Expedited FDA Approval for Breakthrough Therapies: Promises and Pitfalls

By Michael Young

In 2012, the FDA introduced a novel pathway for expedited review of breakthrough therapies. The ‘breakthrough-drug’ designation was carved out by the Food and Drug Administration Safety and Innovation Act (FDASIA), which provided for expedited development and review of any drug “intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”  This pathway added to a variety of other accelerated FDA approval programs aimed at improving access to innovative, safer, or more effective therapies for serious medical conditions.

In a recent New England Journal of Medicine article, Jonathan Darrow, Jerry Avorn and Aaron Kesselheim examine the clinical consequences and ethical dimensions of the breakthrough-drug category, and raise a variety of vital questions about its implications for patients.

The authors incisively point out that although the new expedited approval pathway may provide earlier access to novel treatments, earlier access does not invariably translate into substantially improved patient outcomes.  Due to more limited clinical trials to support new therapies that reach the market via expedited review processes, data on the safety, effectiveness and efficacy of breakthrough therapies may be wanting.  By virtue of these limitations, Darrow and colleagues note that “early access and shortened development review times have also been associated with negative public health outcomes” including drug-related adverse events and other safety problems that become apparent only after drugs have been brought to market. They further contend that “deferring rigorous study until after a drug is approved can also undermine and delay evaluation of [a breakthrough drug’s] risk-benefit profile” and add that “[t]his concern is magnified when deferred study is paired with earlier designations that may be interpreted as official endorsements.”

Instead of occasioning a dramatic increase in the pace and positive utility of pharmaceutical innovation, the authors thus consider the possibility that the new designation might have “created the appearance of progress while enhancing the visibility of promising early-stage drugs that may be no more likely than before FDASIA to confer large benefits to patients” while at the same time amplifying “public pressure on the FDA to approve such products.”  Also introduced is the key question of how to elicit patients’ genuine informed consent to breakthrough-drug regimens with uncertain risk-benefit profiles due to the relative paucity of clinical trial data.

The concerns and questions raised by the authors are compelling, and illuminate a great need for more rigorous post-market monitoring and ongoing research into the safety and clinical utility of breakthrough therapies.  Improving informed consent processes will also be crucial as uses of such therapies expand.  This may require a more robust account of what should be considered a “clinically significant endpoint” when evaluating preliminary evidence.

In his work The Imperative of Responsibility, philosopher Hans Jonas presciently remarked that in light of the uncertain potentials “of our technological processes, ignorance of the ultimate implications becomes itself a reason for responsible restraint – as the second best to the possession of wisdom itself” (22).  Balancing our eagerness to expedite the transition of novel therapies from bench to bedside with appropriate foresight into potential limitations and pitfalls imposed by this impulse will be critical to maximize the benefits of accelerated approval pathways, especially in the face of increasingly complex approaches to therapeutic design and discovery.