FDA exercises rare disease flexibility, page-7

It’s rare that the FDA allows NDA submission before a Phase 3 trial is conducted. It’s probably even rarer that the FDA would accept NDA submission based upon a single-arm, open-label Phase 2 trial in only 29 patients. The FDA states that it may consider “data from one adequate and well‐controlled clinical investigation and confirmatory evidence” to constitute substantial evidence of efficacy but it also states that it wants to see “rigorous blinding and control procedures” in place as early as possible in development to minimize bias. Ultragenyx's clinical trial data alone did not meet that standard.

In Ultragenyx’s case, its 18 mth, single-arm, open-label Phase 2 trial was supported by data from another much shorter trial which had different endpoints, but which was randomized and controlled. But the surprise inclusion in the data accepted, which I think probably swayed the case in Ultragenyx’s favour, was the retrospective medical record review of patients treated as part of a compassionate use protocol and numerous emergency IND cases. The medical record review evaluated the impact of UX007 treatment on the rate and extent of hospitalizations in 20 of 24 patients who had been treated with UX007 for up to 13 years as part of a compassionate use protocol. This study compared the incident rate for the major medical events before and after UX007 treatment, including the total number of hospitalizations and hospital days per year due to all causes, muscle rupture, hypoglycemia, or cardiomyopathy. The emergency IND cases included infants with severe, life-threatening cardiomyopathy. The major reduction in incident rate of major clinical events found in these reviews/case studies supported the finding of a 48.1 percent reduction in the mean annualized rate of major clinical events in the 18 mth, single-arm, open-label Phase 2 trial.

Despite Ultragenyx’s trial design not meeting the usual FDA standard of what may be considered to prove “substantial evidence of efficacy”, the FDA appears to have been quite flexible in this case because of the totality of evidence provided.

By the way, FDA stats show that, from 2008-2016, 78% of FDA-approved rare disease drugs had flexible development applications compared with just 22% for non-rare disease drugs.