All medicines and treatments have to go through lengthy safety and efficacy testing, but this is particularly tricky – and often delayed – for one important age group. Spotlight explores the complexities of conducting clinical trials involving babies, and why those complexities are worth grappling with.
Babies are at risk of developing illness and severe disease yet they are often not included in clinical trials. Because of this, when babies do get seriously ill, doctors sometimes have comparatively little scientific evidence to draw on when making decisions about their care.
The World Health Organisation (WHO) in a 2025 technical report estimates that only a tenth of clinical trials globally include babies, and only a fraction of these are conducted in lower- and middle-income countries. They put this down to a range of constraints including smaller markets for medicines for babies and commercial incentives and ethical and regulatory complexities. Babies are loosely defined as young children, including neonates, infants and younger toddlers under the age of five years old or weighing under 5kg.
Recognition of the problem is not new. One much-cited article published in the British Journal of Clinical Pharmacology in 2015 traces the acknowledgement of children as ‘therapeutic or pharmaceutical orphans’ back to the 1960s. Yet, a half-a-century later, the authors still conclude that: “Safety and efficacy data on many medicines used in children are surprisingly scarce. As a result children are sometimes given ineffective medicines or medicines with unknown harmful side effects.”
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As the saying goes, children aren’t just small adults, and accordingly, simply giving them the same medicines as adults in lower doses often doesn’t work, or in some cases results in severe side effects.
But while the need for more research in infants thus seems clear, the incentives for doing that research is not always there. “Industry may be reluctant to conduct trials in children due to decreased commercial interest, increased cost and greater risk of liability,” wrote the authors of the 2015 study. In addition, behind the question of liability, lurks an additional set of ethical questions about issues such as consent, and the weighing up of potential benefits and harms.
Ethical questions
“If we don’t study young children, there’s a high risk of these children being under-researched and us not having appropriate information on how to manage them,” says Professor Marc Blockman. He is a clinical pharmacologist and chairperson of the Human Research Ethics Committee of the Faculty of Health Sciences at the University of Cape Town (UCT).
While there is some concern around conducting clinical trials in such a young population, Blockman emphasises the importance of doing so. “We obviously have some anxiety, but as long as the clinical situation involves the age group, and it can’t be tested in another group that would give the same answer, then utilising this young population would be appropriate,” he says.
Ann Strode, a Professor in the School of Law at the University of KwaZulu-Natal, says that the basic conditions of research on children are meant to protect their rights, since they are often not able to do so themselves.
There are various frameworks that set out these expectations.
The National Health Act mentions that vulnerable groups, such as children, must be considered when identifying health research priorities, and lays out the need for consent. In South Africa, children under the age of 18 cannot give full medical research consent in most cases. While older children may be able to assent or dissent to show their willingness, this is usually not possible for infants and babies. Parents or guardians can give consent on behalf of infants, although this is only one of several hurdles to clear before research involving infants can proceed.
The South African Health Products Regulatory Authority (SAHPRA) and the National Department of Health published the South African Good Clinical Practice: Clinical Trial Guidelines that mention that consent discussions must specifically explain risks related to embryos, foetuses, and nursing infants. It also notes that the burden of disease and the resource implications of research must be considered together with the health needs of vulnerable groups. The health department’s 2015 Ethics in Health Research document further explain the guidelines, but do not make particular reference to infants.
Three factors
The first factor in justifying a trial in such a vulnerable population is to show that it cannot be done adequately in older children or adults. “The children must be indispensable to the study,” Strode says. New knowledge should be developed and that knowledge must directly benefit children.
Blockman adds that the disease must be particularly prominent in that age group. “We keep in the back of our minds that if the research doesn’t occur, we potentially make the child more vulnerable because we don’t have the data to inform treatment, so we try and get that balance right.”
A second important factor is safety. In adults, a safety trial of an experimental treatment is typically conducted in people who do not have the illness. For children, adult safety data, where available, is usually used to identify the risks. “You can do a study as long as it’s minimal risk, which is defined as the ordinary risk that you’d face in ordinary society with healthcare,” Strode says.
The risk standard is the same across ages, she explains, but with children there is often less data to assess the risk, making it more difficult.
To address this, Blockman advocates for a staggered approach, where tests are run on slightly older children first, with the possibility of feedback and adjustments between age groups to optimise safety.
However, Strode notes that globally and locally in the last decades, there has been a shift to accept babies and children as part of initial trial groups, to speed up results.
Thirdly, since babies are particularly vulnerable medically, researchers and an ethics committee may double up efforts to make sure the parent or guardian consenting fully understands the process and is not personally benefiting in an unreasonable way. “All of these things could be put in place to try and make sure that we don’t make the infant more vulnerable in doing the research,” says Blockman.
He says he has witnessed an encouraging rise in the research done in babies in South Africa over the last few decades. “The regulators, ethics committees, advocates, and sponsors have gotten over themselves a bit, and seen the importance of not just the risk but the benefit of doing research in infants,” he says.
