Clinical trials and their impact on policy during COVID-19: a review

Abstract

Background: Of over 8,000 recorded randomised trials addressing COVID-19, around 80% were of treatments, and 17% have reported results. Approximately 1% were adaptive or platform trials, with 25 having results available, across 29 journal articles and 10 preprint articles.

Methods: We conducted an extensive literature review to address four questions about COVID-19 trials, particularly the role and impact of platform/adaptive trials and lessons learned.

Results: The key findings were: Q1. Social value in conducting trials and uptake into policy? COVID-19 drug treatments varied substantially and changed considerably, with drugs found effective in definitive clinical trials replacing unproven drugs. Dexamethasone has likely saved ½-2 million lives, and was cost effective across a range of countries and populations, whereas the cost effectiveness of remdesivir is uncertain. Published economic and health system impacts of COVID-19 treatments were infrequent. Q2. Issues with adaptive trial designs. Of the 77 platform trials registered, 6 major platform trials, with approximately 50 treatment arms, recruited ~135,000 participants with funding over $100 million. Q3. Models of good practice. Streamlined set-up processes such as flexible and fast-track funding, ethics, and governance approvals are vital. To facilitate recruitment, simple and streamlined research processes, and pre-existing research networks to coordinate trial planning, design, conduct and practice change are crucial to success. Q4. Potential conflicts to avoid? When treating patients through trials, balancing individual and collective rights and allocating scarce resources between healthcare and research are challenging. Tensions occur between commercial and non-commercial sectors, and academic and public health interests, such as publication and funding driven indicators and the public good.

Conclusion: There is a need to (i) reduce small, repetitive, single centre trials, (ii) increase coordination to ensure robust research conducted for treatments, and (iii) a wider adoption of adaptive/platform trial designs to respond to fast-evolving evidence landscape.

Keywords: COVID-19; SARS-CoV-2; adaptive trials; clinical trials; health policy; pandemic; platform trials; treatment.

Figure 1.. COVID-19 Living evidence synthesis project map of COVID-19 trials registered in the WHO trials registry at March 2, 2022.

(from https://covid-nma.com/dataviz/) (Reproduced with permission from website producers).

Figure 2.. Variation in hydroxychloroquine, remdesivir and dexamethasone use across health centres in the US between February 2020 to February 2021 (Redrawn from data from Mehta et al., 2021 Figure 2, 15).

Figure 3.. Variation in hydroxychloroquine across countries and centres between February and December 2020 (Redrawn from data in Prats-Uribe et al., 2021, 17).

Figure 4.. Time trends in corticosteroid use in 439,922 people admitted to hospital with COVID-19 at 720 sites in 49 countries who did and did not receive oxygen therapy between January 2020 and May 2021 (data adapted from ISARIC Clinical Characterisation Group, 2021 Supplementary figure 11 .

Figure 5.. Time trends in use of definitively tested drug treatments in people hospitalized with COVID- 19 in the US between March 2020 and August 2021 (adapted from data presented in Weckstein et al., 2021 , Casadevall et al, 2021 , Prats-Uribe et al., 2021 and Wiltz et al., 2022 ).

Data on time trends in use of dexamethasone, remdesivir, azithromycin and hydroxychloroquine adapted from data presented among 85,970 people in Weckstein et al., 2021 Figure 1 . Data on time trends in use of combined lopinavir and ritonavir adapted from data presented in Prats-Uribe et al., 2021 Figure 6. The data from the largest data base of 77,853 people (IQVIA Hospital CDM) were used. Data on time trends in use of convalescent plasma adapted from data presented in Casadevall et al., 2021 Figure 2, . In this study usage was inferred from the distribution of plasma units to hospitals. Data on time trends in use of monoclonal antibodies among 805,276 people adapted from Wiltz et al., 2022 Figure . Only data from 387,403 people of non-Hispanic ethnicity are presented.

Figure 6.

Incremental cost-effectiveness of Dexamethasone and Remdesivir. Data from one study of monoclonal antibodies was not plotted as cost-effectiveness was found to vary from cost-saving to $22671/quality adjusted life year for different ages and hospitalisation risks (Jovanski et al., 2022 ). Data plotted was adapted from Aguas et al., 2021 , Jo et al., 2021 , Carta et al., 2021 , Congley et al., 2021 , Whittington et al., 2022 , I.C.E.R 2021 , Sun et al., 2021 , Rafia et al., 2022 , Ponce-de-Leon et al., 2022 , Oksuz et al., 2021 , and Gholamhossein et al., 2021 .

Figure 7.. An illustration of a platform trial (Adapted from Park et al. ).

This example starts with two treatment arms plus the common control arm that consists of standard of care. There are two interim analyses planned. At the first interim analysis, intervention 1 is dropped while a new arm (treatment 3) is introduced into the platform. Another treatment (treatment 4) is introduced after the second interim analysis. Treatment 2 finishes enrolment and undergoes its planned final analysis. This hypothetical trial perpetually continues with the control arm and treatment 3 and treatment 4.

Figure 8.

( A). The RECOVERY trial randomized around 15% of all hospitalized COVID-19 patients in the UK. ( B) If recruitment had been 50%, then it could have reported over 2 months earlier and saved an additional 2,880 lives.

Figure 9.. Compression of timeline for vaccine development from 10 to 1 year.

Figure 10.. Key lessons learned for funders and regulators and researchers and their networks.

Figure 11.. The BESSI Collaboration’s “scorecard” comparing the number of drug trials versus trials for Public Health and Social Measures (or BESSI – Behavioural, Environmental, Social & Systems Interventions), from https://www.bessi-collab.net/ (01/04/2022) (Reproduced with permission from the BESSI website producers).

Figure 12.. The time taken to design, gain approvals, and implement a research trial may mean that a large proportion of the first wave recruitment is missed (Figure taken from https://www.remapcap.org/pandemic-preparedness; Reproduced with permission from the website managers).