On January 17, 2017, the Food and Drug Administration (FDA) issued its long-awaited draft guidance on licensure as an interchangeable biological product approved under the Biologics Price Competition and Innovation Act of 2009 (BPCIA). The draft guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” can be found here.

The guidance provides scientific considerations for sponsors seeking to demonstrate that a proposed product is interchangeable with a reference product under the Public Health Service Act (PHSA). While the biosimilar pathway applies broadly to biological products, FDA notes that therapeutic protein products are the focus of the guidance.

By way of brief background, the BPCIA provides for the abbreviated approval of two different categories of biological products: (1) biosimilars and (2) interchangeable biological products. For a product to be licensed as a biosimilar, the PHSA requires a demonstration that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” 42 USC 262(i)(2). For a product to be licensed as interchangeable, however, the PHSA requires that an additional standard be satisfied. Specifically, licensure as “interchangeable” requires (1) a demonstration of biosimilarity and (2) a demonstration that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the 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. 42 USC 262(k)(4).

Licensure as an interchangeable biological product represents FDA’s determination that the product may be substituted for the reference product without the intervention of the prescribing health care provider. 42 USC 262(i)(3).

This Alert provides a brief summary of the guidance and FDA’s proposed points of consideration for demonstrating interchangeability.

Evidence to Support Interchangeability Needed for All Licensed Conditions of Use

The guidance provides that sponsors should submit data and information to support a showing of interchangeability in all of the reference product’s licensed conditions of use to satisfy the BPCIA requirement that the proposed product “can be expected to produce the same clinical result as the reference product in any given patient” (emphasis added). FDA further notes, however, that these data and information submitted to support this requirement may vary “depending on the nature of the proposed interchangeable product and may include, but not be limited to, an evaluation of the data and information generated to support a demonstration of the proposed product’s biosimilarity.” Such data and information may include, for example:

  • critical quality attributes;
  • analytical differences and an analysis of the potential clinical impact of the differences;

  • an analysis of the mechanisms of action in each condition of use;

  • the pharmacokinetics and biodistribution of the product in different patient populations;

  • the immunogenicity risk of the product in different patient populations;

  • differences in expected toxicities in each condition of use and patient population; and

  • any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed.

FDA further notes that the data and information should include a scientific justification as to why any differences that exist between the reference product and the proposed interchangeable product “with respect to the factors described” do not preclude a showing that the proposed interchangeable product can be expected to produce the same clinical result in any given patient.[1]

Notably, the guidance also states that sponsors may include a scientific rationale to extrapolate data and information supporting a demonstration of interchangeability in an appropriate condition of use to the remaining conditions of use for which the reference product is licensed. FDA states that clinical studies other than those necessary to support “other elements demonstrating interchangeability” will likely not be needed to satisfy the statutory requirement that the proposed interchangeable product “can be expected to produce the same clinical result as the reference product in any given patient.”

Degree of Analytical Similarity and Product-Specific Immunogenicity Risk Determines Scope and Extent of Clinical Studies

The guidance provides that the additional data and information needed to support a demonstration of interchangeability, beyond that needed to demonstrate biosimilarity, are dependent on and influenced by multiple factors. FDA intends to consider the “totality of the evidence” provided by the sponsor when determining interchangeability. Similar to FDA guidance documents on demonstrating biosimilarity, the guidance recommends that sponsors use a “stepwise approach” for generating data and information to address “residual uncertainty” about whether the proposed product is interchangeable with the reference product.

For purposes of determining interchangeability, the guidance reiterates that the BPCIA requires FDA to first evaluate whether a sponsor has demonstrated that the proposed interchangeable product is biosimilar to the reference product. With respect to the use of comparative analytical data to demonstrate biosimilarity, FDA suggests that the use of advanced analytical approaches may further help to reduce residual uncertainty about interchangeability. The potential effect on residual uncertainty depends on the degree of analytical similarity between the products and the strength of the evidence for the clinical relevance of the analytical data. To further illustrate, the guidance states that a clinically relevant and thus meaningful “fingerprint-like characterization” may reduce residual uncertainty regarding interchangeability and may lead to a more selective and targeted approach regarding the clinical studies necessary to demonstrate interchangeability. In addition, the guidance states that clinical experience with the reference product and comprehensive product risk assessments—e.g., assessments regarding immunogenicity—may also affect the data and information needed to support a demonstration of interchangeability.

