A Critical Analysis of the FDA Guidance on Clinical Immunogenicity Testing of Insulin

Sarfaraz Niazi

The Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (BPCI

Act) 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recently issued draft guidance on the clinical immunogenicity testing, as part of the biosimilarity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 new biosimilarsi. 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 (PK) or pharmacodynamics (PD)); the FDA has the discretion to determine

that an element described in section 351(k)(2)(A)(i)(I) is unnecessary in a 351(k) applicationii.

The FDA has concluded that insulins are relatively smaller size biologics that are structurally

uncomplicated (few post-translational modifications) and 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 applicationiii

  Decades of insulin products listing 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; 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.”iv.

 Better purification methods developed over time that has reduced the concerns about the risk

of clinical immunogenicity.

Based on the premise presented above, the FDA has determined that the current analytical

tools used to evaluate quality attributes for insulin products can support a comprehensive

analytical comparison leaving little residual uncertainty regarding immunogenicity and have

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 (CMC) information to fulfill

 product quality-related requirements described in 21 CFR 601.2, including a

validated manufacturing process, and to support an inspection of the facility that is

the subject of the application (i.e., 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 (e.g., glucose infusion rate), using a

euglycemic clamp procedure or another appropriate test; and

 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, e.g., the

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 support

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 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 cytokines that too fall in a

similar category of highly characterizable products and particularly the products that

have little immunogenicity risk, like the filgrastim.

i
https://www.fda.gov/media/133014/download
ii
https://www.fda.gov/media/78946/download
iii
European Medicines Agency, Guideline on nonclinical and clinical development of similar biological medicinal
products containing recombinant human insulin and insulin analogues. EMEA/CHMP/BMWP/32775/2005_Rev. 1
(2015)
iv
Docket FDA-2019-N-1132, “The Future of Insulin Biosimilars: Increasing Access and Facilitating the Efficient
Development of Biosimilar and Interchangeable Insulin Products.”