How do we navigate the tricky ethical landscape surrounding clinical trials in developing countries? Hayley Bennett provides an overview of the latest thinking for statisticians and data professionals working with clinical data
In 2022, Cameroon registered 15 clinical trials, total. A lower-middle income country in West Africa, Cameroon has a population comparable in size to Australia. Yet in 2022, Australia registered 2,284 clinical trials.
Many countries in sub-Saharan Africa face a similar situation, resulting not just in a lack of clinical data (on any treatment) from these countries, but also a lack of data on treatments and diseases that are important and appropriate to them.
“Africa bears a huge proportion of the world disease burden, but very few clinical trials are being conducted to develop interventions targeting those conditions that are widely prevalent in Africa,” explains researcher Yauba Saidu, whose work in Cameroon with the Clinton Health Access Initiative and Institute for Global Health (University of Siena) focuses on pharmaceutical development and public health policy.
The problem is a global one. Overall, in 2022, more than 47% of all clinical trials were registered in high-income countries, compared to 17% and 26% in upper- and lower-middle income countries respectively. Only around 0.5% of trials were registered in low-income countries – despite 9% of the world’s population residing in them.
What’s more, trials do not reflect the global disease burden. If they did, there would be more trials testing treatments for diseases that disproportionately affect developing countries, like tuberculosis and neglected tropical diseases. And according to bioethics expert Joseph Millum from the University of St Andrews, more trials are also needed to test the types of interventions that people in developing countries can actually afford. “Take HIV,” he says. “Tonnes of research has been done on antiretroviral drugs. But there’s much less research done on interventions that might be more suitable for poorer countries – that are, say, cheaper or easier to implement.”
This dearth of clinical data from developing nations is an issue of fairness in itself. But the problems are on two levels. On the one, more trials are undoubtedly needed to address developing countries’ needs, while on the other, the regulatory and ethical environments for those attempting to redress the balance are challenging. For example, in Cameroon, as Saidu explains, lengthy, uncoordinated and largely paper-based systems for getting ethical approvals impact the “attractiveness” of the country to potential trial sponsors. A lack of skilled clinical researchers and facilities, and issues with the quality of the data produced may also be high on funders’ lists of concerns. On top of this, the Cameroonian people can be understandably suspicious of trials. “The population is really new to clinical trials and because of that there is a lot of scepticism and resistance each time you want to conduct a trial,” Saidu says.
Even where people are more familiar with trials, research funders, drug developers and the organisations that work on behalf of them face a slew of ethical dilemmas in trying to design trials that balance the pursuit of knowledge with the fair treatment of people. Morally, it is the obligation of everyone involved in the planning, design and analysis of clinical trials – including data and statistics professionals – to be aware of the disparities and the ethical landscape that must be navigated to address them.
What’s the difference?
It is worth being clearer about why we need more data from developing countries in the first place. The fact is that if the data for a drug or vaccine comes largely from high-income countries, then we can’t assume it will be safe and effective everywhere. Even when trials cover multiple sites, they’re not necessarily powered to pick up differences between sub-groups.
As African and Dutch researchers recently highlighted, there are plenty of reasons why populations in developing countries might not respond in the same way to certain interventions. For example, they may have different genetics, age profiles and diets, and may use treatments in a very different way. However, Millum warns that we often overplay the genetic differences: “I think some people still hang on to this idea that racial differences correspond to much more significant differences than in fact they do.”
Whatever the underlying factors, they mean that interventions that work well in, say, the US or Europe won’t necessarily work well in rural Africa. Rotavirus, for example, causes tens of thousands of diarrhoea-related deaths in young children every year and overwhelmingly the biggest burden falls on developing countries. However, while vaccines are now reducing this burden everywhere they are used, historically, they have proven less effective in low-income compared to high-income countries. Water systems and sanitation practices that make it easier for the virus to spread in developing countries may have an important influence.
On the other hand, simply carrying out more trials in developing countries won’t necessarily lead to the same benefits as it does for people in developed nations. Cancer drugs are a case in point. Developing countries will be hardest hit by the rising burden in cancer cases in the next 25 years. Yet, until recently, the overwhelming majority of clinical trials for cancer drugs were conducted elsewhere. One 2021 study showed that between 2014-2017, only 8% of phase III clinical trials were led by low- and middle-income countries. Redressing the balance would involve running more cancer trials in developing countries, as the American Society of Clinical Oncology outlined in a 2024 policy statement. However, it’s a question of which diseases developing countries should prioritise and, as Saidu notes, more trials of cancer drugs wouldn’t change access to the drugs. “In the case of Africa, and Cameroon in particular, I think it’s a clear example of market failure, not really whether the trials have been conducted in Africa or not,” he says. “The products are available, the prices of those products are very high and the revenue of the patient who needs the product is very low.”
Ethical experimentation
The potential mismatch between who takes part in clinical trials and who benefits is a key part of a much more complex ethical context surrounding the design of trials in developing countries. Concerns often centre on informed consent and how to design control or placebo groups in countries where there is sometimes no standard medical treatment for comparison. The evolution of medical ethics and clinical research regulation has been shaped by sometimes ill-advised experiments that have forced clinical researchers to think harder about how they test their treatments on humans.
