FDA’s Accelerated Approval Challenged, But Is it Fair to Blame the Agency?
​[Posted on: Thursday, August 17, 2017]

In JAMA this week, an article raises doubts about the safety and effectiveness of drugs approved by FDA via the accelerated approval program but a critical review shows that despite the concerns raised, the regulatory pathway does its job as intended. Drugs and biologics intended for life-threatening or serious conditions can be approved based on smaller trials using surrogate markers. Manufactures are required to collect additional safety and effectiveness data in post-marketing studies but are frequently behind schedule to complete the post-marketing studies due to practical limitations of such studies. Surrogate markers played an important role in approval of several anti-HIV drugs in the early 1990s and have been instrumental in successful approvals of several drugs in the last two decades. The article points to FDA’s inability or lack of desire to enforce the post-marketing commitments as the reason for concern but the authors seems to miss the point in the practical aspects of regulations. The authors used publicly available data for 24 accelerated approvals between 2009 and 2013, and found that about half of the drugs that received accelerated approval did not complete post-marketing commitments within 3-5 years of approval, hinting that these drugs may not be safe or effective as intended. Further, questions were raised about the integrity of post-marketing trials for not using blinded, randomized, comparator-controlled design. That’s not a fair assessment. First, all the drugs that receive accelerated approval are intended to treat serious or life-threatening conditions, where patients have few alternatives. Cancer drugs dominate this category; 19 of the 24 indications selected by the authors were for cancer. The safety and effectiveness of any drug should be evaluated in context of the target indication. None of the drugs selected by the authors exhibited any safety issues post-approval, and all the drugs for which data was available, were confirmed to be beneficial. Moreover, 11 of the 24 approvals were supplemental meaning that the same drug had been previously approved and hence the need for additional testing was reduced. Second, the authors’ complaint of the lack of blinded, controlled, randomized design for post-marketing studies shows no appreciation of the realities of doing such trials. For an approved drug, it would be hard, if not impossible, to find patients who would be willing to participate in such post-marketing trials, and potentially unethical to withhold the FDA-approved drugs from patients with serious, life-threatening conditions. The only feasible way to confirm the efficacy of the drug in a post-marketing study in such conditions would be an open-label clinical experience study. Lastly, the intent of the accelerated approval program is to expedite patient access to drugs with a potential to help and acceptable risk, based on limited but logical scientific data. The ultimate test of a drug is its utility in the clinical setting in helping patients.  In the examples selected by the authors, no examples were found where patients were unduly hurt by the FDA decision to grant accelerated approval. The issues raised by the authors are definitely appealing from an academic perspective and raise reasonable questions, but this study does not raise concerns that would alarm the patients for whom such drugs are intended, or give FDA a reason to change its process. The accelerated approval program works and should continue.