biosimilars: what every pharmacist needs to...

© 2016 by the American Pharmacists Association. All rights reserved.

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BIOSIMILARS: What Every Pharmacist Needs to Know Edward C. Li, Pharm.D., M.P.H., BCOP

University of New England College of Pharmacy

Portland, Maine

James G. Stevenson, Pharm.D., FASHP

University of Michigan College of Pharmacy

Visante, Inc.

Ann Arbor, Michigan

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Disclosure

• Edward C. Li, Pharm.D., M.P.H., BCOP, declares that he has served on an advisory board and speakers bureau for Hospira and an advisory board for Pfizer Inc. He has also served on advisory boards for Merck and Sandoz and has divested himself of these relationships.

• James G. Stevenson, Pharm.D., FASHP, declares that he has served as a consultant for Amgen Inc. and is an employee of Visante, Inc.

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

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• Target Audience: Pharmacists and Pharmacy Technicians

• ACPE#: 0202-0000-16-014-L04-P

0202-0000-16-014-L04-T

• Activity Type: Knowledge-based

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Learning Objectives

• At the completion of knowledge-based activity, participants will be able to: 1. Discuss the current status of biosimilars in the

United States, including recent FDA activities.

2. Identify potential implications of biosimilars for pharmacists working in various practice settings, including issues of product substitution and interchangeability.

3. Identify and discuss issues related to both product efficacy and patient safety for biosimilar agents.

4. Discuss strategies for determine appropriate formulary placement for biosimilars.

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At least one biosimilar application has been submitted to the FDA for:

A. Adalimumab

B. Trastuzumab

C. Cetuximab

D. Golimumab

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Which FDA Guidance Document is forthcoming and has yet to be released in draft form?

A. Naming

B. Scientific standards

C. Interchangeability

D. Quality considerations

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For a biosimilar to be approved, clinical trials should demonstrate:A. Comparability in efficacy between the biosimilar and

reference using a clinically sensitive endpoint

B. That the biosimilar is safe and effective in all of the reference product’s indications

C. That the biosimilar is safer than the reference product

D. Equivalence in clinical outcomes related to immunogenicity (e.g., rare but serious adverse effects, loss of efficacy) between the biosimilar and reference product

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How does the FDA’s “interchangeable biosimilar” designation impact pharmacist substitution?

A. These products require more pharmacovigilance than for standard biosimilars

B. Current state pharmacy practice substitution laws allow substitution for interchangeable biosimilars only

C. For a reference product where there is more than one interchangeable biosimilar, pharmacists can substitute one interchangeable biosimilar for another

D. The interchangeable designation means the pharmacist does not need to notify the prescriber of the substitution

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Which of the following about the formulary review for biosimilars is true?

A. The P&T committee should review the biosimilar data package exactly the same way it reviews other novel agents that are recently FDA-approved

B. The P&T committee should utilize the generic policy to add the biosimilar to formulary

C. The range of indications for use should be considered when reviewing a biosimilar for formulary consideration

D. Product formulation, device/container, packaging/labeling are non-factors to review because the biosimilar will be the same as the reference product in these domains

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The Patent Cliff and Growth Potential for the Biosimilars Market

www.gabionline.net/Biosimilars/General/Top‐8‐blockbuster‐biologicals‐2013.www.gabionline.net/Biosimilars/General/US‐67‐billion‐worth‐of‐biosimilar‐patents‐expiring‐before‐2020 (both accessed 2015 Dec 3).

10.7

8.9

8.6

8.3

7

6.8

4.4

0 1 2 3 4 5 6 7 8 9 10 11 12

Adalimumab (Humira)

Infliximab (Remicade)

Rituximab (Rituxan, Mabthera)

Etanercept (Enbrel)

Bevacizumab (Avastin)

Trastuzumab (Herceptin)

Pegfilgrastim (Neulasta)

Global Sales 2013, US$ BillionEU Expiry Date

U.S. Expiry Date

2018 2016

Expired 2018

Expired 2016

Expired 2013/2028*

2022 2019

Expired 2019

2017 Expired

*Expiry date uncertain.

