No More Scarlet Letter: FDA’s Scientific Considerations Biosimilars Guidance Clarifies, Adds and Subtracts Various Approval Requirements, But Perhaps the Most Significant Change is to Biosimilar Labeling

By James C. Shehan –

Of the three FDA final guidances that FDA recently released (here, here and  here), the Questions and Answers guidance has received the most attention (see our previous post here).   But our perusal of the ScientificConsiderations in Demonstrating Biosimilarity to a Reference Product guidance also revealed a number of changes that will significantly affect how sponsors collect the data needed to support a biosimilar approval.  Below is a review of our choices for the most significant of these changes, first touching on those that seem to make approval easier and then turning to those that potentially make it more difficult.  And at the end, we discuss major changes made to the guidance that do not fit into the category of scientific data needed to support approval – the scarlet letter referred to above.

The first significant change in the guidance relaxes the requirement that a sponsorcompare its proposed biosimilar product directly with U.S.-licensed reference product.  FDA added the qualifier “unless it can be scientifically justified that such a study is not needed,” thereby opening the door to using product sourced from outside the US.  Another possible boon to biosimilar developers appears when FDA discusses approaches to developing evidence of biosimilarity.  FDA reiterates its preference for a step-wise approach but notes that sometimes tests may be conducted “in parallel.” 

Some animal toxicity study requirements are also relaxed.  For example, FDA notes that “if comparative structural and functional data … provide strong support for analytical similarity to a reference product, then limited animal toxicity data may be sufficient to support initial clinical use.”  FDA deleted a sentence recommending additional comparative in vitro testing if animal toxicity studies are not warranted. 

In the clinical studies section, after providing a list of issues that sponsors need to assess in scientifically justifying extrapolation across indications, FDA added that “Differences between conditions of use with respect to the factors described above do not necessarily preclude extrapolation.  A scientific justification should address these differences in the context of the totality of the evidence supporting a demonstration of biosimilarity.”  FDA now also advises sponsors that in choosing which indication to extrapolate form, they should choose one that is adequately sensitive, as opposed to the draft guidance’s “most sensitive” admonition.  And there is a key change to the FDA recommendation on study populations, a shift from recommending similar study populations as “essential” to FDA now advising biosimilar sponsors that “there are cases where a study population could be different from that in the clinical studies that supported the licensure of the reference product.”

As for possible heightened standards, in the structural analyses section, FDA added that formulation changes and product related impurities should be considered when comparing biosimilars to reference products.  When conducting structural analyses, sponsors also are now asked to consider characterizing lots during process development and to conduct analytical similarity assessments when they make changes in the manufacturing process.  In addition, a suggestion that sponsors might use a stand-alone instead of a comparative animal toxicology study was deleted.   

Most of the changes that may make approval more difficult to achieve occur in the clinical studies section.  FDA added a paragraph that notes that it expects a sponsor to conduct comparative human PK and PD studies, a clinical immunogenicity assessment, and “if residual uncertainty about biosimilarity remains after conducting these studies,” a comparative clinical study or studies.  In discussing PK and PD studies, the agency added a recommendation that sponsors use a population, dose, and route of administration that are “adequately sensitive to allow for the detection of differences in PK and PD profiles.”

The requirements for immunogenicity studies also appear to have been beefed up considerably, e.g., new recommendations for use of a comparative parallel design in treatment-naïve patients and evaluation of a subset of patients to assess whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions.  Sponsors are now also asked to consider the impact of antibodies on pharmacokinetics.  FDA even added that certain immunogenicity safety risks may need to be evaluated through postmarketing surveillance or studies.

The section on comparative clinical safety and effectiveness studies was substantially rewritten by FDA.  New headings on endpoints, study population, sample size and duration of study and study design and analyses, have been added.  These changes add a good deal of clarity.

So what are the labeling changes referenced at the beginning of this blog that we deem to be so significant?  It’s the deletion of the draft guidance’s requirements that the labeling of biosimilars indicate that they are biosimilars and also call out whether or not they are interchangeable.  While such designations may not have made a biosimilar feel like Hester Prynne, it does seem that mandating such terms be present may have led to some shunning in the marketplace that is today’s town green.