Update on Biologics and the Emerging Classifications of...

Update on Biologics and the Emerging Classifications of

Biosimilars

Pharmacy Practice Update Seminar Series August 3, 2015

9:00AM – 10:30AM EDT

This activity was developed by the American Pharmacists Association and supported

by an independent educational grant from Janssen Scientific Affairs, LLC.

© 2015 by the American Pharmacists Association. All rights reserved.

Update on Biologics and the Emerging Classifications of Biosimilars

Activity Description

A recent forecast estimates that by 2015, six out of the top ten selling drugs will be biologics, indicating that these products will be key drivers of the prescription drug market in the United States. The 2010 Affordable Care Act created a pathway for U.S. Food and Drug Administration approval of biosimilar products. This crucial step is expected to invigorate the biosimilars market, which is expected to shadow the booming biologics market, as patents for these agents begin to expire. Come to this session to learn how key issues regarding the clinical impact of biosimilar interchangeability are being addressed and how they are expected to impact the practice of pharmacy.

Learning Objectives

At the completion of this knowledge-based activity, participants will be able to: 1. Describe how biosimilar products differ from biologic products and from conventional

generic drugs. 2. Describe the current approval pathway for biosimilars in the United States. 3. Discuss U.S. Food and Drug Administration requirements for establishing biosimilarity

and interchangeability. 4. Describe the European biosimilar approval and practice experience. 5. Identify and discuss practice issues related to biologics and biosimilar agents including

formulary considerations, product selection, interchangeability, issues at transitions of care, and the need for pharmacovigilance programs.

Target Audience: Pharmacists Activity Type: Knowledge-based Learning Level: 2 Date of Activity: Monday, August 3, 2015 Location: Virtual meeting Time: 9:00 AM–10:30 AM EDT (1.5 hours)

Speaker

Edward Li, PharmD, MPH, BCOP Associate Professor Department of Pharmacy Practice University of New England College of Pharmacy Portland, Maine


Speaker’s Biography

Edward Li, PharmD, MPH, BCOP, is an Associate Professor in the Department of Pharmacy

Practice at the University of New England (UNE) College of Pharmacy in Portland, Maine, and

maintains a practice site as a clinical pharmacist in ambulatory oncology at the New England

Cancer Specialists in Scarborough, Maine. Dr. Li earned his Doctor of Pharmacy degree from

the Philadelphia College of Pharmacy. He also completed a pharmacy practice residency at the

University of Wisconsin Hospital and Clinics in Madison, and an oncology pharmacy practice

residency at the University of Maryland School of Pharmacy in Baltimore. He is a board-certified

oncology pharmacist.

Before joining UNE, Dr. Li was Oncology Pharmacy Manager at the National Comprehensive

Cancer Network and worked on various projects related to oncology policy, including

biosimilars. Dr. Li’s research interests include the analysis of practice trends and outcomes

research using large claims databases such as SEER-Medicare data and the Maine All-Payer

Claims Database.

Disclosures

Edward Li has received honoraria from Amgen, Hospira, Merck, and Sandoz for serving on advisory boards and from Pfizer for serving on the speaker’s bureau. APhA's editorial staff declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see the Accreditation information section at www.pharmacist.com/education .

Accreditation Information

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE). This activity, Update on Biologics and the Emerging Classifications of

Biosimilars, is approved for 1.5 contact hours of CPE credit (0.15 CEUs). The ACPE Universal Activity Number assigned to this activity by the accredited provider is: 0202-0000-15-170-L01-P. To obtain CPE credit for this activity, participants will be required to actively participate in the entire activity and complete the online assessment and evaluation forms located at www.pharmacist.com/live-activities by Thursday, September 3, 2015. This activity was developed by the American Pharmacists Association and supported by an independent educational grant from Janssen Scientific Affairs, LLC.

http://www.pharmacist.com/education


How to Obtain Your CPE Credit

Go to www.pharmacist.com/live-activities and under the Live Activities list, select the Claim Credit link for: Update on Biologics and the Emerging Classifications of Biosimilars

You will need to enter your pharmacist.com Username and Password. If you do not have an account, you can create a guest account for free. Then, continue with the following instructions to obtain your CPE credit for this activity.

Select Add to Cart or Enroll Now from the left navigation and successfully complete the Assessment (use Attendance Code: BIO) and Evaluation. You will need to provide your NABP e-profile ID number to claim credit.

Please visit www.pharmacist.com/cpe-monitor for any questions regarding your NABP e-profile ID number. (Note that it may take up to 3 hours for your NABP e-profile ID number to become activated.)

The filing deadline for this CPE activity is Thursday, September 3, 2015, at 5:00 PM Eastern Time. No credit will be issued after this date.

If you have any questions or require additional information to claim your credit, please contact Anthony Gary, Senior Manager, Education Department, at the American Pharmacists Association by e-mailing [email protected] or calling 202.429.7515.

http://www.pharmacist.com/live-activities

http://www.pharmacist.com/cpe-monitor

mailto:[email protected]


Update on Biologics and the Emerging Classifications of Biosimilars

Monday, August 3, 20159:00 AM–10:30 AM EDT

Edward Li, PharmD, MPH, BCOPAssociate Professor

Department of Pharmacy Practice University of New England College of Pharmacy

1

Development and Support

This educational activity was developed by the

American Pharmacists Association and supported

by an independent educational grant from

Janssen Scientific Affairs, LLC.

2

Attendance Code

BIO

To obtain CPE credit for this activity, you are required to actively participate in this session. The attendance code is needed to access the assessment and evaluation forms for this activity. Your CPE must be filed by September 3, 2015 at 5:00 PM EDT in order to receive credit.

3

1


Accreditation Information

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity, Update on Biologics and The Emerging Classifications of Biosimilars, is approved for 1.5 hours of continuing pharmacy education credit (0.15 CEUs). The ACPE Universal Activity Number assigned by the accredited provider is: 0202-0000-15-170-L01-P.

