Life After COVID-19 for Cancer Clinical Trials

COVID-19 has had a huge impact on clinical research, including ongoing clinical trials of radiation therapy. Although we do not know what course the pandemic will take, cancer will continue to be diagnosed. It is therefore imperative that we pursue our efforts to improve cancer treatments through randomized trials and other well-conducted research. Here, we reflect on the mitigations put in place in the United Kingdom and at our clinical trials unit (CTU) during the pandemic and how they may change the future clinical trials landscape.

Trial Governance

During the pandemic, processes were defined for rapid review of COVID-19 research by ethics and regulatory committees. This may not be scalable across a wider portfolio of clinical research in the long term but, while protecting the scientific, clinical, and ethical integrity of cancer research, we must seize the opportunity to retain some pragmatism and reduce the bureaucracy associated with the setup and regulatory governance of clinical trials. The use of digital signatures that satisfy audit and regulatory requirements would seem a “quick win” in reducing the paper trail that burdens many areas of clinical trial research administration.

Capacity for Clinical Trials

Within many health care systems, priority for research has been given to COVID-19–related initiatives, leading to near zero capacity to support other clinical trials. In the United Kingdom, many sites temporarily paused recruitment of patients into cancer trials and setup of new studies. Where it was safe to do so, sponsors kept trials open. This allowed patients already enrolled to continue with treatment and, recognizing that in multicenter studies the pandemic would peak in different areas at different times, provided access to clinical trials should the local investigator believe this was appropriate. Exceptions were largely where eligibility or safety monitoring required real-time analysis of patient samples at a central research laboratory that was temporarily closed to comply with government “lockdown” conditions. As clinical trial activity resumes, the continued viability of individual trials has been assessed by sponsors and independent oversight committees. Reliance on a single laboratory is a potential “pinch-point” for restart and, where the science allows, should perhaps be avoided in the future.

Risk Reduction for Trial Participants

A number of risk reduction strategies have been widely implemented and have potential to lead to longer-term efficiencies in trial conduct. Telemedicine and approaches to remote consultation rolled out as part of standard care during the pandemic may well endure. Many trials already permit telephone follow-up, and this is likely to increase. Where they are not required for safety, arbitrarily tight or unnecessary timelines on eligibility assessments could be removed or relaxed or local standards accepted. This may improve generalizability of clinical trial results. In the future, we could see more permissive eligibility criteria in phase 3 confirmatory trials, flexibility around where assessments are performed, and triggered visits to the cancer center for patients experiencing side effects or symptoms of relapse rather than visits mandated for all trial participants.

Historically, informed consent has typically involved face-to-face discussions between the clinical team and the patient. These discussions could involve multiple team members at different timepoints; although they usually coincide with visits for clinical assessments, this is not always the case. Where protocols do not mandate face-to-face consultation, we have therefore supported sites moving to remote consent procedures, providing they are adequately documented. If site staff and patients are comfortable with this approach, it will remain as an option post COVID-19. Fully functional e-consent processes will no doubt become more widespread in the future. Whether remote consent and remote follow-up approaches affect recruitment or retention of trial participants remains to be seen.

The risk:benefit ratio of all aspects of treatment needs to be carefully considered while COVID-19 is a pandemic in hospitals and the community. This appraisal of each assessment should be carried over into future clinical trials. Greater distinction between the necessary and the “nice to have,” balancing what is key to ensure patient safety and answer the research question against the opportunity to address secondary research hypotheses, could reduce burden on patients and participating sites alike, making trials sleeker and easier to deliver.

Data Capture

In the United Kingdom, like in many parts of the world, the pandemic led to home working en masse, and CTUs were no exception. At the Institute of Cancer Research-Clinical Trials and Statistics Unit, our established use of electronic remote data capture enabled data collection to continue; there was minimal impact on the ongoing oversight, review, and central monitoring of data, with CTU staff able to remotely and securely review and query data entered by participating sites. The pandemic has accelerated our phasing out of older technologies (eg, use of fax) and forced rapid adaption of other systems that previously required office-based working.

