Introduction
On December 31, 2019, a cluster of cases of pneumonia of unknown etiology was reported in the city of Wuhan, China, and later identified as being caused by a novel coronavirus. 1 The ability of the novel Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2; hereafter referred to as COVID-19)2 to infect human hosts and be transmitted among individuals rapidly evolved into a global outbreak with 2.2 million confirmed cases in 211 countries as of April 17, 2020, 18:00 GMT-6 (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Though the majority (~80%) of the confirmed COVID-19 cases develop a mild condition, a smaller percentage (~15%) of patients with confirmed COVID-19 require hospitalization and some develop a severe condition (~5%) that require mechanical ventilation in the first 24 hours of hospital admission.3 Clinical complications such as profound acute hypoxemic respiratory failure and sepsis requiring vasopressor treatment4, 5 have led to a total number of 153,177 deaths worldwide (https://www.who.int/emergencies/diseases/novel-coronavirus-2019; last updated April 17, 2020, 18:00 GMT-6).
Worldwide, the capacity of the healthcare systems to offer care for patients diagnosed with COVID-19 depends on ICU beds and emergency departments (ED) capability to accommodate the additional care requirements brought by the pandemic. This is of critical relevance considering the high ICU occupancy commonly seen in many locations6 and the long-recognized ED overcrowding and its negative consequences on patient outcomes7-9. Moreover, the current management of patients with COVID-19 is supportive, and recovery time is estimated at around three to six weeks for critically ill patients.10 In this challenging scenario, it is not surprising that, following the recognition of COVID-19 as a Public Health Emergency of International Concern on January, 30, 2020, (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen), there has been a frantic search for effective treatments. On April 6, 2020, there were 788 entries of COVID-19 trials registered on the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP), with more expected.
Clinical trials provide vital evidence to establish the efficacy and safety of new medicines or new indications for existing medicines. To be informative, however, they have to be designed and implemented with appropriate standards to provide meaningful evidence.11 Meaningful evidence fundamentally includes the definition of outcomes that reflect efficacy/effectiveness (beneficial treatment effect) and safety (effects of the treatment that may be harmful to patients).12 Efficacy/effectiveness outcomes should represent clinically meaningful results that directly measure how a patient feels, functions, or survives.13Alternatively, trials may use surrogate outcomes instead of clinical ones. Trials assessing surrogate outcomes may be completed faster and be less expensive. However, surrogate outcomes may or may not predict clinical results and translate in meaningful evidence of efficacy/effectiveness.13, 14
Likewise, safety outcomes are essential in defining the value of a treatment intervention for healthcare providers, patients, and health systems. Despite the importance of finding a treatment that is effective in mitigating or curing patients diagnosed with COVID-19, it is critical to appropriately define and detect the potential adverse events of the treatment options under investigation. There are guidance and legal requirements for protocols of clinical trials to plan the data collection of adverse events, whether applying systematic or non-systematics assessment approaches 12, 15, 16. The objective of this study was to assess whether the randomized clinical trials (RCTs) registered on the WHO-ICTRP for patients diagnosed with COVID-19 include definitions and data collection plans to produce evidence on meaningful efficacy, effectiveness and safety outcomes.