Regulatory Focus™ > News Articles > FDA Finalizes Changes to Orphan Drug Regulation, With Emphasis on Clarifying Existing Policies

FDA Finalizes Changes to Orphan Drug Regulation, With Emphasis on Clarifying Existing Policies

Posted 11 June 2013 | By Alexander Gaffney, RAC

US regulators have finalized a regulation they say makes some relatively minor changes to the orphan drug regulations and largely, but not entirely, finalizes the regulations as released in October 2011.


FDA's orphan drug regulations are intended to create market-based incentives for manufacturers of products for populations with rare diseases. Per the Orphan Drug Act of 1983, a rare disease is defined as any disease affecting fewer than 200,000 individuals in the US in any given year.

The act allows FDA to give the products approved to treat the orphan conditions special marketing protections (7 years of market exclusivity), tax credits to offset some of the costs of development, faster regulatory reviews and additional assistance from FDA reviewers during the development and review process.

The regulations stemming from the Orphan Drug Act have remained relatively constant in recent years, but in October 2011 FDA announced it wanted to make a number of minor revisions to bring its definitions up to date and to make a number of other "minor" tweaks.

Final Rule Issued

The results of the ensuing consultation process have now ended, with FDA issuing its final rule on the changes.

Among the changes is a clarification of the definition of "orphan subset." FDA noted that some companies were, in its opinion, seeking out the narrowest possible subsets of diseases to allow them to obtain incentives like tax benefits or market exclusivity incentives.

"Use of such artificial orphan populations to obtain orphan-drug designation and its related benefits would divert resources away from research and development of drugs for true orphan diseases and conditions," FDA wrote. To that end, it said it would substitute the term "medically plausible" for a definition to stop companies from potentially "gaming" approvals.

But that left sponsors with a question as well: What is an appropriate subset for the purposes of obtaining an orphan drug designation? Under the new definition, FDA explains that a subset is taken to mean the drug is appropriate when used in the subset, but use in a broader population would be inappropriate "owing to some property(ies) of the drug," such as toxicity or the mechanism of action.

This, too, raised a problem for sponsors, who expressed concern that they would have to prove a negative: that the drug would not be useful in a second population. FDA said that while it "understands the concern," it is more concerned about an orphan subset being "artificially narrow." It will not require the same scientific proof for the negative population that it does for the positive one.

Further Clarifications

Industry did get one much-desired clarification, however. Even if a single drug is used to treat multiple applications that would cause it to treat more than 200,000 patients, FDA said it will still see the drug as an orphan treatment for the purposes of the Orphan Drug Act so long as each patient population is under 200,000.

The regulation goes on to clarify that the prevalence of certain disease-related conditions - for example, pneumonia in cystic fibrosis patients - would not be pooled in with the larger subset of the disease, in this case pneumonia cases in general. "They need not, in other words, provide a rationale for why only cystic fibrosis patients with pneumonia (and not patients with community-acquired pneumonia) would be appropriate candidates for the drug," it wrote.

"If FDA considers the disease or condition in question to be a distinct 'disease or condition' for the purpose of orphan-drug designation, then drugs for that disease or condition may be eligible for orphan-drug designation even if they may potentially benefit other patient groups," it continued.

However, different stages of a disease, such as cancer, will not be assumed to be distinct diseases unless the sponsor can justify such a distinction.

In another section, FDA said it was walking back language in which it said that dose changes were an example of inappropriate "evergreening" by companies to obtain extended periods of patent exclusivity. In response to a comment, FDA conceded that new dosage forms - some of them, anyway - may be clinically superior to previously approved dosage forms and "thus eligible for their own seven-year period of orphan exclusive approval."

Further comments on the regulatory changes, which concern the name of the drug, the scientific rationale in a request for orphan drug designation, responding to deficiency letters from FDA, publication of designations and recognition of orphan drug approvals, may be found here.

FDA: Orphan Drug Regulations

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