FDA appeared to be searching for a way to limit the clinical trial requirements for biosimilars during a two-day public hearing on implementing a pathway for the products.

In the run-up to the hearing, the agency hinted it may be willing to consider the possibility that a biosimilar application may not require any clinical trials. And throughout, FDA officials questioned presenters about different prospects of a program that would allow for a limited requirement.

Many presenters, including several brand manufacturers, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods have not advanced enough to make the case. Others, including some generic manufacturers, argued the agency should use discretion in deciding whether trials would be necessary. The agency heard from industry representatives, academics, and patient advocates during the meeting held Nov. 2-3 at FDA's headquarters in Silver Spring, Md. (see chart).

FDA officials tried to carve out a middle ground with both camps. Steven Kozlowski, director of the Office of Biotechnology Products within the CDER Office of Pharmaceutical Science, and John Jenkins, CDER Office of New Drugs director, appeared through their questioning to indicate a strict and extensive clinical data requirement may not get many biosimilars to the market, but an overly lax standard may not uncover some safety concerns before marketing begins.

Bruce Babbitt, principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate it would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

“FDA might be open to establishing comparability using (pharmacokinetic)/(pharmacodynamic) studies in humans head-to-head with a reference (product),” he said.

Babbitt argued during his formal presentation the “totality of the data” of biologic products already establishes a base for proving biosimilarity and should not be ignored.

“We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic,” Babbitt said in written testimony.

Kozlowski followed on that concept by asking if there is a way to use the totality of the data in determining what studies would be required.

“Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?” he asked Babbitt.

Babbitt said the totality of data helps either streamline or expand the data sponsors needed for their application.

Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

“For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated,” Jenkins said to Michael Wenger, global clinical lead at Roche. “Is that really an achievable standard … or is that essentially closing the door for a biosimilar?”

Wenger argued the drugs should be assessed on a case-by-case basis.

How Much Data Is Enough?

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed.

The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Kozlowski seemed to venture into a possible middle ground with Wenger, asking if it was possible to extrapolate some indications using data for others.

“Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?” Kozlowski asked.

Wenger said the idea would depend on the clinical benefit achieved by the innovator drug. If it was a benefit that could be achieved easily, it may be possible, he said. A more complicated benefit, like overall survival in oncology, would require more work, Wenger said.

A Johnson & Johnson presenter also suggested brand sponsors may be willing to help biosimilar companies by sharing manufacturing information through FDA (Also see "Could Innovators Help Biosimilar Manufacturers?" - Pink Sheet, 3 November, 2010.).

Kozlowski asked Vijay Tammara, Nuron Biotech vice president of regulatory affairs, whether requiring PK and PD studies could be sufficient pre-market, saving immunogenicity testing for the post-marketing studies.

That concept came up again later, during questioning of Biotechnology Industry Organization Executive VP of Health Sara Radcliffe. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and post-marketing data to test interchangeability.

Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Determining The Balance

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning, although it appeared somewhere in the middle of the two extremes offered during the hearing.

Kozlowski's questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Rojkjaer’s view of the idea.

Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

“I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back,” he said.

When James Roach, chief medical officer of Momenta Pharmaceuticals, argued the trials should be positioned as supportive to existing data, Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

“We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product,” Jenkins said. “How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?”

Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

Jenkins also expressed concerns about how the agency could track spontaneous adverse events if biosimilars did not have unique names (Also see "FDA Signals Interest In Requiring Unique Biosimilar Names" - Pink Sheet, 2 November, 2010.).

Analysts at J.P. Morgan said in a note the abbreviated path remains unclear, which is good for the innovator companies. They also said it believed clinical trials “look essentially to be a certainty.”

[Editor's note: "The Pink Sheet" is sponsoring a webinar the week after FDA's public meeting on biosimilars to discuss challenges and opportunities for industry. The Nov. 9 event will feature experts from Parexel Consulting and our own editorial staff. To register, call 800-332-2181, email custcare@elsevier.com, or visit http://pages.elsevierbi.net/AC110910LP/ .]

By Derrick Gingery

FDA Searches For Clinical Trial Middle Ground At Biosimilar Hearing

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