To obtain CPE credit for this activity, participants will be required to actively participate in the entire webinar and complete an assessment and evaluation located at www.pharmacist.com/live-activities by September 3, 2015.

Initial Release Date: August 3, 2015

Target Audience: Pharmacists

Activity Type: Knowledge-based

Learning Level: 2

Fee: There is no fee for this activity. 4

Disclosures

Edward Li, PharmD, MPH, BCOP, has received honoraria from Amgen, Hospira, Merck, and Sandoz for serving on advisory boards and from Pfizer for serving on the speaker’s bureau.

APhA's editorial staff declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see the Accreditation information section at www.pharmacist.com/education.

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Learning Objectives

1. Describe how biosimilar products differ from biologic products and from conventional generic drugs.

2. Describe the current approval pathway for biosimilars in the United States.

3. Discuss U.S. Food and Drug Administration requirements for establishing biosimilarity and interchangeability.

4. Describe the European biosimilar approval and practice experience.

5. Identify and discuss practice issues related to biologics and biosimilar agents including formulary considerations, product selection, interchangeability, issues at transitions of care, and the need for pharmacovigilance programs.

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2


Which of the following statements is true?

A. All biosimilars are interchangeable with the originator product and with each other like traditional generic drugs

B. The molecular composition of biologic drugs is virtually impossible to fully characterize

C. The manufacturing process for biologics has minimal impact on stability, structure, or immunogenicity of the product

D. A biosimilar is an exact copy of a reference biologic product and is manufactured in an identical manner

Which of the following aspects of a biosimilar product may be different from the reference product?

A. Formulation (e.g., the vehicle)B. Route of administrationC. Conditions of use (i.e., indications)D. Strength

According to the U.S. Food and Drug Administration (FDA) draft guidance on biosimilars, which of the following is “fundamental” for demonstrating biosimilarity?

A. Studies evaluating structure and functionB. Human pharmacokinetics and pharmacodynamics

studiesC. Clinical safety and effectivenessD. Postmarketing studies, including pharmacovigilance

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State biosimilars legislation typically has addressed all of the following except:

A. Naming of biosimilars

B. Notification of the prescriber and patient

C. Length of recordkeeping

D. Lists of substitutable products

Which of the following statements regarding potential substitution of biosimilars is false?

A. The FDA has created a “Purple Book” to help provide information on interchangeable biosimilar products

B. A number of states have passed legislation addressing the substitution of biosimilar products

C. The FDA has created a category of “interchageablebiosimilars” that would be able to be substituted in a manner similar to traditional generic drugs

D. Substitution of biosimilars has been a widespread practice throughout the countries in Europe

What Is a Biologic (Biopharmaceutical)?

• Technical definition from U.S. Code of Federal Regulations• “Any virus, therapeutic serum, toxin, antitoxin, or analogous product

applicable to the prevention, treatment or cure of diseases or injuries of man”

• Derived from living sources• Various cultures of bacteria or viruses

• Human or animal sources

• “Therapeutic proteins”

U.S. Code of Federal Regulations Title 21 Subchapter F – Biologics. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=600.3

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Differences Between Chemical Drugs and Biologics

Chemical Drugs Biologics

Size Small, low molecular weight Large, high molecular weight

Structure Simple, well-defined Complex, heterogeneous

Manufacturing• Reproducible chemical reactions

• Identical copies can be made

• Living cells or organisms

• Impossible to ensure identical copies

Characterization Completely characterizedImpossible to fully characterize molecular composition

Stability Stable Unstable, sensitive to external conditions

Immunogenicity Mostly non-immunogenic Immunogenic

Declerck PJ. GaBI Journal. 2012;1(1)13-6. 13

Relative Size and Complexity of Small Molecule Drugs and Biologics

DrugBank 4.1. www.drugbank.ca

Acetaminophen

151 daltons

Filgrastim

158,880 daltons

Atorvastatin

558 daltons

Rituximab

145,000 daltons

Insulin Glargine

6,063 daltons

Coagulation Factor VIII

264,400 daltons

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Manufacturing Process for Biologics

Mellstedt H, et al. Ann Oncol. 2008;19:411-9.

Cloning into DNA Vector

Transfer into Host Cell

Expression

Screening / Selection

Cell Production

in Bioreactors

Purification through

Chromatography

Cell

Expansion

Recovery through

Filtration or

Centrifugation

Characterization

and Stability

PurifiedBulk Drug

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5


Biologics Have Varying Risks of Immunogenicity

• Manufactured in living cells• Hamster cells, rabbit cells, bacteria (E. coli), etc.

• The body can detect and attack foreign proteins

• Neutralizing antibodies can be developed by the body

• The more similar a therapeutic protein is to the human protein, the less chance of immunogenicity

• Scientific tools for detecting immunogenicity exist, but they are not precise

U.S. FDA. Immunogenicity Assessment for Therapeutic Protein Products. August 2014. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf

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Changes in Manufacturing Can Have Real Consequences

• Differences in manufacturing can lead to differences in structure, stability, and impurities as well as excipients

• Changes in the manufacturing of an epoetin alfa resulted in a small change in formulation• Decreased protein stability and increased aggregate formation

• Resulted in cases of pure red cell aplasia

• Excessive host cell protein contamination increased immunogenicity with somatropin• Resolved with additional purification

Owens DR, et al. Diabetes Technol Ther. 2012;14:989-96.

Schellekens H. NDT Plus. 2009;2(suppl_1):i27-i36.17

What Is a Biosimilar?

• A biosimilar is a “copy” of a commercially available biologic agent (reference or originator product) that has gone off patent

• A biosimilar is “similar” to the reference product with demonstrated similarity in physicochemical characteristics, efficacy, and safety based on data from analytical studies, animal studies, and clinical study or studies

Weise M, et al. Nat Biotechnol. 2011;29:690-3.

Zelenetz AD, et al. J Natl Compr Canc Netw. 2011;9(suppl 4):S1–S22.18

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What Is a Biosimilar?

