Deborah Plana, Andrea Arfè, Michael S. Sinha
This article was originally published on the Health Affairs Blog.
The COVID-19 pandemic has rapidly transformed much of the medical device, pharmaceutical, and vaccine industries. As Mary McDermott and Anne Newman note in JAMA, “Mitigation efforts [against COVID-19] interfere with all aspects of a successful clinical trial: efficient accrual and randomization, intervention adherence and delivery, and outcome collection.” Quarantine, isolation, and social distancing necessarily limit access to health care institutions for care. Shortages of medical resources and staff are also possible. As a result, many non-COVID-19 trials are being suspended or terminated. Large pharmaceutical manufacturers Eli Lilly, Merck, Pfizer, and Bristol-Myers Squibb have all announced delays in enrollment for ongoing studies and initiation of future studies. According to BioPharmaDive, as of May 15, 2020, nearly 100 companies and 240 trials have experienced disruptions. As such, the COVID-19 pandemic threatens to set back non-COVID-19 clinical trial research by several years.
On March 18, 2020, the Food and Drug Administration (FDA) published “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards.” Updated June 3, 2020, the document focuses on logistical considerations for clinical trial conduct in the setting of COVID-19, including impact on clinical sites, clinical investigators, and trial participants. Similar documents have been published by medical societies (for example, in oncology, radiology, cardiology, and neurology), and academic as well as industry statisticians, which attempt to convey practical advice for ensuring the “rights, safety and wellbeing” of participants while mitigating risks to trial integrity. Although such documents address critical concerns, the need to salvage whatever information can still be obtained from trials during this crisis is also of pressing importance. In particular, more clarity is needed with regard to statistical considerations in ongoing, suspended, or terminated clinical trials.
In addition, existing research efforts are largely being set aside in favor of a new, urgent goal: testing, treating, and preventing the disease caused by the novel SARS-CoV-2 coronavirus. This industrywide push toward solutions for COVID-19 resulted in a pivot away from existing lines of clinical research, which creates uncertainty as to how to proceed with future clinical trials. The FDA’s shift in focus toward COVID-19 vaccines and therapeutics—as evidenced by the transition of Center for Drug Evaluation and Research Director Janet Woodcock, MD, to COVID-19 vaccine development—compounds these concerns.
To address these issues, we discuss ideas on how to maximize the amount of data generated from existing trials, ensure participant safety, and increase the feasibility of clinical studies in times of crisis.
Participants must be central to any decision to adjust ongoing clinical trials due to COVID-19. Below, we highlight some salient and generalizable considerations for individuals participating in clinical trials.
Any change that materially alters the nature of the trial must be addressed by protocol amendments. Given time constraints, amendments to multicenter clinical trials may be most expediently reviewed by a central committee rather than individual Institutional Review Boards. The COVID-19 pandemic has materially altered the risk-benefit assessment that allows for informed participation in clinical trials: an increased risk of SARS-CoV-2 exposure in health care settings without change in potential benefit. This dramatic change must be accounted for through re-consent of all trial participants. Decisions to unblind trials and offer early termination for participants in specific arms of a study or to individual participants who are especially vulnerable to COVID-19 may be warranted. This may be particularly relevant for participants in placebo or standard of care arms of clinical trials, given the relative lack of potential benefit. FDA officials have suggested in the past that use of external controls may have merit when the use of internal control arms is considered unethical. In any case, results should be returned to participants as they become available.
Other participant considerations during the conduct of the trial are also relevant. First of all, it is critical to limit in-person health status monitoring, such as blood tests and imaging, as much as possible. This is especially important for a participant in a high-risk group (such as an elderly oncology participant) or a participant who has to travel to receive care or be accompanied by others (such as children accompanied by a guardian, in which one must balance between care for the participant and risk of infecting others). Where monitoring must be done, participants should be evaluated outside the hospital or clinic setting where possible. Finally, in a slumping economy, attention must also be paid to whether enrollee compensation is ethical. Loss of health insurance or diminished income may coerce participants to remain enrolled in clinical trials, even as risks of leaving the home become more pronounced due to COVID-19. In all cases, the principle of “primum non nocere” (first, do no harm) must be the foremost concern.
