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 (BPCIA
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recently issued draft guidance on the clinical immunogenicity testing, as part of the biosimilarity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, because insulins are relatively smaller- sized biologics that are
structurally uncomplicated and have (few post-translational modifications, they) 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’ 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.”iv.
 Better purification methods developed over time that has have 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 that leaves little residual uncertainty regarding
immunogenicity and have tha 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 (CMC) information to fulfill

product quality-related requirements described in 21 CFR 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 (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;. t 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 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 inhibitorss that too fall in a similar category of highly characterizable products,
and particularly the products that have little immunogenicity risk, like the filgrastim.
The ending thought remains why did it take the FDA four years to accept the thesis that
was already practiced in EU? Perhaps, it was the inevitable pressure to make insulins
more affordable? Fact is that unless we have this level of clarity, it will be difficult to
make biosimilars more accessible.
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.”