• Approved via an abbreviated pathway

• Exhibits “highly similar” efficacy and safety compared with reference product

• Interchangeable biosimilar• Can switch back and forth between biosimilar and reference with

no clinical consequences

• Appropriate for substitution without consulting the prescriber

Weise M, et al. Nat Biotechnol. 2011;29:690-3.

Zelenetz AD, et al. J Natl Compr Canc Netw. 2011;9(suppl 4):S1–S22.

Manufacturing Process for Biosimilars

Mellstedt H, et al. Ann Oncol. 2008;19:411-9.

Possibly samegene sequence

Probably differentvector

Differentcell expression system

Different cell line,growth media,

method of expansion

Differentoperatingconditions

Different methods,reagents,

reference standards

Different cell line,growth media,

bioreactor conditions

Different binding andelution conditions

Cloning into DNA Vector Transfer into Host Cell

Expression

Screening / Selection

Cell Production

in BioreactorsPurification through

Chromatography

Cell

Expansion

Recovery through

Filtration or

Centrifugation

Characterization

and Stability

PurifiedBulk Drug

20

Potential Differences vs Reference

• Primary amino acid sequence

• Modification of amino acids (e.g., glycosylation)

• Higher-order structure• Folding

• Quaternary structure

Zelenetz AD, et al. J Natl Compr Canc Netw. 2011;9(suppl 4):S1-S22.

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Biosimilar vs Generic

• A generic is an identical copy of a chemical drug that has gone off patent

• Biosimilars are not generics• Biosimilars are not identical to the reference product because of

differences in manufacturing processes

• Therefore, an assessment of biosimilarity is much more complex than the assessment of “bioequivalence” for small-molecule generic drugs

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Biosimilarity vs Bioequivalence

• Biosimilarity1

• Unlikely to have “clinically meaningful” differences between biosimilar and reference product

• Recognizes that the two molecules are, in fact, different, but exert highly similar effects

• Bioequivalence2

• “The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study”

• These terms are not equal

1. FDA. Biosimilars: Questions and Answers Implementation of BPCI Act of 2009. February 2012. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf

2. FDA. Bioavailability and Bioequivalence Studies. March 2003. www.fda.gov/downloads/Drugs/.../Guidances/ucm070124.pdf 23

General Principles for Demonstrating Biosimilarity

• Biosimilars approved via an abbreviated pathway

• Demonstration of biosimilarity is a comparability exercise and not a therapeutic equivalence study

• The goal of the biosimilarity exercise is to establish that the candidate biosimilar is not significantly different from the reference product and is unlikely to have any clinically significant differences• Smaller-scale direct comparisons and extrapolation are used

FDA. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. April 2015. http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

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8


Biosimilar vs Reference Product

Characteristic Comparison with Reference

Stability May be different

EfficacyUnlikely to have clinically meaningful differences

SafetyUnlikely to have clinically meaningful differences

Active ingredient Not exactly the same

Manufacturing Different process

Immunogenicity May be different

Understanding Key Differences Between Biosimilars and Small Molecule Generics. Spec Pharm Continuum. 2013:vol 2. IFPMA. Biotherapeutic Medicines: Grasping the New Generation of Treatments. 2012. www.ifpma.org/fileadmin/content/Publication/2012/IFPMA_BiotheraputicsWeb4.pdf 25

FDA Specifications for BiosimilarsBiosimilar ProductSpecification

Comparison with Reference

Formulation May be different

Delivery device/container May be different

Routes of administrationMay obtain licensure for fewer than all routes of administration for which reference product is licensed

Indications for useMay obtain licensure for fewer than all conditions of use for which reference product is licensed

Strength Must be the same

FDA. Biosimilars: Questions and Answers Implementation of BPCI Act of 2009. April 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf

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Projected U.S. Patent Expirations for Major Biologics

Generic Name Brand Name Potential Biosimilar Entry

Filgrastim Neupogen 2014

Epoetin alfa Epogen/Procrit 2014

Insulin glargine Lantus 2015

Pegfilgrastim Neulasta 2015

Palivizumab Synagis 2015

Rituximab Rituxan 2016

Cetuximab Erbitux 2016

Adalimumab Humira 2016

Infliximab Remicade 2018

Trastuzumab Herceptin 2019

Bevacizumab Avastin 2019

Darbepoetin alfa Aranesp 2024

Etanercept Enbrel 2028

Lucio SD, et al. Am J Health-Syst Pharm. 2013;70:2004-17.

www.gabionline.net/Biosimilars/General/US-67-billion-worth-of-biosimilar-patents-expiring-before-2020 27

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Demonstrating Biosimilarity: Things to Keep in Mind

• The clinical efficacy and safety of the biologic molecule has already been demonstrated (i.e., by the innovator)

• The biosimilar sponsor only requires evidence that the candidate biosimilar is not significantly different from the reference product • Goal is not to replicate unnecessary clinical trials

• Smaller-scale direct comparisons and extrapolation

• When a biosimilar is approved, there should not be an expectation that there will be differences in safety and efficacy


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Biosimilar Development Approach

Adapted from: McCamish M, et al. Clin Pharmacol Ther. 2012;91:405-17.www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf

Develop highly similar biologic

Test and confirm interchangeability

Postmarketingmonitoring

Test and confirm biosimilarity

• Analytical methods for structure/function

• Cell lines• In vitro/vivo models• Substance pilot and

final scale• Formulation and final

drug product

• Human clinical trials• Consideration of

clinically sensitive endpoints

• Clinically sensitive patient population

• Immunogenicity• Efficacy and safety

• No explicit FDA guidance• Will be “difficult” to do in

the initial 351(k) application

• EU Guidance and risk management plans

• FDA consultation of proposed approach

• May be mandatory

FDA Approval

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Demonstrating Biosimilarity: A Stepwise Approach

• Compare proposed biosimilar to reference in terms of:1. Structure

2. Function

3. Animal Toxicity Studies

4. Human Pharmacokinetics (PK) and Pharmacodynamics (PD)

5. Clinical Immunogenicity

6. Clinical Safety and Effectiveness

• FDA intends to utilize a “totality of the evidence” approach


30

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Biosimilar and Biologic Development

www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf 31

Structure and Function

• Serve as the “foundation” of biosimilar development

• Useful in determining future studies that are necessary

• Structure

• Amino acid sequence, higher-order structures, glycosylation, pegylation, etc.