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Background on Drugs & Biologics

• Drugs are approved under Section 505 of the FDCA– NDA: Section 505(b)(2); ANDA: Section 505(j)

• Biologics are approved under the PHSA– Originator/reference/follow‐on: 351(a); Biosimilar: 351(k)

• The Biologics Price Competition and Innovation Act was enacted to increase competition with biological medications– Decreased prices (or overall expenditures)

– Increased innovation

• Several older biologics (e.g., insulins) were approved under Section 505– BPCI allows a transition period to allow approval under Section 505

before 2020

Li EC, et al. J Manag Care Spec Pharm. 2015;21(7):532‐39Blackstone EA et al. Am Health Drug Benefits. 2013; 6:469‐78.Heinemann L, et al. Diabetes Technol Ther. 2015;17(7):510‐26.


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Current Status of Biosimilar Activities

2010 2011 2012 2013 2014 20152010 2011 2012 2013 2014 2015

3/2010BPCI Act

passed as part of the

PPACA

2/2012Three FDA draft guidance documents on biosimilars (Scientific, Quality, Q&A)

3/2013Draft guidance on formal meetings

with FDA and sponsors

5/2014FDA draft guidance:

clinical pharmacology

9/2014Purple book announced

3/2015First biosimilar

approved

5/2015FDA draft guidance:

Additional Q&A

4/2015Finalized guidance

documents from 2/2012

8/2015FDA draft guidance: naming

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Biologics: More Complex than Traditional Small Molecule Drugs

Declerck PJ. GaBI J. 2012; 1:13‐6.Illustration courtesy of Olgun Guvench, M.D., Ph.D., University of New England College of Pharmacy.

Human EPO165 amino acidsMW ~ 34,000 Da

Cisplatin(NH3)2PtCl2

MW ~ 300 Da

Biologics• Produced by living systems• High molecular weight• Complex & heterogeneous

structure• Impossible to fully

characterize• Sensitive to external

conditions & manufacturing changes

• Relatively high immunogenicity

Small-molecule drugs• Produced by chemical

reactions• Relatively low molecular weight• Final structure independent of

process• Able to be characterized fully• Stable• Mostly non-immunogenic

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Manufacturing Biosimilars: Sources of Variation

Adapted from Mellstedt H et al. Ann Oncol. 2008; 19:411-9. 16

Regulatory Definitions of a Biosimilar

• Food and Drug Administration (U.S.)– A biological product that is highly similar to a U.S.‐licensed reference

biological product notwithstanding minor differences in inactive components and for which there are no clinically meaningful differences in safety, purity, or potency of the product

• European Medicines Agency – Europe – … structurally highly similar versions of an already authorized

biological medicinal product (the reference product) with demonstrated similarity in physicochemical characteristics, efficacy, and safety based on a comprehensive comparability exercise

http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30).Weise M et al. Nat Biotechnol. 2011; 29:690‐3.

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General Principles for Demonstrating Biosimilarity

• Biosimilars approved via an abbreviated pathway

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

• 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

http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30).

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FDA Specifications for Biosimilars

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf. April 2015 (accessed 2015 Oct 30).

Biosimilar 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


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Biosimilar Development Approach

Adapted from McCamishM et al. Clin Pharmacol Ther. 2012; 91:405‐17.

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

y y

• 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 of1. 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 use a “totality of the evidence” approach


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Biosimilar and Biologic Development

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Feb 15, 2012 (accessed 2015 Oct 30).

351(a)

351(k)

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Structure and Function

• Serve as the “foundation” of biosimilar development

• Useful in determining what future studies 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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Analytical Characterization: Fingerprinting

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM315764.pdf. Aug 8, 2012 (accessed 2015 Oct 30). 24

Four Assessments of Analytical Characterization


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 moretargeted clinical studies

High

Low


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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

• Use crossover and parallel designs


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Comparative Clinical Studies

• 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.

