Approval delays in multi-country COVID-19 trials: the case of COPCOV and the risk of therapeutic inertia.

backgroundMany multi-country COVID-19 clinical trials, including those for widely available repurposed drugs with strong safety profiles, were conceptualised quickly but were unable to influence clinical treatment guidelines. The Chloroquine/Hydroxychloroquine for the Prevention of COVID-19 (COPCOV) trial, a large multi-country clinical trial sponsored by the University of Oxford, sought to determine the efficacy of hydroxychloroquine and chloroquine as a prophylaxis for COVID-19 but faced approval delays and other bureaucratic challenges. Understanding the reasons for these delays will help to guide reform for future multi-country trials responding to health emergencies.

methodsUsing an extensive case study of the COPCOV trial, we aimed to quantitatively and qualitatively analyse the bureaucratic challenges facing academic researchers seeking trial approval across multiple countries during health emergencies. We measured the median time from first COPCOV trial protocol submission to an ethics/regulatory body in each country to first approval and disaggregated the average and median time for approval by ethics committees and regulatory bodies. These data are extracted from official documents in the Trial Master File, records from country investigators, and thousands of stakeholder emails. Additionally, we conducted semi-structured interviews with 65 trial stakeholders to identify barriers to approval, and we analysed these interviews using inductive thematic analysis.

resultsFor the COPCOV trial, investigators sought approval in 76 countries and submitted initial protocols to 22 local/institutional ethics committees or institutional research boards, 19 multisite or national ethics committees, and 14 national regulatory authorities. The median time for the study to receive an initial decision (approval or rejection) in each country was 104 days (IQR 42). Approximately half of the countries to which the COPCOV protocol was submitted had sequential systems for ethics and regulatory review, and those with an expedited review system communicated faster decisions (median 91 days vs. 122 days). Issues with efficiency, flexibility, and decision-making coherence underpinned these approval delays. Efficiency challenges included overlap in comments between ethics bodies and duplicative ethics and regulatory body roles. Delays due to inflexibility resulted from under-awareness of existing risk-based frameworks for repurposed drugs, few mechanisms for streamlining documentation requirements during emergency review processes, and under-utilisation of regulatory agility and reliance mechanisms. Objectivity and coherence of decision-making by trial approval bodies were limited by a lack of stringent regulatory authority transparency and limited communication channels between trial stakeholders.

conclusionsTrial approval challenges are rooted in a combination of conservative good clinical practice interpretation and insufficient international guidance and leadership, which contribute to a dangerous 'risk of therapeutic inertia' in developing evidence during public health emergencies. Governance reforms to address these challenges should be twofold, focused on improving national awareness, buy-in, and financing for existing harmonisation and risk-based structures and establishing a global framework for clinical research during health emergencies.

trial registrationClinicalTrials.gov NCT04303507. Registered on 11 March 2020.