Issues Related To Ongoing Trials: The Role Of Data Safety Monitoring Boards
Both the FDA Guidance and other similar documents recognize that many clinical trials may need to interrupt patient enrollment due to the impact of COVID-19. However, they offer little guidance on which statistical criteria could guide the decision to suspend trial activities, and whether and how to still analyze the data collected on experimental therapies.
In some cases, the Data Safety Monitoring Board could potentially perform an ad-hoc interim analysis based on formal stopping rules. For trials that collected most study outcomes, interim analyses could determine that the primary objective has been reached before the planned end of study. Futility stopping rules could instead help identify trials likely to fail even if continued. Both approaches could help minimize the number of patients that need to be enrolled in a trial during a crisis.
Nevertheless, more guidance is needed on when similar analyses could be appropriate. Two issues should be considered before performing interim analyses for early stopping, especially if unplanned. The first concern is the need to control the false-positive error rate (the probability that a trial would incorrectly produce positive results by chance) at a low, pre-specified level. This risk of false-positive findings is increased when assessing the same hypothesis multiple times, as would be the case in interim analysis. False-positive error rates could be controlled at pre-specified levels using multiple testing methods such as group sequential approaches. The second concern is ensuring the reproducibility of study results. To overcome this potential limitation, any unplanned analysis and decision rule for early stopping should be documented in amendments to the study protocol.
Optimizing Use Of Existing Data And Results: The Importance Of Dissemination
Many trials are likely to shut down during the current pandemic, but this should not translate into a loss of useful data. First, meta-analyses and methods to adjust for missing data, such as multiple imputation methods, can leverage data from discontinued trials to provide important information on the safety and effectiveness of tested therapies. Second, some protocol deviations due to COVID-19 may be unavoidable, which may increase the risk of bias in study results. Robustness of study findings could be evaluated in re-analyses of shared data based on different bias assumptions. Finally, the FDA should promote sharing of anonymous participant data and summary results from trials affected by the pandemic, even those terminated before their final analyses. More generally, it should enforce and expedite the reporting of study results. Even though the Food and Drug Administration Amendments Act requires timely reporting of results of applicable clinical trials to ClinicalTrials.gov, only 13 percent of trials post their results on this site within 12 months of trial completion.
Making the most out of data collected from trials during the current pandemic requires making such information widely available for re-analysis as quickly as possible without compromising participant safety and privacy. Notably, such calls for the widespread implementation of data sharing have been raised with regard to pediatric trials and rare diseases, which outside of a pandemic already face considerable challenges in enrolling limited numbers of participants in trials. In the context of a public health crisis, such populations are even more likely to be vulnerable to accrual problems, discontinuation, and nonpublication of study results.
Decentralization: A Future For Clinical Trials?
The current pandemic highlights a glaring inequity in the way that clinical trials have historically been conducted in the US: They are mostly performed in a few central locations, typically key urban centers. Given the disproportionate effects of COVID-19 on densely populated urban areas, it is expected that non-COVID-19 clinical trials conducted in such locations will struggle with enrollment and monitoring.
In contrast to traditional clinical trials, decentralized clinical trials are “trials executed through telemedicine and mobile/local healthcare providers,” as defined by the Clinical Trials Transformation Initiative. Prior to the pandemic, it had been widely reported that a lack of geographically diverse clinical trial sites negatively impacts study participation, especially for the enrollment of women, as well as participants from rural areas and racial groups traditionally underrepresented in biomedicine. On the contrary, decentralized trials may help increase trial access and participant diversity.
The COVID-19 pandemic highlights an additional advantage for study decentralization: increased robustness of participant accrual in the face of a crisis. Indeed, decentralized trials could ensure continued accrual and monitoring of participants even when in-person care is no longer possible in some study locations. Still, the technical requirements for performing decentralized trials, such as remote monitoring, can make them infeasible for some therapy and disease settings with currently available technology.
Society should invest in the innovation required for widespread adoption of decentralized trials. Such innovation would promote distributive justice, ensuring that all populations affected by a disease have the opportunity to participate in—and reap the benefits of—clinical trials. Investment in technologies to help decentralize clinical trials would additionally increase the resilience of our country’s clinical research programs in the face of large-scale emergencies.