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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; 31:479‐87 and Greene CJ et al. J Trauma Stress. 2008; 21:433‐9.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30).

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Indication Extrapolation Framework

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf (accessed 2015 Nov 4).Weise M et al. Blood. 2014; 124:3191‐6.

Patient Factors• Similarity of biologic disposition: PK/PD

• Organ function• Age, ethnicity, etc.

Disease Factors• Clear MOA?• Similarity of disease (e.g., histology, stage, pathophysiology, etc.)

• Single vs. combo therapy• Clinical manifestation

Endpoint Factors• Efficacy and toxicity• Short‐term vs. long‐term

• Sensitivity of surrogate outcomes

Quantitative Evidence of BiosimilarityIn vitro, preclinical, epidemiological studies, diagnostic studies, clinical trials, and

observational studies

Indication Extrapolation DeterminationNo extrapolation; extrapolation to some indications; extrapolation to all indications

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Immunogenicity Concerns

• All biologics confer a risk of immunogenicity– Related to patient, disease, and product factors

– Consequences include neutralizing antibodies or cytokine release

– Scientific tools for detecting immunogenicity exist, but they do not always translate to clinical outcomes

• Changes to the structure of the protein increase variation in immunogenicity

– Lot-to-lot and between manufacturers

– Variations in manufacturing must be minimized

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

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Immunogenicity concerns• Clinical consequences:

– Loss or diminished efficacy or safety

– Case reports of rare but serious adverse reactions have been reported

• Clinical immunogenicity assessment for biosimilars– 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

U.S. FDA. Immunogenicity Assessment for Therapeutic Protein Products. August 2014. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf Schellekens H. NDT Plus. 2009; 2(suppl 1):i27-i36.


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Biosimilar Pharmacovigilance

Zuñiga L et al. Pharmacoepidemiol Drug Saf. 2010; 19:661-9.

Felix T et al. Nat Biotechnol. 2014; 32:128-30.

Casadevall N et al. Expert Opin Biol Ther. 2013; 13:1039-47.

Pharmacovigilance

• Practical to encourage healthcare provider reporting

• Real-time data• Ensure traceability

Risk minimization

• Healthcare provider communication

• Recalls and alerts• FDA REMS?

Risk Identification andCharacterization

FDA Approval

Healthcare Provider Responsibility for Reporting• Correct attribution of safety event• Maintenance of electronic medical record• Bar code administration• Medication reconciliation• Consideration of transitions of care

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Interchangeability• Appropriate to be “substituted for the reference product without

the intervention of the healthcare provider who prescribed the reference product”

• Standards for determining interchangeability– Must be a biosimilar– Produces same clinical result as the reference in any given patient– Risk of harm 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

• FDA is in process of developing guidance

http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf

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There Will Be Many Types of Biologic Products

351(a)Originator

351(k)Biosimilar

351(k)Interchangeable Biosimilar

351(a)Non-originator biologic

351(a)Next-generation “Bio-better”

Description First-to market biologic molecule; will likely be the reference product

“Highly similar” to reference product; approved via biosimilars pathway

A biosimilar that can be switched to and from the reference with no clinical consequences

It is “another brand name” of an already approved biologic

Biologic that has been altered to achieveimproved clinical outcomes

Data package

Demonstratesafety & efficacy

Abbreviateddata package

Abbreviated data package, more information on switching



Practice Implications

Biosimilar reimbursementper CMS (same margin as reference)

Biosimilar reimbursementper CMS; possible automatic substitution without contacting prescriber

Lower margin if lower cost; automatic substitution issues

New entity

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Biosimilar User Fee Act (BsUFA) Reauthorization• BsUFA allows the FDA to collect user fees in return for a

timely review of the application

• Performance goals: – Review and act on 85% (FY2016) and 90% (FY 2017) of original

biosimilar applications within 10 months of receipt and

– Review and act on 85% (FY2016) and 90% (FY 2017) of resubmitted biosimilar applications within 6 months of receipt

