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Biosimilar Product Development and the BPCI Act

Biological products are the fastest-growing class of therapeutic products in the US, and they also account for a significant and increasing portion of healthcare costs. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amended the Public Health Service Act (PHS Act) and other statutes to establish an abbreviated licensure pathway for biological products demonstrated to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product in section 351(k) of the PHS Act. The abbreviated 351(k) pathway allows biosimilar biological products to be on licensed less than a full complement of product-specific preclinical and clinical data – among other things, 351(k) submissions may rely on publicly-available information pertaining to FDA’s previous determination that the biological reference product is safe, pure, and potent. It is important to note that a 351(k) application for a biosimilar product may only be evaluated against one biological reference product, and no more. The differences between the 351(a) regulatory pathway for originator biological products and the 351(k) abbreviated pathway are detailed in Figure 1.

 

Figure 1. Contrast between the standard 351(a) regulatory pathway for a new biologic product and the 351(k) abbreviated regulatory pathway for biosimilar biologic products

Key Terminology: Biosimilar, Interchangeable Biological Products & Biological Reference Product

Throughout this discussion, key terms related to the development of biosimilar biological products will be used. To ensure clarity, those key terms are defined below.

Biosimilar or Biosimilarity

Biosimilar biological products are highly similar to the reference product, and there are no meaningful differences between the biological product and the reference product when comparing safety, purity, and potency. However, there may be minor differences in clinically inactive components.

Interchangeable Biological Product or Interchangeability

Interchangeable biological products are biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient. Furthermore, for products that are administered to a patient more than once, per Section 351(k)(4)(B) of the PHS Act, “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” The key takeaway for interchangeable biological products is the interchangeable biological product may be substituted for the reference product without the involvement of the healthcare provider who originally prescribed the reference product.

Biological Reference Product

A single biological product which is licensed under section 351(a) of the PHS Act. It is the product against which a biological product is evaluated in an application submitted under section 351(k) of the PHS act (the abbreviated 351(k) licensure pathway).

Frequently Asked Questions about the BCPI Act and Biosimilar Product Development

What is generally required in a 351(k) application?

A 351(k) application must include information demonstrating the proposed biological product:

  • Is biosimilar to the reference product;
  • Utilizes the same mechanism(s) of action for the proposed condition(s) of use, but only to the extent that the mechanism(s) are known for the reference product;
  • The condition(s) of use that are proposed for labeling have been previously approved for the reference product;
  • Has the same dosage form, route of administration, and strength as the reference product; and
  • The facility where the product is manufactured, processed, packed, or held meets standards designed to assure the biological product continues to be safe, pure, and potent

Can the formulation of a proposed biosimilar product be different from the reference product?

According to FDA guidance, it may be acceptable for formulations to differ when comparing a biosimilar product to a biological reference product. The 351(k) application submitted to FDA must contain information that demonstrates the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.

Additionally, applicants need to demonstrate that the biosimilar product has no clinically meaningful differences in terms of safety, purity, and potency. More information about FDA’s interpretation of the statutory standard for biosimilarity can be found in Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product and Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.

Is it acceptable for a proposed biosimilar product to have a delivery device or container-closure system that is different from the reference product?

According to FDA guidance, some differences in the design of the device or container-closure system that is proposed for use with the biosimilar product may be acceptable. If the container-closure or delivery device for the biosimilar product are different from that of the reference product, the proposed biosimilar must meet the statutory standard for biosimilarity. Furthermore, the applicant should include data that shows the alternate container-closure or delivery device is compatible for use with the final formulation of the proposed biosimilar product through appropriate studies, e.g. extractable/leachable and stability studies. If there are design differences in the delivery device or container-closure system, performance testing and a human factors study may be needed.

It is important to note that an applicant will not be able to obtain licensure of a proposed biosimilar product when the difference in the container-closure or delivery device results in:

  • Clinically meaningful differences between the proposed biosimilar and the reference biologic product in terms of safety, purity, and potency;
  • Different route of administration or dosage form; or
  • A condition of use (e.g. dosing regimen, indication) that the reference product was not previously approved, or otherwise does not meet the biosimilar standard.

In some instances where a proposed biosimilar in a delivery device is considered a combination product, a separate application may be required. For information about a delivery device or container closure system for a proposed interchangeable product, FDA recommends consulting Considerations in Demonstrating Interchangeability With a Reference Product.