• Analyze lot-to-lot variability

• Function

• Evaluate pharmacologic activity via in vitro or in vivo experiments

• Functional evaluation that compares candidate to reference


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Four Assessments of Analytical Characterization

FDA. Draft guidance for industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. May 2014. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf

Studies of Structure and Function: Residual Uncertainty

Not similar

Similar

Highly similar

Highly similar with

fingerprint-like similarity

No further development

through 351(k)

Additional information

needed: analytical,

comparative PK/PD, etc.

High confidence; appropriate

for targeted clinical studies

Very high confidence;

appropriate for more

targeted clinical studies

High

Low

33

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Human Pharmacokinetics and Pharmacodynamics

• “Fundamental” for demonstrating biosimilarity

• Both PK and PD will be necessary

• PK: patient population considerations

• PD should study measures that:

• Are relevant to clinical outcomes

• Can be quickly assessed with precision

• Have the sensitivity to detect clinically meaningful difference

• Ideally correlate exposure to clinical outcomes

• Utilize crossover and parallel designs

PK=pharmacokinetics; PD=pharmacodynamics

FDA. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. April 2015. http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. 34

Clinical Studies

• Clinical immunogenicity

• Goal is to evaluate potential differences in incidence and severity of immune responses using endpoints such as antibody formation (binding, neutralizing), cytokine levels, etc.

• FDA recommends a comparative parallel study

• Efficacy and safety: specific clinical trial design will depend on what residual questions remain

• Clinical studies should be designed to demonstrate neither decreased nor increased activity

• Use clinically relevant and sensitive endpoints in the right population

• Biosimilar sponsor to justify comparability delta

Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36.35

Clinical Trial Design: Equivalence

• Establish the equivalence margin (δ) via the 95-95 method• 95% CI should fall between -δ and +δ for equivalence

• However, non-inferiority studies may be appropriate if it is well-established that the biologic saturates the receptors at the clinical dose

Adapted from: Dranitsaris G, et al. Invest New Drugs. 2013;31(2):479-487 and Greene CJ, et al. J Trauma Stress. 2008; 21(5):433-9.www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

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Case Studies: Biosimilar Data for Regulatory Approval

• Products• Filgrastim

• Biosimilar Insulins

• Infliximab

• Disclaimer• Data from a multitude of biosimilar candidates within each class will be

presented for illustration purposes

• When considering biosimilars for formulary, you should assess each product’s data package which should be assessed individually

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Biosimilar Filgrastim (BF)

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm 38

BF: Analytical Tests for Comparability

Category Test Objective

Quantitative analysis of various product-related impurities

RP-HPLC Product-related impurities (oxidized and reduced product)

SE-HPLC high-molecular-weight impurities (aggregates)

Reducing and non-reducingSDS PAGE

high- and low-molecular-weight impurities

Quantitative analysis of various host cell-related impurities

ELISA HCP quantitation

2D gel electrophoresis HCP identification and measurement of pIand molecular weight

UPLC-MS HCP identification and measurement of molecular weight

PicoGreen assay Quantitation of double-stranded DNA

Structural integrity analysis CD spectroscopy Secondary structure

Fluorescence spectroscopy Secondary structure

UPLC-mass spectroscopy Intact mass analysis, peptide mapping, and identification of disulfide linkage positions

Functional analysis In vitro bioassay Biological activity

Rathore AS, et al. Anal Bioanal Chem. 2014;406:6569-76. 39

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BF: Analytical Tests for Comparability

Category Test(s) Summary of Results

Quantitative analysis of various product-related and host-cellrelated impurities

-SDS-PAGE and IEF-SEC-HPLC-RP-HPLC-Ion chromatography

Within acceptance criteria for purity; f-met filgrastim and moreacidic-related impurities were found at higher levels with reference

Structural integrity analysis -Mass spectroscopy Same molecular weights

Functional analysis -in-vitro receptor binding assay-stimulatory effect on myeloid murine leukemia cells

No differences

Additional methods --Peptide mapping with C- and N-terminus AA sequencing-Disulphide bridges and AA sequence determination by peptide mapping

Identical C- and N-terminus amino acid sequences; disulphidebridges consistent with literature

Skrlin A, et al. Biologicals. 2010;38:557-6640

EMEA Guidance: BF PK/PD

• Pharmacokinetics• Single-dose crossover design using SC and IV administration

• Primary endpoint: AUC

• Secondary endpoints: Cmax and half-life

• General principles for demonstration of bioequivalence are applicable

• Pharmacodynamics• ANC relevant PD marker for G-CSF

• Compare biosimilar to reference in healthy volunteers

• CD34 count secondary endpoint

www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003955.pdf

EMEA = European Medicines Agency

41

BF: Human PK/PDParameter,5 mcg/kg SubQ

Biosimilar Filgrastim, mean (geometric SD)

Reference Filgrastim,mean (geometric SD)

Pharmacokinetic

AUC (48h) 157,585 (1.43) 159,426 (1.41)

Cmax 17,976 (1.56) 18,416 (1.56

t1/2 7.81 (1.59) 8.94 (1.25)

Pharmacodynamic

ANC AUC (96 h) 956.93 (1.44) 983.14 (1.25)

ANC Cmax 22.58 (1.27) 21.14 (1.29)

CD34+ AUC (336 h) 1,462.63 (1.53) 1,448.61 (1.47)

CD34+ Cmax 8.42 (1.64) 8.78 (1.46)

Lubenau H, et al. BioDrugs. 2009;23(1):43-51.

