Publications

Several changes have occurred recently in the clinical trials landscape. A Series of six papers published in the Lancet Global Health updates readers on current advances and calls for urgent improvements in areas where progress is lacking.1–6 This Series follows the World Health Assembly resolution 75.8 adopted in 2022 on strengthening clinical trials and WHO guidance for best practices for clinical trials published in September, 2024.7 The WHO guidance provides a global framework for improving clinical trial infrastructure and the enabling environment to enhance the conduct and timely reporting of well designed trials in well maintained, accessible, and curated clinical trials registries. Notably, this framework identified the concerns of patients, healthy participants, and communities, and brought attention to under-represented populations. Development of the framework was led by WHO with stakeholder participation inclusive of representatives from low-income, middle-income, and high-income countries and from both the investigator-initiated and non-commercial trials community and the private sector.

WHO convened a large-scale consultation process over 18 months with six in-person consultations.8 Participants identified four key barriers to enabling clinical trial evidence generation for public health. Firstly, many trials are poorly designed, registered, implemented, or reported. To improve the health of patients and wellbeing of populations, clinical research should select the right questions that are addressed with robust scientific methods and reported appropriately to deliver a definitive outcome. There is extensive research waste literature with more quantitative data on uninformative trials from the COVID-19 pandemic, which outlines how few clinical trials successfully met these criteria.9,10

Secondly, the absence of patient and community engagement during trial design leads to exclusion of target populations. For example, pregnant and lactating women, children, individuals with co-morbidity, and older people are sometimes excluded from trials without valid scientific reason. Although for assumed safety and ethical justification, these exclusions are in contravention of the ethical principle of inclusivity, which can lead to a lack of access to interventions for those populations that might need them the most. All clinical trial stakeholders should ensure that appropriate patient and community engagement is embedded throughout the design, conduct, and reporting of trials, and considerations related to under-represented populations are addressed. Moreover, strengthening clinical trials' sponsorship capacity and increasing access to clinical trials insurance cover, especially in low-income regions, are important for bridging these gaps.

Thirdly, major gaps in trial infrastructure and capabilities remain in low-income and middle-income country settings. It is estimated that fewer than 3% and 5% of trials occur in WHO's African and Eastern Mediterranean regions, respectively and of those, most will have a sponsor in a high-income country.

Lastly, inefficiencies in clinical trial approval processes are widespread around the world and are not necessarily resource dependent. In many high-income regions, multiple uncoordinated approval processes are the status quo and cost time, money, and cause delays in the generation of quality evidence.

The new WHO guidance has a major focus on these four aspects together with a call for risk-proportionate approaches for clinical trials. The guidance will shortly be available in Arabic, Chinese, English, French, Portuguese, Russian, and Spanish. We envisage this guidance will become the key framework for non-commercial trials outside the scope of The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance. Articulation and provision of a systems-oriented framework for improving national clinical trial environments will enable local policy makers to review priorities for their own infrastructure development and efficiency in governance processes, for both investigational product and non-commercial trials as each country needs to invest in its own clinical research capacity to ensure a resilient global ecosystem.

Another major focus of WHO is on embedding ethical research into health systems with fully electronic data capture. Health practitioners can apply the guidance to work collaboratively with researchers to translate research insights into improved patient and systems outcomes.

WHO and ICH are aligned on the need to avoid a one size fits all approach. Until recently, the ICH framework did not fully support such flexibilities and many individuals in research institutions or regulatory authorities are yet to make the transition to a risk-based, proportionate approach. There has been inadequate visibility and training on how to best implement these flexibilities. A major agenda item for change management is how regulators (both dossier assessors and inspectors), ethics authorities, and researchers access and implement training with this approach. The rate-limiting step will be the lack of adoption by any one of these stakeholder groups.

Arising from these strategic considerations, WHO in consultation with stakeholders will develop a global action plan for clinical trial ecosystem strengthening, outlining the required priority actions with a launch date in 2025.

WHO recognises the vital role that national and international research funders play, both in investigator-initiated or non-commercial trials and the private sector in raising the quality from the research investments they make. The panel presents some of these priority actions outlined in the Lancet Global Health Series.