 95:15

186:12underlie 303:15,16underlies 229:14underlying 257:8undermined 35:7underneath 269:5

285:11,12underscore 327:14understand 50:8

55:8 57:1 77:14102:21 103:6175:19 180:11185:7 199:13202:16 212:21213:13 256:11273:13 354:5,8,15358:2,7

understanding21:3 32:16 35:1036:20 49:5 103:4142:21 157:17165:17 181:16189:14 201:19214:22 270:9340:9

understood 113:16125:1,6 251:4259:19 260:22264:21 341:10350:7 352:5

undertake 355:13undertaken 222:4

354:21uneconomical

308:2unethical 42:6

165:13 290:15307:22 336:6

unexpected 203:8296:9

unfortunate 205:9316:5 334:2

unfortunately


117:6 182:19unimportant

303:10unintended 204:15

207:4Union 218:20

226:16 227:5,12232:15 302:3372:1

Union's 220:6unique 115:19

116:3 121:4,11,18122:1,4 183:15184:4 185:15191:5 193:15211:21,22 222:6294:4 325:4 344:1344:4 355:19356:22

uniquely 124:10uniqueness 293:18unit 182:21United 22:21 67:7

67:10 69:12 142:9156:16 218:9,18335:20

unity 157:16universally 90:8University 199:11unknown 73:9

243:15 249:20unknowns 73:10unmet 67:15 88:14

89:9 339:20unnecessary 13:22

14:1,3 34:2035:21 141:4 145:3165:13 206:20290:15 307:22333:22 336:6

unpowered 73:15unpredictable 15:7

286:14unrelated 281:13

281:20 282:1,21284:18,19,22286:22

unsafe 343:7unsustainable

329:3unusable 40:22unusual 178:21

218:8unwanted 248:10

249:7unwarranted 145:4update 114:11

348:8updates 116:2upper 263:16 271:5upside 200:6uptake 120:15upward 21:21urge 169:3 319:7

342:18urges 97:8 319:12urging 349:20usable 22:21USAN 230:10use 6:9 20:14 23:2

24:12,15 27:1532:14 35:22 42:1343:15 50:1 57:1271:18 73:6,1486:8 88:2 89:394:12 95:8 96:996:10 97:8 98:7103:9 106:3 111:7113:17 114:1115:19 119:12122:1 132:15143:4 149:22151:7 154:14166:1 172:2 179:5190:9 191:14192:12 200:9203:1 207:3211:18 213:9220:8 246:4,14248:14 251:17259:1,2 261:22262:13 264:13266:12,21 267:21307:10,11 312:5

313:1 314:11,18315:9,9 319:21320:4 330:19331:22 332:17335:13,16 336:2336:13 343:6344:14 349:21

useful 27:11,1343:7 120:13121:13 122:9177:6 200:16268:5 344:10351:20 352:14369:15

user 8:6 103:21330:21 336:18,20337:2 344:8348:17 349:4,6369:17,19 371:11372:20,22 373:5

users 372:17user's 370:19uses 24:20 178:21

201:18usual 227:9usually 93:9,14

103:13 127:3128:4 273:1328:19

utility 247:9utilize 93:19 96:14

106:10 165:22utilized 63:16

145:9,15 343:20utilizing 160:14

264:17 363:17UV 160:20U.S 1:1 23:4,10,16

23:18,19 24:169:19 75:22 80:1681:4 85:22 89:289:14 92:8 96:16103:15 109:13114:6,7,15,19115:8,10 116:17141:1 142:6,12143:3 149:19

207:20 215:2225:11 241:10247:5 273:17294:4,6,8 302:1302:15 306:16309:3 311:22313:3 319:12320:5,8 328:15334:20 336:3,9366:17 368:7

Vvaccinal 54:1vaccine 171:9vaccines 88:10

109:8 171:4vague 367:12vaguely 50:7valid 63:7 130:11

157:10validated 16:9

83:14 125:20127:8 139:7 145:8

validation 333:8Valtropin 162:22valuable 101:3

114:12 115:3121:11 127:22

value 73:14 172:7258:9 340:22

variabilities 111:14variability 39:1

40:8 57:10 80:1193:3,8,13 97:12111:16 158:19201:20 260:12304:13

variable 295:7300:4

variables 39:5variation 80:10

101:14 119:21124:20 164:18365:11

variations 28:9variety 33:16 237:1

350:15

various 33:6 44:848:4 75:20 117:12168:6 169:11231:11 266:10272:11 358:7

vary 15:12 26:7160:11

vast 221:11 228:16235:13 257:17

vastly 333:6verify 333:1version 68:8 81:2

371:13versions 32:9 76:15

137:2 168:12versus 80:18

100:21 130:5,5131:10 195:3,3,3249:12 262:19271:22 273:17274:1,2 314:3344:15 357:16

