COVID-19: Time to Rethink the Randomized Controlled Trial and Consider More Efficient and Ethical Ways of Gaining Clinical Knowledge

Abstract

Many academics are advocating for the strict adherence to randomized controlled trials (RCTs) in order to find treatments for CoViD-19. The prevailing orthodoxy within the academic establishment is that we should not encourage the use of new treatments for CoViD-19 until those treatments have demonstrated statistically significant clinical benefits in an RCT. Until that point, only patients enrolled in clinical trials should have access to new treatments, no matter how promising the treatment and no matter whether the patient might otherwise be at high risk of death. However, the fundamentalist belief in the RCT fails to acknowledge the limitations of the RCT in a rapidly changing, highly complex, enormously combinatorial and evolving system in which knowledge is continually being generated by clinicians around the world; the situation during the CoViD-19 pandemic. For our patients’ sake, we need efficient and ethical means of both providing treatment and gaining knowledge during this pandemic. The RCT should not be eliminated, but it's primacy reconsidered. From an ethical perspective, discouraging or prohibiting access to off-label/compassionate-use therapies outside of the RCT creates the potential for large disequilibria of the needs of current and future patients, in addition to forsaken clinical information from wide-scale observation. Depending on the pre-test totality of all knowledge of a treatment, it is difficult to even know if the result of an RCT is a true or false result. And importantly, depending on the pre-test probability, the result of the RCT might only give marginal (or no) extra surety regarding the effect of the studied treatment. A crucial, existential concept related to knowledge acquisition is whether the cumulative observation of clinical effects without a control provides any useable information. The RCT attempts to isolate a variable using the scientific method. Yet there are systems constraints within acute clinical medicine regarding reproducibility, and this can significantly affect the fidelity of knowledge that the RCT is able to provide. In this regard, the RCT has proved to be disappointing in providing efficient clinical knowledge in acute care medicine over the decades. Even proponents of the RCT have conceded that there has been a paucity of large RCTs that have shown a clear beneficial treatment effect. A major funding body has de-prioritized the RCT. We are half a year into the lethal CoViD-19 pandemic. Yet, the RCT paradigm has seemingly contributed little and has significantly lagged behind rational treatment innovation guided by increasing understanding of the disease. One well publicized RCT demonstrated a clinical benefit for a drug that otherwise had a high pre-test probability of effect. However, many clinical units were already using this drug as part of their treatment protocols and were achieving highly competitive survival rates; saving lives through rational innovation while continuously updating knowledge of drug and disease-specific effects. Should patients be empowered with the complete accumulated knowledge of an intervention as part of informed consent, before enrolling in an RCT? To be sure, the RCT has a role. However, with it's history of being an inefficient clinical-knowledge-gaining paradigm, we should not necessarily wait for clinical trials before introducing reasoned treatment approaches for our most vulnerable CoViD-19 patients.