Clinical trial participants appear to be well protected in South Africa, particularly as the country's guidelines recognise the risks of research with international collaborators. The sudden end of US-funded clinical trials, however, is exposing some limitations of ethics codes and guidelines, argues Dr Andy Gray.

Participation in a clinical trial that involves the use of an investigational product, such as an unapproved medicine, can be viewed from two different perspectives.

On the one hand, it may represent an opportunity for someone with an unmet medical need to access a promising new treatment or a means to prevent a condition for which the individual is at high risk. On the other hand, it can be seen as an altruistic act, accepting possible risks from the use of the investigational product in order to contribute to the development of new knowledge.

Modern research ethics procedures recognise the vulnerability of trial participants and seek to protect them from exploitation and potential harms.

The 2003 National Health Act created a new structure in South Africa, the National Health Research Ethics Council (NHREC). Appointed by the Minister of Health, the NHREC is required to develop guidelines for health research ethics committees, register and audit such committees, and set the norms and standards for conducting clinical trials. Section 73 of the Act requires every institution or health establishment where health research is conducted to "establish or have access to a health research ethics committee" registered by the NHREC. The necessary regulations that enabled Section 73 to come into effect were finally published in 2014.

In addition, all clinical trials of medicines require prior approval by the South African Health Products Regulatory Authority (SAHPRA). A SAHPRA staff member also forms part of the NHREC. At first glance, therefore, clinical trial participants in South Africa appear to be well protected.

Two locally developed official documents guide the appraisal of applications by health research ethics committees and SAHPRA. The National Department of Health issued an updated, third edition of the South African Ethics in Health Research Guidelines: Principles, Processes and Structures in 2024. The guidelines were developed by the NHREC, in accordance with its legislative mandate. The third edition of the South African Good Clinical Practice: Clinical Trial Guidelines were issued by the department, with SAHPRA, in 2020.

Both of these documents acknowledge the existence of global guidance documents and codes, most notably the World Medical Association's Declaration of Helsinki, which was last updated in late 2024. Although developed by a federation of medical associations, the Declaration of Helsinki is considered to be authoritative and is commonly referenced by national guidelines and regulatory documents.

The revision of the Declaration of Helsinki, which commenced in 2022, involved reconsideration of a number of clauses, including the protection of participants in economically vulnerable settings, and post-trial provisions and benefits. Post-trial access ensures that those who have been shown to benefit from a new medicine are not denied the use of that medicine until it is routinely available in their country and health system. These provisions are even more important when new and expensive medicines may not be accessible in low- or even middle-income countries because of high prices or delays in marketing.

Clause 20 now reads: "Medical research with individuals, groups, or communities in situations of particular vulnerability is only justified if it is responsive to their health needs and priorities and the individual, group, or community stands to benefit from the resulting knowledge, practices, or interventions. Researchers should only include those in situations of particular vulnerability when the research cannot be carried out in a less vulnerable group or community, or when excluding them would perpetuate or exacerbate their disparities."

Clause 34 now reads: "In advance of a clinical trial, post-trial provisions must be arranged by sponsors and researchers to be provided by themselves, healthcare systems, or governments for all participants who still need an intervention identified as beneficial and reasonably safe in the trial. Exceptions to this requirement must be approved by a research ethics committee. Specific information about post-trial provisions must be disclosed to participants as part of informed consent."

When studies are stopped abruptly

Since January 2025, a number of executive orders issued by the new United States administration and other actions have led to the abrupt cessation of USAID-funded clinical trials being conducted in South Africa. There is ongoing uncertainty regarding trials that are funded by other US federal agencies, notably the National Institutes of Health. These include multi-centred studies conducted by the Division of AIDS clinical trials networks.

Hence the question: are participants in South Africa protected, sufficiently, when a sponsor withdraws support for an ongoing clinical trial?

That South African trial participants are particularly vulnerable is indisputable. In a country still marked by poverty and high unemployment, combined with a high burden of HIV and tuberculosis, and with most of the population dependent on an over-stretched and under-resourced public health sector, participation in a clinical trial offers the opportunity to access services that might not otherwise be available or of an acceptable standard.

However, whether "the individual, group, or community stands to benefit from the resulting knowledge, practices, or interventions" is less clear. Long-acting injectable antiretrovirals for the prevention of HIV remain out of reach, despite the contribution of South African participants in the pivotal trials of these technologies. That such trials could be conducted most efficiently in areas of high HIV incidence adds to the moral imperative to ensure access to the benefits that accrued.

Apart from standard provisions for the fair selection of participants, the South African guidelines recognise the risks of research with international collaborators. The guidelines call for explicit memoranda of understanding covering expectations, roles and contributions, including financial arrangements. The Good Clinical Practice guidelines state that a "signed declaration must be provided by the Sponsor which states that there are sufficient funds available to complete the trial".

SAHPRA has a specific guideline on post-trial access (PTA) or continued access (CA) which states: "Where appropriate and available, the possibility of PTA/CA should be disclosed to and discussed with potential participants during the initial informed consent process or via a separate consent process."

US funding for clinical research in South Africa is incrementally being cancelled. This is happening through at least two processes. Spotlight and GroundUp break down the current situation. @JesseCopelyn @MRCzahttps://t.co/pu3mOJ5PS0

-- Spotlight (@SpotlightNSP) May 9, 2025

The abrupt withdrawal of funding for clinical trials has meant that researchers have had to take immediate action to protect participants from potential harm. For example, when USAID funding for a vaginal ring study was withdrawn, participants were brought back to the trial clinic to remove the rings and provide counselling on alternative HIV prevention options. Researchers are trying to cover the costs of ethically closing studies, providing final clinic visits and referral for all participants.

However, the sponsors of these prematurely cancelled studies appear to be evading their responsibilities, even to the extent that they are covered in codes and guidelines. The limitations of those codes and guidelines have been cruelly exposed.

South African researchers involved in US-funded studies are required to complete Human Subjects Protection training, covering such US documents as the 1979 Belmont Report and the "Common Rule". Every training course includes coverage of the object lessons from the "Tuskegee Study of Untreated Syphilis in the Negro Male" - a study conducted between 1932 and 1972 that grossly violated several basic principles of medical ethics.

Will the events of 2025 and the consequences for clinical trials participants who consented in good faith, only to be abandoned for ideological and political reasons, be among the examples of unethical conduct provided to future health researchers undergoing ethics training?

*Gray is a Senior Lecturer at the University of KwaZulu-Natal and Co-Director of the WHO Collaborating Centre on Pharmaceutical Policy and Evidence Based Practice. This is the third of a new series of #InsideTheBox columns he is writing for Spotlight.