The Food and Drug Administration has repeatedly emphasized that biosimilar approvals are based on the “totality of evidence.” However, the agency has emphasized that analytical comparability of biosimilars with reference products comprises by far the most important share of the evidence considered. Phase 3 clinical trial evidence contributes less to biosimilar approval decision making, as opposed to approval decisions for reference biologics.
Views in the biosimilar industry are evolving with the science and the accumulating evidence. And there is a lot of it: not only the European experience consisting of tens of millions of patient-days of use but the US approval of 34 biosimilars and 21 launches.
At the Festival of Biologics USA 2022 meeting, several thought leaders advocated for a further deemphasis on large-scale, phase 3 clinical trials for biosimilar approval. These late-stage studies have not revealed significant safety or efficacy issues with biosimilars, and their cost is thought to be a considerable obstacle to new manufacturers entering the biosimilar competition for existing and future products. Not only are these studies, encompassing hundreds of patients and dozens of study centers, expensive to administer, but the cost of obtaining reference product samples for study can cost prohibitive amounts.
Hillel Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, explained that the “analytical tools available today are far better at characterizing these molecules than they were 20 years ago. This includes carbohydrate analysis, and the ability to build cell lines to get precisely the molecule that you want.” In other words, the science has moved forward. “Today, the clinical and efficacy tools are much less specific than what we can achieve with the analytic studies,” he said. We should consider modifying “our regulatory expectations based on the current scientific capability.”
Juliana Reed, Executive Director of the Biosimilars Forum, agreed, saying “We should not have the expectation that every biosimilar should have a clinical trial.” The information about the molecule that is obtained through analytics is so detailed today. “We know that the reference product is efficacious, and we know its safety profile. The analytics tell us that the biosimilar is a very close copy.” The inference is, why are we spending resources to confirm what is fairly obvious?
The FDA has now approved a few biosimilars that had not been the subject of a phase 3 trial (e.g., Udenyca®, Nyvepria®, Nivestym®). These have been generally in drug categories where other biosimilars were already approved. Even in those circumstances, phase 1 and/or phase 2 study data were available.
At the conference, David Charles, MD, Medical Director and Founder of the Alliance for Patient Access, and a physician specializing in the treatment of movement disorders, said that “biologics have been a part of my practice since 1995.” He was strongly against eliminating clinical trial evidence for the approval of biosimilars: “The notion of bringing a biosimilar to market without a clinical trial would be a nonstarter for me. These are complex disease states. I feel that clinical trials remain important.” He does believe “the FDA is by and large getting it right—adapting as the science is progressing. But at the end of day, safety and efficacy is most important to me.” Eliminating these phase 3 trials will undermine physician and patient confidence, Dr. Charles stated.
Although I don’t agree with Dr. Charles’ position, he does has a point. Several years after approval of infliximab biosimilars, gastroenterologists and rheumatologists remain well behind oncologists in their acceptance of biosimilars. This will likely change rapidly after the introduction of adalimumab biosimilars, and payers will move to force utilization changes through their coverage policies. For specialists who have not had biosimilar experience to date, introducing new biosimilars to their practice may certainly run into barriers of confidence, without phase 3 trial experience. This can only slow provider adoption.
This seems to be a debate of the mind versus the gut. The mind understands that if analytic characterization says that the biosimilar is essentially the same as the reference product, the gut still wants data it can digest.
In the meantime, Emanuela Lacana, PhD, Deputy Director, Office of Therapeutic Biologics and Biosimilars, FDA, confirmed that “eliminating human clinical trials is not likely, because they provide a level of comfort to practitioners.”
It is worthy to note that biosimilar makers seeking to bring a product to market need to decide on the need for a phase 3 trial several years before actually filing a new 351(k) application. The FDA’s clinical development program is attempting to play a strong proactive role, consulting with these manufacturers on the potential need for phase 3 trials. If that expensive clinical trial barrier will be put aside for new reference drug categories tomorrow, the FDA will likely have to put a stake in the ground today.
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