Emphasis on Product-Specific Evaluation
CDER’s director Janet Woodcock, M.D., is among four FDA officials who discussed the challenges associated with reviewing biosimilars in an article published in August in The New England Journal of Medicine. They concluded that science has evolved to the point where the agency can conclude that some biosimilars are similar to the reference product. But that conclusion, the co-authors added, must vary from drug to drug to reflect differences in the composition of those biologic drugs.
“Given the complex nature of biologics, it’s unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed. Instead, FDA scientists will need to integrate various types of information to provide an overall assessment that a biologic is similar to an approved reference product,” the FDA officials wrote.
That “totality of the evidence” approach, as the authors label it, reflects the reality that biosimilars differ by size as well as composition of molecule. They can also differ not just by attribute but by combinations of attributes.
“It’s very hard to fashion rules that govern all biologics because they range from compounds like insulin, which are relatively on the smaller side although still much bigger than traditional small molecule drugs, all the way up to factor 8, which is a very large product, a very sensitive product,” Sara Radcliffe, evp for health with the Biotechnology Industry Organization (BIO), told GEN. “Fashioning rules that govern all of them is complicated. At the same time, they as a regulator need to provide guidance for biosimilar sponsors so that they can understand what needs to be submitted to the agency.”
In the NEJM article FDA said that their strategies may include a fingerprint-like identification of very similar patterns in a number of different products. Fingerprint studies could reduce the extent of testing required for protein biosimilars, according to FDA. They add, though, that both animal and human testing “will generally be needed for protein biosimilars for the foreseeable future.” But for those studies to be most effective, FDA’s eventual guidance should better define fingerprint tests, both in terms of qualities to be studied and the degree of detail needed.
In their article, FDA also explained that its evaluation of biosimilarity “must consider the product’s complexity, its formulation, its stability, and the usefulness of biochemical and functional characterizations and incorporate these factors into a risk-based approach” similar to that used to evaluate new drugs.
Another critical factor, the officials asserted, is immunogenicity—something they said the agency will evaluate in a risk-based manner. While the risk-based approach has slowed down review and approval of new drugs in recent years, Radcliffe said that was more the case as FDA was implementing its Risk Evaluation Mitigation Strategy and less so now as the agency and drug developers have learned what is required.
FDA noted that the new abbreviated pathway will require the agency to carry out “an in-depth review of comparative analytic characterization and in vitro data,” which they describe as “a more extensive product review than for a traditional IND.” The agency is still figuring out how such interactions might be structured and how they will affect the user-fee program that Congress has mandated for biosimilars.
Madeleine M. McDonough, a partner with the law firm Shook Hardy & Bacon, anticipates a lot more such interactions as the FDA makes clear that it wants to spend more time in dialogue with biosimilar developers. “I think industry is going to need to probably pay higher fees to fund those. But I think early communication and collaboration are going to be key to figuring out a pathway to biosimilars.
“The medical risks are going to depend on how close the biosimilar is to a reference product and what the hypothetical mechanism of action would be that could cause adverse effects or untoward effects. And I don’t think you can do that with some broad brush. I think it’s really going to be compound specific.”
FDA agrees, saying its eventual process for biosimilars must include product-specific safety monitoring as well as tracking of products and their manufacturers for even small changes, though the agency did not offer more specifics in the article. Radcliffe explained that “for some products, one might want to set up product-specific registries, for example. For other products, maybe there could be prospective clinical trials in the postmarket.”
Another important way FDA can track biosimilars, she said, is by insisting on a unique nonproprietary name for each biologic so that it will be possible to trace adverse events once a biologic enters the market.