Biosimilar Guidances Finalized – How to Use Data on Non-US-Licensed Product and How to Extrapolate Data to Get Approval in Other Indications Are the Topics Changed the Most in the Q&A Guidance

May 3, 2015

By James C. Shehan

On April 28th, FDA finalized the three biosimilar guidances that it issued in 2012.  Covering the topics of questions and answers regarding BPCIA implementation, scientific considerations in demonstrating biosimilarity, and quality considerations in demonstrating biosimilarity of proteins to reference products, the final guidances make a few significant changes to the drafts but the bulk of the draft guidances remain unchanged.  This posting will discuss the significant changes to the Q&A guidance and later ones will review the other two.  For a review of the draft Q&A guidance, see our post here.

After an introductory section, the questions and answers are grouped into three major categories: Biosimilarity and Interchangeability, What is a “Biological Product” and Exclusivity.  About three-quarters of the questions are related to the first category, Biosimilarity and Interchangeability. 

In that category, the largest changes have been made to the answer regarding use of non-US-licensed versions of reference product to generate biosimilarity data.  The draft guidance required that analytical studies, at least one clinical pharmacokinetic study and at least one pharmacodynamic study (if required), use US-licensed reference product.  The final guidance repeats that general rule but adds a possible exception – “unless it can be scientifically justified that such a study is not needed.” 

This answer in the final guidance also delves heavily into the topic of bridging studies.   FDA states that if non-US data is relied upon, analytical, PK and PD studies should directly compare all three products (biosimilar, US reference product and non-US comparator product).   FDA also added to the final guidance that the analytical studies should include  “degradation profiles under stressed conditions.” 

FDA lists a large number of factors that may affect the amount of bridging data needed:

  • higher order structure;
  • post-translational modifications (e.g., glycosylation);
  • degree of heterogeneity;
  • whether the formulations, dosage forms, strengths and routes of administration of the US-licensed reference product and the non-US-licensed comparator products are the same;
  • the design of the physicochemical and biological/functional assessments and the use of multiple orthogonal methods with adequate sensitivity to detect differences among the products; and 
  • the scientific justification for the selection of the non-US-licensed comparator lots used to establish the scientific bridge and how the selected lots relate to the material used in the nonclinical and clinical studies.  The scientific bridge should include a sufficient number of lots of non-US- licensed comparator product to adequately capture variability in product quality attributes. When possible, the non-U.S.-licensed comparator lots used in the nonclinical or clinical studies should be included in the assessment performed to establish the analytical bridge.

Given this level of complexity, it is unsurprising that in this answer FDA encourages sponsors are encouraged to discuss bridging with FDA during the development process.  It is also unsurprising that, as in its draft guidance, FDA notes that comparisons to non-US product are unlikely to be able to support an interchangeability determination.

FDA also significantly expanded its answer on how to extrapolate clinical data on one indication to support approval in another indication.  Immunogenicity of the biosimilar in different patient populations was added to the list of issues that should be addressed in justifying extrapolation.  In gathering the clinical data that will be extrapolated, sponsors are urged to choose a use that “would be adequately sensitive to detect clinically meaningful differences between the two products.”  And in perhaps the most significant change, FDA recommends that sponsors do not try to extrapolate from indications approved under Subpart E, accelerated approval.  Considering the “potential complications in the event that postmarketing trials fail to verify the clinical benefit of the reference product for the condition of use,” this seems to be a prudent addition to the guidance.

In its answer to the question discussing whether applicants can request licensure for fewer routes of administration than those approved for the reference product, the draft guidance noted that FDA may require studies using a route of administration for which the biosimilar sponsors is not requesting approval.  The final guidance adds that such an FDA request will be made only “in a limited number of circumstances.” 

Four biosimilarity\interchangeability Q&As from the draft guidance are not in the final guidance, but FDA promises to finalize them in the future and add them to the guidance.  These Q&As deal with (1) the need for biosimilars to perform cardiac repolarization and drug-drug interaction studies;
(2) the length of the retention period for samples from PK and PD studies; (3) what constitutes “publicly available information” that a reference product is safe, pure and potent; and (4) how to obtain a determination of interchangeability.  Reinforcing its intent to answer these questions, FDA did not renumber Q&As in the final guidance.  The precise timing of finalization is not provided. A chart in the guidance states that revisions to #s 1 & 2 are “forthcoming,” but does not do so for #s 3 & 4.  This may be a typographical error. 

In the second category, of Q&As, FDA retained its proposed definition of a “protein” as an amino acid polymer of more than 40 amino acids in size. It amended this definition however, by noting that the amino acids do not need to be in a contiguous sequence for a product to be a protein.  FDA slightly changed the wording justifying the basis for its 40 amino acid test, referencing a lack of clear scientific consensus for distinguishing proteins from peptides.  Given the potential consequences of this issue, it would not surprise this author if FDA sees future challenges on this point.

In the last category, Exclusivity, FDA removed a Q&A addressing how a sponsor may request 12 year reference product exclusivity. The afore-mentioned chart promises that a revision of this question is also forthcoming.  A separate draft guidance from 2014, covered in our post here, deals exclusively with biologics exclusivity. 

Additional guidances on interchangeability, biosimilars naming and statistical approaches to proving biosimilarity are expected later this year.