Assessing Drug Efficacy After Multiple Negative Trials-Gepirone's Journey Through the FDA

Area of Science:

• Pharmacology
• Clinical Trials
• Regulatory Science

Background:

• Patients and clinicians may overestimate drug efficacy and safety post-US Food and Drug Administration (FDA) approval.
• Recent FDA drug approvals often rely on fewer than two adequate and well-controlled trials.
• Current regulations lack guidance on evaluating drugs with conflicting trial evidence.

Purpose of the Study:

• To examine how the FDA evaluated a single investigational drug with both positive and negative preapproval trial results.
• To analyze the regulatory decision-making process for drugs with mixed evidence.

Main Methods:

• A case review of gepirone extended release (ER), approved for major depressive disorder.
• Analysis of 13 preapproval trials (12 acute, 1 maintenance).
• Examination of FDA review history, including multiple rejections and a dispute resolution request.

Main Results:

• Gepirone ER efficacy was based on 2 positive acute trials out of 13 total trials.
• The FDA rejected the drug application four times due to conflicting evidence, including statistical inferiority to an active comparator in three trials.
• Despite an FDA Advisory Committee vote against efficacy, FDA leaders approved the drug in 2015, citing statistical significance in positive trials.

Conclusions:

• The gepirone ER case illustrates FDA's use of "regulatory flexibility" in drug approval, sometimes prioritizing statistical significance over clinical significance.
• This approach can lead to the approval of drugs with limited demonstrated benefits.
• Transparent reporting of all trial outcomes, not just positive results, is crucial for informed clinical prescribing decisions.