FDA should use its regulatory flexibility to require fewer pre-approval clinical pharmacology studies, with increased emphasis on post-marketing studies and mandatory registries, to speed development of orphan drugs, the agency’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology said.

The panel wholeheartedly endorsed the drug development paradigms used for pediatric and oncologic therapies as model processes that can be followed for new molecular entities or “re-purposed” drugs intended for orphan indications, thereby reducing the amount of data needed prior to approval.

The committee’s recommendations, rendered at a March 2 session in Dallas that coincided with the annual meeting of the American Society for Clinical Pharmacology and Therapeutics, could find their way into an FDA guidance on clinical pharmacology requirements for orphan drugs.

FDA sought the experts’ views on the amount and types of clinical pharmacology data most important to assessing the pre-approval safety and efficacy of orphan drugs, given the limitations inherent in studying small populations (Also see "Orphan Drug Safety: FDA Asks How Much Pre-Approval Data Is Enough?" - Pink Sheet, 28 February, 2011.).

The committee’s recommendations follow in the footsteps of lobbying efforts by industry and rare disease advocacy groups, which seek increased agency flexibility toward clinical trial design and data requirements when evaluating orphan drugs (See related story, Also see "Does The Orphan Drug Act Need A Facelift? Advocates Consider Changes" - Pink Sheet, 21 March, 2011.).

Advisory Committee Votes

Committee voted 14-0 that the drug development paradigms for regulatory approval of pediatric and oncologic drugs are well-suited as model processes for re-purposing of approved drugs for rare diseases and for providing substantial evidence of efficacy needed to meet statutory standards.
Committee voted 11-3-1 that current drug development programs and clinical pharmacology stuides for orphan drugs provide sufficient safety information given the limitations to conducting large pivotal efficacy trials with safety data collection.

Guidances Focused On Orphan Drugs

FDA proposed improvements to its orphan drug program in the PDUFA V reauthorization negotiations currently under way, with agency and industry representatives having reached agreement on plans to increase agency staffing and issue new guidances on rare disease drug development (Also see "PDUFA V Agreement Set In Four Areas, But Broad FDA/Industry Talks Continue" - Pink Sheet, 7 March, 2011.).

Guidances on drug development for rare and neglected tropical diseases also were required under the House conference report accompanying FDA’s fiscal 2010 appropriations measure. However, the agency must first submit a report to Congress on the recommendations of two internal review groups related to rare and neglected diseases. That report is currently in the final stages of agency clearance, FDA said.

In addition to more general guidance on orphan drug issues, the agency is considering issuing a guidance “that would lay out a blueprint for good clinical pharmacology as it applies to rare disease and orphan drugs,” Office of Clinical Pharmacology Director Lawrence Lesko told the advisory committee. “The input you give today is going to be very valuable in that context.”

Learning From Pediatrics, Oncology …

FDA sought the committee’s views on whether the threshold of evidence developed for approval of pediatric and oncologic drugs is an appropriate model for orphan products.

Although there is no consensus on what constitutes ideal drug development for orphan indications, “the lessons we’ve learned from the application of clinical pharmacology and pharmacometrics and genetics to the areas of pediatric and oncology drug development can be also applied to rare diseases” and may help to expedite drug development, Lesko said.

FDA Division of Clinical Pharmacology III Director Dennis Bashaw explained that in pediatric drug development, information on basic pharmacokinetics, drug-drug interactions and drug metabolism is gathered in adults, for whom a product is usually approved first, and then applied in the pediatric setting.

He suggested this approach could be followed for “re-purposed” drugs that are already approved in one indication but are being studied for use in a rare disease.

With a re-purposed drug, there is already extensive clinical pharmacology information, Bashaw said, and the pediatric drug development approach would allow for the harnessing of that data to the rare disease setting.

Similarly, NMEs for rare diseases could track the path now followed by oncologic products, which often cannot be studied in healthy subjects. “Maybe there’s not that pivotal dose-ranging trial of 40 subjects and escalating dose, but you’ve got some small proof-of-principle studies, you’ve got some animal data, you’ve got some in vitro cell data that all together gives you your world view that you can move forward with,” Bashaw said.