– 90% in 10 months for original supplements and in 6 months for resubmitted supplements with clinical data

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicAppl

ications/Biosimilars/UCM281991.pdf

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Biosimilar Applications to the FDA

BsUFA Workload and Volume: Interim Report. http://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM459686.pdf

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FDA has been busy



37

Biosimilar Applications and FDA Staff Involved


38

Additional 351(k) BLA Applications

• Pegfilgrastim (Sandoz) – 11/18/2015 http://www.gabionline.net/Biosimilars/News/FDA-accepts-application-for-pegfilgrastim-biosimilar

• Adalimumab (Amgen) – 11/27/2015 http://www.gabionline.net/Biosimilars/News/Amgen-submits-biosimilar-adalimumab-application-to-FDA

• Etanercept (Sandoz) – 9/10/2015 http://www.gabionline.net/Biosimilars/News/FDA-accepts-application-for-etanercept-biosimilar

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Insulin: Biosimilar or Follow-on?

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm

“Basaglar is the first insulin product approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act. A 505(b)(2) application was submitted for Basaglar that relied, in part, on the FDA’s finding of safety and effectiveness for Lantus (insulin glargine injection) to support approval. The applicant demonstrated that Basaglar was sufficiently similar to Lantus to scientifically justify reliance, and also provided Basaglar-specific data to establish the drug’s safety and efficacy for its approved uses.”

40

Labor Estimates


41

BsUFA Reauthorization: Public Meeting on 12/18/2015

• Not a biosimilar policy negotiation

• Theme: how can the FDA ensure timely review?

• Eight 351(k) BLA applications– Action date passed for 5; 1 approval; 1 complete response letter

• Lots of time spent on developing biosimilar policy

http://www.raps.org/Regulatory-Focus/News/2015/12/18/23792/Biosimilar-User-Fees-Public-Meeting-Kicks-Off-Negotiations-for-BsUFA-II/

“FDA needs…to hire and retain scientists that can work on biosimilars, particularly as they are highly sought-after by

industry, which offers more competitive salaries.”

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Practice Implications: Mabs

Cancer

BevacizumabTrastuzumab

Inflammation

AdalimumabEtanerceptInfliximab

Rituximab

High Impact on:• Physician clinics• Hospital outpatient

infusion centers• Specialty pharmacy

HospitalsClinics Specialty Rx


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Insulins

Filgrastim, Pegfilgrastim, Epoetin

Practice Implications: non-Mabs

Hospitals PharmaciesClinics Specialty Rx

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What Is 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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Key Takeaways

• There is a robust pathway for the approval of biosimilars in the US

• There is currently one FDA‐approved biosimilar and another product approved under Section 505 allowed via the BPCI Act during the transition period before 2020

• The FDA has been busy writing policy and is overworked with sponsor meetings and reviewing applications

46

Useful Resources

NCCN biosimilars white paper

• Zelenetz AD, Ahmed I, Braud EL et al. J Natl Compr Canc Netw. 2011; 9(suppl 4):S1‐22.

Biosimilars: the science of extrapolation

• Weise M, Kurki P, Wolff‐Holz E et al. Blood. 2014; 124:3191‐6.

Pharmacist substitution of biological products

• Li E, Ramanan S, Green L et al. J Manag Care Spec Pharm. 2015; 21:532‐9.

47

Growing Role of Biologics in Pipeline

Source: IMS Data, December 2010.

11%

89%

38%

62%

89%

62%

11%

38%

0%

20%

40%

60%

80%

100%

in Market in Phase III

% o

f D

rug

s in

U.S

. M

arke

t

Small Molecules Biologicals

48

Biological Prescription Cost Implications in U.S.

