Date of Award

January 2014

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Joseph S. Ross

Subject Area(s)

Medicine, Pharmaceutical sciences


The U.S. Food and Drug Administration (FDA) has three principal responsibilities: approving novel therapeutics in a timely manner, maintaining a standard of approval that characterizes the potential benefits and risks of novel therapeutics and promoting the translation of promising scientific innovations into new medicines. The agency's performance with respect to each of these components of its mission has not systematically been studied.

Three principal analyses, each evaluating a component of the FDA's mission, are presented in this thesis. First, using publicly available information, the speed of the FDA's regulatory review of novel therapeutics approved between 2001 and 2010 was benchmarked with that of the European Medicines Agency (EMA) and Health Canada. Second, the pivotal efficacy trials that the FDA used as the basis of its approval decisions between 2005 and 2012 were classified according to their design features and magnitude of exposure to the novel therapeutic. Third, novel therapeutics approved by the FDA between 2005 and 2012 were classified according to their degree of novelty: first-in-class, advance-in class and addition-to-class. Subsequently, regulatory review times and the features of pivotal trials supporting the approval of novel therapeutics were stratified by therapeutics' degree of novelty.

The FDA approved novel therapeutics more quickly than its international peers: the first review time at the FDA was 303 days (interquartile range [IQR]: 185-372), 366 days (IQR: 310-445) at the EMA and 352 days (IQR: 255-420) at Health Canada (p<0.001). Among the subset of applications approved by all three regulators, the FDA made approval decisions approximately 90 days faster.

The median number of pivotal efficacy trials used as the basis of FDA approvals between 2005 and 2012 was 2 (IQR: 1.0-2.5), with 36.8% of indications approved on the basis of a single pivotal trial. Approximately one third of indications were approved solely on the basis of randomized, double-blinded, controlled pivotal efficacy trials that measured a clinical outcome or scale. Pivotal efficacy trials using surrogate outcomes were the exclusive basis of approval of 45.3% of indications. The quality and quantity of evidence generated in pivotal trials differed when stratified by drug type, therapeutic area, length of treatment, orphan status and accelerated approval.

The proportion of novel therapeutics approved between 2005 and 2012 that were first-in-class was steady. Although the FDA took longer to review these more innovative therapeutics, there were few differences in the characteristics of the pivotal efficacy trials supporting approvals of first-in-class therapeutics compared to less novel therapeutics.

This thesis highlights that the FDA is making prompt approval decisions, but established that the agency's approval standard is flexible, as some novel therapeutics were approved on the basis of multiple high-quality clinical trials, while other approvals relied on preliminary evidence, such as surrogate outcomes or single trials. The FDA did not have a different standard of approval for first-in-class therapeutics, but it was slower to approve these promising new medicines. Future efforts to improve drug regulation should seek to better communicate the FDA's flexible approval standards to patients and physicians and promote the development of innovative therapeutics.