The Impact of COVID-19 on Clinical Trials.

The coronavirus disease 2019 (COVID-19) pandemic has upended our lives, with millions of people infected and thousands of deaths around the globe.[1] Social distancing has emerged as the recommended strategy to reduce the spread of the virus and mitigate its deadly effects. This has caused critical challenges in daily human life and has burdened health care systems with an increasing need for adequate healthy staff, ventilators, diagnostic testing, and personal protective equipment.[2] These unprecedented circumstances have also presented a challenge for the conduct of clinical trials. The paramount concern is the dreaded possibility of dissemination of the virus among—but not limited to—clinical trial participants, other patients, and health care workers. Furthermore, shortages of medical and support staff, inadequate monitoring, travel restrictions, interruptions of supply chains for investigated products, shortages of medical equipment and personal protective equipment, uncertainty over continued funding, and restrictions imposed by sponsoring institutions are some of the many obstacles facing clinical trials during the pandemic.

SUSPENDED CLINICAL TRIALS

We queried the US National Library of Medicine's website ClinicalTrials.gov to identify clinical trials that were suspended as a result of this burgeoning pandemic.[3] We chose March 1 to April 26, 2020 as the search period given the significant rise in COVID-19 cases from March forward in the United States. The reason for the suspension was recorded as reported by the studies. We identified a total of 1052 suspended clinical trials during the specified period, out of which at least 905 reported the reason for the suspension as the COVID-19 pandemic.

GUIDELINES AND ALTERNATIVES FOR CLINICAL TRIALS

The suspension of clinical trials has a significant impact on patients, especially those with end-stage diseases (eg, stage IV cancer) that have not responded to traditional treatment regimens; for these patients, drugs offered by clinical trials often present their only hope for potential survival. Patients who live with debilitating chronic conditions also stand to lose the potential therapeutic benefits offered by clinical trials.

The United States Food and Drug Administration issued several guidelines to aid clinical investigators in deciding whether to continue or “temporarily” suspend a study.[4] Similar guidelines have been issued by other regulatory agencies throughout the world (eg, the Medicines and Healthcare Products Regulatory Agency in the United Kingdom,[5] the European Medicines Agency,[6] and the Australian Therapeutic Goods Administration[7]).

The key consideration in the decision to suspend or continue clinical trials is the safety of trial participants. Clinical investigators should assess the risk-benefit ratio of conducting the study and whether the study's benefit to patients outweighs the potential harm imposed by COVID-19. This decision should be made in light of whether local transmission of COVID-19 is controlled, patients’ medical status, clinical response, investigational product availability, and institutional, state, and federal regulations. Indeed, this decision could be individualized to each participant's condition and clinical status. When feasible, investigators may consider the use of virtual visits and telemedicine as alternatives to in-person clinical visits. If diagnostic assessments (eg, labs and imaging) are required and/or medications require administration in a health care setting, local centers and providers could be an alternative. For example, if a participant who requires in-hospital infusion of an investigational drug is not able to come to the clinical trial site, an arrangement for home infusion by trained personnel should be considered. However, the safety of the investigational product and adequate storage conditions should be assessed and monitored on a regular basis. When the risk of COVID-19 limits the ability to obtain signed informed consent, electronic methods could be employed, among other provisions to enable online study enrollment. Information technology could also be used to allow on-site monitoring given travel limitations and inadequate staffing.

When alternatives are not available or not feasible, and/or the risk of becoming infected by the virus outweighs the benefit of the trial, investigators may consider delaying assessments and return to standard-of-care treatments, if available. Studies may deviate from the original protocol's frequency of clinical visits, lab testing, imaging, and other interventions. Any modifications to protocols or any missing information as a result of the pandemic (eg, missed visits or testing) should be clearly documented in a way that explains the reason for the deviation from the original protocol (eg, “due to COVID-19”) and reported to the institutional review board. Changes that are intended to reduce or eliminate COVID-19's risk to patients’ lives could be implemented before institutional review board or Food and Drug Administration approval.[4] Patients should be kept informed and updated about all study changes.

RESUMPTION OF CLINICAL TRIALS

As many countries pass the peak of COVID-19 infections and deaths, and as the world adapts to the pandemic, lockdown restrictions are being eased worldwide, which could allow for the resumption of clinical trials. The same guidelines that govern the continuation of clinical trials could be applied to resuming them. The key factors are assessing the risk of disease transmission to both the study participants and staff in light of the clinical benefit of the trial and the number of positive cases in the community. Virtual and off-site visits could be used whenever feasible to minimize the risk of transmission. At our institution, we implemented a phased clinical research reopening, starting with studies in which all research staff are working remotely and patients are demonstrating benefit from the trial and then prioritizing studies that do not increase in-person visits, blood transfusions, or biopsies and that can be conducted with remote research staff. Departments will prioritize studies based on available resources and the clinical benefit and relevance of the study. All routine monitoring visits are currently being conducted remotely. This escalation plan will be adjusted according to predefined metrics assessing the trends in positive cases and the available healthcare resources in the community.

CONCLUSIONS

Ensuring patient safety should assume the greatest importance in decisions to continue or temporarily suspend a clinical trial in compliance with institutional and governmental regulations. Whenever feasible, alternatives to the original protocol could be sought to allow the continued enrollment of study participants in clinical trials and protect them from the risk of contracting the virus. Awareness of regulatory provisions whilst adapting, planning, and maximizing use of all available technology can help mitigate the paralyzing impact of the pandemic on landmark high-quality studies and ensure continued scientific progress whereas strictly monitoring patient safety.