Credit: Esther Dyson
New research suggests that drugs are often rejected by the US Food and Drug Administration (FDA), not because they are unsafe or ineffective, but because there is not enough evidence to determine the drugs’ safety and efficacy.
Investigators reviewed about 300 drug applications and discovered a number of reasons why drugs were denied approval on the first try.
The FDA cited issues with dosing, trial populations, study endpoints, and inconsistencies in data as reasons for denial.
Leonard V. Sacks, MBBCh, of the FDA in Silver Springs, Maryland, and his colleagues conducted this research and reported the results in JAMA.
The team reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the US) first submitted to the FDA between 2000 and 2012.
They used FDA correspondence and reviews to determine the scientific and regulatory reasons approvals were delayed or denied.
Of the 302 NME applications, 222 (73.5%) ultimately achieved marketing approval.
Half of all NMEs (151) were rejected on the first try, but 71 (47.0%) of these were approved following resubmission. The median time to approval was 435 days after the first action letter (range, 47-2374 days).
Drugs were denied approval for a number of reasons, including:
- Uncertainty about the optimal dose to maximize efficacy and minimize safety risks (15.9%)
- Inconsistent results for multiple predefined study endpoints (13.2%)
- Trial endpoints were unsatisfactory (13.2%)
- Inconsistencies in efficacy for portions of the study population (11.3%)
- The populations studied did not reflect the populations likely to use the drug (7.3%).
The investigators also found that the frequency of safety deficiencies was similar among never-approved drugs and drugs with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals.
There were 48 drugs with initial efficacy concerns, and only 31.3% of these were eventually approved, compared to 61.5% of the 39 drugs with safety concerns alone.
There were 20 drugs (13.2%) that, despite showing superiority to placebo, were considered to have inadequate efficacy compared with the standard of care.
The investigators said that, taken together, these findings suggest there is room for improvement in new drug applications. But if drug sponsors increase communication with the FDA, particularly with regard to study design, they could reduce delays in drug approval.