As an example provided at one end of the spectrum, the guidance posits that an appropriately designed switching study may be sufficient to support a demonstration of interchangeability where the proposed product (i) has relatively low structural complexity; (ii) has been demonstrated to have meaningful fingerprint-like analytical similarity to the reference product as a part of the biosimilarity demonstration; and (iii) has a low incidence of serious adverse events related to immunogenicity.[2]

As an example provided at the other end of the spectrum, the guidance states that post-marketing data for the product as a licensed biosimilar, in addition to an appropriately designed switching study, may be required to support a demonstration of interchangeability where the proposed product (i) has high structural complexity; (ii) has been demonstrated to be highly similar to the reference product as a part of demonstrating biosimilarity but has no demonstration of meaningful fingerprint-like analytical similarity; and (iii) has known serious adverse events related to immunogenicity.

In this scenario, the guidance suggests that post-marketing surveillance data from the licensed biosimilar product, in addition to data from an appropriately designed switching study, may be needed to address residual uncertainty and to add to the totality of the evidence supporting a demonstration of interchangeability.

Switching Studies Needed for Products Administered More Than Once to an Individual

The guidance discusses FDA’s expectation that a sponsor of a proposed interchangeable product will submit data from a switching study or studies in one or more appropriate conditions of use when the proposed product is intended to be administered more than once to an individual. This requirement is intended to address the PHSA requirement that the information submitted by the sponsor is sufficient to show that “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.” 42 USC 262(k)(4)(B).

The guidance recommends that the design of a switching study:

  • include two or more alternating exposures (switch intervals) to the proposed interchangeable product;
  • focus on clinical pharmacokinetics and pharmacodynamics as primary endpoints because these assessments are more likely to detect changes in immunogenicity and/or exposure arising from switching than are efficacy endpoints;

  • use patients instead of healthy subjects, because switching studies are designed to mimic how the proposed interchangeable product will be used in clinical practice; and

  • choose the most immunogenic route of administration if the product is approved for more than one route of administration.

Further, the guidance recommends that sponsors select a condition of use that would support subsequent extrapolation of data to other licensed conditions of use. FDA states that once a proposed product meets the statutory requirements for licensure as an interchangeable product in an appropriate condition of use, the sponsor may, with appropriate scientific justification, seek licensure by extrapolation for additional conditions of use for which the reference product is licensed. The guidance provides that the scientific justification for extrapolation should address the following issues:

  • the mechanism(s) of action in each condition of use for which the reference product is licensed;
  • the pharmacokinetics and biodistribution of the product in different patient populations;

  • the immunogenicity risk of the product in different patient populations;

  • differences in expected toxicities in each condition of use and patient population; and

  • any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed.

The guidance indicates that differences between conditions of use with respect to these factors do not necessarily preclude extrapolation. FDA recommends, however, that the scientific justification address any such differences in the context of the totality of evidence supporting a demonstration of interchangeability.

Use of a U.S.-Licensed Reference Product Strongly Recommended in a Switching Study

The guidance strongly recommends that sponsors use a U.S.-licensed reference product in switching studies designed to support a demonstration of interchangeability. This recommendation differs from FDA’s position on the permissible use of non-U.S.-licensed comparator products for purposes of demonstrating biosimilarity.

FDA offers several reasons to support its position that the use of a non-U.S.-licensed comparator product is generally not appropriate in switching studies. In particular, FDA notes that the proposed interchangeable product and the non-U.S.-licensed comparator product may have subtle differences in the levels of specific structural features and impurities and that such differences could augment the overall immune response to these products following multiple exposures to each product as a result of switching or alternating. FDA also advises that establishing interchangeability with a biological product that patients will not receive in the U.S. would generally not be appropriate because the objective of a switching study is to determine whether a proposed product is interchangeable with—i.e., capable of being substituted for—a reference product that is licensed for use in U.S. clinical settings.

