By guest contributors Piero Olliaro and Josephine Bourner Outbreak clinical research presents special challenges, the most pressing one being speed. Long-lasting pandemics…
By guest contributors Vasee Moorthy, John Reeder, Soumya Swaminathan
When Randomized Controlled Trials (RCTs) answer relevant research questions, employing robust scientific methodology in ethically appropriate ways, they are the strongest tools we have to allow decisions in healthcare to be based on solid evidence. The COVID-19 pandemic led well-meaning researchers around the world to initiate over 17,000 RCTs. Less than 10% of the randomization arms in the therapeutic trials led to the great bulk of the useful evidence generated; vast resources were spent on trials that contributed nothing to health. Progress in many non-COVID areas of work stalled, partly as a result of this research waste. Strong recommendations either for or against use of interventions in WHO’s COVID-19 therapeutics guidelines were largely based on evidence from only a few generally very large trials with public health policy relevant outcomes and high-quality designs.
The ultimate decision-making body of the World Health Organization (WHO) is the World Health Assembly (WHA) which meets every May in Geneva, giving equal voice to every one of our 194 Member States. At the 2022 WHA a Resolution (WHA75.8) was adopted entitled “Strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination”. This is the first resolution focused on RCTs since the 2005 Resolution (WHA58.22) establishing WHO’s International Clinical Trials Registry Platform, enabling global standards for clinical trials registries.
WHA 75.8 recognizes “that well-designed and well-implemented clinical trials are indispensable for assessing the safety and efficacy of health interventions” and “The importance of promoting equity in clinical trial capability, … both by strengthening the clinical trial global ecosystem to evaluate health interventions and by working to strengthen country capacities to conduct (high quality) clinical trials”. The resolution encourages “research funding agencies to prioritize and fund clinical trials that are well-designed and well-implemented, conducted in diverse settings and include all major population groups the intervention is intended to benefit, and have adequate statistical power, and relevant control groups and interventions in order to generate the scientifically robust and actionable evidence needed to inform public health policy, regulatory decisions and medical practice while preventing underpowered, poorly designed clinical trials and avoiding the exposure of clinical trials participants to unjustified and unnecessary risk, in normal times as well as in Public Health Emergencies of International Concern”. The resolution also encourages member states to map then strengthen their clinical trial capabilities, and improve priority setting, information sharing and coordination between different stakeholders related to clinical trials. Part of strengthening capabilities, according to the resolution, is ensuring a focus on the critical quality questions to ensure well-designed and well-implemented, scientifically and ethically appropriate trials, and rapid regulatory and ethics authority decision-making in times of emergency. In addition, there is a focus on ensuring results are suitable to enable policy change through updating guidelines as well as submission to regulatory authorities in the case of medical products.
While these elements are all described in the resolution, there is also a call on WHO to conduct a stakeholder consultation to receive inputs on possible recommendations on “best practices and other measures to improve the global clinical trials ecosystem.” A public consultation is open now until November 11 to collate and submit your inputs to WHO on the key lessons learned from COVID-19, and other recent experience, for improving the clinical trials ecosystem, and bottlenecks that need to be addressed. There are many initiatives that have been working to address gaps in the RCT ecosystem, for example to avoid delays in generation of pediatric medicine formulations, to address R&D in epidemics, in drug development for highly resistant bacteria, for neglected tropical diseases, to ensure results are reported and data is shared. WHO has developed a global benchmarking tool to assist in strengthening of national regulatory systems and is piloting a research ethics capacity benchmarking tool. The International Clinical Trial Registry Platform provides standards for registries worldwide, and the Global Observatory on Health R&D maintains the most extensive visualizations of inputs, processes and outputs of the system.
In terms of guidance on quality of trials, ICH-Good Clinical Practice (E6) is the cornerstone of standards for submission of medical product data to regulatory authorities, and is being updated, while from the ethical perspective the declaration of Helsinki and CIOMS/WHO guidance are international standards. In addition, there are two recent complementary initiatives which, unlike ICH-GCP, are not limited in scope to trials of medical products,.
During October 2022, and as directed by resolution WHA 75.8, WHO is soliciting inputs on possible recommendations “on best practices and other measures to improve the global clinical trials ecosystem.” Inputs can be made through a link available from this website Public consultation related to the WHA 75.8: Strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination (who.int). This is an opportunity for any current initiatives and clinical trials stakeholders to summarize lessons learned from COVID-19 for improvements to the clinical trials ecosystem.
According to the wording of the resolution, inputs can be received from Member States through Ministries of Health, and from Non-State Actors including in the following categories: patient groups, international business associations, philanthropic foundations and academic institutions.
Please see this link to make the submission.
Only by hearing from you can we collate input, following our declaration of interest and screening processes, into the report on the topic to be discussed at WHA in May 2023. From that discussion a set of recommended actions for WHO, Member States and other Stakeholders may arise. Let us know what you think they should be. What are the gaps in the clinical trials ecosystem to meet the world’s needs, and what can be done to fix them?
About the authors:
Vasee Moorthy is a Senior Advisor, Research for Health Department.
John Reeder is the Director, Research for Health Department.
Soumya Swaminathan is the Chief Scientist.
 Trends in COVID-19 therapeutic clinical trials. Bugin K, Woodstock J. Nature Reviews Drug Discovery. 25 Feb 2021.