Two Studies Point to Inadequate Evidence Supporting Many FDA Drug Approvals

December 2015, Vol 6, No 11

Two related studies have documented significant deficiencies in the way the FDA approves expanded or new indications for drugs, using its expedited approval processes with limited evidence.1,2

In the first study, Aaron S. Kesselheim, MD, JD, MPH, Director, Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, and colleagues showed that between 1987 and 2014, 76% of cancer drugs were approved under the priority review designation and 61% were approved using the orphan drug legislation.1

The FDA is using these programs, even though they "were intended to be limited in scope, applying only to investigational agents offering the greatest promise of therapeutic advance to patients with no other reasonable therapeutic choices," Dr Kesselheim and colleagues noted.

In the second article, Bo Wang, PharmD, and Dr Kesselheim found that 80% of FDA reviews of supplemental indications between 2005 and 2014 were not accessible to the public.2 Among the ones that are accessible, 94% of the approved expanded indications involve approval for pediatric patients, but only 11% of the indications were supported by ≥1 trials using an active comparator. Drs Wang and Kesselheim suggest that the FDA should bolster its postapproval surveillance system (ie, the Sentinel Initiative), which was started with the Mini-Sentinel in 2008 for indications that expand eligible patient populations.

Discussing his presentation at the FDA regarding his team's findings, Dr Kesselheim told Value-Based Cancer Care (VBCC), "I presented the results of these studies at a general FDA meeting about PDUFA [Prescription Drug User Fee Act] reauthorization in July." It remains to be seen if these findings will affect the FDA's approach to drug approval.

Stephen King, Consumer Safety Officer of the FDA's media relations department, told VBCC, "FDA is currently working to transition from Mini-Sentinel to the Sentinel system. We expect all the policies and procedures to transition the Mini-Sentinel Operations Center to the Sentinel Operations Center to be in place this year." He added, "The Sentinel Initiative is an important tool to complement FDA's other existing postmarketing surveillance tools. The capability of Sentinel will continue to evolve as the types of data increase and our ability to link and analyze these data mature."

Cancer Drugs

Using the Drugs section of the FDA's database, Drs Wang and Kesselheim found 295 supplemental indication approvals between 2005 and 2014 for 164 drugs. Of these, 137 approvals were for new indications, including 80 for oncology drugs.

Of the 137 modified indications, 51% of 93 approvals were supported by ≥1 trials with an active comparator versus 30% of 136 new indications and 11% of 65 expanded patient populations. Furthermore, 34% of 65 expanded population approvals were supported by uncontrolled trials; 14% were not associated with any efficacy trials.

Overall, 55% of the 80 approvals for cancer drug supplemental indications were supported by active comparator studies compared with none for psychiatric drug supplemental indications. Yet, 70% of the studies supporting oncology supplemental indications involved only surrogate outcomes rather than clinical outcomes.

Oncology drug approvals included 76% of 107 priority reviews, 61% of 107 orphan drugs, 48% of 107 fast track drugs, and 30% of 107 accelerated approval drugs. The authors are concerned that these expedited approvals are driven by drugs that are not first in class.

"Less innovative products moving through the FDA's expedited development and review programs can divert limited governmental resources," wrote Dr Kesselheim and colleagues.

Common Exceptions

They also noted that the breakthrough therapy designation is magnifying these trends, by granting 68 approvals in its first 2 years, even though the legislation intended it to apply to only a few drugs annually. They noted that new legislation could create an expedited pathway for more approvals, further supporting approvals without clinical trials; these exceptions have "become more common than the rule," according to Dr Kesselheim and colleagues.


  1. Kesselheim AS, Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ. 2015;351:h4633.
  2. Wang B, Kesselheim AS. Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review. BMJ. 2015;351:h4679.

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