Biosimilar Applicants Must Anticipate Regulatory Differences Among Countries

Stay ahead of developments in federal and state health care law, regulation and transactions with timely, expert news and analysis.

By John T. Aquino

Oct. 28 — The U.S., Canada and the EU all have differences in regulations that biosimilar applicants must address, regulators said at a conference Oct. 28.

This issue is compounded by the fact that countries are revising their guidances to address concerns such as biosimilar interchangeability and the definition of a biosimilar, panelists at the DIA 2016 Biosimilar Conference in Washington said.

In the U.S., for example, the Biologics Price Competition and Innovation Act (BPCIA) was created to define biosimilars and establish an abbreviated regulatory pathway for their approval, said Leah Christl, associate director of the Food and Drug Administration’s Center for Drug Evaluation and Research’s (CDER) Office of New Drugs (OND).

In Canada, biosimilar products are regulated as new biologic drugs, and additional biosimilar legislation wasn’t necessary because its new drug regulations had been so flexibly written, said Cathy Parker, director general of the biologics and genetic therapies directorate of Health Canada. “However, because of this, biosimilar products in Canada are called ‘subsequent entry biologics’ and stakeholders have requested that this confusing name be changed to ‘biosimilars,’" Parker said.

Christl urged biosimilar applicants, who should consider the possibility that their product will be marketed in many countries even if that isn’t part of their initial plan, to anticipate problems due to the differences in regulations and the challenges the agencies are encountering. They should seek advice from relevant regulators, and in some cases, joint agency discussions will be necessary.

“We may not be able to harmonize our advice, but we will strive to align scientific concepts and note and address differences,” Christl said.

Revisions of Biosimilar Guidances

The BPCIA defines a biosimilar as a biologic product that is highly similar to an FDA-approved biologic product and for which there are no meaningful clinical differences between the biosimilar and the original biologic, known as a reference product (RP). Under the BPCIA, the biosimilar partly relies for approval on data that were submitted for approval of the RP.

Christl said that as of Oct. 28, 66 products were enrolled in the FDA’s Biosimilar Product Development Program and that CDER has received meeting requests to discuss the development of biosimilars for 20 RPs.

“We are committed to finalizing or revising several biosimilar guidances. And there is a lot of interest in our release of our interchangeability draft guidance,” Christl said, referring to the additional FDA designation of interchangeable to an approved biosimilar, which would allow a pharmacist to substitute a biosimilar for a biologic without physician approval. “We are working on it. But the FDA cannot commit to having it out by the end of the year, although we are aiming for by the end of 2017.”

Parker said: “We in Canada are at a critical stage regarding a revision of our biosimilar guidance document, which focuses on submission requirements and which was first published in 2010. We asked sponsors what in the 2010 document was problematic for them. In addition to terminology, there were discussions about the nonclinical data requirement and whether there is a need for environmental studies and international alignment.”

There was also concern that the Health Canada guidance document wasn’t sufficiently clear about extrapolation of data in the approval of a biosimilar, she said, something that Jenkins had noted was a concern in the U.S. as well.

“You will not see any quality changes in the document. What you see will be clarification,” Parker said.

As to interchangeability, Parker said there was a particular problem in Canada because regulatory authorization by Health Canada isn’t a declaration of equivalence. “We are under a lot of pressure from various stakeholders to provide direction on this. Designation of a drug as interchangeable is under the purview of the provinces, and we are looking to see the FDA guidance in the area.”

Martina Weise, head of licensing division 2, BfArM, German CHMP Alternate, BfArM Germany, said the European Medicines Agency’s (EMA) biosimilar guidances are considered “living documents” that are frequently reassessed and reconsidered.

Best Practices for Sponsors

Christl offered some best practices for global biosimilar development.

“Have a plan to address and manage differences in advice you receive from regulatory agencies,” she said. “If you don’t interact with the FDA while you’re doing your development program because you want to launch in Europe first, you will lose that opportunity, and when you go to the FDA, you may have to marshal more resources that you could have consolidated from the beginning. The better informed we are, the better advice we can give you.”

Share the feedback from each regulatory agency, Christl said. “You own your analytical data, so it’s up to you as to how you share it. We advise that you are as transparent as possible and specific when you talk to regulators. Ask questions and seek clarity. Be your own development advocate.”

Biosimilar applicants can request parallel scientific advice from the FDA and the EMA, Christl said. “You don’t do this at initial meeting. Seek advice separately first, identify differences in advice and concern, and then seek targeted feedback. You can also request a more informal ‘joint’ discussion of advice from national agencies.”

Parker noted there is a perception that biosimilars are “second-rate drugs.” She said, “This misconception permeates so many of the issues we have been talking about. This is why education and training about biosimilars is so important.”

To contact the reporter on this story: John T. Aquino in Washington at

To contact the editor responsible for this story: Randy Kubetin at

Copyright © 2016 The Bureau of National Affairs, Inc. All Rights Reserved.

Request Health Care on Bloomberg Law