Orphans Wanted: FDA Offers New Ideas For Rare Disease Drug Development

Top review managers tell NORD conference they are eager to find ways to accelerate development and comer­cialization of orphan drugs. CDER’s Woodcock suggests new partnership models focused on translational researc  h as key component. CBER’s Yetter notes flexibility of regulatory standards and creative ideas for trial design

FDA's top review managers have a message for drug developers: they are eager to find creative ways to work with sponsors to bring new treatments for rare diseases to market.

During the National Organization for Rare Disorders' recent Partners in Progress Summit in Washington, D.C., Center for Drug Evaluation & Research Director Janet Woodcock suggested building on the success of the Orphan Drug Act, which has provided regulatory and market-protection incentives for private-sector firms to develop therapies for very small populations.

Woodcock and other speakers raised the idea of a coordinated effort between academia, advocacy groups and the private sector to bring a greater number of drugs for rare diseases into the market.

Francis Collins, former director of NIH's National Human Genome Research Institute, suggested a similar idea, one in which academic and government researchers would work together to de-risk the process of developing drugs for orphan and other rare conditions, before turning the work over to a pharma or biotech company in exchange for a licensing fee.

Collins noted that out of roughly 7,000 diseases known to man, about 6,000 are rare diseases (defined in the Orphan Drug Act as meaning they afflict 200,000 Americans or fewer). Yet, fewer than 200 of these diseases have a currently marketed therapy (¹ (Also see "NORD Advocacy Agenda Includes End To Lifetime Caps, Reimbursement Of Some Off-Label Uses" - Pink Sheet, 18 May, 2009.)).

Woodcock suggested moving the process forward by having NORD and disease advocacy groups focus on funding translational research that would eliminate an expensive early step for private-sector companies that might be wary of the financial risk involved in developing a drug for a small population.

Patient constituent groups can provide an infrastructure for innovations to be translated and tested, Woodcock said, by developing patient registries so that subjects are available for clinical trials, locating academics that have interest and expertise in their particular disease, and developing partnerships.

Pharma and biotechs should be more interested in the rare disease/orphan drug space, she added, considering a current business environment in which the blockbuster drug model isn't very viable, exacerbated by a pipeline productivity crisis.

Pre-development help from constituent groups could produce development models offering better predictive capacity and yielding high-value drugs due to higher pricing and other incentives, Woodcock suggested

Robert Yetter, associate director for review management in the Center for Biologics Evaluation & Research, added that FDA already is taking steps to make the IND and clinical trials processes more flexible for sponsors of orphan/rare disease therapies.

"I want to stress our willingness -and this is not just CBER's willingness, this is the agency's willingness to work with advocacy communities, to work with sponsors, to develop these products which are necessary to treat rare diseases," he told the conference.

"We are more than willing to look at innovative ways to demonstrate the safety and efficacy of these products."

Specifically, Yetter cited revised protocols CBER's Office of Blood Products approved to enable the development of Baxter's Ceprotin for protein-C deficiency, CSL Behring's RiaSTAP for afibrinogenemia, and GTC Biotherapeutics' ATryn to prevent perioperative and peripartum blood clots in hereditary antithrombin-deficient patients.

CBER's Office of Cellular Tissue and Gene Therapies offers a "pre-pre-IND" process to help sponsors facilitate rare disease drug development at the earliest stages, Yetter added.

Various Tools Used To Streamline Approvals

FDA is also willing to allow parallel access to therapies prior to approval, Yetter stressed.

"We will and we have approved treatment INDs to run concurrent with IND studies because, as has been said, while the best thing is an approval, you still want to make these technologies available," he said.

Other tools CBER uses to streamline drug development include accelerated approval with surrogates, priority reviews and post-market surveillance to further study both safety and efficacy.

"We use historical controls when that's possible, and sequential trials are not uncommon," continued Yetter. "This usually involves early stopping rules in case of strong negative or positive information. We use adaptive trials in which during the course of the study, the treatment regimens [and] dosing schedules … can be varied, and also crossover trials in which the subject himself can serve as his own control."

Citing the example of the need for an anti-venom for coral snake bites, Yetter noted the challenges of designing a trial to test a therapy for the several hundred cases that occur essentially at random in the U.S. During a recent public workshop on that specific issue, FDA discussed applying the animal efficacy rule, which permits approval based on animal data when there is no ethical way to do clinical trials.

That model may not be appropriate for anti-venom, Yetter noted, but indicates the degree of flexibility FDA can apply in the orphan drug space.

CBER also has managed cases in which blinding was not feasible for a pivotal clinical trial, he added.

"In many cases, patients are not willing to enter a randomized trial because they are not willing to take the risk of being assigned to a control group," Yetter explained. However, if "there is potentially a large treatment effect, that allows you to use a smaller population of subjects with dual primary endpoints to reach a significant conclusion [and] allow us to balance risk and benefit."

Baxter's Ceprotin, for example, was approved in March 2007 based on data from an 18-patient, open-label, non-randomized, historically controlled study. CBER determined this study provided sufficient efficacy data, although it extended the safety review through a post-marketing registry. "[That's] one of the tools we use to ensure that the decisions we make are valid and can stand the test of time," Yetter said.

Yetter's message of regulatory flexibility is certainly an encouraging one for the sponsor. However, at a conference the following week, former TKT CEO (and current Social Security Commissioner) Michael Astrue suggested that the thoughtful policy articulated by top FDA managers does not always translate to front-line review staff. He urged greater attention to that issue by FDA's new leaders. (See ² (Also see ""Regulatory Predictability" Is Key Barrier To Orphan Drug Development, Social Security Head Astrue Says" - Pink Sheet, 1 Jun, 2009.).)

Roadblocks To Rare Disease Drug Development

Collins congratulated FDA for "thinking boldly" about the issues surrounding rare disease drug development, but added that NIH's Roadmap human genome project could play a larger role than it has to date. Three roadblocks typically stand in the way of development of drugs for rare diseases: (1) target discovery, (2) the high cost and low success rate of preclinical trials, and (3) the lack of patients available for clinical trials.

NIH's four Chemical Genomics Centers can help ameliorate the first two problems, Collins explained.

The NCGC, created in 2004, is staffed with 65 scientists from private industry and has run through more than 100 projects and produced 30-plus publications on promising new compound discoveries to date, Collins said. But the centers have the capability to do much more.

"NCGC can screen 300,000 compounds in 48 hours, with each compound being tested at seven different concentrations so you have a very good sense of what's a true positive and what's a false positive," he said. "And with a well-designed assay, it is usual that you get several hits from this that are promising starting points towards therapeutics."

Congress appropriated $24 million for the current fiscal year for NIH's Therapeutics for Rare and Neglected Diseases initiative, Collins said, but to tackle the unmet need for therapies for rare diseases, an annual amount between $100 million and $200 million would make a greater number of projects feasible.

Pointing to efforts by the Cystic Fibrosis Foundation to raise funds and play a role in drug development, Collins said that should be a model for the larger orphan/rare disease drug development issue (³ (Also see "Venture Philanthropy Reaches Out To Biotechs" - Pink Sheet, 22 May, 2009.)).

"I think the pieces are beginning to fall together, but it won't happen without partnership between all the necessary parties," he concluded.

"The idea here is not to supplant what biotech and pharma would be doing in any way. It is to de-risk projects so that as they come through this pipeline, they reach the point of economic attractiveness."

- Joseph Haas ([email protected])