Lessons From Europe: Is It Time for a Regulatory Course Correction?

What has a decade of European experience with biosimilar development and use taught us about their safety and efficacy? According to the authors of a paper published in Lancet Oncology, we may have gathered enough evidence to begin to consider altering how these agents are approved, to speed their path to approval.

Investigators from The Netherlands, Austria, Luxembourg, and the United States wondered whether the need for more comparative clinical data to assess biosimilar safety and efficacy will be necessary in the future.

Although the first-generation products epoetin and filgrastim were a good fit for the EU’s biosimilar regulatory pathway requirements, evaluating the clinical benefits of the next- generation oncology products, the monoclonal antibodies, is a bit more complicated. They noted that in some cases, the clinical effect of the monoclonal antibody may be modest, complicating the question of clinical equivalence or similarity. “Even in the case of monoclonal antibodies that have shown efficacy as monotherapies, such as trastuzumab or rituximab,” these agents are commonly prescribed with various combinations of chemotherapy, which complicates “the decision with regard to the most appropriate indication and patient population in which to perform trials to show biosimilarity,” stated the authors. This is especially important in extrapolating indications (consider oncology agents that are used to treat a wide array of tumors).

They pointed out that the European Medicines Agency “is moving away from double-blind equivalence trials and large postmarketing safety studies as the standard to show clinical similarity, because regulatory agencies are realizing that comparative clinical trials are not sensitive enough to show possible differences in safety and efficacy.” This points, once again, to the greater importance placed on the physiochemical description of the biosimilar and on in vitro assays to demonstrate similarity between the biosimilar and the reference product. These authors believe that “requiring clinical investigation in the most sensitive patient populations and strong scientific justification to support extrapolation to other indications” is critical, but the need for additional confirmatory clinical trials would undermine the ability to increase access to potentially cost-saving biosimilars.

They stressed, “To demand confirmatory trials in all possible indications would waste valuable patient, staff, and monetary resources for no substantial gain, and such requirements should be avoided unless extrapolation cannot be justified on the basis of mechanism of action and existing data.”

On the basis of roughly 400 million patient-days of biosimilar experience in Europe without the appearance of any serious safety signals, they believe it may be time to learn from this experience and correct course for the upcoming wave of oncology biosimilars.