Post on 22-Feb-2015
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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
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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.
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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
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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?
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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."
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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
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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
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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.
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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.
11 DR. BEHRMAN: Thank you for your
12 comments. Are there questions from the panel?
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
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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
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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
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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.
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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?
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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
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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.
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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.
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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
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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.
15 DR. BEHRMAN: Our next speaker is
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
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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
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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
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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
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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
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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
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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
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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,
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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
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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.
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1 DR. BEHRMAN: Thank you for your
2 comments. Are there questions from the panel?
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
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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
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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.
13 DR. BEHRMAN: Dr. Jenkins.
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
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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
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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?
17 Thank you for your comments.
18 DR. REITSMA: Thank you.
19 DR. BEHRMAN: Our next speaker is
20 Anshuman Patwardhan.
21 DR. PATWARDHAN: Good morning,
22 everyone.
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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
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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
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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
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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
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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
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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.
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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-
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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.
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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
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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
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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.
8 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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.
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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
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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.
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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
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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.
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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
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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.
14 DR. BEHRMAN: Thank you for your
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
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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
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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
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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.
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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
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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
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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
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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
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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.
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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,
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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
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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.
11 DR. BEHRMAN: Thank you for your
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
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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
5 interchangeability.
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.
22 DR. BEHRMAN: Dr. Kozlowski.
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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
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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.
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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
16 interchangeability.
17 DR. BEHRMAN: Other questions?
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
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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
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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.
5 DR. BEHRMAN: Dr. Jenkins.
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
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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.
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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
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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
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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.
12 DR. BEHRMAN: Okay. Thank you for
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
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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
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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
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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
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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
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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
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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
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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.
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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.
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1 Thank you.
2 DR. BEHRMAN: Thank you for your
3 comments. Questions from the panel? Dr.
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-
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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?
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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
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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.
20 DR. BEHRMAN: Other questions?
21 Ms. Maloney.
22 MS. MALONEY: I just wanted to go
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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.
20 DR. BEHRMAN: Dr. Jenkins.
21 DR. JENKINS: I want to follow up
22 on that because I misread your slide earlier.
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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.
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1 Thank you for your comments.
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-
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
7 DR. BEHRMAN: Thank you for your
8 comments. Questions from the panel? Dr.
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
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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
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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
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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
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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.
10 DR. BEHRMAN: Dr. Kozlowski.
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?
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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,
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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.
21 DR. BEHRMAN: Dr. Jenkins.
22 DR. JENKINS: I'd like to go back
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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
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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.
11 DR. BEHRMAN: Okay. Thank you for
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
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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
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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
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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
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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
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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
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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,
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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.
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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.
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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
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1 in establishing requirements on a case-by-case
2 basis.
3 Thank you.
4 DR. BEHRMAN: Thank you for your
5 comments. Questions from the panel? Dr.
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
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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
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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
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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.
11 DR. BEHRMAN: Dr. Jenkins.
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
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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,
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1 the quality of the studies that were conducted
2 and how supportive they are.
3 DR. BEHRMAN: Any other questions?
4 Thank you for your comments.
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
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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
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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
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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
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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?
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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
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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
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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
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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
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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.
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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
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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.
6 DR. BEHRMAN: Thank you for your
7 comments. Questions from the panel? Dr.
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
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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.
17 DR. BEHRMAN: Other questions?
18 Thank you for your comments.
19 DR. TAMMARA: Thank you.
20 DR. BEHRMAN: Our next speaker is
21 Terence Ryan from iBio, Inc.
22 DR. RYAN: I'm like to open my
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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
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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-
12 translational modifications.
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
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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
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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
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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
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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.
22 DR. BEHRMAN: Thank you for your
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1 comments. Questions from the panel? Dr.
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?
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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.
10 DR. BEHRMAN: Dr. Jenkins.
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
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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?
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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,
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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.
18 DR. BEHRMAN: Dr. Kozlowski.
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,
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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
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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.
18 DR. BEHRMAN: Any other questions?
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
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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
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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.
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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
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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-
15 translational modifications.
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,
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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1 DR. BEHRMAN: Thank you for your
2 comments. Questions from the panel? Dr.
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,
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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
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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?
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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
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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.
16 DR. BEHRMAN: Other questions?
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
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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.
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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.
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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
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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.
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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
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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
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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
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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
6 interchangeability.
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
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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.
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1 DR. BEHRMAN: Thank you for your
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
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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
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1 next step, to work on those.
