FDA Issues Final Rule on Orphan Drug Regulations

The updates issued by the FDA address the rules and language from the Orphan Drug Act governing orphan-drug designation and orphan-drug exclusivity.

In October 2011, the FDA announced plans to update regulations in the Orphan Drug Act to address problems that have arisen since sponsors began submitting applications and designation requests for orphan drug products.

The final rule was released on June 12, 2013, and will go into effect on August 12, 2013. Here are some of the most important changes or clarifications as they relate to orphan drug development.

The definition of “orphan subsets”

In the FDA’s opinion, some drug developers seeking orphan drug designation for their products have been seeking approval for the “narrowest” possible set of disease states to allow them to qualify for the tax credits and 7-year market exclusivity incentives that come with the designation. This concern prompted the agency to alter the regulations to prevent companies from selecting an “artificially narrow” subset for the purpose of orphan-drug designation. The agency noted that selection of such a subset could “permit a non-rare disease or condition to be artificially subdivided into smaller groups for establishing subsets that are under the prevalence limit for designation” and that this type of patient grouping could prevent access to promising therapies for patients with diseases or conditions not included in the orphan drug application who could potentially benefit from treatment.

The FDA clarified the definition of “orphan subset” to mean that use of the drug is appropriate for patients within the subset, but use for patients outside the subset would be “inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug.”

Multiple indications for 1 orphan drug

Sponsors were concerned that if a drug were given 1 orphan drug designation, it could not be considered for subsequent orphan indications. The FDA responded by clarifying that a drug that shows promise in multiple rare diseases may be eligible for multiple indications, provided that the prevalence of each disease or condition is under 200,000 patients in the United States. “If, however, the drug is for a disease or condition that exceeds the prevalence limit of 200,000, then the sponsor would need to establish an orphan subset based on some property(ies) of the drug,” the FDA wrote. In other words, if a disease has a prevalence of more than 200,000 patients in the United States, sponsors would need to demonstrate why only a subset of this patient group would benefit from the drug.

The FDA rule also noted that new dosage forms for an orphan drug release must demonstrate clinical superiority to already approved dosage forms in order to be eligible for their own 7-year exclusivity period.

Future FDA guidance specific to product type

The final rule also included FDA responses on orphan drug designations for products that were previously approved but could have orphan indications. The FDA wrote that it is “considering the feasibility of issuing a draft guidance document on what may constitute a plausible hypothesis of clinical superiority for certain categories of products, for example plasma-derived products, which may help address some of the concerns articulated previously.”

The FDA document noted that 124 of the 324 requests for orphan-drug designation in 2010 “were denied or placed into abeyance so that the sponsor could submit additional material to respond to the deficiencies.” Of these, 79 failed to identify an appropriate “medically plausible subset” of a population with a non-rare disease or condition that the drug was designed to treat. In addition, the FDA observed that a number of sponsors have sought orphan drug status for drugs that were already approved for other conditions. In order to qualify for orphan designation under these circumstances, the FDA noted that it would require additional information demonstrating the drug’s clinical superiority.

To read the FDA’s clarifications about product naming, re-submitting a previously denied or withdrawn orphan application, the FDA’s agreement to publicly announce when a drug loses orphan drug status, and more, read the final rule in its entirety.