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September 3, 2020

The Day After COVID-19—Time to Rethink Oncology Clinical Research

Author Affiliations
  • 1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
JAMA Oncol. 2021;7(1):23-24. doi:10.1001/jamaoncol.2020.4240

The declaration of the coronavirus disease 2019 (COVID-19) as a pandemic by the World Health Organization on March 11, 2020, has led to unprecedented measures such as social distancing and economic lockdown by many international governments to combat viral spread and to prevent health care systems from collapsing. Regardless of its ensuing course, the pandemic’s effect will undoubtedly linger in many aspects of cancer care and research, including oncology clinical trials.

New Competing Risks in Decision-making

There is a general consensus among multidisciplinary teams that life-saving and value-proven interventions should be offered to patients with cancer despite the risks of COVID-19. While the conduct of clinical trials has been a core component of cancer care, both as a tool to advance the field and as an access to investigational treatments, the risk-benefit ratio for trial participation has become obscured during the pandemic.

Clinical trials, particularly those evaluating novel agents, mandate frequent tests and hospital visits for assessment without a guaranteed return of therapeutic benefit. The risk of treatment-related adverse events, compounded by the threat of increased exposure to the contagion, may negatively tilt the balance for many patients and physicians who are contemplating clinical trial options. Conversely, many patients with cancer who are enrolled in clinical trials have expressed a strong interest in continuing trial participation despite the heightened risk.1 Multiple surveys are now under way to elucidate the views of patients and physicians on the provision of cancer care and conduct of clinical trials in the COVID-19 era.2,3

Improving the Value of Clinical Trials

The true effect of COVID-19 on cancer research has yet to be fully determined, but the early effects have been profound. As a consequence of government-sanctioned city lockdowns and social distancing, many research laboratories around the world underwent temporary closure, and multiple clinical trials were paused or terminated. Recruitment has slowed or ceased, and yet running costs remain substantial. Resources must be prudently allocated to optimize the value of clinical trials and prevent a deceleration of this critical facet of cancer research. The following are important considerations on the road ahead.

Raising the Bar in Clinical Research

Combinatorial approaches in the current oncology drug development environment have been largely empirical or based on insufficient scientific rationale. Likewise, go-no-go decisions from early to late phase studies are often made without data-driven directions. The message from the pandemic wake-up call is clear—our society can no longer accept incremental clinical trials. The scientific community must share its collective wisdom to raise the bar to conduct clinical trials that have the greatest potential to yield meaningful outcomes, supported by strong biological hypotheses and guided by validated predictive biomarkers.

Revamping Trial Design to Increase Efficiency

Unvalidated surrogate end points should not replace overall survival and quality of life as the most relevant outcomes in randomized clinical trials.4 The use of adaptive trial designs, such as in the I-SPY2 study,5 provides agility to the drug development process, potentially expediting the availability of novel, efficacious treatments.

Avoiding Waste

The sharing of nonclinical and clinical protocols, methods, and results within the research community will reduce redundancy and should be possible in the precompetitive and postcompetitive stages of drug development. Investigation of “me-too” drugs or drug combinations without a clear path to improve therapeutic index should be discouraged.

Addressing Relevant Questions

Research endeavors challenging value-unproven practices that consume resources and time should be supported. An example is the evaluation of optimal duration of immune checkpoint blockade among durable responders. Emerging technologies such as ultrasensitive liquid biopsies may shed light on this question.

Rethinking Clinical Trial Dogmas

Over the years, clinical trial operations have become progressively more complex in an effort to increase transparency, maximize data accuracy, and ensure pharmacovigilance. Despite the incorporation of modern tools, such as web-based data sharing and capture platforms, trials remain heavily bureaucratic. The pandemic has led to a careful scrutiny of the value of some practices that were once thought to be compulsory. For example, the interminable wet-ink signatures for trial documents should be reduced to what is essential and converted to validated and environmentally friendly digital sign-offs. Duplicate requests by different sponsors for investigator credentials, site feasibility, and declaration of conflicts may be circumvented using an open online database containing accessible information for all.

