The application process

Even without final guidance, FDA officials say they're ready to evaluate biosimilar applications on an individual basis. "We were open for business a year ago," said Steven Kozlowski, director of CDER's Office of Biotechnology Products, at the "Future of Biosimilars" conference in May 2011, jointly sponsored by the Drug Information Association (DIA) and the Food and Drug Law Institute (FDLI). So far, no manufacturers have attempted the 351(k) approval route for biosimilars authorized by BPCI and are instead continuing to use established drug-approval procedures for some follow-on versions of proteins. If FDA testing requirements and other policies make the biosimilars pathway too arduous, manufacturers say they may use the traditional biologic license application (BLA) and sidestep the 351(k) route altogether.

In devising guidance, FDA has to tackle some basic issues, such as which products fall under the new regulatory program. BPCI extends the definition of biologics to most proteins beginning in March 2020. That definition raises questions about how the change will affect manufacturers of human growth hormones and other proteins, and how they should proceed during the nine-year transition period.

A thorny subject is whether FDA can approve a biosimilar based on a reference product that is approved overseas, but not in the United States. BPCI says that reference products have to be licensed by FDA, but biosimilars manufacturers want flexibility to permit comparison with a biologic licensed by a foreign regulatory body under certain circumstances. This approach is important for global biosimilar-development programs, pointed out John Pakulski, head of US biopharmaceutical regulatory affairs at Sandoz, at the DIA/FDLI conference. If every country or region requires local trials using locally sourced products, he observed, that could undermine efforts to establish a less-costly abbreviated development program.

Pakulski and others propose a science-based approach that permits the use of foreign reference products when they are made by a US manufacturer or in a facility inspected by FDA; licensed in highly regulated markets, such as Europe or Japan; and have a sufficient postmarketing history to confirm safety, purity, and potency. Additional scientific data could be required on a case-by-case basis to establish comparability between a US and foreign-sourced reference product.

Another contentious question is whether biosimilar manufacturers can extrapolate data from a clinical study to other indications of the reference product. European regulatory authorities permit this if the added indication involves the same mechanism of action and same receptor, and if extrapolation of immunogenicity data applies to a lower-risk population or route of administration. Biosimilar-drug sponsors indicate that extrapolation may be appropriate if supported by open-label safety studies for each indication.