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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, a US Food and Drug Administration (FDA)-licensed biological reference product in section 351(k) of the PHS Act.

The abbreviated 351(k) pathway allows biosimilar biological products to achieve licensure with 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, and biological reference product

For clarity, the key terms related to the development of biosimilar biological products used throughout this article have been defined below.

Biosimilar or biosimilarity

Although there may be minor differences in clinically inactive components, biosimilar biological products are highly similar to the reference biologic product. When comparing safety, purity, and potency, no meaningful differences are observed between the biosimilar product and the reference biologic product.

Interchangeable biological product or interchangeability

Interchangeable biological products are expected to produce the same clinical result as the reference product in any patient, as they are biosimilar to the reference biologic. Per section 351(k)(4)(B) of the PHS Act, when an interchangeable biological is administered to a patient more than once, “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.” Furthermore, interchangeable biologics may be substituted for the reference product without the intervention of the healthcare provider who initially prescribed the reference biologic.

Biological reference product

A biological reference product is a single biological product licensed under section 351(a) of the PHS Act, and when an application is submitted under the abbreviated 351(k) licensure pathway (section 351(k) of the PHS Act), it is the product against which the biologic in the application is assessed.

Frequently asked questions regarding the BPCI act and biosimilar product development

What does a 351(k) application generally require?

The following information must be included in a 351(k) application to demonstrate that the proposed biological product:

• Is biosimilar to the reference biologic;
• 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 in which the product is manufactured, processed, packed, or held meets standards which have been purposefully designed to ensure the continued safety, purity, and potency of the biological product.

Is it acceptable for the formulation of a proposed biosimilar product to differ from the reference product?

When comparing a biosimilar product to the biological reference product, per the FDA guidance, it may be acceptable for formulations be different. Notwithstanding minor differences in clinically inactive components, 351(k) applications submitted to the FDA are required to contain information demonstrating the proposed biosimilar product is highly similar to the reference biologic.

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

Does the FDA find it acceptable for a proposed biosimilar product to use a delivery device or container-closure system that is different from the reference product delivery device or container-closure system?

Per FDA guidance, some differences may be acceptable when considering the design of the device or container-closure system proposed for use with the biosimilar product. The proposed biosimilar must meet the statutory standard for biosimilarity if the container-closure or delivery device for the biosimilar is different from that of the reference product. Furthermore, data should be included in the regulatory submission to demonstrate that 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 and leachable (E&L) and stability studies). It is important to note that performance testing and a human factors study may be needed if there are design differences in the container-closure system or the delivery device.

Furthermore, applicants will be unable to obtain licensure of a proposed biosimilar product when the difference(s) in the container-closure or delivery device result 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, and/or
• A condition of use (e.g., dosing regimen, indication) for which the reference product was not previously approved, or otherwise does not meet the biosimilar standard.

A separate application may be required in some cases where a proposed biosimilar in a delivery device is considered a combination product. The FDA recommends consulting guidance titled Considerations in Demonstrating Interchangeability with a Reference Product for further information regarding delivery device or container closure systems for proposed interchangeable biologic products.

If there are fewer routes of administration for a proposed biosimilar product when compared to the number of routes of administration an injectable reference product is licensed for, can licensure still be obtained?

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, delivery device, or container-closure system) for which a reference product is licensed?

Yes, as there are no requirements stating applicants must obtain licensure of a proposed biosimilar product for all presentations the reference product is licensed for. Nevertheless, if an applicant is looking to secure licensure for a condition of use or particular indication corresponding to a specific presentation of the reference biologic, licensure may need to be sought for that specific presentation.

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

Yes. In general, 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 occurrences, information must be included in the 351(k) application 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”. For further detail, refer to 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 pharmacokinetic (PK) and/or pharmacodynamic (PD) studies to support a 351(k) application? Are there specific criteria governing the storage of these samples?

According to the FDA draft guidance, the Agency recommends the sponsor of a proposed biosimilar product retain reserve samples for a minimum of 5 years following the date on which the 351(k) application is licensed, or, if such application is not licensed, no less than 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) intended to support a submission under section 351(k) of the PHS Act. Additionally, the FDA recommends samples of both comparator products be retained, in addition to samples of the proposed biosimilar product, for 3-way PK similarity studies.

For the majority of protein therapeutics, the Agency recommends the following quantities of product and dosage units be retained, as 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, the FDA recommends that the sponsor contact the 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, and/or
• Biological products other than protein therapeutics.

Can a designation of interchangeability between the proposed and reference biological product be obtained by a 351(k) applicant in their original 351(k) application?

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

Choosing the right CDMO to support biosimilar product development and 351(k) submissions

Choosing the right contract development and manufacturing organization (CDMO) partner is critical to the entire biosimilar product development life cycle. Along with historic niche expertise with Q1/Q2(Q3) deformulation, which possesses some similarities to the 351(k) regulatory pathway, Сòòò½APP’s team of consultative, expert scientists stand ready to support the 351(k) licensure pathway with a suite of comprehensive services designed to support the entire biosimilar drug development life cycle, from preclinical through post-market surveillance. Ensure your application addresses the data required for the 351(k) abbreviated regulatory pathway with our deep expertise in protein characterization and chemistry, manufacturing and controls (CMC).