WHO: Shadow boxing continues around clinical trials
This week, the global clinical trials ecosystem is back on the agenda at the annual World Health Assembly, the WHO’s governing forum. In this guest blog, the People’s Health Movement explains what the discussions are about.
In Item 15.1, WHA76 will continue to discuss the "clinical trials ecosystem", in particular, as it relates to emergency preparedness and response.
WHO positions on trial transparency
The issue of clinical trials registration and transparency has been on WHO’s agenda for a long time.
In WHA63.21 (May 2010) the Assembly adopted the WHO strategy on research for health. This focused on the registration of clinical trials ("the adoption by all countries of the registration of clinical trials according to WHO standards”). See International Clinical Trials Registry Platform.
The issue of clinical trials integrity and transparency came to the fore again following the 2014 Ebola outbreak. In Jan 2015, at the Special Session on Ebola of the EB, the Board considered EBSS3/INF./1 on fast tracking the development and roll out of vaccines, therapies and diagnostics. The Board adopted EBSS3.R1 which asked the DG “to develop guidance on the value and limitations of the data obtained from the clinical trials, giving particular attention to ethics, quality, efficacy and safety”.
Ebola clinical trials
In May 2015 WHO held a Ebola R&D Summit which included discussion about clinical trials:
Participants stressed that data generated by clinical trials and other research during future public-health emergencies, including negative results, should be openly shared, and where possible should be comparable. A body of knowledge based on data sharing during outbreaks would enable more effective choices, effective use of funding, and appropriate prioritization of candidate products.
… It was not acceptable that human clinical trials of vaccines for EVD began approximately 40 years after the first Ebola outbreak. Among the apparent reasons for the delay was that there was little chance that such a vaccine would be profitable.
… At times during the crisis, there was intense competition and a lack of coordination between the clinical trials carried out, which suggests that frameworks and procedures should be set in advance to reduce confusion and improve efficiency.
…Concepts of across-the-board cooperation – built on those which proved their value during the 2014-2015 Ebola epidemic – should include the open sharing of data, including negative results, generated by clinical trials and other research during public-health emergencies in developing countries. Where possible, such data should be comparable. Lack of sharing resulted in duplication of effort and wasted research in West Africa.
WHO position on data sharing
In April 2016, WHO published a Policy Statement on data sharing. On clinical trials the policy statement says:
All interventional clinical trials must be prospectively registered in a primary clinical trials registry, conforming to standards agreed by WHO International Clinical Trials Registry Platform.
During a public health emergency, each research protocol should make a specific commitment to share results in a pre-specified, expedited timeline before each trial begins. WHO’s position will be that the public disclosure of results will be the norm, in the expedited timeline as dictated by the research protocol. Outside public health emergencies the norm is for public disclosure of results within 12 months of completion of a trial.
The issues raised in the R&D Summit were noted by the IHR Review Committee on the Ebola Response (A69/21, May 2016). The Assembly, in decision WHA69(14), asked the DG for a plan for the implementation of the Review Committee’s recommendations.
The 2017 WHO Joint Statement
In May 2017 the Joint Statement on Public Disclosure of Results from Clinical Trials was published:
Some of the world’s largest funders of medical research and international non-governmental organizations agreed on new standards that will require all clinical trials they fund or support to be registered and the results disclosed publicly. Currently, about 50% of clinical trials go unreported, often because the results are negative. These unreported trial results leave an incomplete and potentially misleading picture of the risks and benefits of vaccines, drugs and medical devices, and can lead to use of suboptimal or even harmful products.
WHO and Covid trials
Moving on, from Ebola to Covid …
The Independent Panel on the Covid Response (2021) noted the commitment to data sharing which had been articulated after Ebola and commended CEPI for its sponsorship of clinical trials. The Independent Panel called for:
[the transformation of] the current ACT-A into a truly global end-to-end platform for vaccines, diagnostics, therapeutics, and essential supplies, shifting from a model where innovation is left to the market to a model aimed at delivering global public goods;
The Independent Panel noted the launch of the Solidarity Trial in April 2020 but failed to comment on the reluctance of the vaccine developers to participate in head-to-head trials of their vaccines. In large degree, the funding of vaccine trials was mediated by generous advance purchase agreements by rich country governments rather than deliberative funding of proposed trials.
See also the joint statement in May 2021 by the International Coalition of Medicines Regulatory Authorities and WHO on transparency and data integrity. This is a strong statement with a call for transparency and integrity in submissions from product sponsors to regulatory authorities.
The 2022 clinical trial resolution
In May 2022 the Assembly considered (in A75/17) the final report of the WG on Preparedness and Response to Health Emergencies and, addressing the clinical trials issue, adopted WHA75.8.
