FDA may be able to talk in theoretical terms about the flexibility it is afforded for orphan products approvals, but others seem to want more tangible evidence. For its part, the agency wants more than general complaints about its regulations; it wants an open discussion of specific roadblocks.

Industry wants clarity on several aspects of the regulatory process, but at least one company representative says a guidance document will not eliminate the existing uncertainty. Sponsors also say they need FDA to recognize that orphan products will not fit into conventional approval policies.

The agency insists it already employs a flexible approach and will work with sponsors to answer their questions, saying more policies could actually decrease its ability to find alternative clinical trial designs and endpoints.

FDA may have some evidence for its position in a new report outlining orphan approvals that demonstrated its flexibility. But both sides appear to be waiting for the other to move to spur more rare disease drug development.

Jonathan Leff, managing director of private equity firm Warburg Pincus, argues that FDA should adjust its regulations to be more receptive to new orphan therapies because investors are not funding the research as often as in the past.

That concept was a common theme throughout the Oct. 11-13 U.S. Conference on Rare Diseases and Orphan Products and a nearly universal request from industry, investors and patient advocates.

The problem may actually boil down to perception. Leff said at the meeting that FDA is viewed to have become more risk-averse in the last decade, making it tougher for orphan drug sponsors to gain approval. He said the agency will have to demonstrate flexibility over time to improve the rare disease landscape.

Even with evidence of flexibility, funding decisions are difficult to make because investors never know when or if FDA will use that power in considering an orphan application, Leff said.

“What we need to see is not just a statement that [FDA] is flexible,” he said in an interview at the conference. “We need to see evidence that actual day-to-day decisions that affect the cost of development are beginning to shift. Changing the culture takes time. What I think we need to be after is, over the next decade, changing the way risk-benefit decisions are made.”

The law already requires flexibility. Bob Temple, CDER deputy center director for clinical science, called it the “sort of flexibility that I think people dream about.” But he also admitted people “probably are not convinced we always apply” that flexibility.

The National Organization for Rare Disorders unveiled a paper at the conference showing the majority of orphan drug approvals between 1983 and June 2010 made it to the market with a form of regulatory flexibility (Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 October, 2011.).

An FDA official asked for specific examples of issues that could be addressed, rather than generalized complaints (Also see "Regulatory Reform: FDA Pushes Back, Asks For Specific Problems To Fix" - Pink Sheet, 17 October, 2011.).

Would Flexibility Policy Limit FDA Flexibility?

The NORD report could end up becoming a strong asset for FDA to better illustrate its flexibility to sponsors.

CDER Director Janet Woodcock said the center has not written and published its precedents based on past approvals, which could help sponsors understand the agency’s tendencies.

Woodcock also said she and Temple are considering updating the 1998 evidence guidance because it is more than a decade old. Woodcock said examples, like those outlined in the NORD report, are helpful in relaying policies to scientific personnel.

Additional regulations describing the extent of agency flexibility does not seem likely. Office of New Drugs Director John Jenkins said writing a formal policy may ultimately limit the agency’s rare disease program.

“It’s really hard when people say ‘Well you need to be more clear in defining your policy about your flexibility,’” Jenkins said. “I think we have a track record of showing flexibility across many of these areas, and I worry that a policy where we define our flexibility will lock us in more than our historical precedent where we’ve applied a lot of flexibility.”

Woodcock said legislative changes to the Orphan Drug Act also are not advisable in the existing legislative landscape (Also see "Woodcock Says Blowing Up Orphan Drug Act Not Advisable In Current Climate" - Pink Sheet, 17 October, 2011.).

“I’m Not Looking For A Memo”

Some industry members at the conference gave seemingly conflicting recommendations to improve regulatory clarity.

Jeffrey Siegel, Genentech senior group medical director, product development inflammation, asked for more definitive FDA statements on the types of clinical trial designs and endpoints that would be acceptable for a rare disease trial. The agency needs to be more proactive in detailing what it wants, he said.

“The FDA’s often in a situation of reacting to proposals by industry rather than stating publicly what evidence would be acceptable for approval,” said Siegel, who also is a former FDA clinical reviewer and team leader.

However, David Meeker, Genzyme COO, said it likely is inconceivable that one guidance could answer all sponsors’ questions and provide regulatory certainty in every case.

Meeker said he would like FDA to recognize that rare disease trials are in fact uncharted territory and be willing to consider alternative methods.

“I’m not looking for a memo that tells me how to develop in rare diseases,” he said. “I don’t think any of us are sending a message in asking for a guideline on flexibility to lower the bar. It’s a recognition of the challenges. ... So the question is how do you get to the bar in a way that recognizes whatever the individual challenge is?”

More guidance and public meetings about orphan drug policy were included in the Prescription Drug User Fee Act commitment letter with industry.

The law is scheduled for reauthorization in 2012 and the pending agreement allows user fees to be spent on additional rare disease staff as well as reviewer training (Also see "PDUFA V Commitment Letter Front-Loads Guidance, Meeting Milestones" - Pink Sheet, 5 September, 2011.).

FDA also has proposed some minor changes and clarifications to its 1992 Orphan Drug Regulations, which could encourage more orphan drug development (Also see "Orphan Disclosures Could Increase Under Tweaks Proposed By FDA" - Pink Sheet, 18 October, 2011.).

By Derrick Gingery

Regulatory Flexibility Staring Contest: Will Industry Or FDA Blink First?

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