FDA is on the lookout for the effects of personalized medicine on the orphan drug program and the potential for all diseases to be defined in such a way that they become eligible for orphan status.

As the therapeutic principles behind personalized medicine continue to develop, there may be more drugs targeted at smaller, more specific populations of common diseases. This could open the door for requests for those subsets to be given orphan status and gain exclusivity and other incentives.

Eventually, FDA may have to consider adjusting its orphan designation approval policy. But for now it appears content to look for a trend.

Gayatri Rao, director of the FDA Office of Orphan Products Development, said agency officials are talking about how to potentially deal with the possibility.

She said the agency is watching whether orphan designation trends are moving toward diseases like a “smaller slice of, say, lung cancer” as opposed to a historically rare disease like Duchenne Muscular Dystrophy.

“A lot of conversations that we’re having internally [are] about how everything’s going to be an orphan eventually and what does that mean for the incentives associated with the act? Does everything now all the sudden get seven years of exclusivity and user fee waivers?” Rao said during the recent World Orphan Drugs Congress.

“That’s an interesting philosophical question. I don’t think we’re anywhere close to that, but it’ll be interesting to see where it’s going to go.”

FDA issued a proposed rule in October 2011 that clarifies how disease subsets would be considered for potential orphan drug designation.

The agency said in the proposed rule that its “medically plausible” terminology to determine a subset has been misinterpreted “to mean any medically recognizable or any clinically distinguishable subset of persons with a particular disease or condition.”

The rule would not change the process for determining a valid disease subset, but further describe how it can be determined, such as pharmacological property or previous clinical experience.

Comments have been received, but FDA has not finalized the rule.

Consultant Tim Coté, a former director of the Office of Orphan Products Development, said in an interview that there still does not appear to be evidence that common diseases are becoming are disappearing.

“People have been bringing up for many years the possibility that everything will become an orphan,” he said. “That is not the case today.”

Rare disease advocates already are worried about orphan drug prices. Opening more drugs to exclusivity and small populations could create more pricing problems.

NORD, the rare diseases advocacy organization, expects to be talking with Congress about orphan prices amid ongoing efforts to better control health care costs Also see "Orphan Drug Prices To Face Fiscal Cliff Scrutiny, NORD Expects" - Pink Sheet, 9 January, 2013..

Orphan Designations Dip In FY 2012

Among the reasons FDA is watching the personalized medicine trend is that designation levels have risen over the past few years, Rao said, though there is some indication that designations have peaked.

After recording 214 designations in fiscal year 2011, the total dropped to 184 in FY 2012, according to agency performance data, a decrease of 14% (see chart).

Orphan Drug Designations By Fiscal Year

Designations for FY 2011 through the first quarter of FY 2013.

Source: FDA

Through the first quarter of FY 2013, 49 designations have been approved. The 16.3 designation per month average so far this fiscal year is higher than the FY 2012 average of 15.3 designations per month. But both are lower than the FY 2011 average of 17.8 per month.

More than a third of the designations in FY 2012, 36%, were for oncology products, according to Rao’s presentation. Another 13% were for neurology products.

The agency said it does not have data on the number of orphan designations that are for subsets of common diseases or “how many would constitute a targeted therapy.”

Rao also said the recent dip still is on par with the orphan designation trend. But it also suggests that there is no large bolus of new personalized medicine products looking for designations to treat subsets of common diseases.

FDA is expecting more orphan drug applications in the coming years. The FDA Safety and Innovation Act, which reauthorized the prescription drug user fee program, included allocations for reviewer training and other tools to improve orphan product reviews Also see "User Fee Discussions Include Funding Parts Of FDA Regulatory Science Plan" - Pink Sheet, 25 October, 2010..

Industry concerns with agency approval policy also may have affected investment in the space, and by extension, the number of designation requests and developer interest.

A rare disease advocate group is working on a white paper it hopes will inform FDA’s upcoming guidance on expanding the use of accelerated approval, which also was required in FDASIA Also see "Regulatory Freelancing: Rare Disease Group Hopes To Shape FDA Guidance" - Pink Sheet, 22 April, 2013..

The guidance is expected to include more information on surrogate endpoints and other techniques commonly needed to develop orphan drugs and could allow more growth in the space Also see "PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements" - Pink Sheet, 17 September, 2012..

Pediatric PRV Could Be Tricky

FDA is also wrestling with the implications of another program designed to encourage more orphan drug applications – offering a priority review voucher (PRV) for sponsors of a rare pediatric disease product.

The program, modeled on the tropical disease voucher system (which itself has gotten off to a slow start) creates a transferable priority designation that can be used for a speedy review for another of the sponsor’s own products or sold to different firm.

Rao said program implementation is complicated because of the requirements laid out in the FDASIA provisions creating the program.

One challenge is the definition of a rare pediatric disease. It is listed in FDASIA as a condition primarily affecting people age birth to 18. But the Center for Drug Evaluation and Research defines pediatric diseases as birth to 16 years, Rao said.

“One of the things to consider implementing this is how do you define whether a disease primarily affects individuals within this age,” she said. “Is it age of onset? Is it when the manifestation appears? … How do you define what primarily affects means?”

FDA does not expect to receive a request for a pediatric orphan voucher in the near term, which is not surprising given that the existing priority review voucher program for tropical diseases has not proven popular.

Novartis AG redeemed a voucher for Illaris (canakinumab) in gouty arthritis, but the application received a “complete response” letter. That has left the value of a PRV somewhat undetermined Also see "Priority Review Voucher Value Still Confounds, But Remains An Incentive For Sponsors" - Pink Sheet, 21 September, 2011..

The agency also said in President Obama’s FY 2014 budget request that no PRVs are anticipated during the year because no sponsor gave notice one year in advance as required of its intention to redeem a voucher.

The pediatric orphan PRV program requires a GAO study of its effectiveness once the third voucher is issued. FDA also was required in FDASIA to write a strategic plan to encourage faster development of pediatric rare disease therapies Also see "FDASIA Study Mandates Focus On Performance, But Could Slow Reviews" - Pink Sheet, 20 August, 2012..

All expedited approval pathways are expected to be described and clarified in an upcoming comprehensive guidance Also see "FDA To Provide Expedited Approval Desktop Reference" - Pink Sheet, 29 October, 2012..

Targeted Therapies On FDA’s Orphan Designation Radar

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