• Biologicals and specialty pharmaceuticals are the fastest growing pharmaceutical expense in the U.S.

• The Economist estimates that biologics could make up 32% of total big pharma sales by 2023

• 7 of top 10 drugs by sales in 2014 were biologics

• Significant interest on the part of payers/employer groups in managing the specialty cost trend

• Estimate savings of approximately 20%‐30%

http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf (accessed 2015 Dec 26). http://www.economist.com/news/business/21637387‐wave‐new‐medicines‐known‐biologics‐will‐be‐good‐drugmakers‐may‐not‐be‐so‐good (accessed 2015 Dec 26).


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Why are Biologics Important?

Schumock GT et al. Am J Health‐Syst Pharm. 2015; 72:717‐36. 50

Significant Impact of Biosimilars on Pharmaceutical Expense Trend

• Estimate of $250 billion savings in U.S. over next 10 years from just 11 biosimilar products (Express Scripts)

• 2008 Congressional Budget Office (CBO) estimated a $25 billion reduction in U.S. expenditures on biologics by 2018

• Rand Corporation (2014) predicts that biosimilars will lead to a $44.2 billion reduction (range $13B‐$66B) in direct spending on biologic drugs from 2014 to 2024

There will be significant pressure from payers to use biosimilars to control healthcare costs

http://lab.express‐scripts.com/insights/industry‐updates/the‐$250‐billion‐potential‐of‐biosimilars. (accessed 2015 Dec 26).https://www.cbo.gov/publication/24808 (accessed 2015 Dec 26.http://www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf(accessed 2015 Dec 26).

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Prescription Benefit Implications in U.S.

• Expect plans to use established formulary‐review processes to review each drug on its own merit

• If two drugs are considered “therapeutically equivalent,” the plan will decide benefit tier, prior authorization requirements, and payment policies

• For infused therapies, CMS has already normalized the margin between the reference biologic and biosimilars (removed financial disincentive to use of biosimilars)

• Plans likely to use patient financial incentives to drive the use of biosimilars (tiered copayments/co‐insurance)

https://www.cov.com/~/media/files/corporate/publications/2015/04/cms_releases_new_reimbursement_guidance_for_biosimilars.pdf(Accessed 2015 Dec 26).

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The Patent Cliff and Growth Potential for the Biosimilars Market

www.gabionline.net/Biosimilars/General/Top‐8‐blockbuster‐biologicals‐2013.www.gabionline.net/Biosimilars/General/US‐67‐billion‐worth‐of‐biosimilar‐patents‐expiring‐before‐2020 (both accessed 2015 Dec 26).

10.7

8.9

8.6

8.3

7

6.8

4.4

0 1 2 3 4 5 6 7 8 9 10 11 12

Adalimumab (Humira)

Infliximab (Remicade)

Rituximab (Rituxan, Mabthera)

Etanercept (Enbrel)

Bevacizumab (Avastin)

Trastuzumab (Herceptin)

Pegfilgrastim (Neulasta)

Global Sales 2013, US$ Billion

EU Expiry Date

U.S. Expiry Date

2018 2016

Expired 2018

Expired 2016

Expired 2013/2028*

2022 2019

Expired 2019

2017 Expired

*Expiry date uncertain.

53

Current Biosimilars(?) in the USProduct US Approval

PathwayUS Biosimilar EU Biosimilar

enoxaparin 505(b)(2)-abbreviated pathway under FDCA

No Yes

tbo-filgrastim 531(a) No Yes

filgastim-sndz 531(k) Yes Yes

Insulin glargine 505(b)(2) No Yes

54

Biosimilar Development in the USBrandName (US or EU)

INN ManufactureraBLA

submittedFDA

approval

Zarxio filgrastim-sndz Sandoz 7/2014 3/2015

Remsima infliximab Celltrion 8/2014

pegfilgrastim ApotexSandoz

12/201411/2015

Retacrit epoetin zeta Hospira 1/2015

Grastofil filgrastim Apotex 2/2015

etanercept Sandoz 10/2015

adalimumab Amgen 11/2015

http://www.gabionline.net/Biosimilars/News/. Accessed 2015 Dec 26.