Can licensure be obtained for a proposed biosimilar product with fewer routes of administration than an injectable reference product is licensed for?

Yes! Licensure may be obtained for fewer than all routes of administration the reference product is licensed for. Applicants must demonstrate there are no clinically meaningful differences between the proposed biosimilar product and the reference biological product in terms of safety, purity, and potency.

Can licensure of a proposed biosimilar product be obtained for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?

Yes. There are no requirements that applicants obtain licensure of a proposed biosimilar product for all presentations for which the reference product is licensed. However, if an applicant looks to secure licensure for a condition of use or particular indication that corresponds to a specific presentation of the reference product, the applicant may need to seek licensure for that particular presentation.

Can licensure be obtained for a proposed biosimilar product for fewer than all conditions for which the reference product is listed?

Yes! Generally, applicants may obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed. In these instances, the 351(k) application must include information demonstrating that that “the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling submitted for the proposed biosimilar product have been previously approved for the reference product” (see section 351(k)(2)(A)(i)(III) of the PHS Act).

How long should sponsors keep reserve samples of biological products used in comparative clinical PK and/or PD studies intended to support a 351(k) application, and how should they be kept/stored?

According to FDA draft guidance, FDA recommends that the sponsor of a proposed biosimilar product retain reserve samples for at least 5 years following the date on which the 351(k) application is licensed, or, if such application is not licensed, at least 5 years following the date of completion of a comparative clinical PK and/or PD study of the reference product and the proposed biosimilar product (or other clinical study in which PK or PD samples are collected with the primary objective of assessing PK or PD similarity) that is intended to support a submission under section 351(k) of the PHS Act. For a 3-way PK similarity study, FDA recommends that samples of both comparator products be retained, in addition to samples of the proposed biosimilar product.

For most protein therapeutics, FDA recommends the following quantities of product and dosage units be retained. These quantities are expected to be sufficient for evaluation by analytical methods:

  • A minimum of 10 dosage units of the proposed biosimilar product, reference product, and if applicable, non-US licensed comparator product. Generally, this should be equal or greater to 200mg in volume equal or greater to 10mL.

Furthermore, FDA recommends that the sponsor contact FDA’s review division to discuss appropriate quantities of reserve samples in the following situations:

  • A product mass of equal or greater than 200mg in volume equal or greater than 10mL requires a large number of dosage units; or
  • Biological products other than protein therapeutics

Can a 351(k) applicant obtain a determination of interchangeability between the proposed and reference biological product in an original 351(k) application?

Yes. Additional information can be found in FDA’s draft guidance, Considerations in Demonstrating Interchangeability with a Reference Product.

Choosing the Right CRO to Support Biosimilar Product Development and 351(k) Submissions

Having the right CRO partners is critical to the entire biosimilar product development lifecycle. Along with historic niche expertise with Q1/Q2(Q3) deformulation, which possesses some similarities to the 351(k) regulatory pathway, Avomeen’s team of consultative, expert scientists stand ready to support the your 351(k) licensure pathway. Our comprehensive services support preclinical through post-market surveillance. Rely on our team’s expertise in protein characterization and chemistry, manufacturing and controls (CMC) to ensure your application addresses the data required for the 351(k) abbreviated regulatory pathway. Are you ready to discuss your needs? Get in touch with an expert.

 

Our featured expert is Khanh Ngo Courtney, Ph.D., Director of Biologics at Avomeen. Khanh provides clients with unparalleled expertise and tactical knowledge of protein biochemistry and molecular biology. Her experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. This understanding of the entire process helps guide successful and productive collaborations across different laboratories, sites, and functions. Khanh is also adept at protein expression and purification from E. coli and mammalian cells, in vitro potency assays, protein/DNA/peptide binding studies, ELISAs and other immunological methods, analytical chromatography, forced degradation studies, product quality investigations, and manufacturing investigations. Her technical background provides the foundation for effective authorship of analytical sections in BLAs and MAAs, as well as responses to requests and questions from the FDA, EMA, and PMDA.

 

Our featured blogger is Bob Plourde, Ph.D., Avomeen’s Senior Director of Business Development for the Western USA. Bob has been involved in many aspects of the biopharmaceutical industry for more than 20 years, including carrying out drug discovery and development, roles in project management, and most recently serving in business development roles for organizations that provide solutions for biopharmaceutical research and development.

 

 

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