No differences were statistically significant

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EMEA Guidance: BF Clinical Studies

• Clinical efficacy studies• Many indications recognized

• “Recommended” model is prophylaxis of severe neutropenia following cytotoxic chemotherapy known to cause severe neutropenia in a homogenous patient group, emphasis on first chemotherapy cycle

• Two-arm comparability design if one chemotherapy regimen used and frequency/duration of neutropenia is well known

• Three arms (with placebo) may be needed if other chemotherapy regimens used

• Allows extrapolation to other indications of the reference product if the mechanism of action (MOA) is the same


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EMEA Guidance: G-CSF

• Clinical safety• Collect data from repeat dosing preferably in a comparative clinical trial

• Total exposure should correspond to routine clinical practice

• Total follow-up for at least 6 months

• Adequate numbers to asses bone pain and laboratory abnormalities

• Immunogenicity data to be collected

www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003955.pdf44

BF: Phase 3 StudiesStudy XM02-02-INT1 XM02-03-INT2 XM02-04-INT3

Tumor type Breast cancer Lung cancer NHL

Intervention Tbo vs. G-CSF vs. placebo

Tbo vs. G-CSF Tbo vs. G-CSF

Mean duration of severe neutropenia (days)

1.1 vs. 1.1 vs. 3.8 0.5 vs. 0.3 0.5 vs. 0.9

Mean ANC nadir (106/L)

700 vs. 700 vs. 200 2100 vs. 2900 1700 vs. 1100

Mean time to ANC recovery (days)

8 vs. 7.8 vs. 14 6.3 vs. 4.5 6.0 vs. 6.7

Incidence of FN (%) 12.1 vs. 12.5 vs. 36.1 15 vs. 8.8 11.1 vs. 20.7

www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/MedicalImagingDrugsAdvisoryCommittee/UCM350157.pdf. Accessed May 2014.1. del Giglio A, et al. BMC Cancer. 2008;8:332.2. Gatzemeier U, et al. J Thorac Oncol. 2009;4:736-40.3. Engert A, et al. Leuk Lymphoma. 2009;50(3):374-9.

Safety evaluations found no clinically meaningful differences in adverse effect profile

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us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/08-18-14-fda-grants-tentative-approval-lilly-boehringer-ingelheim-basaglar-insulin-glargine-injection.html

Biosimilar Insulins (BI)

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BI: Analytical Tests for Comparability

• Physiochemical characteristics• Product-related substances/impurities

• Process-related impurities

• Functional characteristics• Comparative receptor binding for human insulin and IGF-1 receptors

• Receptor autophosphorylation

• Metabolic activity, including glycogen formation, lipogenesis, inhibition of stimulated lipolysis and glucose transport

• Mitogenic activity


47

BI: Analytical Characterization Example

Category EMEA Assessment

Physiochemical characteristics• Product-related substances/impurities• Process-related impurities

• “Only observed difference being the presence of low levels of citrate in the [reference] samples detected by NMR”

• “Total impurities were lower in [biosimilar]”• “One impurity, not found in measurable amounts in

[reference] but present in [biosimilar]...is below the ICH threshold for toxicity.”

Comparative receptor binding for human insulin and IGF-1 receptors• Receptor autophosphorylation• Metabolic activity, including glycogen

formation, lipogenesis, inhibition of stimulated lipolysis and glucose transport

• Mitogenic activity

• “Average relative potency was comparable for all…batches”

• “Provided biological identity test data from [biosimilar] and [reference] with batches tested concurrently, which were demonstrated to be comparable”

EMEA Assessment report: Abasria. Accessed July 2015. www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/002835/WC500175383.pdf

Initially did not follow CHMP guidelines for comparing batches to the reference product, but the company provided follow-up data using the correct batches

“Overall, comparability between [biosimilar] and the reference…has been satisfactorily demonstrated from the quality perspective.”

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Human PK and PD Requirements for BI Development• Pharmacokinetics:

• At least 1 clinical study on the relative PK properties of biosimilar insulin vs reference after subcutaneous administration

• Single-dose, crossover design preferably in patients with type 1 diabetes

• Primary endpoint: AUC

• Secondary endpoints: Cmax, Tmax, half-life

• Pharmacodynamics:• Euglycemic glucose dose clamp

• Double-blind, crossover with collection of PK

• No specifics regarding study population

• These may be sufficient for market approval (efficacy)

Heinemann L, et al. J Diabetes Sci Technol. 2011;5:741-54.49

BI: Human PK and PD Example


Pharmacokinetics

Pharmacodynamics

Biosimilar

Reference

Biosimilar

Reference

“PK and PD equivalence …has been established based on an extensive comparability exercise performed in five studies, which tested several dose levels and were conducted in healthy

volunteers as well as patients with type 1 diabetes.

Biosimilar compared to reference in 3 pivotal studies

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Immunogenicity

• Concern regarding antibodies to human insulin• Antibodies to human insulin occur frequently but often without major

clinical consequences

• Possible loss of efficacy, altered pharmacokinetics, lipoatrophy, allergy, etc.

• Study design• Longitudinal (6–12 months)

• Primary endpoint: incidence of antibodies to biosimilar insulin and reference insulin

• Allow for the analysis and correlation of immunogenicity with clinical data

Heinemann L, et al. J Diabetes Sci Technol. 2011;5:741-54. Van Haeften TW. Diabetes Care. 1989;12(9):641-8. Chen JW, et al. Eur J Endocrinol. 2005;153(6):907-13. Shivam C., et al. Johns Hopkins POC-IT Guides. Insulin Antibodies. www.hopkinsguides.com/hopkins/ub/view/Johns_Hopkins_Diabetes_Guide/547076/all/Insulin_Antibodies

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BI: Clinical Studies Example

• Two randomized comparative studies

• Type I diabetes: ELEMENT 1

• Type II diabetes: ELEMENT 2

• Hypotheses and Result

• Non-inferiority of biosimilar, as measured by change in baseline HbA1c at 24 weeks

• Discussion

• “For the purpose of the clinical biosimilarity exercise for biosimilar insulin products, the CHMP is of the view that the evaluation of HBA1c is not a sensitive endpoint and therefore efficacy studies evaluating HBA1c are not generally anticipated”