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Manufacturer Considerations

Considerations for Formulary Selection of Biosimilars

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

• 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

• 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/SafetyProduct

ConsiderationsHospital and Patient Factors

*CSTDs = closed system transfer devices

56

Formulary Selection Considerations: Efficacy and Safety

• Clinical data and populations studied in FDA approval

• Range of indications

• Presence of biomarker to assess efficacy and safety

• Experienced vs. de novo patients

– Immunogenicity concerns due to switching


57

Extrapolation of Indications• Extrapolation of data from a clinical trial in one disease to support approval for additional indications

• Factors to be considered

– Clinical experience with the reference product

– Mechanism(s) of action in each indication

– Target receptors

– Product structure and target/receptor interactions

– Pharmacokinetics in different patient populations

– Differences in the safety/immunogenicity profile between indications

Weise M et al. Blood. 2014; 124:3191‐6.http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm428732.pdf(accessed 2015 Dec 26). 58

Available G-CSFs in the US and Approved Indications

Filgrastim(Neupogen)

Tbo-filgrastim(Granix)

Filgrastim-sndz(Zarxio)

Peg-filgrastim(Neulasta)

Approval Pathway BLA BLA Biosimilar 351(k) BLA

Reference Product None None Filgrastim none

Cancer patients receivingmyelosuppressive chemotherapy

Patients with acute myeloidleukemia receiving induction or consolidation chemotherapy

--- ---

Cancer patients receiving bone marrow transplant

--- ---

Patients undergoingperipheral blood progenitor cell collection and therapy

--- ---

Patients with severe chronic neutropenia --- ---

59

Formulary Selection Considerations: Manufacturer Considerations

• Expertise manufacturing biologics

• Supply reliability

• Supply security and anti‐counterfeit measures

• Patient assistance programs

• Reimbursement support programs

Griffith N et al. Hosp Pharm. 2014; 49:813‐25. 60

Formulary Selection Considerations: Product Considerations

• Product packaging and labeling from safety perspective

• Bar coding

• Compatibility with closed system transfer devices (if NIOSH hazardous drug)

• Preparation and administration considerations

• Storage requirements

• Dosage forms meet needs of patient populations



61

Formulary Selection Considerations: Payer, Provider, and Patient Factors

• Economic considerations

– Payer

– Provider

– Patient out‐of‐pocket cost – impact on adherence

• Management of transitions of care

– How many products in “preferred” status

– Consistency of product provided

62

Will P&T Committees review a biosimilar through the routine P&T process or handle like a “generic”?

a. Full P&T reviewb. Abbreviated review c. Manage like a generic

63

Operational Challenges: Financial Analysis

• Pricing information comparison (provider, payer)

– Portfolio pricing

• Reimbursement implications for healthcare provider

• Patient assistance and out‐of‐pocket expenses

• Determine financial impact from various perspectives

Lucio SD et al. Am J Health‐Syst Pharm. 2013; 70:2004‐17. 64

Do you think that formularies will only have one biologic in a therapeutic category, or will there be both the reference product and biosimilar(s)?

a. Only the reference productb. Only a biosimilar

c. Both

65

Do you think that formularies will only have one biologic in a therapeutic category, or will there be both the reference product and biosimilar(s)?

a. Only the reference productb. Only a biosimilar

c. Both

• If more than one, under what circumstances will each be used?

66

How do you think formulary systems will manage biosimilars and reference products?

a. Biosimilar preferred for all patients through copay tiers or co‐insurance

b. Biosimilar preferred for new starts only, with reference product available at preferred tier for existing patients

c. Reference product on par with biosimilar – choice up to prescriber with no patient incentives

d. Unsure


67

If a biosimilar is added to an inpatient formulary, will a therapeutic interchange be used for patients who are admitted on the reference product?

a. Yesb. No c. Unsure

• If an interchange is done, how will patients be informed/educated?

