Regulatory Focus™ > News Articles > FDA Exercising 'Extraordinary' Flexibility on Drugs for Rare Diseases, New Study Finds

FDA Exercising 'Extraordinary' Flexibility on Drugs for Rare Diseases, New Study Finds

Posted 04 May 2015 | By Alexander Gaffney, RAC

FDA Exercising 'Extraordinary' Flexibility on Drugs for Rare Diseases, New Study Finds

The US Food and Drug Administration (FDA) is a reasonable regulator. That's the conclusion of a new analysis looking at the measures taken by FDA to review and approve new drugs intended for use in rare diseases affecting small populations of patients.


The root of this "reasonable" argument starts with a law intended to facilitate the development of new therapies for patients with rare diseases.

Under the 1983 Orphan Drug Act, a rare disease is one which affects fewer than 200,000 patients in the US. If a company develops a new drug or therapy for a rare disease, it is eligible for a special, seven-year period of marketing exclusivity during which time the product is shielded from competition from generic drugs. Other incentives include tax credits, grants and user fee waivers.

These incentives are important because rare diseases have historically suffered from a serious lack of investment. Prior to the passage of the Orphan Drug Act, there were just a small handful of orphan drug approvals each year—just two orphan drug approvals in 1983. In contrast, FDA approved 49 orphan drug products in 2014.

 FDA-Approved Orphan Drugs

Despite the success of the law, which has led to similar legislation around the world, approximately 95% of the estimated 7,000 rare diseases currently lack approved treatments according to rare disease advocacy groups.

Standards of Approval

Contrary to popular belief, being designated as an orphan drug does not automatically permit FDA to approve it more quickly or with less evidence than drugs intended for non-orphan populations. The orphan drug regulations at 21 CFR 316 make no mention of an expedited approval process for orphan drugs.

"In other words, the standard of approval for orphan drugs is legally the same as the standard of approval for all other drugs," write the authors of a new paper in the journal Therapeutic Innovation and Regulatory Science.  "Since 1962, the standard has been that for FDA to approve a new drug, there must be 'substantial evidence' of effectiveness derived from 'adequate and well-controlled investigations,'" wrote Frank Sasinowski, Erika Panicoband and James Valentine.

While the statutory language of the Federal Food, Drug and Cosmetic Act (FD&C Act) provides FDA with a certain amount of "flexibility" with which to conduct regulatory reviews, it demands no such flexibility when it comes to orphan drug approvals, the authors wrote.

But even without those statutory commands, FDA has still approached orphan drug products with "meaningful and reasonable flexibility in its review and regulatory actions," the authors wrote, confirming earlier research conducted by Sasinowski.

FDA's Flexibility

The study looked at 27 orphan drugs approved between July 2010 and June 2014 for non-cancer indications (cancer drugs are frequently afforded large amounts of regulatory flexibility). The authors then analyzed each approved drug and characterized the amount of evidence needed to approve it based on one of three criteria:

  1. "conventional" quantum of evidence (i.e. evidence from two adequate, well-controlled studies)
  2. evidence consistent with a formal FDA system for exercising discretion or "administrative flexibility" (e.g. accelerated approval, fast-track designation, single-study approvals under FDAMA Part 115, etc)
  3. evidence that is consistent with a "case-by-case flexibility"

After categorizing each orphan drug approval, the study authors found that flexible approvals were the rule—not the exception—for orphan drugs.

Type of Efficacy Evidence
Administrative Flexibility
Case-by-Case Flexibility

The authors note that just eight of the 27 orphan drugs approved by FDA were held to "conventional" standards of evidence to obtain approval. The other 19 were approved using a "flexible" regulatory approach.

The most recent analysis indicates that FDA's regulatory flexibility has remained "remarkably" consistent. A previous analysis by Sasinowski found that between 1983 and June 2010, FDA held one third of all orphan drugs to "conventional" standards, and the other 66.7% of drugs to "flexible" standards.

"These findings further support Sasinowski’s conclusions in 2012 that FDA has demonstrated extraordinarily reasonable flexibility in its review of certain applications for orphan drugs," the authors conclude. "This study reinforces that the FDA component of this system has a proven vast capacity for exercising reasonable flexibility in advancing the availability of new therapies for those with this great unmet medical need."


Quantum of Effectiveness Evidence in FDA’s Approval of Orphan Drugs: Update, July 2010 to June 2014

FDA Law Blog


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