60th anniversary of the Declaration of Helsinki: ethical challenges in the 10th amendment

Emerging ethical challenges in medical research and the 10th DoH revision

The field of medical research is currently navigating a complex array of emerging and persistent ethical challenges that the ongoing DoH review will need to address. These challenges are stimulated by the impact of global health emergencies and inequalities and unprecedented rapid technological advances, including the rise of digital technology, artificial intelligence and molecular breakthroughs such as CRISPR. These developments are driving considerable changes in research designs and require a comprehensive reassessment of ethical frameworks to address these evolving dynamics effectively.

The COVID-19 pandemic has dramatically transformed the ethical contours of medical research, spotlighting the difficulty of balancing rapid scientific advances with ethics and integrity. ¹ This has underscored the necessity for discussion regarding human challenge studies and the implementation of scientifically robust designs to reduce waste. ⁴ It also calls for a re-evaluation of the use of unproven interventions in clinical practice, and emphasises the enhancement of medical research’s social value through equitable benefit sharing, especially given the glaring disparities in access to vaccines, treatments and testing across the globe.

The ongoing revision of the DoH, initiated by the WMA Council in April 2022 and spearheaded by the American Medical Association, embodies a collaborative effort informed by global expert meetings and represents a concerted effort to ensure the document remains at the forefront of ethical medical research. ² Over two years, the revision process of the DoH utilises a series of regional and topical meetings to engage with a wide spectrum of perspectives from both local and international experts, and emphasises the importance of inclusivity and stakeholder feedback through the establishment of two distinct public comment periods. ²

Anticipating challenges and innovations: navigating the 10th amendment of the DoH

The 2024 DoH updates upgrade its ethical guidelines to align with today’s medical research needs. These revisions focus on enhancing participant protection through inclusive language, improved data privacy and consent processes that prioritise participants’ preferences and values. They emphasise adequately resourced ethics committees with qualified staff, advocate for efficient study designs to reduce ‘research waste’ and stress the importance of social and environmental responsibility. Additionally, the amendments aim to ensure equitable access to research benefits, particularly in resource-poor settings, and to foster community engagement and fairness. Updates will also refine guidelines on compassionate interventions, justice in participant selection and the involvement of patients as research partners, addressing contemporary ethical challenges effectively.

From its inception in 1964 until 1999, the DoH specifically targeted physicians. In 2000, the Declaration broadened its scope to encompass other clinical research professionals. By 2008, it was once again directed at physicians, ⁵ and as of 2024, it will once more broadly recommend its ethical guidelines to everyone involved in clinical research.

The DoH’s history underscores an ongoing discussion about including extremely vulnerable subjects in research. In the 1950s and 1960s, attention centred on institutionalised groups like prisoners and orphans. Notably, these groups were explicitly omitted from the 1964 DoH, ⁶ diverging from earlier drafts.^6,7 Subsequent reviews of the DoH from 1975 to 1983 brought the issue of vulnerable populations to the forefront, notably in research involving children. ⁵ From the 1990 s onwards, the globalisation and outsourcing of clinical research raised concerns over the exploitation of impoverished populations, especially in low- and middle-income countries. ⁵ The 10th revision of the DoH aims to comprehensively address research on vulnerable groups, including children, the elderly, pregnant individuals and people with disabilities, and to reevaluate ethical considerations in conducting clinical research in resource-poor settings.

The issue of obtaining free, informed and ongoing consent remains central, particularly with the challenges posed by new technology and artificial intelligence. First, the digital divide – the gap between those advantaged and disadvantaged by digital technologies – increases the vulnerability of people already in vulnerable situations. ⁸ Additionally, to encourage the sharing and accessibility of research data, some authorities have suggested the possibility of obtaining broad consent. This new approach to consent can raise several issues, such as loss of control over the data by the participant and the researchers, loss of participant autonomy and an increased risk of re-identification.

Minor changes to the DoH terminology include replacing ‘subjects’ with ‘participants’ to honour their rights, agency and significance. This update recognises medical research participants as encompassing both patients and healthy volunteers. However, the DoH is not expected to revert to distinguishing between these two categories. Healthy participants are typically involved in Phase I or non-therapeutic trials, while patient participants often blend their involvement with receiving medical care, thus requiring enhanced protections from the DoH due to their vulnerability. The 2013 removal of the distinction between therapeutic and nontherapeutic investigations marked a decrease in protection for these participants, ⁹ leading to the development of two separate medical ethics: one for medical research (DoH) and another for medical care (Declaration of Geneva – The Physician’s Pledge). Restoring the distinction between therapeutic and non-therapeutic research could harmonise medical ethics, aligning the DoH with the Declaration of Geneva and simplifying discussions on the use of placebos in the presence of proven therapies and the issue of post-study access to beneficial interventions. Nonetheless, it is anticipated that the debate between proponents of the conventional placebo orthodoxy and advocates for using active agents as controls to prevent double standards will persist.

A significant enhancement in the 2024 DoH is the explicit inclusion of social value (encompassing individual and public health) as a key objective of conducting medical research. The DoH clearly states that ‘While the primary purpose of medical research is to generate new knowledge, this goal can never overshadow the rights and interests of individual research subjects,’ ¹⁰ reinforcing the imperative to prioritise participant rights in all research endeavours. Therefore, this acknowledgment of social value must not serve as a pretext for conducting research that infringes upon the rights of participants.

Highlighting the social value of medical research is crucial, especially as pharmaceutical innovation faces limitations due to the industry’s profit-driven motives. This includes a tendency towards researching ‘me too’ drugs and conducting studies in resource-poor countries where the resulting treatments often remain inaccessible to the local population. This inaccessibility may result from the medication not being registered in those countries or the prohibitive costs associated with it. ¹¹ Consequently, this situation presents a significant challenge for the DoH concerning post-trial provisions, emphasising the need for equitable access to research benefits for host populations.

The 2013 version of the DoH falls short in ensuring that research participants are guaranteed post-trial access and fails to secure benefits for host communities, particularly vulnerable populations. ¹² It is hoped that the working group will advance in terms of post-trial provisions, extending beyond individual participant access after trials, to include the sharing of benefits arising from scientific research, as outlined in UNESCO’s Universal Declaration on Bioethics and Human Rights. ¹³

Final considerations

Celebrating its 60th anniversary, the DoH has significantly shaped the ethics of human research globally. The 2013 and 2024 revisions introduced more participatory, transparent and inclusive processes, reflecting the WMA’s commitment to diverse geographical and cultural perspectives and to addressing complex ethical challenges in medical research. However, establishing universal ethical guidelines remains a challenge due to ethical diversity, conflicts of interest and power disputes, highlighting the tension between scientific advancement, market demands and the protection of research participants.

The DoH not only marks six decades of ethical guidance but also underscores the WMA’s dedication to ensuring the DoH continues as a fundamental standard in ethical medical research. The 10th amendment is poised to reinforce the DoH’s status as a foundational element of medical ethics, maintaining its relevance and reliability.