Clinical Trials in the Age of Pandemics
Authors: Martin J. Edelman, Crystal S. Denlinger, Eric A. Ross, Margaret von Mehren
Journal: Journal of the National Comprehensive Cancer Network (2020)

C linical trials play a unique role in the treatment of patients with cancer.Although only a small percentage of patients actually enter studies, enrollment onto a trial is considered a "standard of care" for virtually all patients with advanced or locally advanced cancer.Even for diseases for which therapeutics have achieved high cure rates, there are trials evaluating strategies to minimize duration and toxicity of treatment.The effort required to formulate, activate, accrue, and analyze trials is considerable; even small trials require substantial resources.Large, definitive trials may consume hundreds of person-hours, span the globe, and cost in excess of $100 million.Before the current pandemic, experts recognized that the existing system imposed an undue regulatory and administrative burden on investigators and had arbitrary entry criteria that restricted enrollment. 1,2he COVID-19 pandemic has disrupted all aspects of social, work, and economic life throughout the world. 3,4Although completion of clinical trials in cancer is certainly not the most pressing issue at this time, it is important to patients, physicians, and sponsors.The substantial morbidity and mortality for patients with cancer is not going to go away.Furthermore, patients with cancer with COVID-19 infection are at high risk for adverse outcomes. 5A marked decline in screening and accrual to trials within the National Clinical Trials Network has been noted. 6Regulations governing clinical trials allow for the occurrence of study modifications to be implemented before Institutional Review Board (IRB) approval without adverse action only when it is necessary to eliminate apparent immediate hazards to the subject. 7his allows investigators to modify protocol-required visits or make other protocol changes if it is in the best interests of the subject.These deviations must be reported to the IRB of record within 5 days.][10] As previously noted, modifications can be made in the interest of patient safety without adverse action.Additionally, if modifications to protocol assessment schedules can be proactively identified to minimize risk to subjects, these can be submitted to the IRB of record as a planned deviation before implementation, with short turnaround times from submission to IRB approval to optimize subjects' outcomes.The NCI guidance contains procedures for forwarding some investigational agents directly to patients.However, the guidance is nonbinding on industry, may result in further confusion, and does not address the next disruptive event.The NCI guidance applies only to NCI-sponsored research, and the FDA guidance can be interpreted variably by sponsors.Critically, substantial burden is placed on investigators and their institutions in terms of absorbing the risk of being deemed noncompliant with the IRB-and sponsor-approved protocol.Such risk could include significant financial liability if sponsors penalize institutions for such "noncompliance" as well as the potential for adverse action by the FDA (eg, issuance of a form 483).It is important to recognize that, regardless of when the current pandemic ends, similar disruptive events from disease and/or natural or manmade disasters will inevitably occur in the future.Planning for such events is a necessity.The following are a series of specific proposals for emergency trial guidelines that we hope will start discussions and policies in anticipation of future disruptive events to mitigate their impact on clinical research efforts in oncology.