Before issuing its long-awaited draft guidance on biosimilars, FDA has offered some hints about how it will address biosimilar approvals. Despite those hints, questions remain about the issues FDA will cover in its guidance as well as how those rules will mesh with the Biologics Price Competition and Innovation Act of 2009 (BPCIA), which authorizes the agency to develop a pathway that avoids unnecessary biosimilar tests.
Among the questions: How should biosimilars be defined? What standards should be set for biosimilarity and the even higher standard of interchangeability? What evaluation process will emerge for assessing immunogenicity? How should products be named? How should pharmacovigilance issues be addressed?
FDA has yet to spell out which of these topics will be addressed by its draft guidance but maintains that it is on track to release rules later this year, a spokeswoman for the agency’s Center for Drug Evaluation and Research (CDER) told GEN. “The guidance will cover various areas of biosimilar development,” CDER’s Lisa Kubaska said.
“It may be possible to exceed a current state-of-the-art analytic characterization by evaluating more attributes and combinations of attributes at greater sensitivities with multiple complementary methods. This may involve new technologies or improvements in current technologies. The methodology may also vary depending on the complexity of the biological product being evaluated.”
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.
Europe Could Be More Attractive
On May 31 EMA finished accepting comments on its own draft guideline on biosimilar mAbs. The guidance lays out qualities to be studied, including the use of populations, pharmacodynamic markers, and endpoints sensitive to the potential differences between products.
“In principle, the most sensitive model and study conditions (pharmacodynamic or clinical) should be used in a homogeneous patient population since this reduces variability and thus the sample size needed to prove similarity and can simplify interpretation,” EMA stated in the guidelines.
EMA explicitly urges pharmacokinetic study as well as pharmacodynamic endpoints: “Pharmacokinetic data can be helpful to extrapolate data on efficacy and safety between different clinical indications of the reference monoclonal antibody. Pharmacokinetic studies can be combined with pharmacodynamic endpoints where available. Sponsors should always explore possibilities to study dose concentration-response relationships since this approach, if successful, may provide strong evidence of biosimilarity.”
EMA’s development of guidelines may have the effect of drawing biosimilar developers to Europe, where they can use its abbreviated pathway, establish a record of safety in the marketplace, and only later on pursue FDA approvals. “It used to be that a lot of companies wanted to get FDA approval first because so many countries relied on FDA approval to shorten the pathway to approval in those countries. I wonder if, at least for biosimilars, that whole paradigm will be reversed, and that biosimilars will be approved far later in the United States than in Europe,” McDonough told GEN.
Balancing Access and Innovation
The federal government took an important step toward accelerating development of biosimilars with the enactment of BPCIA. Last year it was folded into title VII, subtitle A of President Barack Obama’s healthcare reform measure, the Patient Protection and Affordable Care Act. The act created a long-awaited statutory framework for the FDA to evaluate and approve biosimilars. This framework sought to balance the government’s interest in bringing cheaper medicines to market with the interest of drug developers in keeping their drugs exclusive for a particular amount of time.
BPCIA allows biosimilars to pursue interchangeability assessments from FDA, in which the agency decides that pharmacists can substitute between biologics without a prescriber’s intervention. In the NEJM article, FDA said that it will consider a biologic interchangeable with a reference product “if the developer demonstrates that it can be expected to produce the same clinical result in any given patient and that the risk associated with alternating or switching between the two products is not greater than that involved in continuing to use the reference product.
“The FDA will carefully consider what data will be necessary for this purpose and translate that assessment into effective regulatory standards,” the FDA authors promised. BPCIA does not permit a biosimilar application to be submitted to FDA until four years after the date on which the reference product was approved. The reference product will enjoy a 12-year exclusivity period, and once that ends, a biosimilar may not be allowed if the innovator drug is still covered under a patent.
Many of the biosimilar approvals currently being pursued are for products based on reference drugs introduced to the market over the past decade or so. The draft guidance that FDA eventually releases should go far toward bringing more lower-cost biosimilars to market—one ostensible purpose of healthcare reform. How far it goes and how helpful it is to biologic drug developers will depend on how many of the blanks left by its article in NEJM FDA fills in over the next few weeks.