FDA Biosimilars and Interchangable Products

Biosimilar and Interchangeable Products: What Do Pharmacists Need to Know?

Thursday, July 29, 2021

Handouts for today’s presentations can be found at:

www.nabp.pharmacy/webinar

NABP Webinar – July 29, 2021 1 Biosimilar and Interchangeable Products: What Do Pharmacists Need to Know?

Biosimilar and Interchangeable Products: What Do Pharmacists Need to Know?

Sarah Yim, MD Sarah Ikenberry, MA Director Senior Communication Advisor Office of Therapeutic Biologics and Biosimilars Center for Drug Evaluation and Research

Learning Objectives

1. Describe how biologics differ from small molecules (size, complexity, manufacturing).

2. Explain why most biologics cannot be copied exactly.

3. Compare and contrast the development, statutory requirements, and approval process for new biologics and for biosimilar and interchangeable products.

4. Review the use of biosimilar and interchangeable products in practice.

5. Describe and explain the resources available for health care providers to learn more about biosimilar and interchangeable products through the enhanced Purple Book and other FDA educational resources.

4 4

NABP Webinar – July 29, 2021 2 Biosimilar and Interchangeable Products: What Do Pharmacists Need to Know?

Introduction to Biological Product Concepts and Development

Approved / Marketed Biosimilars Reference Product Approved Biosimilars

Amjevita Cyltezo Hyrimoz Hadlima (adalimumab‐ Abrilada Hulio Humira (adalimumab) (adalimumab‐atto) (adalimumab‐adbm) (adalimumab‐adaz) bwwd) (adalimumab‐afzb) (adalimumab‐fkjp)

Mvasi Zirabev Avastin (bevacizumab) (bevacizumab‐awwb) (bevacizumab‐bvzr)

Retacrit Epogen (epoetin‐alfa) (epoetin alfa‐epbx)

Erelzi Eticovo Enbrel (etanercept) (etanercept‐szzs) (etanercept‐ykro)

Zarxio Nivestym Neupogen (filgrastim) (filgrastim‐sndz) (filgrastim‐aafi)

Renflexis Ixifi Avsola Inflectra Remicade (infliximab) (infliximab‐abda) (infliximab‐qbtx) (infliximab‐axxq) (infliximab‐dyyb) Semglee Lantus (Insulin Glargine) (insulin glargine‐yfgn) Fulphila Udenyca Ziextenzo Nyvepria Neulasta (pegfilgrastim) (pegfilgrastim‐jmdb) (pegfilgrastim‐cbqv) (pegfilgrastim‐bmez) (pegfilgrastim‐apgf)

Ogivri Herzuma Ontruzant (trastuzumab‐ Trazimera Kanjinti Herceptin (trastuzumab) (trastuzumab‐dkst) (trastuzumab‐pkrb) dttb) (trastuzumab‐qyyp) (trastuzumab‐anns)

Ruxience Riabni Truxima Rituxan (rituximab) (rituximab‐pvvr) (rituximab‐arrx) (rituximab‐abbs) 6 *Approved biosimilars in green boxes are currently marketed 6

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Biological Products . Biologics are generally large and recombinantly produced from living systems . They range in size and complexity . Examples: therapeutic proteins, vaccines, monoclonal antibodies

7 H Mellstedt. European Journal of Cancer Supplements. 2013;11:1‐11. 7

Biological Products: Complexity

. Cells can make exact copies of protein sequences, but other add‐ons and changes may occur, resulting in different versions of the molecule . Millions of slightly different versions of the same protein or antibody per dose or batch

. Biologics manufacturers try to keep a consistent mix of variants across batches of their products and over time 8

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Can Most Biologics Be Copied Exactly? No. . Most biologics are mixtures of variants

. Using advanced scientific analysis, molecular patterns and profiles emerge

. Biosimilars try to match the patterns and variations of the reference product

. Both the reference product and biosimilar contain these variants and try to keep a consistent mix

Generic vs Biosimilar

Generic (Orange Book) Biosimilar (Purple Book) Assessment Same Active Ingredient Highly Similar PK Bioequivalence No Clinically Meaningful Differences

Example schematic of product comparisons. = Comparative Analytical data expected for both Reference Generic products. Listed Drug Drug

