Extrapolation and interchangeability appear to be the linchpins for biosimilar sponsors mulling whether to send applications to the emerging 351(k) pathway or the traditional novel biologics approval system.

Sponsors that expect to eventually seek a designation that their biosimilars are interchangeable with their reference products, as well as those that want the ability to extrapolate multiple indications, will need the 351(k) pathway, said Gillian Woollett, Engel & Novitt LLP's chief scientist.

Sponsors that do not require either characteristic for a biosimilar likely are better off using the 351(a) full BLA pathway, she said May 5 during a Drug Information Association and Food and Drug Law Institute conference on biosimilar issues.

Her view of the biologics pathway likely would result in alternative biologics meant to treat one indication and take market share from a brand name product in a specific area, like a “me-too” drug, filing an application as a novel biologic.

However, those products intended to apply generic competition in the small-molecule drug sense of the phrase, and eventually gain recognition as an alternative choice to the brand product, would use the biosimilar pathway under 351(k).

“Its value is probably greatest in terms of extrapolation between indications and the potential for interchangeability,” said Woollett, former Biotechnology Industry Organization vice president of science and regulatory affairs.

“If you don’t need either of those two, you’re probably going to be better off going with the benefit of greater predictability and the greater responsiveness of the FDA to an ‘(a)’ application.”

The advice, if embraced widely by pharma, could cause sponsors to make the (k) vs. (a) decision late in the development program, but still would seem to provide some clarity for an industry begging for guidance, even if it doesn’t come from FDA.

Cecil Nick, Parexel Consulting vice president of biotechnology, said the decisions should still be made on a case-by-case basis.

“If you’ve got a product with an easy-to-prove endpoint and one indication, then there is limited value to go I think, the [351(k)] route,” Nick said in an interview. “If you are developing a monoclonal and you are only interested in one indication for commercial purposes, then maybe you could consider going [the 351(a)] route. But if you want all the indications, and you want the label that you actually have a biosimilar, then companies would use the [351(k)] route.”

Data Requirement Is Key Factor

Nick said the data requirements for a biosimilar application also will play an important role in the decision about whether to go with a 351(a) versus a 351(k).

“If the FDA takes a very conservative approach, I think it will push the decision towards going the full blown [351(a)] route,” he said. “I would expect that these products are going to be developed as biosimilars and decisions about the regulatory route will be made.”

Issues related to biosimilar data requirements have been a consistent criticism of the new pathway. Rep. Henry Waxman, D-Calif., said recently the data requirements for biosimilars likely will dissuade sponsors from using the pathway and said it should be adjusted.

Waxman also said biosimilars would enter the market at a disadvantage because they would not be considered identical to their reference products (Also see "Waxman Says Biosimilar Pathway Will Push Applicants To BLA" - Pink Sheet, 22 November, 2010.).

One generic manufacturer continued the assault on the potential for large data requirements during the conference, specifically the notion that reference products are only acceptable if they have been licensed by the regulator. FDA is required to accept only U.S.-licensed reference products.

John Pakulski, director of the Sandoz Inc. U.S. Biopharmaceutical and Regulatory Affairs Group, said there would be nothing abbreviated about a pathway where countries only accepted reference products that had been licensed in their respective jurisdictions.

“If each regulatory agency around the world expects their own study on their own reference product, then it just defeats the whole intent and purpose behind an abbreviated pathway,” Pakulski said. “I’m sure that you’ve all heard companies come public, even Sandoz, saying that there’s really a debate within the companies as to whether they’re going to use the biosimilar pathway versus the full BLA pathway because of some of the issues associated with the statute.”

Among the issues are the patent challenge procedures (see related story, Also see "Could Judges Require Independent Experts To Explain Biosimilars?" - Pink Sheet, 23 May, 2011.).

Generic and brand manufacturers sparred over data requirements during an agency public hearing about the biosimilar pathway in November 2010.

Both were on opposite sides of the spectrum and agency officials probed the potential for a compromise, given that too high a requirement would not provide enough incentive to get biosimilars to the market while an overly lenient standard may not adequately identify potential safety concerns (Also see "FDA Searches For Clinical Trial Middle Ground At Biosimilar Hearing" - Pink Sheet, 8 November, 2010.).

Pakulski also argued for a harmonized biosimilars system between FDA and the European Medicines Agency, saying if the two agencies cannot agree on the number and structure of the required studies, the pathway would bog down.

FDA Office of Biotechnology Products Director Steven Kozlowski, who was in attendance, indicated the agency was interested in the idea, but said it would take some work to achieve.

“We would need to figure out a way to make sure that everybody was scientifically comfortable with that,” he said.

Agency Already “Busy” With Biosimilars

Kozlowski said the agency has been busy dealing with potential biosimilar applicants, even though it has not determined how it will handle the pathway.

The agency said it has conducted 14 pre-IND meetings with likely candidates, while it also is working on guidelines. EMA wrote its biosimilar guidelines in a similar fashion (Also see "FDA “Busy” With Biosimilars; Sponsors Already In Pre-IND Meetings" - Pink Sheet, 16 May, 2011.).

FDA also is preparing to begin negotiations for a biosimilar user fee and is expecting to use a different strategy in its upcoming dealings with industry. The agency said in a proposal published in the Federal Register it will conduct several industry-stakeholder meetings where trade associations and potential sponsors can give their input on a potential user fee program.

It is a departure from typical agency behavior toward user fees. Usually, the agency selects a small handful of trade associations to represent industry interests at the negotiating table and refuses to negotiate with individual companies because it would not be possible to accommodate everyone (Also see "Biosimilars: FDA Trying Group-Think Negotiating Strategy For User Fee" - Pink Sheet, 16 May, 2011.).

By Derrick Gingery

Biosimilars Pathway Dilemma: When Should Sponsors Pick (k) Before (a)?

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