Two new articles and an accompanying editorial from former US Food and Drug Administration (FDA) commissioner Robert Califf published Tuesday in JAMA raise questions about the risks and clinical trial designs of new drugs and medical devices sped to market without enough preliminary evidence that they are effective.
In one of the articles, which evaluated the use of FDA’s accelerated approval pathway, questions were raised on the use of surrogate measures as outcomes in both confirmatory and preapproval trials.
Co-author Huseyin Naci of the department of health policy at the London School of Economics and Political Science told Focus: "A key question raised by our study findings is whether the surrogate measures used in the confirmatory trials of drugs granted accelerated approvals are adequate to compensate for the data limitations at the time of approval. Since these drugs enter the market on the basis of surrogate measures that are only ‘reasonably likely’ to predict clinical benefit, it is essential that the required confirmatory trials evaluate clinically meaningful outcomes."
The investigation found that among 22 drugs with 24 indications granted accelerated approval by FDA from 2009 to 2013, efficacy was often confirmed in postapproval trials a minimum of three years after approval, although confirmatory trials and preapproval trials "had similar design elements, including reliance on surrogate measures as outcomes."
But industry group PhRMA took issue with the study. Andrew Powaleny, Director of Public Affairs at PhRMA, told Focus: "The use of surrogate endpoints to predict clinical benefit, as agreed upon by both a sponsor organization and the FDA, has allowed many patients with no other treatment options to sooner reap the benefit of innovative new drugs and biologics. Recent studies have demonstrated that such medicines provide substantial health gains."
Another JAMA article evaluating the characteristics of trials used for FDA approval of high-risk device supplements found that "fewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points. These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved."
Califf’s accompanying editorial points out that both articles "raise concerns about whether the US regulatory system has become too permissive by not requiring traditional randomized controlled trials (RCTs) for postmarketing evaluation of drugs approved through the accelerated approval pathway and for supplemental design medications of medical devices thought to be sufficiently risky to warrant human studies."
While acknowledging that policies governing premarket evaluation criteria and postmarketing assessments "have undergone substantial evolution since they were first enacted," Califf also writes that both articles "provide empirical evidence that the current regulatory system does not always impose the most rigorous standard of clinical evidence."
Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration
Characteristics of Clinical Studies Used for US Food and Drug Administration Approval of High-Risk Medical Device Supplements
Balancing the Need for Access With the Imperative for Empirical Evidence of Benefit and Risk
Article updated 8/16 with comment from PhRMA.