68

Operational Challenges: Information Systems

• Differentiate between similar biologics in electronic systems

– Pharmacy information systems

– CPOE and ePrescribing systems

– Dispensing systems and automation

– eMAR

• Order sets, protocols

• Medication reconciliation

• Patient’s own home medicine

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

69

Operational Challenges: Inventory Management

• Purchaser needs adequate information (NDC, etc.)

• Will multiple products be stocked?

– Reference and biosimilar

– Multiple biosimilars

• Product storage, placement on shelf, etc.

• Inventory costs

• Wrong product dispensing errors

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

Interchangeability

• The biological is biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient, and the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alteration or switch

• State substitution laws will impact practice

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm.http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx (both accessed 2015 Dec 26).

71

Operational Challenges: Product Substitution

• State legislation to clarify pharmacist authority to substitute

• FDA “Purple Book”

• Challenges

– Care transitions

– Medication reconciliation

– Differences between federal and state regulations

http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx. (Accessed 2015 Dec 26). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm. (Accessed 2015 Dec 26).

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• Designed to enable a user to determine if a biological product is biosimilar or interchangeable with a reference biologic per FDA evaluation

• Cross‐references biological products licensed under 351(a) with biosimilar or interchangeable products licensed under 351(k)

Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm (accessed 2015 Dec 26).


73

http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx (accessed 2015 Dec 26).

74

Typical Features of State Legislation

• Prescriber can prevent substitution with DAW

• Prescriber must be notified of substitution

• Patient must be notified and consent

• Records of substitution must be retained

• State should keep a list of interchangeable products

http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐edications‐and‐substitution‐of‐biosimilars.aspx (accessed 2015 Dec 26).

75

Pharmacovigilance

• Important to assure safety

– Consider risks seen in reference product

– Are there any new safety concerns?

– Population‐based assessments gives larger n to identify rare safety concerns

– Might be mandatory for some products

• How will products be differentiated for pharmacovigilance purposes?

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm (accessed 2015 Dec 26). 76

The Conundrum of Biosimilar NamingBiosimilars should have

the exact same INN as the reference product

Biosimilars should have a distinct INN to differentiate from reference and other

biosimilars

Pros• Communicate that these products are “highly similar”

• Facilitate adoption and substitution of interchangeable biologics

Cons• Hard to trace for pharmacovigilance

Pros

• Improved pharmacovigilance• Recognize as distinct productsCons

• Confusion about whether they are “interchangeable”

• May impede adoption• Issues with substitution

Traynor K. Am J Health-Syst Pharm. 2014; 71:446-7.

Carroll J. Manag Care. 2013; 22:6-7.

77

Biosimilar Naming Precedent

• WHO proposed guidance

– Biological qualifier: INN + 4‐letter, randomly assigned suffix

• EMA – approved with identical INN; differentiated with brand names

• Filgrastim in the U.S. (approved indications vary)

– Filgrastim (reference biologic, Neupogen)

– tbo‐filgrastim (not biosimilar [351(a)], Granix)

– Filgrastim‐sndz (biosimilar [351(k), Zarxio)

http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf. Revised July 2014. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name (both accessed 2015 Dec 26).

78

FDA Proposed Guidance on Naming• INN with an added random four‐letter suffix for all biologics (including reference products)

– replicamab‐cznm

– replicamab‐hixf

• Benefits

– Ability to differentiate products for pharmacovigilance purposes

– Common INN will group similar biologics in electronic systems

– Having suffix for all products reduces perception that biosimilar is inferior to reference product

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf. August 2015 (accessed 2015 Dec 26).


