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September 12, 2023

GHTC submitted the following comments in response to a World Health Organization (WHO) public consultation seeking input on its draft guidance for best practices for clinical trials. WHO is developing this guidance in response to the adoption by the 75th World Health Assembly of a resolution on strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination.

Please provide general comments on addressing context-specific issues, considerations, and implications for adapting and implementing the guidance, as well as identifying gaps in the evidence that should be addressed through future research. Please also provide any comments about the strengths of the draft guidance. Feedback to specific content to enhance clarity, address technical errors, and provide any missing information will be in the suggested amendments.

The Global Health Technologies Coalition (GHTC) is a coalition of more than 45 nonprofits, academic institutions, and aligned businesses advancing policies to accelerate the creation of new drugs, vaccines, diagnostics, and other tools that bring healthy lives within reach for all people. GHTC’s Secretariat has gathered input from members to contribute to the public consultation on World Health Organization (WHO) guidance for best practices for clinical trials. In particular, the coalition asked its members to assess additional ways the guidance on clinical trials could be strengthened, with a particular eye towards equity and inclusion, leveraging existing resources, and connecting the work on clinical trials to broader capacity-building initiatives.

Please provide general comments for Section A: Key scientific and ethical considerations for good clinical trials.

Clinical data requirements for licensure need to be clearly defined. Placebo-controlled, randomized, double-blind studies are typically used to demonstrate the efficacy and safety of new vaccines but are not always needed for licensure. In some circumstances, like the Ebola outbreak, it would be considered unethical to administer a placebo to at-risk individuals. The design of clinical trials must consider these regulatory and ethical requirements.

Good clinical trials are collaborative and transparent (section A, 2.3), and the text of the guidance should refer more explicitly to the importance of integrating ethical considerations into trial design and execution.

Section A, 2.3.3 on transparency alludes to the need for transparency in data sharing. However, the guidance should also touch upon transparency in sharing knowledge, skills, and benefits, as well as on the need for equity in data sharing to ensure that the data generated from trials conducted in resource-limited settings are accessible to all partners and to foster a collaborative approach to knowledge dissemination.

There must also be stronger mandates for trial registration from the outset, including data sharing requirements with platforms like WHO’s International Clinical Trials Registry Platform (ICTRP) and other internationally recognized platforms. 

Concerning the size of the clinical trials (section A, 2.1.3), expanding on what is recommended for pediatric trials in section A, 4.3, reference should be made to using, whenever appropriate, newly available technologies, notably modeling and simulation techniques (pharmacometrics), to implement decentralized trials and consolidate trial design. For example, synthetic control arms should be used to minimize exposure to a well-documented intervention, reduce sample size, and maximize the value of the research.

Please provide general comments for Section B: Guidance on strengthening the clinical trial ecosystem.

As for section A, section B should also include reference to the need for equity in representation at all levels, including in governance and management, to ensure that a wide range of perspectives and experiences are incorporated. 

The guidance should also touch on ways to improve international collaboration and coordination among member states on key research priorities and multiregional clinical trials, where appropriate. At present, effective coordination mechanisms are lacking for clinical trials, and funding for clinical trials across all WHO regions and disease areas is insufficient. Furthermore, improved coordination around global research agendas could enable more timely capacity-building of clinical trial sites.

The WHO guidance should also support new trial modalities, such as decentralized and paperless clinical trials that incorporate patient perspectives, mobile technologies, and telemedicine, and increased use of adaptive, multicountry platform trials.

Investing in research capacity-strengthening in low- and middle-income countries (LMICs) is critical to effectively combating disease. This could also entail investing in training and strengthening scientific capacity at the local level, as well as building or upgrading physical infrastructure. In section B, 3.1.1l discussing the physical infrastructure, the role of central laboratories should be added, as well as the need to set up central/reference laboratories for certain assessments to ensure standardization (for example, for pharmacokinetics and microbiology assessments).

This encompasses investing in building regulatory capacity in LMICs, including further building on progress across the African Medicines Regulatory Harmonization programme and supporting the operationalization of the African Medicines Agency. Continued investment in regulatory strengthening will be critical to expanding clinical trial capacity in LMICs.

Please provide general comments for Section C: Addressing under-represented subpopulations.

GHTC was pleased that the guidance includes a full section focused on addressing underrepresented subpopulations in clinical trials. Women, girls, and other gender-diverse persons of childbearing potential remain vastly underrepresented in research and clinical trials, particularly those who are pregnant and lactating. At a time of rapid medical innovations, this exclusion limits data, prevents understanding of sex- and gender-based differences in health outcomes, and restricts the availability of therapeutic options for more than half the global population.

In addressing the need for enabling clinical trials in resource-limited settings (section C, 4.1), local regulators should be encouraged to develop guidelines for investigational plans for underrepresented populations, such as children, women, and gender-diverse persons who are pregnant and lactating, and such plans should be a requirement for marketing authorization approval.

GHTC strongly supports the emphasis on the need to address the underrepresentation of pregnant and lactating women in clinical trials, with the objective of broadening the availability of therapeutic options for these populations and allowing equitable and timely access to crucial interventions. We would nevertheless broaden the scope of this group to include pregnant and lactating girls because adolescents are often underrepresented in clinical trials, as well as gender-diverse persons, because not all persons of childbearing potential identify themselves as women. Referring to women and gender-diverse persons of childbearing potential facilitates the inclusion of transgender and nonbinary persons who are also underrepresented in key clinical research areas. For diseases with high fatality for which no alternative treatments are available, preclinical animal reproductive-toxicity studies should be expedited, and pregnant individuals should be included in the very early pre-licensure clinical trials of new treatment (for example, diseases such as Ebola, and the early stages of the SARS-CoV-2 pandemic).

The guidance for pregnant and lactating individuals should also look to leverage relevant resources, evidence, and data points to ensure a comprehensive approach. This includes integrating the guidelines on the Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, as well as excerpts from the Journal of the International AIDS Society that included specific recommendations on how to accomplish this pre-drug approval, as well the critical need for surveillance of maternal and neonatal outcomes with drug use in pregnancy.

The pediatric section does include some more robust references, though we would suggest adding the WHO Toolkit for Research and Development of Pediatric Antiretroviral Drugs and Formulations, as well as the report from the Paediatric HIV and TB: Rome Action Plan, which came from the High-Level Dialogue convened by the Vatican.

Please provide general comments for ANNEX 2: Recommendations for Member States, research funders and researchers.

We are not sure that the last recommendation in 2.11, which calls for the establishment of pregnancy registries in LMICs, should be included. It may not be the best way to look at surveillance of pregnancy outcomes, as there is no “control” of unexposed individuals to which to compare findings in exposed individuals, making the data much less useful.