Jill Wechsler

Codes and coverage

Setting a Pathway

The challenge for FDA is to establish science-based standards for documenting biosimilar safety, purity, and potency that acknowledges reference drug data and market experience. FDA held a public meeting in November 2010 to launch the process for establishing a biosimilar testing process to ensure there are no "clinically meaningful differences" between the new biologic and the reference product; the new drug has to use the same mechanism of action and have the same route of administration, dosage form, and strength. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), recently indicated that general guidance should appear this year, and that its requirements for human testing will vary according to how well a biosimilar can document sameness to the innovator product. Although biosimilars generally will need additional clinical studies to document equivalent efficacy in at least one approved indication, even innovator firms acknowledge that the biosimilar pathway will involve less animal toxicity testing and probably no dose finding or Phase II clinical studies.

Another key step is to set a user fee schedule for biosimilars. The agency has proposed application fees similar to those for innovator drugs and biologics, but with a new approach to help finance FDA involvement in steering sponsors through the development process. The plan is for companies to pay a product development fee of $150,000 when it submits an investigational new drug application and annually thereafter; those upfront payments then will be subtracted from the eventual application fee.

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 a May biosimilars conference, 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 authorized by the BPCIA, but many are talking to FDA and considering their options.

Meanwhile, FDA is tackling some very basic issues, such as which products fall under the new regulatory program. The BPCIA redefines most proteins as biologics, beginning in March 2020. FDA thus has to set new policies for manufacturers of proteins long regulated as drugs and address the nine-year transition period.

Another thorny topic is whether FDA can approve a biosimilar based on a reference product that is approved overseas, but not in the US. The BPCIA says that reference products have to be licensed by FDA, but biosimilar makers want flexibility to permit comparison to a biologic licensed by a foreign regulatory body. This is important for global biosimilar development programs, pointed out John Pakulski, head of US biopharmaceutical regulatory affairs at Sandoz, at the DIA/FDLI conference. He and others propose to permit the use of foreign reference products that are made by a US manufacturer or in a facility inspected by FDA; licensed in highly regulated markets such as Europe or Japan; or present 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.

Also contentious is whether biosimilar sponsors 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 sponsors want a similar approach from FDA, probably with support from open-label safety studies for each indication.