• “PK and PD comparability is the cornerstone on which the biosimilarity is established for new biosimilar insulin products”

• These studies provided good information about immunogenicity (comparable antibody development profiles)


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Biosimilar Infliximab (BIX)

http://www.raps.org/Regulatory-Focus/News/2014/08/11/20001/FDA-Receives-First-Ever-Biosimilar-Application-for-Monoclonal-Antibody/

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Monoclonal Antibodies (mAb): Analytical Tests for Comparability

• Physiochemical characterization• Determination of the class, subclass, light chain composition (kappa and/or

lambda chain) and primary structure• Deduce the amino acid sequence from DNA sequencing and confirmed

experimentally by appropriate methods; analyze the variability of N- and C-terminal amino-acid sequences

• Free sulphydryl groups and disulfide bridges• Carbohydrate content, glycosylation and glycan structures• Higher-order structures

• Functional characterization• Binding to target antigen(s)• Binding to representative isoforms of the relevant three Fc gamma

receptors• Fab-associated functions• Fc-associated functions (ADCC, CDC, complement activation)

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003074.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf

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BIX: Physiochemical Characterization Example

Jung SK, et al. MAbs. 2014;6:1163-77.

Pep

tid

e m

app

ing

Hig

her

-ord

er s

tru

ctu

res

Charged isoforms

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BIX: Human PK/PD Requirements

• No specific EMEA guidance for infliximab (general mAbguidance)• Design of the study depends on various factors, including clinical

context, safety, and the PK characteristics of the antibody

• Purpose: show comparability in pharmacokinetics of the biosimilarwith the reference medicinal product in a sufficiently sensitive and homogeneous population

• If feasible, a single-dose study in healthy volunteers is recommended

• PD markers should have a clear dose-response relationship and is an accepted surrogate marker for patient outcomes• May skip this if not available

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf

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BIX: Example of Human PK

Park W, et al. Ann Rheum Dis. 2013;72(10):1605-12.

• Patients with ankylosing spondylitis• Randomly assigned 1:1 to reference

infliximab or BIX• Required 196 patients to demonstrate

equivalence• 229 patients completed the 30-week

study

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BIX: Efficacy and Safety

• Efficacy• Guiding principle is to demonstrate similarity, not patient benefit per

se

• The most sensitive patient population and clinical endpoint is preferred

• Safety• Based on reference product adverse event profile using same

definitions

• “Systematic and comparative evaluation and discussion of immunogenicity is important”

• Rare but serious adverse events may require postmarketpharmacovigilance

www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf 58

BIX: Efficacy and Safety Example• Randomized, double-blind, parallel-group study

• BIX vs reference infliximab, both with methotrexate in patients with rheumatoid arthritis

• Required 584 patients to demonstrate statistical equivalence; 606 patients treated

• Primary endpoint: ACR20 response criteria at week 30

• Antibodies to infliximab at weeks 14 and 30 were the same for both arms

ADE BIX (%) Inflix(%)

ALT increased 4 3.7

Latent TB 4.3 4.7

Infusion-related reactions 6.6 8.3

Neutropenia 1 0.7

RA flare 2.3 1.3

Yoo DH, et al. Ann Rheum Dis. 2013;72(10):1613-20.59

Biosimilar Products: Summary

• A comprehensive comparability exercise is conducted for biosimilar products in preparation for regulatory approval• Physiochemical characterization is foundational to the data package

• Efficacy and safety studies assess equivalence to the reference product

• Insulins present a challenge in the United States because they are approved via the new drug application (NDA) pathway

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Biosimilar Development Approach

Adapted from: McCamish M, et al. Clin Pharmacol Ther. 2012;91:405-17.www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf

Develop highly similar biologic

Test and confirm Interchangeability

Postmarketing Monitoring

Test and confirm biosimilarity

• Analytical methods for structure/function

• Cell lines• In vitro/vivo models• Substance pilot and final

scale• Formulation and final drug

product

• Human clinical trials• Consideration of

clinically sensitive endpoints

• Clinically sensitive patient population

• Immunogenicity• Efficacy and safety

• No explicit FDA guidance• Will be “difficult” to do in

the initial 351(k) application

• EU Guidance and risk management plans

• FDA consultation of proposed approach

• May be mandatory

FDA Approval

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Postmarket Monitoring: EU Risk Management Plans• “Comprehensive and proactive application of scientifically based

methodologies to identify, assess, communicate, and mitigate risk throughout a drug’s life cycle so as to establish and maintain a favorable benefit-risk profile”

• Mandatory for biologics (immune reactions)

• Four steps for a particular risk:

Zuñiga L, et al. Pharmacoepidemiol Drug Saf. 2010;19:661-69.

Step Description Risk Management Plan

1. Detection Identify riskPharmacovigilance

2. Assessment Understand/monitor risk

3. Communication HCP educationRisk minimization

4. Minimization Act to reduce risk

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FDA Guidance:Postmarketing Monitoring for Safety

• Important to assure safety for all biologics

• Consider risks seen in reference

• Are there any new safety concerns?

• Population-based assessments gives larger N to identify rare safety concerns

• Might be mandatory for some products

• Biosimilar manufacturers should work with FDA early to discuss approach

• Current pharmacovigilance guidances by FDA

FDA. Guidance for industry. February 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf

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Pharmacovigilance Challenges:Enoxaparin Case Study in the United States

• Commercial claims data analysis of patients receiving prescriptions for enoxaparin• No statistical difference

between branded vs generic with incidence of HIT (1.2% vs 1.5%, P<0.0001)

• Increasing market share of generic products after loss of exclusivity in 2010 (to about 44% in 2012)

Grampp G, et al. Expert Opin Drug Saf. 2015; ePub early online.

