“It was the best of times; It was the worst of times”
COVID-19 has forced a re-think of clinical trial design, enrollment, and execution. Among the challenges of clinical trial investigators are the ethical principles of compassionate (“off-label”) use of investigational therapies vs. randomized, placebo-controlled trials [1-2], as well as the logistical challenges of manufacture and distribution of investigational therapies .
Here, we discuss a peculiar and paradoxical challenge of clinical trials accrual in a pandemic. For any clinical trial – whether it be for cancer, Alzheimer’s disease, or diabetes – identifying and enrolling patients is a well-known challenge. For example, targeted therapies for cancers may enroll patients with rare mutations, who may be difficult to identify and to enroll onto a clinical trial at a limited number of cancer centers . It is peculiar that, as millions of patients are infected by SARS-CoV-2, that there are insufficient patients for clinical trials, whose accrual goals are typically a few hundreds of patients.
For diseases like cancer or Alzheimer’s disease, the incidence is relatively constant. In contrast, for a pandemic like COVID-19, the incidence can change dramatically with aggressive public health interventions such as social distancing, masking, etc. At a given hospital, by the time clinical trials are open to enrollment, the majority of patients with COVID-19 may have largely recovered or died (Figure 1). For example, China’s CanSino Biologics is unable to test and develop its SARS-CoV-2 vaccine candidate (Ad5-nCOV) in phase III trials domestically , because SARS-CoV-2 has been so well controlled in China. Similarly, an early randomized controlled trial of convalescent plasma was terminated early due to declining incidence of COVID-19 in Wuhan, China .
Clinical trials accrual for COVID-19 is not just a problem in China . As inDemic Foundation’s scientific advisory board member – Dr. Robert Dickson at University of Michigan – describes, “Enrollment has been a real problem…they ramped up clinical research operations at centers like [ours] during the surge, and now we’ve just got a trickle of cases. Meanwhile, there are loads of cases elsewhere but that’s not where the research coordinators are.”
Hundreds of COVID-19 therapies and vaccines are being developed in the USA and around the world. The strength of an “investigator-initiated” approach is in fostering diverse ideas and independent thinking. However, because of the unique challenges of the pandemic, clinical trials investigators may also consider “just-in-time” or “consortia or cooperative group” approaches, similar in spirit to NSABP or Alliance in cancer research. In addition, a “virtual trial design” may allow for geography-agnostic patient enrollment, as COVID-19 shifts from a few urban centers to many rural communities.
Undoubtedly, declining COVID-19 incidence in any region is a blessing. Because the worldwide incidence of COVID-19 is stable or even rising, centers of clinical excellence that conduct clinical trials must develop novel ways of enrolling patients. That way, regions & countries that suppressed an initial wave of COVID-19 will be better prepared for the future. This may require public-private or intergovernmental collaboration, but it is the only way to protect the world against COVID-19 and future pandemics.
 Kalil, Andre C. “Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics.” Jama 323.19 (2020): 1897-1898.
 Lurie, Nicole, et al. “Developing Covid-19 vaccines at pandemic speed.” New England Journal of Medicine 382.21 (2020): 1969-1973.
 Cocco, Emiliano, Maurizio Scaltriti, and Alexander Drilon. “NTRK fusion-positive cancers and TRK inhibitor therapy.” Nature Reviews Clinical Oncology 15.12 (2018): 731-747.
 Zhu, Feng-Cai, et al. “Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial.” The Lancet (2020).
 Li, Ling, et al. “Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial.” Jama (2020).