Some of the higher profile cases have included Pfizer’s antibiotic trials in Nigeria – which raised questions about the nature of informed consent – as well as the US government’s trials of HIV drugs in pregnant (largely African) women, many of whom gave birth to HIV-infected babies in the 1990s after being randomly assigned to placebo groups. Meanwhile, in 2005, in Cameroon, ethical concerns and media coverage surrounding a US-led trial of the HIV drug tenofovir convinced the public health ministry to suspend the study. Saidu’s interpretation is that there was a lot of “political noise” around the trial, but that ultimately claims used to suspend it may have been ill-founded. Yet, such controversies unsurprisingly damage the prospects for future trials.
From Millum’s perspective, the issue is not usually that pharmaceutical companies are trying to find places where they can “get away with” unethical research. “Just thinking from a purely commercial point of view, that’s not the game for them,” he says. Instead, they’re looking for locations to carry out their trials cheaply and efficiently, and perhaps in countries where there are lots of patients who are not already being treated.
However, there will always be opportunities for ethical missteps. One 2024 study on the clinical trial landscape in Pakistan, for instance, highlights low literacy levels (58%), the country’s patriarchal society and its lack of any regulatory body to monitor clinical trials as concerns when obtaining informed consent. At the same time, more trials are being registered in Pakistan and trials for diseases like tuberculosis, hepatitis and HIV interventions are badly needed. So would it be a mistake for Pakistan to become a hub for clinical research? It’s an open question. Ethical concerns are just plain hard to navigate.
What guidance, then, can those involved in trials draw on to advocate for research that best serves the needs of those in developing nations? The foundations of medical ethics were laid in 1947 with ‘The Nuremberg Code’, a text emerging from the criminal trials of Nazi doctors who carried out “horrendous, non-therapeutic, nonconsensual” research on prisoners in concentration camps during World War II. The Code prioritised informed consent in medical research, but for many doctors, was superseded by the more flexible approach to consent outlined in the World Medical Association’s ‘Declaration of Helsinki’ in 1964.
The Declaration of Helsinki has since undergone several reworkings, however. With regards to developing countries, in 2000 it included new provisions to give participants access to the “best proven” treatments at the end of trials, and for those in control groups to get the “best current” treatments instead of placebos. These updates irritated those in developed countries who felt that it would be impossible to offer those in other countries the same standards of medical care. (All references to the declaration were eventually removed from US Food and Drug Administration regulations, although its principles do still provide the basis for laws governing medical research in Europe and the UK.) A current consultation should lead to strengthening of provisions in relation to health inequities, informed consent, approval of trials in international research collaborations and access to treatment for participants following trial completion – all of which could benefit developing countries, if they are put into practice.
Ethical guidelines published by the Council for International Organizations of Medical Sciences (CIOMS) have also made important contributions to research ethics for research in developing countries, whilst the 1976 Belmont report on ‘Ethical principles and guidelines for the protection of human subjects of research’ led to the establishment of the ethics committees overseeing medical research today and was translated into US legislation governing research in humans. The report drew special attention to the weighing of risks versus benefits for those involved in research, providing an important basis for thinking about how developing countries and specifically people involved in trials are compensated.
However, while the medical community knows of these guidelines and regulations, there is little research to show how well they are observed. They may also have a limited impact on improving access to clinical trials (or even create barriers to research) in countries where the ethical implications could be seen as particularly challenging.
A difficult balance
The problem remains that clinical trial sponsors are often based in the developed world. Even with the proliferation of international research partnerships centred on clinical trials, those involved must find ways to ensure a more equal balance of power between nations. In the past, such partnerships have often failed. “How to have genuinely equitable and effective collaborations is something that people are still working on,” says Millum. Partly, it is about ensuring that efforts are designed with the intention to help developing countries expand their own research capacities and infrastructure, and strengthen systems for carrying out ethical reviews.
The Global Health European and Developing Countries Clinical Trials Partnership (EDCTP), established in 2003, is one example of a partnership where developing nations’ needs appear to take precedence. The EDCTP aims to fund research on diseases affecting sub-Saharan Africa and build African clinical research capacity, with last year’s calls for proposals focusing on ethics and regulatory capacity, and African networks for clinical research training.
Such efforts may be helping. But, as always, the situation is different everywhere. “We tend to see a few countries with a high volume of trials,” Saidu says, referencing South Africa in particular. “But in other countries, particularly in the central African corridor, we tend to see very, very few.” Indeed, in Cameroon, registrations have remained steadfastly low (25 or less per year) for the past two decades. Saidu’s recent paper aims to address some of the “bottlenecks” in setting up African clinical research projects – this involves starting a dialogue with all potential supporters and opponents early on in the process, including everyone from community groups to government authorities. For countries like Cameroon, unblocking the pathway towards trials that are ethically sound remains extremely challenging.
Hayley Bennett is a science writer based in Bristol, UK.
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Photo: Mbouda West, Cameroon – January 20th, 2024. Sid Mbogni/Shutterstock