WHA75.8 takes a broad view of the ‘clinical trial ecosystem’ including capacity building, finance, coordination, and best practice in terms of design and management. The resolution calls on research funders and administrators to ensure clinical trials are registered in a recognised registry and for the timely reporting of positive and negative results, preferably in open-access publications.
WHA75.8 requested the DG to identify and propose to member states “best practices and other measures to strengthen the global clinical trial ecosystem” and “to provide to Member States … guidance … on best practices for developing the legislation, infrastructure and capabilities required for clinical trials”. The DG was asked to report to WHA76 through EB152 on the implementation of WHA75.8.
EB152/13 provides the requested progress report. It reports on an extensive consultation which “supported the role of WHO in convening and thus generating research priorities at the global level”.
The consultation found that “The major strategic gap lies in the overarching system for strengthening the clinical trials ecosystem so that capabilities that exist in normal times can be applied in emergencies”; it identified the need to strengthen national regulatory authorities; and called for harmonisation of review procedures. The consultation reflected an expectation that WHO will continue to develop guidance in these matters. In response the Secretariat proposed “to develop self-assessment tool with indicators for the maturity of the clinical trial ecosystem at national and international levels, aligned with the framework of the resolution”
The Supplementary report (produced after EB152/13 was published) provides a more comprehensive overview of progress on the areas of work requested in WHA75.8. The detailed report of the outcomes of the consultations is particularly useful.
The Executive Board (PSR13 and PSR16) endorsed the general directions outlined in the Secretariat reports, including the proposed self-assessment.
Proposed pandemic treaty
Meanwhile the INB has not lost sight of clinical trials. The Zero Draft of the proposed pandemic treaty includes, in Article 8.2(c), the following provisions:
measures to foster and coordinate national, regional and international high quality clinical research/trials
measures to ensure equitable access to investment in clinical trials, so that resources are deployed optimally and efficiently
measures to support the transparent and rapid reporting of clinical research/trial results, to ensure evidence is available in a timely manner to inform national, regional and international decision-making
measures related to disclosure of disaggregated information on research and development and clinical trials of vaccines, diagnostics, pharmaceuticals and other products relevant to pandemic preparedness and response
The People’s Health Movement (PHM) affirms that the objectives for the reform of clinical trials practice (in routine and emergency contexts) must include:
Mandatory registration
Standardised data collection for registration, including funding transparency
Mandatory publication of negative as well as positive results
Support for collaboration, including master designs, platform trials etc
Prompt information sharing in emergency context
Institutional continuity, eg keeping clinical trials capacity alive between crises
Collaboration and coordination to support best practice in study designs
Capacity building in the Global South
Including diverse demographics
Effective governance structure (funders, regulators, journal editors, pandemic treaty)
Coordinated prioritisation and funds mobilisation
What is missing?
Most of these items appear on most lists included in the policy papers cited above. However, while governance and funding are commonly mentioned, there have been no detailed proposals for effective governance of clinical trials or for coordinated prioritisation, co-design, and funds mobilisation. These are critical for the emergency context but apply more generally.
Vaccine trials in the context of Covid were largely funded through generous advance purchase agreements by rich country governments rather than deliberative funding of clinical trial proposals. The refusal of vaccine developers to participate in WHO’s Solidarity Trials (and avoid head to head comparisons) was supported by those same governments.
Despite 24% of the global population residing in south Asia, this region is the setting of only 5% of all RCTs worldwide. Sub-Saharan African countries (a population of 1·1 billion people in 2019) are the setting of an even smaller proportion of RCTs, at 2% (Park et al 2021). Another study of RCTs globally, found that the first author of 90% of the sample of RCTs had an affiliation to an institution in high income countries (Hakoum et al 2017).
The lack of research into countermeasures for Ebola until the 2013 epidemic (40 years after its identification) illustrates the inequitable consequences of these disparities.
What should happen next?
The People’s Health Movement (PHM) urges member states to request further work by the Secretariat on options for effective governance disciplines across the global clinical trials ecosystem including guidance on the roles which can be played by funders, regulators, and journal editors and how such might be mandated.
PHM urges member states to request the DG to:
include clinical trial research capability in the Universal Health and Preparedness Review;
encourage the Pandemic Fund to include support for research capability in its work to transform HEPR capacities;
encourage the G20 Joint Finance and Health Taskforce to include support for research capability in its work to transform HEPR capacities.
The full PHM commentary on this item provides more detail, including references.
This blog was originally published under the title “Shadow boxing continues around clinical trials: agreement on principle but governance disciplines too hot to handle” as a WHO Watch news update by the People’s Health Movement. TranspariMED added some sub-headings to the original text, which is otherwise unchanged.