Enoxaparin thrombocytopenia reports by sponsor: FDA AERS Analysis

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Pharmacovigilance:Challenges in the United States

• Health care providers need to correctly attribute the safety signal

• How? • Traceability and attribution

• Naming

• Codes: NDC vs HCPCS

• Data

• Prospective registries

• Administrative claims

• Electronic health record

• Linked databases

• Spontaneous adverse event reporting

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Interchangeability

• Safety standards for determining interchangeability

• Must be a biosimilar

• Produces same clinical result as the reference in any given patient

• Risk of safety or diminished efficacy due to alternating or switching between biosimilar and reference is no more than using the reference product with no switching

• Will be “difficult” in the initial 351(k) application due to the sequential nature of the assessment

• Appropriate to be “substituted for the reference product without the intervention of the health care provider who prescribed the reference product”

Public Health Service Act, section 351(k)(4). www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf

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Interchangeability Study Design

• FDA interchangeability criteria: switch between reference (R) and biosimilar (B) with no clinical consequences

• What is switching?

R B B R B

B R R B R

R R

B B

• Various designs proposed

• Standard two-sequence, two-period crossover

• Balaam’s 4 x 2 crossover design

Chow SC, et al. Stat Med. 2013;32:442-8. 67

The Biosimilar Experience: European Union

Myths about biosimilars

• Low quality

• “Similar but not identical” is inferior

• Safety unknown

• Postmarketing surveillance

• Poor efficacy

U.S. challenges for biosimilars

• Indications

• Interchangeability

• Naming

• Traceability

Weise M, et al. Blood. 2012;120:5111-7. 68

Key Points

• There is a robust regulatory pathway for the approval of biosimilar agents in the United States

• A biosimilar’s analytical characterization serves as the foundation for further studies

• EU guidance documents outline data that is necessary for market authorization; FDA will likely use the same approach

• Interchangeability and pharmacovigilance are important but unresolved issues in the United States

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Learning Objectives

1. Describe how biosimilar products differ from biologic products and from conventional generic drugs.

2. Describe the current approval pathway for biosimilars in the United States.

3. Discuss U.S. Food and Drug Administration requirements for establishing biosimilarity and interchangeability.

4. Describe the European biosimilar approval and practice experience.

5. Identify and discuss practice issues related to biologics and biosimilar agents including formulary considerations, product selection, interchangeability, issues at transitions of care, and the need for pharmacovigilance programs.

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European Union Biosimilar Experience

• Biosimilars are high-quality products with strict regulations in manufacturing and scientific development

• Similar vs identical debate is not unique to biosimilars (applies to each biologic for lot-to-lot comparability)

• Safety data is required pre-approval (including immunogenicity)

• Postmarketing surveillance (mandatory) seeks to identify residual concerns; not unique to biosimilars

• Efficacy comparison trials will use the most clinically sensitive endpoint

• Be aware of indication differences and extrapolate if appropriate

• Interchange practices highly variable

Weise M, et al. Blood. 2012;120:5111-7.

Substitution/Prescribing Policies in Several EU Countries (2014)

Adapted from Hans Ebbers from Huub Schellekens Group, Utrecht, The Netherlands. Niederwieser D, et al. Eur J of Haematol. 2011;86:277-88.

Biological substitution prohibited by law

Substitution only for other biosimilars

Substitution possible only forpatients starting treatment

All substitution (including SM generics) prohibited

No guidance, but substitution happening (no official figures)

Biologicals/biosimilars not considered substitutable (or not on national substitution list)

Spain

France

UKIreland

Norway, Sweden,

Finland

Germany

Netherland

sPoland

Italy

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Use of Biosimilars in European Union

•Market uptake has been somewhat slow with 11% of total EU biologic sales (5% to 20%); but growing at a rate greater than other market segments

• Costs generally 15% to 30% below reference products

• EU biosimilars have enhanced market competition and helped stabilize health care costs – even without high uptake

• EMA has not identified any specific safety issues for approved and marketed biosimilar products – even with relatively robust pharmacovigilance programs

IMS Institute for Healthcare Informatics. Assessing biosimilar uptake and competition in European markets. October 2014.

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Issues and Considerations: Premise Statements

Biosimilars are not generics

• Different regulatory pathway vs generics

• Different data submitted to FDA to establish efficacy and safety vs originators

Product and data differencescreate operational and clinical challenges

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Operational Challenges

Domain Elements Institutional Risk

Formulary analysis • Product approval pathway anddata package

• Appropriate indications (on-label and off-label) for use

• Extrapolation considerations• Therapeutic interchange +/-

guided use policies• Transitions of care• Payer mix

• Institution’s use results in poor clinical outcomes

• Over-burdensome policies• Poor considerations of

transitions of care lead to logistical problems

• Off-policy requests (time waste)

Order management and information systems

• Differentiate biosimilar and reference in electronic systems

• Order sets, protocols, MARs• Medication reconciliation

• Poor documentation of product actually received and impact on transitions of care

• Incorrect attribution for ADE reporting

Adapted from: Lucio et al. Am J Health Syst Pharm. 2013; 70(22):2004-1775

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Operational Challenges

Domain Elements Institutional Risk

Inventorymanagement

• Buyer needs adequate information (NDC code, etc.)

• Both biosimilar and reference in stock?

• Product storage

• Medication errors: wrongproduct dispensed and/or administered

• Procurement delay

Financial analysis • Pricing information comparison (base, contract, reimbursement,margin)

• Staff management time• Patient assistance and out-of-

pocket expenses• Determine financial impact

• Margin and time not considered (outpatient) –financial loss

• Dollars saved/earned may not be worth the unmitigated risks (above)

Education • Drug information and education to all providers (clinical info, policies, etc.)

• Patient education materials

• Providers provide wrong information to patients

• Point-of-care confusion (time waste)

Adapted from: Lucio et al. Am J Health Syst Pharm. 2013; 70(22):2004-17 76

Pharmacist Substitution

• State law gives pharmacists the authority to act independently of the prescriber to dispense the lowest-cost, equivalent medicinal product

• Framework• Product criteria

• Orange book (ANDA generics)• Purple book (351(k) biosimilars)

• DAW• Communication with prescriber/patient• Record keeping• Hospital/health system exemption

Li EC, et al. J Manag Care Spec Pharm. 2015;21(7):532-3977

Biosimilar Legislation by State

National Conference of State Legislatures. www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed December 1, 2014.