2 DR. BEHRMAN: Dr. Jenkins.
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.
22 DR. BEHRMAN: Other questions?
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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
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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.
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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
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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
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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.
17 DR. KOZLOWSKI: To follow up on
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?
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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.
10 DR. BEHRMAN: Any other questions?
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.)
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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
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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
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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
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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
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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,
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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.
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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
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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
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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
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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
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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
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1 development of the BPCIA itself.
2 Thanks very much.
3 DR. BEHRMAN: Thank you for your
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
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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.
17 DR. BEHRMAN: Other questions?
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
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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
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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
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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
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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
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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
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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.
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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
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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?
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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.
11 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
20 DR. BEHRMAN: Thank you for your
21 comments.
22 Questions from panelists? Mr.
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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
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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
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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
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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
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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.
8 DR. BEHRMAN: Thank you for your
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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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1 manufacturing.
2 Thank you for your time and
3 attention.
4 DR. BEHRMAN: Thank you for your
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
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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
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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
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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.
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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
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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
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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
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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
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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.
17 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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-
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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.
9 DR. BEHRMAN: Thank you for your
10 comments.
11 Questions from the Panel?
12 MS. ESPOSITO: Thank you for your
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?
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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
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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
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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
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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
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1 realities that don't make it such a place.
2 DR. BEHRMAN: Thank you for your
3 comments.
4 MR. RHEE: Thank you.
5 DR. BEHRMAN: Our next speaker is
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
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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
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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.
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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
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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
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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.
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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
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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
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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.
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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.
12 Thank you for your comments.
13 MS. GUSTAFSON: Thank you.
14 DR. BEHRMAN: Our next speaker is
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
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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.
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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
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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
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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
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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
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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
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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
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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.
13 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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.
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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
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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.
6 DR. BEHRMAN: I have one question
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
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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.
14 DR. BEHRMAN: Okay. Thank you for
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.)
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
20 DR. BEHRMAN: Thank you for your
21 comments.
22 Questions from the panel? No.
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1 Thank you for your comments.
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
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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.
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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.
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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
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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
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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.
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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
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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
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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
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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.
20 DR. BEHRMAN: Thank you for your
21 comments.
22 Questions from the panel? Dr.
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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
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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.
11 DR. BEHRMAN: Our next speaker is
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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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.
11 DR. BEHRMAN: Thank you for your
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
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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.
13 DR. BEHRMAN: Dr. Kozlowski.
14 DR. KOZLOWSKI: To follow up on
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
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1 product.
2 MS. RADCLIFFE: I think we should
3 separate two different things. One is
4 biosimilarity and the other is
5 interchangeability.
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
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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
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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.
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1 DR. KOZLOWSKI: Oh, right. So,
2 post-market for biosimilarity, pre-market for
3 interchangeability.
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
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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.
18 DR. BEHRMAN: I have one question
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
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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
17 interchangeability.
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-
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1 proprietary name.
2 DR. BEHRMAN: Other questions?
3 Ms. Esposito.
4 MS. ESPOSITO: Thank you for your
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
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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
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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.
16 DR. BEHRMAN: Thank you for your
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.
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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
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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
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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
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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.
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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.
12 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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.
18 DR. BEHRMAN: Thank you for your
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
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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
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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
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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
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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
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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
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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
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AAB 285:13abbreviated 7:1
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abbreviation 351:7351:10
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107:15 120:19176:3 179:4 195:7215:6 362:18
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228:17accelerated 127:5
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26:22 27:3 61:13
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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
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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
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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
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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
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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
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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
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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
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88:21 172:10decreased 106:19deemed 17:22
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208:22definition 7:19
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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
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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
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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
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distinction 271:21distinctive 237:15distinctness 226:5distinguish 357:14distinguishable
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201:15 202:5203:22 216:5247:4
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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
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295:17documentation
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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
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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
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DSC 160:21due 87:7 89:4
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141:5 165:13308:1
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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
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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
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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
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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
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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
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ongoing 37:2 92:22105:7 327:15
on-rates 178:7open 4:17 11:7,16
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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
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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
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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
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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
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parties 11:18182:13 222:22374:9
partner 217:8parts 18:8 134:20
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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
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323:8 343:1pharmacodynamic
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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
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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
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prevention 109:7prevents 190:3previous 43:17
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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80:12 170:20188:15,16 192:4195:19,20 267:2
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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
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202-234-4433Neal R. Gross & Co., Inc.
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