Biosimilar Experts Debate Divergence in Regulatory Standards

In the court of expert opinion, clinical efficacy studies for evaluating biosimilar equivalence to reference products increasingly stand in a gray area. Many experts agree they are not sensitive enough in comparison with other tests to provide convincing evidence of biosimilarity, but regulators in the United States and Europe still hold onto their right to require these tests for biosimilar approval. The United Kingdom’s recent decision not to require these tests, therefore, is “revolutionary,” said Martin Schiestl, PhD, who leads Regulatory Affairs Policy at Sandoz and spoke at the Festival of Biologics USA conference.

“This is the way the future will look, so we will see more complex biologicals, which can be developed as biosimilars, without the need for these very large efficacy studies, and the evidence to ensure the safety and effectiveness of biosimilars will be collected by other means,” such as pharmacokinetic studies, Schiestl said.

Too Much Divergence

Such regulatory changes can significantly improve the landscape for biosimilar development and acceptance, panelists at the conference agreed, but too much divergence between national policies can be a hindrance, as it adds complexity, said Julie Maréchal-Jamil, MSc, director of Biosimilar Policy and Science for Medicines for Europe, an industry group for generics and biosimilars producers. “Complexity is never really linked to access or availability in the end. That is just an additional hurdle.”

But it’s important to note that biosimilar approvals are based on the “totality of evidence,” and although the data that regulators will require may be voluminous and diverse, it is certainly not “one size fits all,” panelists said. In other words, US and European regulators are willing to be flexible in their requirements for individual biosimilar applications.

“I think we’re going to see the FDA and the European Medicines Agency be more open, and hopefully that will influence other regulators about what types of data and studies are really necessary to demonstrate biosimilarity," said Leah Christl, PhD, executive director of Global Biosimilars Regulatory Affairs and Regulatory and Research and Development Policy at Amgen.

Christl previously headed up the therapeutic biologics division at the FDA, and drawing on that experience, she said the FDA has tended not to provide micro-level, rigid guidance about biosimilar approval requirements simply because it makes sense to stay flexible so that it’s possible to adapt to changing needs and situations.

“You can target the data you need to look at—are there clinically meaningful differences between the products?—and look across the spectrum of different scientific studies, whether they are in the analytical space, looking at functional data or pharmacodynamic end points, vs those traditional clinical end points. I expect that the FDA is going to keep moving forward with that same type of approach,” she said.

Perceptions about what data are essential for biosimilar characterization may change, but ultimately one of the hurdles that must be crossed is the acceptance factor among providers and patients. They’re the ones who need to be convinced, ultimately, that biosimilars are safe and efficacious, so the requirements for regulatory review have to be tailored, somewhat, in that regard, said Eva Temkin, JD, who served 8 years with the FDA, most recently as acting deputy director of Therapeutic Biologics and Biosimilars.

“There’s a real push-and-pull that regulators are grappling with around these issues," she said. "On the one hand, there’s a desire, and I think appropriately, to have efficiencies wherever we can and to really harness the flexibility that’s built into the 351(k) biosimilars approval pathway, and to exercise that flexibility appropriately. On the other side of that coin is that we also have patients and health care providers who need to be driving uptake and utilization of these products for that piece of this puzzle to be successful.” Temkin is now in private practice with King & Spalding in Washington, DC.

Insulin Template

Insulin products, which are now approved under the Biologics Price Competition and Innovation Act, could help open the door for simplification of regulatory requirements, such that gaining FDA approval for substituting these biosimilars with established brands will be put on an easier gradient, said Stacie Ropka, PhD, of Axinn, Veltrop & Harkrider. “I’m sincerely hoping that because insulin is so well understood and such a simple protein, the FDA will be able to work with those who are seeking an interchangeable designation so that the immunogenicity clinical trials, which seem to drive up the cost of development for follow-on biologics, will not be required.”

That, in fact, is the direction the FDA wants to go, Temkin said. “My understanding is that the elimination of that requirement will save many, many months and potentially millions and millions of dollars from the development of biosimilar and interchangeable insulins, which can hopefully catalyze some additional development of those products.”