Same Presentation as Reference Product Recommended

FDA advises sponsors of proposed interchangeable products to evaluate that product’s presentation, including product design and interface, relative to the reference product.

As a general matter, the guidance recommends that a sponsor developing an interchangeable product not seek licensure for a presentation for which the reference product is not licensed. For example, the guidance states that if the reference product is marketed only in a vial and a prefilled syringe, a sponsor should not seek licensure for a different presentation, such as an auto-injector. This, too, appears to represent a departure from FDA’s position with respect to acceptable differences in presentation for purposes of demonstrating biosimilarity. As FDA notes elsewhere in the guidance, however, and distinct from licensure as a biosimilar, a determination of interchangeability reflects that the product may be substituted for the reference product “without the intervention of the prescribing health care provider or additional training before use” (emphasis added). FDA advises sponsors considering developing a presentation for which the reference product is not licensed to consult with FDA so that it may evaluate whether such a presentation could support a demonstration of interchangeability.

Further, the guidance recommends that sponsors analyze the presentations of a proposed interchangeable product to identify differences in design compared with the presentations licensed for the reference product. As discussed in the guidance, a proposed interchangeable product with a differently designed presentation than the reference product may raise uncertainty about whether the difference in presentations would impact the ability of end users, including patients or caregivers, to appropriately use the proposed product.

To assist sponsors in analyzing presentations of the proposed interchangeable product and reference product and to identify any differences in design, the guidance recommends that sponsors conduct three types of “threshold analyses”: (1) a labeling comparison; (2) a comparative task analysis; and (3) a physical comparison of the interchangeable product and the reference product, along with their respective container closure systems and/or delivery device constituent parts. When no differences in the design of the presentations are identified, the guidance suggests that additional data to support the appropriate use of the proposed interchangeable product by the end users, including data from comparative use human factors studies, will not be necessary to support licensure as an interchangeable product.

However, if the threshold analyses determine that there are non-minor3 design differences present, the guidance recommends that sponsors provide appropriate data from additional studies to support these differences. The guidance suggests that these data may be gathered in a focused comparative use human factors study, which, as further discussed by FDA, is a study to assess any differences in the use error rate between the reference product and the proposed interchangeable product. A technical description of comparative human use factors studies intended to support a demonstration of interchangeability, including relevant considerations, is provided as an appendix to the guidance (“Appendix A: Comparative Use Human Factors Studies”).

Post-marketing Safety Monitoring Considerations

The guidance also includes a brief discussion on post-marketing safety monitoring considerations for interchangeable biological products. Specifically, FDA recommends that such monitoring first consider the following factors: (i) any particular safety or effectiveness concerns associated with the use of the reference product and its class; (ii) the proposed interchangeable product in its development and, if marketed ex-U.S., its clinical use; (iii) the specific condition of use and patient population; and (iv) patient exposure in the interchangeability development program. In addition, FDA notes that post-marketing safety monitoring for an interchangeable product should also have adequate pharmacovigilance mechanisms in place. Finally, the guidance also notes that, as applicable to all biological products, FDA may require a post-marketing study or a clinical trial to evaluate specific safety risks.

No Recommendations for Labeling or Naming of Interchangeable Products

In prior guidance documents pertaining to licensure as a biosimilar, FDA stated its intent to provide specific recommendations on the labeling and naming of interchangeable products in future guidances. Thus, there was an expectation among some stakeholders that FDA might use this guidance as an opportunity to address these or other outstanding issues. Notably, however, this guidance includes no such discussion.

Additional Input Solicited by FDA

In the Federal Register announcement of the availability of the guidance, FDA has also invited general comments on interchangeability, including comments on regulation of an interchangeable product over its life cycle, as well as feedback on the following two questions:

1. With respect to interchangeable products, are there considerations in addition to comparability assessments that FDA should consider in regulating post-approval manufacturing changes of interchangeable products?

2. How, if at all, should FDA consider conditions of use that are licensed for the reference product after an interchangeable product has been licensed?

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Anyone wishing to submit written comments or suggestions to the draft guidance, including a response to the specific additional input solicited by FDA, should do so by March 20, 2017 [Docket No. FDA–2017–D–0154]. Comments may be submitted electronically to www.regulations.gov.