Credit: FDA
New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.
When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.
Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.
The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.
These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.
To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.
The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.
Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.
Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.
Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.
Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.
Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.
Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.
The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.
An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.