Clinical Pharmacology Demonstrate PK Bioequivalence Demonstrate PK/PD similarity, when applicable Studies Other clinical study(ies) ‐ Assess immunogenicity; may further evaluate safety and efficacy Both are “abbreviated” development pathways that have distinct statutory requirements and scientific expectations supporting their approval. 10

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FDA’s Approach to the Development of Biosimilars

Different Goals for ‘Stand‐alone’ vs Biosimilar Development

“Stand‐alone”: 351(a) BLA “Abbreviated”: 351(k) BLA Goal: To establish de novo safety and Goal: To demonstrate biosimilarity (or efficacy of a new product interchangeability) to a reference product

Clinical Safety and Efficacy (Phase 1, 2, “pivotal” 3)

Clinical Pharmacology

Nonclinical

Analytical

What does this difference mean from a development perspective? 12 12 12

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Key Definitions from the BPCI Act

Reference Product

Reference A reference product is the single biological product, already approved by FDA, Product against which a proposed biosimilar product is compared

Biosimilar Product

Biosimilar A biosimilar is a biological product that is highly similar to and has no clinically Product meaningful differences from an existing FDA‐approved reference product

Interchangeable Product ‐Is a biosimilar ‐Expected to produce the same clinical result as the reference product (RP) Interchangeable Reference Product Product in any given patient ‐Switching between the proposed product and the RP does not ↑safety risks

13 or ↓eﬀecveness compared to using the RP without switching 13

Standards for Interchangeable Biosimilar Products

. An interchangeable biosimilar product may be substituted for the reference product (RP) without the intervention of the health care provider who prescribed the reference product, subject to state laws . An applicant provides information or data intended to help inform what might happen with substitution and to demonstrate: — Switching between the proposed product and the reference product does not increase safety risks or decrease effectiveness compared to using the reference product only —The proposed product can be expected to provide the same clinical result as the reference product in “any given patient”

Time Using the RP without switching

Time

Switching between the proposed product and the RP 14

NABP Webinar – July 29, 2021 7 Biosimilar and Interchangeable Products: What Do Pharmacists Need to Know?

Scientific Considerations for Biosimilar and Interchangeable Insulins

. Insulin is a relatively small, structurally uncomplicated, and well‐characterized protein generally allowing for a comprehensive analytical evaluation to leave little or no residual uncertainty . Decades of clinical experience with approved insulin products support a lack of a correlation between immunogenicity and safety or effectiveness . If a comprehensive comparative analytical assessment supports that a proposed biosimilar or interchangeable insulin product is “highly similar” to its reference product, there would likely be little or no residual uncertainty regarding a difference in immunogenicity, making a comparative clinical immunogenicity study generally unnecessary

Draft Guidance: Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products (Nov 2019) https://www.fda.gov/media/133014/download 15

Using Biosimilar and Interchangeable Products

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Using Reference, Biosimilar, and Interchangeable Products . Patients and health care providers can be confident that biosimilar and interchangeable biosimilar products provide the same safety and effectiveness as the reference product.

. Health care providers can prescribe biosimilar and interchangeable products by name, just as they would prescribe reference products. Interchangeable biosimilar products may be substituted for the reference product without Reference Product the intervention of the health care prescriber, subject to state pharmacy laws. 17 17

Labeling of Biosimilar Products . Approved prescribing information summarizes the scientific information that health care practitioners need for safe and effective use of the product.

. Labeling: – The Highlights Section contains a “Biosimilarity Statement” describing the biosimilar product’s relationship to its reference product. – FDA recommends that biosimilar product labeling incorporate relevant data and information from the FDA‐approved labeling for the reference product, Biosimilar Interchangeable Product Product along with any appropriate modifications specific to the biosimilar product. – A biosimilar product is not required to have the same labeling as its reference product. Biosimilar product labeling may differ from the reference product labeling for a variety of reasons. – For specific product information, visit Drugs@FDA.

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Biological Product Naming Convention . Most biological products, including more recently approved originator biologics, biosimilar, and interchangeable products, are subject to FDA’s naming policy. . The naming convention for biological products is a proper name consisting of a core name and a unique 4‐letter suffix. . The suffix will be attached with a hyphen to the core name of each product. – Core name: component shared among biological products that contain related drug substances (eg, filgrastim, epoetin alfa) – Suffix: four lowercase letters that are unique and devoid of meaning (eg, ‐cznm, ‐hixf) – Proper name: core name + suffix . For example, for hypothetical products sharing the fictitious core name replicamab, the proper names would replicamab‐cznm include a unique suffix: Core Unique 4‐letter ― Originator biological product: replicamab‐cznm name suffix ― Related biological product: replicamab‐rzbh ― Biosimilar product: replicamab‐hixf ― Interchangeable biosimilar product: replicamab‐tkpl 19

Key Takeaways Fact: FDA’s high standards for approval mean that health care professionals and patients can be confident in the safety and effectiveness of a biosimilar product.