Identifying safe ARV dosages
One area in which the abstractions of research ethics has become very concrete in South Africa is HIV. Since a substantial number of babies still become HIV-positive at, or relatively soon after birth, establishing the best treatments for babies with HIV has been, and remains, an urgent research question.
Professor Adrie Bekker, a neonatologist at the Department of Paediatrics and Child Health at Stellenbosch University and Tygerberg Hospital, has worked on many a clinical trial that included babies.
Some of her recent work was aimed at figuring out the correct dosages to use of an antiretroviral drug called abacavir in babies born to mothers living with HIV. Previously, abacavir was only investigated in babies aged three months or more. Bekker and her team expanded on this work by pooling pharmacokinetic and safety data from three completed studies – two in South Africa and one in the USA – to find an abacavir dosing that can be given to newborns from birth.
The three studies were done at Tygerberg Hospital, across two South African cities, and in the USA. In the case of the American study, some of the data had been lost for decades, and Bekker and her team had to unearth it. “We went on a search, contacting everyone we know, and in the end someone managed to extract it from some central database where it was buried for 20 years,” she says.
Bekker’s team combined and analysed the data from the three trials, which tested various formulations including abacavir on different infant cohorts. For instance, the Tygerberg Cohort and the USA PACTG 321 trial used single doses of abacavir on neonates, while the other South African trial focused on low birthweight infants on antiretroviral therapy.
Together, this data helped define the dosing guidelines for abacavir in newborns, laying the foundation for other work, like the PETITE trial, where these dosages were tested in infants. In short, the researchers went the extra mile to make sure that the dosages they used in new clinical trials were as safe as possible for participating infants.
“It’s difficult to study drugs in children and to enrol neonates into clinical trials, but that should not prevent us from doing so,” Bekker says.
Tasty treatments for TB
Children under the age of five are at high risk of developing tuberculosis (TB), especially the more severe forms. As the Director of the Desmond Tutu TB Centre and a Distinguished Professor in Paediatrics and Child Health at Stellenbosch University, Anneke Hesseling, has dedicated much of her life to finding better solutions for this age group.
Since TB treatment typically takes four or six months in children, Hesseling wants to make sure that adherence and treatment completion are high. To do this, she has worked on making treatment as palatable and easy to dispense as possible.
“If it’s bitter and tastes disgusting, it will actually negatively impact adherence, and outcomes,” she says. Accordingly, her work aims to make the treatment courses as short and simple as possible, ideally by using pills that can be divided and dissolved, as opposed to syrups and capsules.
Hesseling finds that monitoring the reactions of babies and children to certain medications is helpful, even though they may not be able to consent in the traditional way. For example, in 2025 she worked on a study that evaluated children’s preferences for certain dispersible tablet formulations. In this process, they gave healthy child volunteers samples of three different flavours of specific drugs, and asked them to rank them according to their preference and acceptability. This showed that most children preferred new options over existing flavours.
“It’s important that people consider these things before medicine is commercially available and marketed, because once they’ve done that, then no one has any incentive to go back and make more effort,” she says.
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However, Hesseling says she has encountered some systemic hesitancy to support the cause of treatment clinical trials in children. In particular, she explains that TB tends to occur in lower-income communities, which may be less profitable for pharmaceutical companies, slowing down research. “We’re working on the disease of poverty, and we’re looking at people having financial incentives to make drug formulations for kids, and so there’s a bit of a tension there,” she says.
An RSV example
Most of the time, researchers want to know how to adjust existing treatments for adults for babies. That works for diseases that impact both adults and babies, but clinical trials are also needed for illnesses that impact infants significantly more or more severely than adults.
Respiratory syncytial virus (RSV) can lead to severe illness in infants and has become a focal point for the Research Centre for Adolescent and Child Health (REACH) at the South African Medical Research Council’s Unit on Child and Adolescent Health at Red Cross War Memorial Children’s Hospital in Cape Town.
Project Manager Cynthia Biddle Baard explains that the REACH team has been focusing on testing the monoclonal antibody clesrovimab to decrease infant hospitalisation for RSV.
“One of the benefits of enroling infant participants in the trials has been the 24-hour monitoring that we do as a unit,” Baard explains. She says they tend to monitor a child for up to two years for hospitalisations and adverse events. “Providing that extra care and that extra dialog has really helped us develop the relationship with the parents.”
Her experience has been that babies can be easier trial patients than toddlers. “In this infant space, they’re so small that procedures are not as difficult as in the two to five year olds,” she says. The clinicians are usually able to give the parents choices in whether they would like to stay in a room or leave during procedures, and there are trained counsellors that are able to hold the babies in the best ways to keep them calm.
While young patients are particularly affected by RSV, they have also been responding especially well to prevention trials.
Put it all together, and whether it is RSV, HIV, or TB, there appears to be a growing body of evidence showing that infants can safely be included in clinical trials, that the unique risks of research in this age group can be managed, and maybe most importantly, that this research has resulted in real benefits for infants.
“It’s incredible to be involved in trials that are making real differences in reducing the severity of illness and frequency of hospitalisations in young children,” says Baard. “The evidence is so tangible and making a real difference to the health of small children.”