The FDA's definitions, designations, and drug approvals: too daring?

Abstract

In the past month, there have been various reports discussing the perilous imbalance in drug designations and approvals by the US Food and Drug Administration (FDA). The main concern has been on whether clinical studies can keep up the pace to fully exclude drugs with potential toxic effects and leading to serious adverse events before the FDA enacts rapid review and approval of a drug to treat any given condition. Case in point, the Journal of Clinical Oncology (JCO) published two research articles along with an editorial this June challenging the FDA's breakthrough-therapy designation initiative, defined within the FDA Safety and Innovation Act (FDASIA), which includes the 2014 Guidance for Industry Expedited Programs for Serious Conditions-Drugs and Biologics. This initiative is “intended to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the benefits justify their risks” and where “preliminary clinical evidence demonstrates that a drug (alone or in combination with one or more other drugs) proves to be substantially beneficial over already existing therapies on one or more clinically significant endpoints”. This initiative would be specifically applied when aiming to treat a serious or life-threatening disease or condition. The breakthrough therapy initiative was approved by US Congress in 2012 and when a drug is designated as breakthrough therapy, the FDA accelerates the review process and approval of the drug. The recent articles in JCO presented findings highlighting that, for breakthrough cancer drug therapies between January 2012 and December 2017, treatment outcomes in solid tumours did not substantially differ from those without breakthrough designation. Furthermore, the time to FDA approval for breakthrough drugs was approximately 2 years shorter than for those that were not breakthrough. In addition, between January 2006 and December 2016, results showed that cancer drugs lacking support from randomised controlled trials were more likely to receive accelerated FDA approval, breakthrough designation, but also postmarketing safety-related label modifications, than drugs that had been approved with the appropriate supportive evidence from randomised trials. We must therefore continue stressing the concerns of having accelerated FDA drug approval when scientific evidence does not rigorously support the use of these drugs. Expedited approvals and breakthrough designations can substantially undermine the protection of patients from serious adverse events, including death. But clearly, this is not a simple matter: one can reasonably argue that for patients with life-threatening conditions and in urgent need of treatment, experimental approaches and breakthrough therapies are a desired option. And, for instance, as discussed this July at the ASH Summit for “Emerging Immunotherapies for Hematological Diseases”, there is a long waiting list for patients with cancer wishing to receive CAR-T cell therapy; hence, it would be absurd not to offer these patients alternative options and timely recourses, when few of these options are available. To be fair, the FDA does stop clinical trials when there are safety concerns. A recent example is the halt of the KEYNOTE 183 and 185 phase 3 randomised controlled clinical trials of pembrolizumab (PD-1/PDL-1 checkpoint blockade) with other drug combinations to treat patients with multiple myeloma, where cases of serious adverse events including myocarditis, were reported. However, this halt has been highly controversial, as leaders of these trials have noted benefits of these therapies in subgroups of patients. Notwithstanding, the FDA's obligation should be that patient safety must not be sacrificed over expedited review and drug approval, and it must not unduly hasten drug breakthrough designations, or other definitions for that matter. When considering adverse effects of CAR-T cell therapies such as neurotoxicity, one must bear in mind that there can be great heterogeneity in the categorisation of neurotoxic events by researchers, and hence, the interpretation of what may be considered a successful therapy can be skewed. Hence, a balance must be struck between facilitating patient access to promising new therapies for life-threatening conditions versus the rushed, and simply daring approval of drugs with high risk that might not be that safe after all.