COVID-19 trial co-enrolment and subsequent enrolment

The COVID-19 pandemic has led to many clinical trials around the world assessing all stages of infection, from prophylaxis to the treatment of severely ill patients who are dependent on a ventilator. In our experience, if the patient's medical condition deteriorates despite the intervention of one clinical trial, the attending physician, patient, or family members might request that the patient be enrolled in a second or third clinical trial.

This request is causing much confusion among clinicians and patients. Industry sponsored trials often prohibit co-enrolment or sequential enrolment and institutional review boards will often not allow this as well.¹ However, there is no regulatory prohibition on co-enrolment in the USA and in many other countries. The enrolment of one patient into more than one study (when a patient fulfils all inclusion criteria and has no exclusion criteria for both studies) has been studied sporadically in trials of mechanical ventilation and resuscitation, and in adult and paediatric critical care.2, 3

Concerns about co-enrolment centre on safety, consent issues, health-care worker reluctance, and scientific integrity. Yet available literature suggests that co-enrolment does not influence a patient's safety, the trial outcome, or adverse effects provided that the eligibility criteria of every study are correctly applied and that single-study treatments are not subadditive or superadditive.⁴ Guidelines can be created for applicable criteria to be satisfied before co-enrolment is approved.⁵ The statistical hurdles can be addressed. In most cases, each trial can be analysed separately and validly with the use of standard intention to treat principles; selection and other biases can be avoided if enrolment into the second trial is not dependent upon randomised treatment in the first trial; and valid interaction analyses can be done for each trial by considering the patient's status in the other trial at the time of randomisation in the index trial.¹

The cornerstones of ethical conduct of research include respect for patients, beneficence, and justice. With COVID-19 infection, access to a second treatment protocol where no other treatment is available should, at times, be strongly considered. In reviewing studies, both the Institutional Review Board and physician researchers should look more in depth at prohibitions on co-enrolment and ask for a justification of any prohibition if it will not affect the goal and the implementation of the study.