FDA’s Flexibility in Subpart H Approvals: Analysis Shows Wide Variances Between the Quantum and Quality of Evidence for Approval

August 4, 2016

A breakthrough paper by Hyman, Phelps & McNamara, P.C’s Frank Sasinowski and Alexander Varond concerning FDA’s Subpart H approvals has just published in the Food and Drug Law Journal. Titled “FDA’s Flexibility in Subpart H Approvals: Assessing Quantum of Effectiveness Evidence,” the paper examines the strength of scientific and clinical evidence for FDA’s 19 non-AIDS, non-cancer Subpart H approval determinations over the accelerated approval program’s 24-year existence. The authors conclude that, despite the agency’s infrequent use of accelerated approval for non-AID, non-cancer therapies, FDA exercises extraordinary regulatory flexibility in its Subpart H approvals—much more than is expressly provided for in the Federal, Food, Drug and Cosmetic Act, FDA’s regulations, or FDA’s 2014 guidance, entitled Expedited Programs for Serious Conditions.

Sasinowski and Varond researched the bases for FDA’s determinations when an unvalidated surrogate or intermediate clinical endpoint is “reasonably likely to predict clinical benefit.” For the 19 precedents, the authors found wide variances between the quantum and quality of evidence on each of the three key factors outlined in Section VII of FDA’s Expedited Programs Guidance. The authors conclude from this that, to FDA, a lack of robust evidence on any single factor does not disqualify a therapy from Subpart H consideration, according to FDA’s own precedents.

The three key factors in FDA’s Expedited Programs Guidance are

  1. Understanding of the disease;
  2. Understanding of the relationship between drug effect and disease process; and
  3. Clinical evidence for (a) the unvalidated surrogate, and (b) the clinical benefit.

The figure below provides a snapshot of the flexibility FDA has employed in its 19 Subpart H approvals.


The critical takeaway from the paper is that a robust showing on the key factors in FDA’s May 2014 Guidance is not required, or, as the authors write: “you don’t need to knock it out of the park” on all 3 factors.

For their efforts, the authors “hope to promote a better understanding of the circumstances under which Subpart H may be employed in order to facilitate the development and expedited review of new drugs with the potential to address unmet medical needs for serious and life-threatening illnesses and to mobilize expanded FDA use of Subpart H.”

Of particular interest to readers may be the 2-4 page case analysis summaries provided in the second half of the paper. Each of the 19 approved drugs presents a distinct set of facts and circumstances that highlight how Subpart H is employed by FDA and emphasizes the degree of flexibility FDA has exercised.

This paper comes on the heels of Frank Sasinowski and James Valentine’s 2015 paper analyzing the quantum of effectiveness evidence that is required to secure FDA approval of orphan drugs from 2010-2014, which updated Sasinowski’s seminal analysis on the orphan drugs approved from the 1983 enactment of the Orphan Drug Act through 2010.