On June 12, 2013, FDA issued a Final Rule amending the 1992 Orphan Drug Regulations to implement the Orphan Drug Act. The Final Rule largely reflects the 2011 Proposed Rule (see our previous blog on the draft rule here) to amend the Orphan Drug Regulations with several changes for clarity and accuracy. FDA explicitly stated that the Final Rule has no effect on the scope of, or eligibility for, orphan-drug-exclusive approval, because it merely clarifies existing and longstanding FDA practices. The Final Rule will take effect on August 12, 2013.
The two most important amendments and clarifications in the final rule are the new definition of "orphan subset" and the various clinical superiority requirements for designation requests and exclusive approvals for a subsequent drug for the same use or indication.
To qualify as an "orphan subset" drug (21 CFR §316.3(b)(13)), the drug sponsor must show that while the drug is safe and effective in the orphan subset population, the drug is not suitable for use in those persons outside of the orphan subset (i.e., those persons who have the same non-rare disease or condition). Such non-suitability must be based on either a pharmacokinetic property (such as toxicity and mechanism of action), or previous clinical experience with the drug.
After the Proposed Rule was published, the pharmaceutical industry expressed concern that to satisfy the rule, they would have to prove a negative (i.e., that the drug would not be useful in the non-subset population). To address this concern, FDA explained that it is more concerned about an orphan subset being "artificially narrow." Thus, it will not require the same scientific proof for the precluded population as it does for the subset population.
A subsequent drug sponsor seeking orphan drug designation in the face of an existing approved drug for the same use or indication must include a plausible hypothesis of clinical superiority in its designation request. But the plausible hypothesis is not required if the first applicant's drug has yet to be approved.
To attain exclusivity, the sponsor of the subsequent drug must demonstrate clinical superiority of its drug over the first-approved drug, regardless whether the first-approved drug has orphan-drug exclusivity. Demonstrating clinical superiority is required even if a designation request for a subsequent drug was filed without a plausible hypothesis of clinical superiority, because no drug had been approved at the time of filing.
Demonstrating clinical superiority does not require proving the specific hypothesis in the designation request. As long as the subsequent drug sponsor demonstrates clinical superiority in either safety or efficacy, FDA may approve the drug as an orphan drug even if the original hypothesis for clinical superiority was incorrect. FDA indicated that while direct comparative clinical trials to demonstrate greater safety are necessary in only "some cases," direct comparative clinical trials to demonstrate greater effectiveness are necessary in "most cases." Some new dosage forms may be "clinically superior" to previously approved dosage forms of the same drug for making a "major contribution to patient care." FDA will decide this issue on a case-by-case basis based on factors, such as convenient treatment location, duration of treatment; patient comfort, reduced treatment burden, advances in ease and comfort of drug administration; longer periods between doses, and potential for self-administration.