The risks posed to patients with cancer by the current COVID-19 pandemic demand rapid structural changes in healthcare delivery, with many positive changes likely to continue long term. An immediate critical reassessment of trial methodology based on clinical and scientific priorities is essential to ensure the resilience of clinical cancer research and optimize patient-centered care.
Adaptations of clinical care and research in response to COVID-19
Institutions offering clinical trials typically embed research into normal practice settings, reflective of the normalization of research participation, with trial treatments becoming bona fide treatment lines. Oncologists now routinely use a wide variety of drug classes, managing dosing and myriad toxicities to balance patient safety and anti-cancer efficacy for patients in trials and those not in trials. Although patients in trials might be assumed to be at greater risk than those not in trials, given the uncertainty of novel treatments or combinations, the latter are also exposed to certain risks from standard-of-care treatments, which are often substantial yet do not often mandate trial-like patient-monitoring intensity. Therefore, considering successful adaptations to standard-of-care management that optimize patient safety and anti-cancer efficacy during the COVID-19 pandemic may also be informative about positive adaptations to clinical trial protocols.
National and international clinical authorities, including NHS England, ESMO and ASCO, have released recommendations for how anti-cancer treatment should be prioritized or adapted during the COVID-19 pandemic. The consensus is to focus on treatments that provide greatest clinical benefit, to reduce potential risk to patients by adapting treatment regimens and to lessen COVID-19 exposure by minimizing hospital visits. Physicians and patients have quickly adapted to new ways of interacting (e.g., through telephone or video consultations2) and new ways of perceiving and balancing risks (e.g., reducing the number of blood tests or imaging evaluations, or altering treatment regimens, including avoiding immunosuppressive drugs and those with a propensity to cause pneumonitis). Some adjustments are evidence based, while others are simply rational or pragmatic and therefore have uncertain short- and long-term impact. Given these uncertainties, such adjustments are therefore best made through shared decision-making with patients, with due regard to the local situation and outlook.
Many physicians and patients hope that certain adaptations made in response to COVID-19 will continue beyond the pandemic and will stimulate further innovation in healthcare and research delivery. These changes present an opportunity for new trials to more closely mirror new real-world treatment standards and methods while still ensuring trial integrity and scientific validity and, in parallel, addressing concerns that clinical trial populations do not closely resemble real-world populations treated for the same condition. The extent to which changes should be implemented will vary by trial type and phase. For first-in-human, dose-finding and new drug-class trials, some adaptations may be harder to implement, given the balance of competing risks, but should still be considered. Conversely, for randomized phase 3 trials with a standard-of-care comparator, the study design should maximize translatability to routine practice.
Furthermore, patients may understandably not be attracted to randomized trials with a ‘standard-of-care’ arm with a greater intensity of study assessments and hospital visits than normal practice. All efforts must be made to ensure trials are as patient centered as possible, and this will help increase research efficiency.
National regulatory authorities have responded rapidly by facilitating protocol flexibility and adaptations to ongoing trials during the COVID-19 pandemic, ensuring that these trials can continue in a safe and patient-centered manner5. Many study centers have stopped enrollment into ongoing studies and have stopped opening new studies, with considerable uncertainty about how long restrictions will continue. Some major challenges for clinical cancer research will persist long term. Therefore, ‘future-proofing’ of trials must be considered on the basis of the assumption that the COVID-19 challenge might not fully dissipate and that further zoonotic disease may emerge. Robust adaptations should render the field more resilient to future pandemics. However, it remains important to distinguish between trial-protocol adaptations that should occur regardless of COVID-19 and contingency measures that should come into effect if perceived risks for certain protocolized trial visits or assessments become too high. Where these do not fully coincide, a robust contingency plan should be included prospectively in new and ongoing trials.
Specific considerations from the COVID-19 crisis
COVID-19 presents specific challenges to clinical research for study centers, investigators and patients. The precise risks posed to specific cohorts of patients with cancer remain unknown and will become clearer in the next few months with prospective registry studies, including the UK Coronavirus Cancer Monitoring Project, although early indications suggest a particularly high risk to some patients. Potential risks associated with COVID-19 must be discussed with new patients at the time IC is provided, and with ongoing patients at the next available opportunity, contextualized with the patient’s own background risk.
Many study centers are halting trial enrollment and delaying the opening of new trials14. A shortage of study personnel on site, due to staff redeployment, shielding or illness, affects the ability to deliver clinical trials safely and to minimize risks for patients and staff. The geographical variance of the pandemic and distinct methods used by countries to contain their own (often regional) epidemics will make COVID-19 risk assessment for clinical research a local issue for study sites, at least for the time being. It seems prudent not to open new trials while there is a rising or high prevalence of COVID-19. The optimal strategies and timings for restarting normal trial activity remain unclear. However, progress in cancer research must continue. In areas in which COVID-19 is epidemic or endemic, study centers should ideally have a low-risk area for patients in trials, where all patients and staff who enter are screened for common COVID-19 symptoms and fever. All patients and staff should wear appropriate personal protective equipment. The value of screening potential or ongoing study participants for COVID-19 through the use of RT-PCR, antigen and/or serology tests is currently unclear, but such screening seems prudent where available, as does regular testing of staff. It is unclear how patients with COVID-19-like imaging changes, symptoms or confirmed infection on trial (or during screening) should be managed — protocols should include trial-specific guidance. In addition, whether COVID-19-positive patients should contribute to certain trial endpoints and dose-limiting toxicity assessment where COVID-19 is a possible cause of death or adverse events needs to be assessed, as well as how to perform sample-size calculations that account for new background rates of COVID-19-related infection, morbidity and mortality in the trial population. This is a major issue for ongoing trials, and aside from possible requirements for sample-size adjustment, imbalances between study arms in their infection rates may affect the interpretation of results. Trial-specific solutions are required, informed by policy and emerging data. In general, we would advocate a pragmatic approach, with the assumption that COVID-19 will become endemic and its associated morbidity and mortality will become new realities that must be accounted for throughout the spectrum of clinical cancer research, with protocols having inbuilt contingencies, flexibilities and appropriate sample sizes. Prioritization of primary trial objectives over other objectives will help ensure scientific integrity while still allowing researchers to learn as much as possible from each patient (as is safe and practicable). Changes and compromises made can be ‘de-escalated’ as COVID-19 recedes and depending on the availability of effective vaccination and therapeutics. The inflexibility of current protocols has been exposed by the current pandemic, and a new level of robustness is needed for resilience to COVID-19 and potential future threats.
Research studies should be prioritized for (re-)opening on the basis of risk/benefit assessments, and this should mirror the methods used for the prioritization of standard-of-care treatments1. While all phases of drug development should continue as fully as possible, where required, prioritization should be given to trials with the greatest likelihood of therapeutic success (balanced with acceptable study risks) or for which patient populations have the poorest prognosis or no standard treatment options. ‘Placebo-only’–controlled studies should generally be given lower priority. Patients must be counseled about the competing risks of COVID-19, including treatment interruptions and potential difficulties in dealing with treatment complications.
Remarkable changes in healthcare have occurred rapidly in response to the COVID-19 pandemic, many of which are positive and will be continued in the longer term. Unmitigated challenges will have a profound ‘knock-on’ effect on clinical cancer research. To find new therapies, researchers and clinicians must therefore continue to adapt to the new normal of healthcare delivery and risk management. Adopting a patient-centric view of clinical research and modernizing clinical trial protocols may enhance patient safety and experience while improving research efficiency and outcomes.
Reference & source information: https://www.nature.com/
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