The Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) requires that on March 23, 2020, an approved application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) will be deemed to be a license for the biological product under section 351 of the PHS Act (42 U.S.C. 262).

In anticipation of the licensing of insulin products under the BPCIA in 2020, the FDA has recently issued draft guidance on the clinical immunogenicity testing as part of the biosimilarity determination for biosimilars. To be licensed as a biosimilar, an application submitted under section 351(k) must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies demonstrating that the proposed biosimilar is highly similar to the reference product, animal studies, and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics); the FDA has the discretion to determine that an element described in section 351(k)(2)(A)(i)(I) is unnecessary.

The FDA has concluded that, because insulins are relatively smaller-sized biologics that are structurally uncomplicated and have few post-translational modifications, they can be well-characterized analytically to leave little residual uncertainty regarding the risk of clinical impact from immunogenicity.

The FDA further states that there is minimal or no clinical relevance of immunogenicity with insulin product use. The FDA determination comes from:

• Recommendations from the European Medicines Agency, which published a revised guideline in 2015 that no longer recommends a clinical immunogenicity study to support a biosimilar marketing application

• Decades of insulin products’ listings in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”) with little concern for any meaningful clinical impact of immunogenicity on the safety or efficacy of insulin product use

• Decades of clinical experience with approved insulin products, including the lack of a correlation between immunogenicity and safety or effectiveness as reflected in approved product labeling for insulin products, and published literature indicating a poor correlation between immunogenicity in insulin-treated patients and clinical impact on safety and efficacy

• Public comments received by the FDA in response to the May 2019 public meeting, “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient Development of Biosimilar and Interchangeable Insulin Products”

• Better purification methods developed over time that have reduced the concerns about the risk of clinical immunogenicity

Based on the premise presented above, the FDA determined that the current analytical tools used to evaluate quality attributes for insulin products can support a comprehensive analytical comparison that leaves little residual uncertainty regarding immunogenicity and that has minimal or no risk of clinical impact from immunogenicity. In such cases, a comparative clinical immunogenicity study would generally not be necessary to support the licensure of a proposed biosimilar or interchangeable product.

The FDA now recommends that, to secure licensing under the 351(k), the developers will need to provide:

• Adequate chemistry, manufacturing, and control information to fulfill product quality-related requirements described in 21 Code of Federal Regulations 601.2, including a validated manufacturing process, and to support an inspection of the facility that is the subject of the application (ie, a facility in which the proposed biological product is manufactured, processed, packed, or held)

• A comprehensive and robust comparative analytical assessment between the proposed insulin product and the proposed reference product demonstrating that the proposed insulin product is “highly similar” to the reference product

• A comparative clinical pharmacology study between the proposed insulin product and the reference product that provides a time-concentration profile and a time-action profile over the duration of action of each product based on reliable measures of systemic exposure and glucose response (eg, glucose infusion rate), using a euglycemic clamp procedure or another appropriate test

• An immunogenicity assessment justifying why a comparative clinical study to assess immunogenicity is not necessary to support a demonstration of biosimilarity; this justification may reference other data and information in the application, eg, a comparative analytical assessment with very low residual uncertainty. Where differences in certain impurities or novel excipients give rise to questions of residual uncertainty related to immunogenicity, these should be adequately addressed and may not require clinical testing.

Of greatest significance is a clear direction to developers that a comparative clinical immunogenicity and efficacy study is not required if the analytical assessment supports high similarity. Further, the design of clinical pharmacology study need not be complicated if the duration of action is determined based on reliable measures of systemic exposure and glucose response.

The draft guidance on clinical immunogenicity testing for insulin products is indeed a historic event: a bold step by the FDA that shows a determination that there is a need to bring into market lower-cost alternates to the reference products if the clinical studies that contribute to the majority of cost and time are not required.

I anticipate FDA issuing similar assessments of other biological products like the cytokine inhibitors that too fall in a similar category of highly characterizable products, and particularly the products that have little immunogenicity risk, like the filgrastim.

An ending thought remains: Why did it take the FDA 4 years to accept the thesis that is already practiced in European Union? Perhaps it was the inevitable pressure to make insulins more affordable. The fact is that, unless we have this level of clarity, it will be difficult to make biosimilars more accessible.