Fact: Differences between the biosimilar and reference product may be expected due to both product’s molecular complexity, but such differences are not clinically meaningful.

Fact: Biosimilar labeling is not required to be the same as the reference product but is expected to incorporate relevant data and information from reference product labeling.

Fact: FDA’s approval of an interchangeable biosimilar product does not indicate a higher standard of biosimilarity. Companies must submit specific data to support approval as an interchangeable biosimilar to allow it to be substituted for the reference product without consulting the health care prescriber, depending on state pharmacy laws.

Fact: Patients and health care providers do not need to wait for a biosimilar product to “become” an interchangeable product. Biosimilars are as safe and effective as the reference product they were compared to. 20 20

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Resources for Health Care Providers

The Purple Book Database

The Purple Book can be found at PurpleBookSearch.fda.gov.

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Purple Book’s Features The database provides patients, payers, clinicians, and others with an accessible, easy‐to‐use online search engine with more information about FDA‐approved biological products, including biosimilar and interchangeable biological products.

The searchable database utilizes features tailored to different user needs, including:

• Simple and Advanced Search options • Auto‐suggest search function • Additional search filters • Data download options • Export and print search results • Links to product labels • Ability to show/hide sortable columns of information • Searchable glossary of terms 23

Simple Search

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Simple Search

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Product Label Information

Simple Search

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Product Details Page

Advanced Search

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The Purple Book Database

The Purple Book can be found at PurpleBookSearch.fda.gov.

Education and Outreach

. FDA is committed to developing effective communications to improve understanding of biosimilars among patients, health care providers, and payers

‒ Engaging with health care professional and patient stakeholders

‒ Developing educational materials for health care prescribers, pharmacists, and patients

. Education is an undertaking that requires multi‐stakeholder engagement

FDA is committed to fulfilling its important role as one of many stakeholders.

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Health Care Provider Materials

Web Content and Infographic:

. Uses patient‐friendly language and imagery

. Addresses topics, concerns, and misconceptions shown to be most important to patients

. Tested with patients treated with a biologic and patient advocacy organizations

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FDA Biosimilar Materials in Spanish

Future Education and Outreach Plans

. Continue developing materials and resources for patients: ‒ Videos ‒ Additional infographics and graphics ‒ Enhanced Social Media Strategy

. Create additional materials and resources for health care providers: ‒ Educational curriculum/teaching resources for medical, nursing, and pharmacy schools ‒ Updated continuing education course ‒ Fact sheets and videos

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Resources

. Visit www.fda.gov/biosimilars for access to all the education materials and information about biosimilar and interchangeable products.

. Visit purplebooksearch.fda.gov for information on biological products, including if products are biosimilar to a reference product.

. Visit www.fda.gov/drugsatfda (Drugs@FDA) for information on all CDER‐approved drug products, including labeling and review information.

. Check with your state board of pharmacy for information about biological product substitution laws. 37

Assessment Question #1

Which statements are true about biosimilar and reference biological products?

A. Both biosimilar products and reference products contain millions of slightly different versions of the same protein or antibody per dose or batch of molecules. B. Minor differences between the biosimilar and reference product are expected due to their complexity but do not result in clinically meaningful differences. C. Most biologics cannot be copied exactly and so the biosimilar framework reflects scientific considerations to support abbreviated development. D. Reference products are exactly the same and do not contain variations. E. A, B, and C

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Assessment Question #2

How does FDA ensure that biosimilars are as safe and effective as the reference product?

A. Approving biosimilars after a careful review of data, studies, and tests B. Monitoring safety and effectiveness after approval C. Checking for medication quality during production D. Reviewing patient safety reports made to FDA E. All of the above

Assessment Question #3

True or False? An interchangeable biosimilar is safer or more effective than other biosimilars.

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Assessment Question #4

True or False? A biosimilar or interchangeable product can only be used in patients who have never taken a reference product before.

Thank You www.fda.gov/biosimilars

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