79

FDA Proposed Guidance on Naming

• Concerns

– Unless interchangeable biosimilar has the same suffix, it will inhibit interchange

– Potential for errors when using four‐letter suffix “devoid of meaning” (alternative to represent manufacturer)

– More complex naming system increases likelihood that errors could occur, actually harming pharmacovigilance

– Need to change name of current biologics on market creates confusion

http://www.healio.com/rheumatology/psoriatic‐arthritis/news/online/%7Bfd74beb9‐177e‐4618‐8a94‐aab7cd3f77b7%7D/physician‐groups‐support‐proposed‐fda‐biosimilar‐naming‐convention‐but‐also‐call‐for‐maker‐idhttp://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf. August 2015 (Both accessed 2015 Dec 26).

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What strategies will you use to track the appropriate product the patient is taking in your electronic systems and during medication reconciliation?

a. Order & document with full product name (INN plus suffix)

b. Order & document with full product name PLUS brand name

c. Order and document with INN (minus suffix) PLUS brand name

d. Other

81

Operational Challenges: Education

• Education of all providers to avoid confusion (clinical information, policies, appropriate use, etc.)

• Patient education

• Managing transitions of care

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

.

82

Recommendations for Biosimilars for Pharmacists• Use 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

• Prepare IT systems to facilitate effective pharmacovigilance programs

• Consider processes for transitions of care

• Meet educational needs of patients and providers

83

Resources for Pharmacists and Technicians

• ASHP Resource Center on Biosimilars

– http://www.ashp.org/menu/PracticePolicy/ResourceCenters/Emerging‐Sciences/Biosimilars.aspx (accessed 2015 Oct 30).

• American Journal of Managed Care Resource Center

– http://www.ajmc.com/resource‐center/biosimilars (accessed 2015 Oct 30).

• Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health‐system pharmacists. Am J Health‐Syst Pharm. 2013; 70:2004‐17.

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Key Points

• Biologics are complex drugs that are not considered “generic”; still waiting for guidance on “interchangeable biosimilars”

• The FDA approval process to demonstrate that a biosimilar is “highly similar” to a reference biologic is scientific, robust, and regulated

• No specific safety issues have been identified for approved and marketed biosimilars in Europe

• Incorporation of biosimilars into clinical practice offers cost savings and increased patient access


85

Key Points

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

• European biosimilar experience has been good

• Federal and state regulatory actions, pricing, and reimbursement policies will play key roles in determining future use of biosimilars and product selection in the U.S.

86

Key Points

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

• Key issues yet to be resolved include naming, interchangeability criteria and requirements, and pharmacovigilance requirements

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

87


A. Adalimumab

B. Trastuzumab

C. Cetuximab

D. All of the above

88


A. Naming



D. All of the above

89

For a biosimilar to be approved, clinical trials should demonstrate:

A. Comparability in efficacy between the biosimilar and reference using a clinically sensitive endpoint




90


A. Adalimumab

B. Trastuzumab

C. Cetuximab

D. Golimumab


91


A. Naming



D. Quality considerations

92

For a biosimilar to be approved, clinical trials should demonstrate:A. Comparability in efficacy between the biosimilar and

reference using a clinically sensitive endpoint




93

How does the FDA’s “interchangeable biosimilar” designation impact pharmacist substitution?

A. These products require more pharmacovigilance than for standard biosimilars

B. Current state pharmacy practice substitution laws allow substitution for interchangeable biosimilars only

C. For a reference product where there is more than one interchangeable biosimilar, pharmacists can substitute one interchangeable biosimilar for another

D. The interchangeable designation means the pharmacist does not need to notify the prescriber of the substitution

94

Which of the following about the formulary review for biosimilars is true?

A. The P&T committee should review the biosimilar data package exactly the same way it reviews other novel agents that are recently FDA-approved

B. The P&T committee should utilize the generic policy to add the biosimilar to formulary

C. The range of indications for use should be considered when reviewing a biosimilar for formulary consideration

D. Product formulation, device/container, packaging/labeling are non-factors to review because the biosimilar will be the same as the reference product in these domains

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