At the height of the pandemic, other priorities at sites and the move to home working saw a reduction in data submissions. Where trial visits or assessments were missed or delayed owing to COVID-19, consistent recording will assist with the interpretability of trial data. The UK clinical trials community are engaging with NHS Digital so that COVID-19–related data for clinical trial patients can be captured through routine data sets. Greater sharing of data and a paradigm shift in access to data routinely submitted to national data sets could revolutionize data collection in clinical trials. We must capitalize on the rapid progress that COVID-19 research has driven in this area.

The collection of patient-reported outcomes, often key in trials of radiation therapy, has perhaps been more affected by COVID-19 than physician-assessed toxicity assessments. In our trials, paper questionnaires are typically given out in the clinic or mailed to the patient’s home address directly by CTU staff; in many cases, this has paused during home working. The use of electronic patient-reported outcomes in academic multicenter clinical trials is increasing, but implementation requires careful thought and many envisage that a mixed-methods approach will be preferable to minimize participation bias. The increase in digital literacy and the drive for app-based COVID-19 symptom reporting and alert tools is, however, an opportunity to revolutionize how we interact with and collect data from trial participants.

Data Analysis

The impact of COVID-19 on the analysis of clinical trials will depend to some extent on the stage of the trial during the pandemic. The risk of COVID-19 infection, comorbidities, and mortality will need to be accounted for, or factored in. Advanced cancer trials with death as a primary endpoint, where data were maturing around the time of the pandemic, may need to account for competing risks. Trials in good-prognosis early disease with progression endpoints for which recruitment was just taking off and events are not expected to accrue for several years will be less affected. The impact of missing data, including patient-reported outcomes, will also need to be carefully assessed on a trial-by-trial basis.

Case Studies

Trials testing radiation therapy hypofractionation or treatment de-escalation are anticipated to be among the first to restart widely. PACE-C (NCT01584258; testing 5-fraction prostate radiation therapy in high-risk patients) continued to recruit throughout the height of the pandemic, albeit with recruitment in April and May 2020 at 17% of pre–COVID-19 levels. Enthusiasm for the trial remains high given the reduction in patient visits for those allocated 5-fraction treatment, with accrual in June already at pre–COVID-19 levels. The protocol has been amended to temporarily relax entry criteria relating to the duration of hormone therapy permitted before radiation therapy, reflecting the change in clinical management during COVID-19. This will mean that a cohort of patients will still have the opportunity to join the trial, albeit later than they might have otherwise done. Hormone therapy duration will be accounted for in statistical analyses.

PRIMETIME (ISRCTN41579286) is a single-arm study evaluating omission of radiation therapy in patients with very low-risk breast cancer. Risk scoring requires central testing of Ki67 performed at 1 of 3 central laboratories. One laboratory temporarily closed due to COVID-19, and the other 2 had reduced capacity; therefore, new registrations to the study for Ki67 testing were halted. Samples already received were shipped to the 2 open laboratories for processing, and recruitment into the main trial during April and May was maintained at 28% of pre–COVID-19 levels. The study has now fully reopened.

The restart of more complex radiation therapy trials is likely to be slower. PIVOTALboost (ISRCTN80146950; testing prostate + pelvic node radiation therapy with or without an imaging defined tumor boost) was recruiting at a rate of 34 patients per month before the pandemic and had reached approximately 40% of its accrual target. In April and May 2020, recruitment fell to 4% of pre–COVID-19 levels. Many UK departments are now restarting prostate radiation therapy, but estimates suggest it may take up to 6 months for recruitment rates to achieve prepandemic levels; the increased complexity of planning and treatment delivery required for the trial may limit a site’s capacity while the backlog of patients awaiting treatment are seen. Coincidentally, a recent protocol amendment permitted the use of cone beam computed tomography for image guidance as an alternative to fiducial markers. We anticipate that this option will accelerate restart activities in sites where surgical capacity for insertion of fiducials remains limited. Although the recruitment period may be a little longer than planned, the extended follow-up period of patients recruited before the pandemic may offset timelines for analysis that is event driven.

Summary

The COVID-19 pandemic has raised the profile of clinical research and randomized trials among the general public. This could be an opportunity for wider engagement and participation in cancer clinical trials. As a community we need to make our clinical trials more efficient: accelerating the time from study concept to changing practice, building on routine clinical practices, and utilizing routinely collected data where appropriate to reduce research waste. Now more than ever we must strive to design and deliver efficient clinical trials that answer key questions that have the potential to improve the lives of patients with cancer.