Clinical trials operate under regimented protocols, often necessitating multiple visits. Phase 1 studies in particular require several safety visits during early treatment cycles, and many of these are for routine physical examinations. The value of serial physical examinations in asymptomatic patients is the subject of scrutiny.6 In the COVID-19 era, these extra, perhaps clinically excessive, visits may increase the contagion exposure hazard for both patient and provider. However, care must be taken not to compromise vigilance, as physical examination remains a crucial assessment tool. Nonetheless, for most cases, a telemedicine appointment with blood tests collected in local laboratories may suffice, negating safety concerns and potentially saving time and resources.

Further, eligibility criteria of unproven value should be eliminated in clinical trial protocols. An example is the exclusion of patients living with HIV despite an undetectable viral load from immuno-oncology trials.7 The same is true for patients with chronic, controlled infectious diseases such as hepatitis B or C. These dogmas have been reproduced in protocols over time without sound justifications. By excluding such patients, the external validity of studies is compromised, and resources may be required to investigate experimental agents specifically in these populations.

An Opportunity for Decentralization

The COVID-19 pandemic has prompted physicians to adapt their clinical practice and design innovative methods to safely provide optimal care. Academic interactions have now gone virtual; patient cases are discussed in multidisciplinary teams via remote tumor boards. Many clinic visits have been deferred or conducted via telemedicine networks, and certainly in the future this option may be preferred for patients who otherwise would have to travel long distances. Dosing schedules of cancer drugs have been modified where acceptable, and oral treatments, where available, have been leveraged to limit hospital visits. Administration of treatment in local satellite centers has also been explored as well as the feasibility of local or even home-based blood draw services and treatment infusions.8

A potential future framework may see patients undergoing tissue diagnosis, molecular characterization, and staging locally. Virtual tumor boards and discussions may take place before any hospital visit with participation of physicians from local and academic centers. Centralized artificial intelligence models could facilitate the search for suitable clinical trials; if eligible, the patients’ initial appointments with the principal investigators may be conducted via telemedicine to further determine suitability and interest from both parties. In the event that no suitable options exist, alternative treatment pathways may be provided.9

A Restart: A Call for Action

The COVID-19 pandemic has had a profound effect on societies worldwide. The effects, both physical and psychological, will remain long after its eradication. However, our resilience to adapt has been showcased in efforts to overcome this devastating virus. Lessons learned from this pandemic can reshape our clinical practice for the better. Clinical research must be leaner and more efficient. It is time to incorporate new technologies, revisit old practices, and move forward toward better outcomes for our patients.

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Article Information

Corresponding Author: Lillian L. Siu, MD, Princess Margaret Cancer Centre, 700 University Ave, Hydro Building, Seventh Floor, Room 7-624, Toronto, ON M5G 1Z5, Canada (lillian.siu@uhn.ca).

Published Online: September 3, 2020. doi:10.1001/jamaoncol.2020.4240

Conflict of Interest Disclosures: Dr Araujo reported receiving honoraria from GlaxoSmithKline (GSK). Dr Watson reported receiving travel grants from Bristol Myers Squibb and AbbVie and honoraria from Pfizer. Dr Siu reported receiving compensation in 2020 from Merck, Pfizer, Celgene, AstraZeneca/MedImmune, MorphoSys, Roche, Geneseeq, Loxo Oncology, Oncorus, Symphogen, Seattle Genetics, GSK, Voronoi, Treadwell Therapeutics, Arvinas, Tessa Therapeutics, Navire Pharma, Relay Medical, Rubius Therapeutics, Novartis; receiving research grant support (clinical trials for institution) from Novartis, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, GSK, Roche/Genentech, Karyopharm Therapeutics, AstraZeneca/MedImmune, Merck & Co, Celgene, Astellas Pharma, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks Labs, Avid; and being a stockholder in Agios Pharmaceuticals (spouse), and her spouse is the cofounder of Treadwell Therapeutics.

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