Global Gaps in Standards Threaten Biosimilar Development

Although biopharmaceutical companies and regulatory authorities have made considerable progress in establishing policies for bringing biosimilars to market, key differences and gaps in requirements for testing and documenting product similarity still characterize the European Union, the U.S. and other regions.

The EU’s European Medicines Agency (EMA) has set the regulatory pace, with 18 products approved since 2006, reported Niklas Ekman of the Finnish Medicines Agency at the Drug Information  Association (DIA) conference in Washington, D.C. last week. Health Canada has two approved subsequent-entry biologics (SEBs), and the Korean Ministry of Food and Drug Safety also has approved two biosimilars. The first biosimilar application has been filed with the U.S. Food and Drug Administration, setting expectations for approval next year.

Despite this visible progress, disagreement over data requirements, testing approaches and legal frameworks threaten to discourage broader biosimilar development. One key issue is whether biosimilar sponsors may extrapolate data from clinical studies for one indication to support approval of additional uses. A prime case is the EMA’s decision to approve – and Health Canada to reject – use of the biosimilar version of Remicade (infliximab) for treating inflammatory bowel disease (IBD) and Crohn’s disease. The EU tends to be more flexible here, in this case permitting extrapolation of data supporting rheumatology conditions to multiple indications for the new Inflectra; Catherine Parker of Health Canada admitted that her agency is “fairly rigid” in not assuming that a lack of evidence of harm ensures that extrapolation will not have negative consequences.

More foreign comparators
Conversely, Health Canada is more flexible in permitting sponsors to use reference products not marketed domestically, recognizing that its small market necessitates broader access to viable comparators. Although EU legislation requires EMA-approved reference drugs, regulators are softening that stance, recognizing that such curbs on comparators will lead to duplicative clinical trials, which raise ethical concerns and costs. Ekman noted that it may be possible to use non-EU authorized comparators for certain clinical and preclinical testing, with bridging studies to support results. But European authorities reserve the right to assess the acceptability of such approaches on a case-by-case basis.

Differences in data and market exclusivity periods for Canada, the U.S. and the European Union, moreover, establish different time frames for submitting and approving biosimilar applications. FDA recently published draft guidance on reference product exclusivity, which raises the tricky issue of calculating the date of first licensure of the innovator product and subsequent developments that may extend exclusivity.

Probably the most heated policy dispute involves product “naming” to distinguish innovators from biosimilars. There is growing support for the World Health Organization (WHO) proposal that all biologics carry a unique biological qualifier in addition to an International Non-Proprietary Names (INN) identifier, but that approach doesn’t have much support among U.S. and EU innovator firms.

Meanwhile, regulatory authorities in other regions are working to harmonize policies for biosimilar development. Regulators from Korea and Canada are particularly active in efforts to development a common “biotherapeutics roadmap” for the Asia-Pacific Economic Cooperation (APEC) group, and Korea chairs the biosimilarity working group of the International Pharmaceutical Regulators Network.