Verthelyi 42:20viable 259:10Vice 52:18 182:14

317:5 339:15videotape 10:10view 21:22 22:6

23:1 29:1 43:2286:10,19 92:20100:8 121:5123:20 126:6129:7 130:2,10,14131:5,11 135:16137:1,12 140:4172:8 205:19228:10,12 237:7243:17 254:2263:14 264:10267:3 290:14295:7 309:9 328:9334:1 338:8354:22 357:10371:4

viewing 5:5viewpoints 47:17

266:20


317:17 318:9374:13

vigilance 343:15Vijay 2:7 3:18

155:5,9viral 172:1 298:11virtually 226:6visual 160:20vis-a-vis 81:13vital 202:1 293:19vitro 75:12 114:22

125:16 145:14,22240:5 265:5267:12 273:15,16366:14

vivo 48:22 125:4240:5 260:18

Vodicka 2:20 4:12317:2,4,5 369:21371:20

voluntarily 316:7voluntary 204:17voting 282:9

WWaal 225:14waiting 345:1

370:17waive 321:22waived 14:4waiving 11:11

321:17want 11:12 12:14

12:20 29:17 45:660:5,17 63:1272:5 78:13 100:1101:21 102:20121:21 152:14166:15 176:3177:7 207:18210:3 230:12231:20 275:9309:9 338:7 369:8

wanted 47:13 53:1160:18,19 69:2282:18 85:12120:22 134:15

139:3,4 176:17270:1 271:1368:21

warrant 326:11warranted 130:14

136:8Washington

199:10 217:10washout 56:6

192:18,19wasn't 79:1 351:18watched 228:18Watson 3:15

140:13,15Waxman 357:20way 34:12 42:13

58:7 62:9 63:1369:8 91:4 108:5116:16 120:11129:15 130:17133:14 136:21138:8 139:19141:12 179:7198:10 206:12213:15,17 215:16228:20 229:22232:20,20 234:16268:9 272:3,20273:11 274:11334:21 336:1353:22 355:16360:17 370:13

ways 116:14 121:16142:4 151:7201:13 211:16298:17 330:14335:15 336:10355:12 373:5

web 224:5webcast 5:6 373:17website 10:16WEDNESDAY 1:9week 33:21 64:18weeks 59:5,8 64:20

64:20,22weight 220:17welcome 5:6 19:3

31:18 217:3293:20 317:3364:11

welcomed 140:16welcomes 309:2well-established

128:9well-executed

191:18well-known 132:21well-recognized

187:19Wenger 2:5 3:14

123:4,5,8,9 133:4134:4 135:5 137:1138:5 139:12

went 53:14 60:7108:17 180:2216:21 230:21316:21 350:5

weren't 62:16we'll 72:22 88:3

94:16 108:15110:21 156:3278:10,21 279:2291:8 316:17,17373:10

we're 5:20 31:1244:5 61:1 62:881:7 95:12 102:3106:14 107:7108:14 138:17139:14 144:3148:6 156:1 157:2159:20 179:12194:21 202:8,12213:5 214:7 217:3266:9 275:4,11276:2,15 279:22280:12 310:14368:13

we've 25:17 95:8107:9 117:12121:6 137:2139:12 159:8171:18 175:12179:1 181:3

199:19 203:4,5204:17,20 205:8206:22 209:10212:7 239:8 250:8252:10 272:18279:9 304:8,19313:16 316:4,16338:2 350:15359:18

wheel 45:13 306:16White 1:13wholesales 162:20

162:21wide 69:2 216:5widely 242:2 352:4wider 51:18wife 88:22Windisch 2:19 4:10

301:18,19 310:11311:14 312:11313:6,10 314:16315:14

window 112:6,13192:18,19

wise 53:13 356:22wish 22:13 210:13

249:17wished 291:19withdrawn 204:10wondering 51:6

107:2 151:12wont 288:12word 348:16worded 75:2wording 326:8words 95:4 195:12

251:19 260:5263:16 272:4

work 50:10 62:1892:4 123:9 140:8151:9 173:14179:10 185:6209:20 210:1225:13 230:10,18232:11 267:12,12275:6 302:9306:18 309:4

