Clinical Trials Before, During, and After COVID-19 Pandemic.

Abstract

To the Editor: Ever since COVID-19 unleashed in December 2019, it has wreaked havoc across nations, families and individual life along ongoing clinical trials getting globally delayed, interrupted or not initiated. In addressing the onslaught of COVID-19, medical community faced threats of another kind, ie, obstacles in the clinical trials leading to a drop in new patients enrolled, increased number of drop-out/lost to follow-up patients, restrictions on on-site monitoring which makes source data verification difficult, and delayed data collection, statistical analyses, results, approval of patents and delivery of life-care products and effective medicines to the awaiting patients. This entails the urgent demand for innovative strategies to ensure continuity of patient treatment/patient retention, and therefore, continuity of clinical trials along with a critical assessment of new clinical trials before commencement during the pandemic. US Food and Drug Administration (FDA) and European Medicines Agency have noted that they expect to see increase of protocol deviations in clinical trials as a result of coronavirus and reiterated their commitment to being flexible. The FDA continues to work with interested sponsors to help expedite additional clinical trials clinical countermeasures against COVID-19 while ensuring the safety and wellbeing of patients.1 As per ClinicalTrials.gov, from December 2019 to May 2020, a total of 2522 clinical trials were stopped, suspended or terminated, with 44% reporting COVID-19 as the reason.2 From May to July 2020, around 2005 trials were stopped, terminated or withdrawn during (Table 1).3 To grasp the impact of such suspensions: there was a combined enrolment of 39,405 patients in the trials stopped due to COVID-19 from December 2019 to May 2020.2 According to Medidata, there was a 65% average decrease in patient-enrolment during March, which regionally translates into 43% decrease in Japan, 84% reduction in India, 67% decrease in the United States, and 68% decrease in China.4 A myriad of pharmaceutical companies such as Eli Lilly, Pfizer, Bristol-Myers Squibb, Addex Therapeutics, Provention Bio, and contract research organizations IQVIA and Icon are either pausing or postponing non-COVID clinical trials.5 The reduction was disease-dependent, with 80% decline observed in endocrine diseases trials, 47% for infectious disease studies, 48% for oncology, and decrease for cardiovascular diseases trials at 70%. Ironically, the pandemic is an opportunity for improvement of traditional design of clinical trials. Conventionally, clinical trials comprise of 3 phases where in phase I safety of a drug is established at an optimal dose for use in phase II and phase III. In phase II efficacy of a drug is determined while success is these 2 earlier phases lead to randomized trials are governed to establish the treatment efficacy and safety compared with current treatment regimens involving hundreds to thousands of individuals. Phase II assesses a drug’s efficacy. If early trials succeed, an experimental treatment progresses to phase III where trials are randomized to investigate the treatment’s safety and efficacy compared to current standard of care. Allowing midtrial changes in design and protocol for early termination without penalties is a logical way forward. An expedited approach toward fast tracking phase II trials to phase III is mandated in the current crisis, while a switch from centralized traditional trial to decentralized trials may enhance data collection of ongoing clinical trials. Further, accepting the proposed alternatives to the P-value cut point of significance to > 0.05 for certain designs might also help.6,7 Although FDA, published the guidelines regarding ongoing clinical trials yet the statistical analyses of data from ongoing and terminated trials needs more clarity. Virtual clinic trials, telemedicine, telepharmacy, and virtual data collection have been a hot-topic in recent years, but implementation challenges such as the device validation, data accuracy, and data security and privacy were the major hurdles in adaptation. Currently, there is an upward trend in virtual trials, via remote monitoring and teleconferencing for collection of digital data where pharmaceutical companies like Pfizer, AstraZeneca, and GSK have adopted these moves for ongoing clinical trials. Clinical SCORE survey reported 36% of the trial sites have switched all trials to virtual visits.8 Author suggested technology-based adaptations to pandemic-affected clinical trials such as: restricting on-site monitoring visits, and in-person patient meetings to minimize viral exposure, including telemedicine, remote electronic medical record access. Such measures must include all stakeholders, ie, patients, investigators, research organizations, ethical committees, regulatory authorities, and sponsors. There is a dire need of being authentic with the quality and reality of the data, while being synthetic with an expedited trial design to mitigate the operational and logistic challenges as well as risk of exposure. For instance, synthetic or virtual control arms can be recruited from historical trial data using artificial intelligence (AI) algorithms to reduce the number of participants in a control group, as well as the use of AI toward individualized therapies in experimental arms ensuring patient safety. For instance, in the vein of improvising during the pandemic, Gilead changed the design and outcome measures mid-trial for Remdesivir by increasing the number of COVID-19 patients, and changing the endpoint from clearance of symptoms in 14 days to odds of improvement on a 7-point scale that runs from death to not TABLE 1. Total Number of Clinical Trials From December 2019 to July 2020