Maurie Markman, MD, highlights the ongoing regulatory concerns that demand attention of the FDA in the cancer arena amidst evolving issues regarding COVID-19.
It is difficult to overstate the current challenges facing the FDA. From decisions regarding the use of COVID-19 vaccines in children to the polarization among government officials and the scientific community associated with approval of COVID-19 booster shots, our nation’s drug regulatory agency appears to increasingly be a topic of discussion in the mainstream and social media. Unfortunately, much of this attention, and the headlines generated, are not favorable to the mission of this critical federal scientific public health agency.
For example, consider the still poorly understood decision by the FDA to approve the Alzheimer’s drug, aducanumab-avwa (Aduhelm). The decision was made despite the overwhelming disapproval of the agency’s own advisory committee, highlighting a concerning degree of dysfunction within what is arguably one of most vitally important government organizations.1
And although likely not high on the list of priorities, several issues reported in the scientific press await review, careful consideration, and possible action from the FDA. These include the potential evidence of scientific misconduct according to a self-reported survey from Dutch scientists that if widespread throughout the scientific community has the realistic potential to influence reports of pharmaceutical drug efficacy and/or safety2; evidence of inadequate protection of research subjects by investigators and institutional review boards in federally funded research projects such as a recent study of vitamin D supplementation in asthmatic children3; and potentially problematic editorials related to cancer pharmaceutical agents, which are regulated by the FDA, among individuals with a financial relationship with industry.4
The FDA has suffered from what some might appropriately argue is a stunningly ineffective public communication strategy with an apparent inability to clearly explain both the safety of established vaccines in the United States and provide clarity on the extensive multistep regulatory process required before any vaccine product is approved for noninvestigative use.
The example often stated of the rushed approval of the COVID-19 mRNA–based products is an important case to highlight. mRNA-based drugs—not COVID-19 vaccines— have been under active clinical investigation and FDA oversight for almost 10 years in the oncology arena and more than 3 years in the management of infectious diseases prior to the COVID-19 pandemic.5 Therefore, the FDA had extensive experience with the potential safety and manufacturing issues associated with mRNA COVID-19 vaccines before clinical trials in this area were initiated. One might inquire why it has been so difficult for the FDA to clearly communicate these and other objective facts and observations regarding the development of these remarkably safe, effective, and life-saving vaccines?
Outside of communications related to COVID-19, it is not difficult to create a list of items requiring meaningful consideration from the agency.
For example, evolving issues include the future approval processes and potential restrictions of use of antineoplastic pharmaceutical agents. To eliminate the risk of bias in the review of imaging studies, most commonly CT scans, defining the time to disease progression for women on ovarian cancer trials, the FDA has routinely mandated independent blinded radiology review vs accepting the opinion of the local-site radiologist as to when the cancer has progressed.6 However, strong evidence exists that independent radiographic review results in outcomes very similar to that of the treating team.6 Based on these data, how much longer will this time-intensive and extremely costly third-party review effort be required?
Recent studies have demonstrated the impressive effect of PARP inhibitors in both the therapeutic and maintenance settings in the treatment of ovarian cancer and other malignancies including breast, prostate, pancreatic cancers. However, evolving and not terribly surprising data have suggested the development of myelodysplastic syndrome and acute leukemia in a small, but likely not rare, group of patients receiving one of this class of drugs.7,8 How should the FDA respond to this information in terms of advising clinicians regarding the overall risk and/or strategies to mitigate that risk?
Finally, there is the issue of establishing appropriate control arms in a phase 3 trial during which a previously approved strategy in the clinical setting is being tested. What is the FDA’s guidance for deter-mining an appropriate comparator arm in a scenario where clinicians may not routinely treat patients with the specific approved regimen?
Consider the FDA’s approval of bevacizumab (Avastin) plus one of 3 cytotoxic chemotherapeutic agents in platinum-resistant ovarian cancer, based on data from the landmark AURELIA trial (NCT00976911).9 Should a novel drug strategy in platinum-resistant ovarian cancer be required to demonstrate superiority to chemotherapy alone, such as in the FORWARD 1 study (NCT02631876),10 or should chemotherapy plus bevacizumab, the superior study arm in the AURELIA trial, be used? If a direct comparison to the chemotherapy plus bevacizumab regimen in AURELIA is not mandated, one might suggest that an explanation from the FDA is required because in the absence of such data, it is quite uncertain how clinicians will objectively determine the more effective regimen for their patients with platinum-resistant disease.
Although the proceeding examples highlight the ongoing regulatory concerns that demand attention of the FDA in the gynecologic cancer arena because of the specific clinical and research interest of the commentator, these issues extend to other areas of oncology and put into perspective the scope of the areas where FDA holds influence.