LAUSR

Adverse event reporting for patients on clinical trials has two main purposes: (1) informing sponsors and regulators of potential new risks of a given agent and (2) informing patients and investigators of those risks. While the first goal can help determine the future development of an agent or a class of agents, the latter has the potential to help patients on existing trials or those considering enrolling on an active trial. The analysis of the survey of stakeholders published by Perez et al. through the Clinical Trials Transformation Initiative (CTTI) suggests that in oncology, our system for expedited reporting of suspected adverse events are failing on both counts. The CTTI and US Food and Drug Administration (FDA) present in this issue of Clinical Trials a survey which is well conducted, despite its limited scope. Only a handful of sponsors and investigators are interviewed, and there is no indication that they amount to a representative sample. Regardless, the interviewed subjects do provide useful feedback to the changes on the final rule. Clearly, the FDA’s revision of the final rule in 2011 was intended to improve the utility of safety reports. In spite of this intent, the FDA has previously reported that the vast majority of expedited reports filed to the FDA are uninformative. The previous analysis and these survey results suggest that we have a long way to go before that changes. The question for the FDA and other regulatory authorities is how cancer researchers can truly inform all relevant parties of the risks inherent in investigational clinical trials and improve the system. Oncology is a challenging field for a variety of reasons, among them the potentially life-threatening nature of the disease and the risk–benefit ratio that must be employed in cancer drug development. The most active area for cancer drug development involves therapy for metastatic disease. The FDA has been tasked with accelerating drug development for patients with often terminal diagnoses and few available treatment options. As the risk of disease progression and mortality is an ever-present danger for most cancer patients, a higher rate of toxicity may be tolerated in oncology as compared to drug development in most other fields of medicine. That risk tolerance is shaped almost entirely by the potential benefits that may be seen with newer therapies. Patients and regulators may agree that a few additional months of a median overall survival advantage may well be worth the potential toxicity, given the alternatives. The concerns exhibited by Jarow et al. and the CTTI survey suggest that over-reporting is the norm. A low threshold for expedited event reporting may be appropriate for drugs that are early in development with relatively few clinical trials. If fewer than 100 patients, or if fewer than 1000 patients, have been treated with an agent, investigators, sponsors, regulators, and patients should take a cautious approach to adverse event reporting. Aggressive adverse event monitoring and expedited filing early in development of a given agent serve to inform all stakeholders of the nature of the risks associated with a drug. The problem arises from the application of those same principles for agents that have been approved but are currently in clinical trials for additional settings or other indications. One example is the class of immune checkpoint inhibitors, including the FDA-approved agents nivolumab, atezolizumab, and pembrolizumab. One recent article reported that there are over 1000 ongoing clinical trials evaluating the use of immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) and its ligand PDL1. Some of the existing trials are large phase 3 trials with thousands of