- 8 states enacted statutes- 1 state passed but vetoed- 10 states did not pass- 4 pending

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Sample of Enacted Biosimilar Substitution Laws

State DAW Product’s criteria forsubstitution/interchange

Prescriber/patientcommunication

Record Keeping

DE Yes FDA designated interchangeable or therapeutic equivalent

Inform patient; inform prescriber in 10 days

Same as generic law

FL Yes FDA determined interchangeable

Inform patient same as generic; EMR notification for institutions

2 years

VA Yes FDA determined interchangeable

Inform patient of cost; inform prescriber within 5 days

2 years

MA Yes FDA determined interchangeable

Inform patient and prescriber (no timeline)

1 year

http://delcode.delaware.gov/title24/c025/sc06/index.shtmlhttp://www.flsenate.gov/Session/Bill/2013/0365/BillText/er/PDFhttps://leg1.state.va.us/cgi-bin/legp504.exe?131+ful+CHAP0412 http://www.foleyhoag.com/publications/alerts-and-updates/2014/june/massachusetts-enacts-new-biosimilars-substitution-law

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Pharmacy Practice Implications

• Generic substitution may not be appropriate for biosimilars, but therapeutic equivalence programs are likely within health systems

• Pharmacists will need to lead evaluation of biosimilars for formulary inclusion• Range of indications

• Therapeutic equivalence

• Process for therapeutic interchange within health systems

• Information systems to enable pharmacovigilance

Clinical Issues and theDesired Use of the Biosimilar

Reference biologic labeled indications

Biosimilar labeled indications

Desired use within

institution

P&T determinationMust incorporate patient, disease and endpoint factors

with biosimilarity data

“Appropriate” indications

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Considerations for Formulary Selection of Biosimilars

CSTDs = closed-system transfer devices

• Clinical data• Range of

indications• Immunogenicity

concerns• Potential for

therapeutic interchange

• Number of similar agents on formulary

• Pharmaco-vigilance requirements

• Supply reliability• History of drug

shortages• Supply chain

security• Anti-counterfeit

measures• Patient

assistance programs

• Reimbursement support

• Product packaging and labeling

• Bedside bar coding

• Compatibility with CSTDs*, robotics

• Product preparation and administration

• Storage requirements

• Economic considerations Hospital Payer Patient

• Payer policies• Transitions of

care• IT and

medication system changes

• Educational requirements

Efficacy/SafetyManufacturer

ConsiderationsProduct

ConsiderationsHospital and

Patient Factors

Griffith N, et al. Hosp Pharm. 2014;49:813-25.

Major Challenges for P&T Committees With Biosimilars

• Indication extrapolation by the P&T Committee

• Product naming and impact on ordering, errors, traceability, and pharmacovigilance

• Evaluation of overall economic impact of use of biosimilars• Combined inpatient and outpatient impact

• Challenges of portfolio pricing

• Impact on patient out-of-pocket expense

• How many “similar” products to carry on the formulary

• How to manage transitions of care• Desire to minimize switching

• Reduced chance for error

• Avoid potential immunogenicity problems

• Analogy with generic immunosuppressants in transplant recipients?

Recommendations to Pharmacists for Biosimilars

• Utilize existing formulary system and processes to evaluate for formulary inclusion

• Carefully consider scope of indications for use

• Conduct sophisticated economic analysis, considering costs, reimbursement, and patient impact

• Plan for therapeutic equivalence and guided-use policy and processes

• Consider processes for transitions of care

• Prepare information technology (IT) systems to facilitate effective pharmacovigilance programs

• Meet educational needs of patients and providers

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Conclusion

• Biosimilars present significant opportunities and challenges for pharmacists managing formularies and providing patient care

• A framework for biosimilar introduction has existed in Europe and is being defined in the United States

• European biosimilar experience has been positive

• Pharmacists must educate themselves to be prepared to play leadership roles in the safe and appropriate introduction of biosimilars

Conclusion (continued)

• Integration of biosimilar agents into clinical practice present many operational and clinical challenges

• Key issues yet to be determined include interchangeability, pharmacovigilance requirements, naming, and traceability

• Pharmacists should take leadership in planning a strategy for successful operational/clinical use of these agents

• Transitions of care and medication reconciliation will be ongoing practice management issues

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Which of the following statements is true?

A. All biosimilars are interchangeable with the originator product and with each other like traditional generic drugs

B. The molecular composition of biologic drugs is virtually impossible to fully characterize

C. The manufacturing process for biologics has minimal impact on stability, structure, or immunogenicity of the product

D. A biosimilar is an exact copy of a reference biologic product and is manufactured in an identical manner

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Which of the following aspects of a biosimilar product may be different from the reference product?

A. Formulation (e.g., the vehicle)B. Route of administrationC. Conditions of use (i.e., indications)D. Strength

According to the U.S. Food and Drug Administration (FDA) draft guidance on biosimilars, which of the following is “fundamental” for demonstrating biosimilarity?

A. Studies evaluating structure and functionB. Human pharmacokinetics and pharmacodynamics

studiesC. Clinical safety and effectivenessD. Post-marketing studies, including pharmacovigilance

State biosimilars legislation typically has addressed all of the following except:

A. Naming of biosimilars

B. Notification of the prescriber and patient

C. Length of record-keeping

D. Lists of substitutable products

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Which of the following statements regarding potential substitution of biosimilars is false?

A. The FDA has created a “Purple Book” to help provide information on interchangeable biosimilar products

B. A number of states have passed legislation placing limits on the substitution of biosimilar products

C. The FDA has created a category of “interchangeable biosimilars” that would be able to be substituted in a manner similar to traditional generic drugs

D. Substitution of biosimilars has been a widespread practice throughout the countries in Europe

Attendance Code

BIO

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• Login

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• “Enroll” in the activity

• Complete the ASSESSMENT and EVALUATION (links provided)

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