329:20 331:19335:16

worked 13:7155:19 230:17

working 45:9 46:8128:15 155:17218:11 222:21267:6 284:4336:19

workload 348:21372:20

world 76:1 90:17134:20 186:16207:14 210:6,11218:10 221:4235:17 291:20294:11 316:12331:22

worldwide 87:19worrisome 273:21worry 120:3 253:10

314:4worth 329:11worthwhile 331:2worthy 240:14wouldn't 79:1

82:18 83:17269:15

written 131:2301:5 340:6 373:4373:11

wrong 200:6wrote 155:16,17

XX 49:6

Yyear 76:3 276:1,12

277:5 279:8280:11 281:1,7283:4,22 285:20285:21 286:2,7290:12,17 291:13326:5,12,18328:20 371:14

years 14:16 19:968:17 88:6,22


89:1 105:11,18110:11 112:1133:14,15 134:1151:21 155:13199:10 217:11218:10 239:8240:14 262:10269:21 277:2302:7,19 304:11306:11,11 309:5310:3 313:17331:8 335:9,11355:15 357:16360:6 364:4367:17

yeast 171:14yellow 20:17 206:5yesterday 21:15

22:19 27:20 29:2146:4 47:12 55:964:2 93:6 106:15115:17 117:13118:13 122:3211:8 288:21290:11 291:2309:18

Yetter 1:22 9:7,7yielded 338:6

ZZarzio 163:3zeta 231:1

$$10,000 76:3$100 108:9$100,000 76:3$200 108:6$30 329:10$70 108:9$800 334:19

11 75:11 107:18

178:15 194:12257:4 282:22283:17 309:1

1A 283:3,20

1B 283:12 284:6,16284:20

1-antitrypsin 293:91:00 216:191:01 217:21:02 216:2210 136:210:03 108:1610:15 108:1510:18 108:18100 291:20,21,21

328:17100,000 196:9102 232:12108 3:1310903 1:1411 204:5,10 205:2111:55 6:1112 3:4 59:5,18

64:20,22 133:14133:15 134:1276:1,12 277:2279:8 280:11281:1,7 283:4,22285:19,21 286:2,7290:12 291:13326:5,12,18

12-year 347:13,1812:00 216:2112:55 6:111200 60:21228 60:2123 3:14140 3:16144 3:1715 1:6 5:6 10:5

292:9 302:7316:17

15-minute 6:3,41503 1:13155 3:1816 251:4167 3:2018 155:12 223:3182 3:22199 3:231990s 161:9

22 12:2 60:22 75:14

107:18 178:16279:3 280:10283:16,17 286:16

2,000 60:212-4 290:172:34 316:212:48 316:2220 21:22 30:17 59:7

218:10 256:720,000 151:222000 161:92001 68:13 219:132003 220:2 235:112005 220:52009 6:20 328:112010 1:10 161:92011 283:1,192012 110:12015 283:4,212017 283:11 284:4

284:62018 329:122021 283:13 284:72023 284:10 285:152027 283:6 284:22033 283:1521 9:14 340:3217 3:252183 220:1 232:13238 4:224 59:8 64:17,20

199:10 223:324-week 65:225 335:8,11 360:6255 4:427 222:19274 4:6275 4:6292 4:8

33 1:10 107:18

244:15 279:22286:19 333:2

3:00 316:18

3:42 374:2130 10:17 76:12 88:6

89:130-fold 68:1530-year 203:2300 60:10301 4:1031 1:1331st 11:17 374:8317 4:1232 3:6328 4:13339 4:1535 88:22351(a) 344:15351(k) 36:9 40:22

65:18 186:2 193:7271:8 298:8344:15 349:19350:1

351(k)(8)(a) 294:21351(k)(8)(e)(i)

295:15360 4:18364 4:19373 4:22

44 60:22 349:34X 48:144:30 5:2248-week 64:18

55 3:2 59:14 136:1,25X 48:145,000 152:3,750 106:20 118:21

196:9 282:9,16505 149:1052 3:8

666 3:967 78:1 85:14

77 311:20 349:15

7:30 5:20

88:30 1:12 5:218:32 5:280 59:14 118:22

172:1180s 141:1287 3:11

990 60:18 172:1294 79:14 80:995 59:19 80:6

FDA-2010-N-0477-0012

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Transcript of FDA-2010-N-0477-0012