The panel voted 14-0 that the pediatric and oncologic models were well suited to the orphan drug setting.

“I voted yes; it was a no brainer,” committee Acting Chairman Jurgen Venitz, Virginia Commonwealth University, said. His comments were echoed by several committee members.

“I think there are enough useful paradigms and approaches that have been developed for pediatrics and oncology that would apply for orphan drugs,” temporary voting member Kenneth Thummel, University of Washington, said.

… But Oncology May Not Be The Answer

However, Merrill Goozner, the panel’s consumer representative, cautioned against relying too heavily on the oncology model for answers.

He drew the panel’s attention to the Oncologic Drugs Advisory Committee’s recent deliberations on pre-and post-marketing study requirements for accelerated approval of cancer drugs. At its Feb. 8 meeting, ODAC recommended FDA push for randomized, rather than single-arm, studies before approval and two post-marketing confirmatory studies in most cases (Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 February, 2011.).

“I think it is instructive to take a look at what’s been going on in the world of oncology, where you have marginal drugs that got approved in single-arm trials through accelerated approval, and now when they go back they’re finding that very often the actual efficacy wasn’t there,” Goozner said. He also pointed to difficulties in ensuring that oncology post-marketing studies are completed.

ODAC’s recommendations suggest cancer drug approvals are moving in the direction of requiring more extensive data both pre- and post-approval, Goozner said. “They’re moving in the sort of opposite direction, and I think that needs to inform the orphan drugs division as it takes a look at this.”

Lower evidentiary requirements might be appropriate if a drug is a “slam dunk,” he said. “A single-arm trial with a surrogate marker makes perfect sense in an enzyme replacement situation, but where you’re trying to mediate a possible cascade of events inside the body that is triggered by something, where you’re going to have potentially marginal efficacy, then you would have a different standard. It’s not easy to turn this into a black or white question.”

Prioritizing Studies

The panel also discussed what types of clinical pharmacology studies, particularly for NMEs, could be delayed until after orphan drug approval.

“I would make a pitch for just prioritizing the clinical pharmacology studies you want to do,” committee member Jerry Collins, National Institutes of Health, said. “I think there should be more flexibility in terms of which clinical pharmacology studies are most important pre-approval versus post-approval.”

Venitz agreed, suggesting that in some situations special population and drug-drug interaction studies could be post-marketing commitments.

Similarly, while studies on organ dysfunction and food effects could be key for some disease states, in others they could probably be postponed until after approval, committee member Howard McLeod, University of North Carolina-Chapel Hill, said. “I get the impression the agency has the flexibility to change the prioritization based on the dynamics of the disease, but I think it needs to be more explicitly stated in future guidance.”

A Focus On Registries

The committee voted 11-3, with one abstention, that current orphan drug development programs and clinical pharmacology studies provide sufficient information on drug safety.

Panelists in both the majority and minority called on FDA to consider consistently requiring patient registries as part of orphan drug approvals, and they urged the agency to make better use of patient advocacy groups both in terms of designing clinical trials and assessing post-marketing safety and efficacy.

Although registries are frequently required in conjunction with orphan drug approvals, they are not mandatory, FDA Associate Director for Rare Diseases Anne Pariser said.

In addition to tracking drug safety and efficacy, registries provide insight into disease progression over time, temporary voting member Caldwell said.

Given the small number of patients studied pre-approval, registries provide a good backstop, suggested temporary voting member Michael Caldwell, Marshfield (Wisconsin) Clinic Research Foundation, who nevertheless voted “no” on the safety question due to its phrasing.

“I think many people would feel a lot more comfortable because of the vagaries of assessing efficacy and safety in small numbers of patients in these trials if we knew that there was an ongoing observation of what’s actually happening with these medications in these patients over time and it also helps us to understand progression of disease as well,” Caldwell said.

Committee members said patient advocacy groups, which often include a medical board of specialists in the rare disease area, provide an invaluable resource for collecting registry data, designing pre- and post-approval studies and developing meaningful clinical endpoints. FDA should increase its interactions with such groups as a means for driving safety and efficacy assessments, committee members said.

By Sue Sutter

Orphan Drugs Warrant Flexibility On Clinical Pharmacology Data, FDA Panel Says

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