FDA Panel on Biosimilars: Analytics Should Trump Clinical Trials

Before marketing a “biosimilar” after the patent expires on a current biological drug, the onus will be on the manufacturer to demonstrate an exhaustive molecular and functional understanding of both the new product and the approved “reference drug”, FDA officials said during the American College of Rheumatology conference yesterday. The hall was packed with rheumatologists eager to know the future of the monoclonal antibodies that have proved so successful (at considerable cost) for the conditions they are treating.  

The agency is looking to sponsors for analytical information, speakers said, in an effort to avoid launching large-scale clinical trials. The FDA’s goal for biosimilars is not to establish safety and efficacy, which was already achieved for the reference drug. The focus is on establishing that the biosimilar is so identical functionally that existing clinical data is entirely applicable.

Describing many levels of a “step-wise process” through which manufacturers would be required to document similarity, speakers said that no boilerplate application processes had (or probably would be) established, because each biological is so unique. During the question period one speaker waved off concerns that patients might not want to be randomized to biosimilars in clinical trials, saying that the ethical issues are no different than those for any other kind of drug under testing.

No formal licensure requests for biosimilars have yet been filed with the FDA since 2009, when the Biologics Price Competition and Innovation Act became law as part of the Affordable Care Act. But the agency is in discussion with sponsors about roughly 50 proposed applications involving about 10 reference drugs, said Leah Christl, PhD, associate director for therapeutic biologics at FDA’s Center for Drug Evaluation and Research.

The Act mandates that approved biosimilars must:

•    be “highly similar” to the reference drug (except for chemically inactive components), and
•    have no “clinically meaningful” differences from the reference drug in terms of safety, efficacy, and potency.

The products should be interchangeable, so that there would be no risk in switching between them, Christl said. However, pharmacies would not be allowed to substitute biologicals in the way they can substitute generics in some states, unless the agency decides to allow this for a specific product.

How the approval process proceeds will depend in large part on the individual sponsors; the more analytical data they provide, and the more clearly they can establish that no major differences exist, the fewer full-scale safety and efficacy studies will be required. For products with a short half-life and few safety issues, safety and immunogenicity tests in healthy volunteers rather than patients may suffice, because any rheumatic disease would be presumed not to affect basic pharmacokinetics..

“The key is to understand which protein attributes matter and which don’t,” Christl said. “To be completely honest with you, we understand more about some proteins and products than we do about others. It really depends on their complexity.”

Among the many issues the FDA expects sponsors to document in detail are:

•    the chemical nature of the target antigen
•    the density of the antigen on the cell surface
•    the antibody’s affinity
•    cross-reactions
•    its precise effects: apoptosis, signal transduction, complement-dependent cytotoxicity and more.

Another complex issue is post-translational modification, the molecules that may be added to the antigen during the process of creating its 3D structure. Of particular concern are the N-linked glycans, sugar molecules added to the emerging protein, which modulate folding, sorting, and degradation. Many of these have specific effects on the immune system, and changes in these variants may also affect potency.

Clinical data would be required to answer what the FDA calls “residual uncertainties” that cannot be answered without resource to human tests. As to immunogenicity of a biosimilar, it may not be possible to predict or fully identify the protein impurities introduced by cells as they manufacture the product.

“Even today’s advanced analytical methods may not be able to determine that two compounds are structurally identical,” said Nikolai Nikolov, MD, a clinical reviewer for the FDA.  Also, in some cases existing trial information may not be adequate because, for instance, the standard ACR20 score may not  discriminate sufficiently between two treatments with similar activities. Possible approaches may be to identify endpoints, time points, and dosages in the steep part of a dose-response curve, he said, or to use methods analogous to those employed in testing generic drugs.

Responding to a question about the use of non-US drugs as comparators, the FDA panel responded that certain studies may be considered relevant, but that the agency would be “unlikely” to support an application based on comparisons with non-US reference drugs unless the latter were used in a 3-arm analysis that also includes a US reference drug.

Another audience member asked whether separate procedures should be established for biosimilars intended for pediatric patients. “I don’t think we’ve actually decided how to deal with products case by case,” replied Sarah Okada-Yim MD, a clinical team leader in the division of rheumatology drugs. “We’re trying not to have to re-prove safety in every population.”

Asked how patients or doctors (or IRBs) could be asked to support a trial in which a known-effective, approved drug is the “control” arm and a biosimilar is the “treatment,” and in which exposure to the biosimilar might theoretically cause an immune response that would render the subject unable ever to take the reference drug, the director of FDA’s Division of Pulmonary, Allergy, and Rheumatology products had a complex but firm answer. Calling such studies unethical is no different than wondering after the fact how you could ever have mounted a trial of a drug ultimately found to increase mortality risk, said Badrul Chowdhury, MD. The listener’s question presumes that you know before the trial that the biosimilar is not equivalent to the reference drug.

Once you have established to the best of your ability that the two drugs are sufficiently “biosimilar,” he said, there is no ethical problem with the trial.

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