The first pregnant woman with malaria was enrolled in a clinical trial in Mali to compare three different malaria treatment regimens earlier this month – a historic event as pregnant and breastfeeding women and babies are seldom included in clinical trials despite being more vulnerable to several illnesses.

But there is growing momentum for including “under-represented groups” in clinical trials to ensure that medicines developed are suitable for all those who need them most.

Malaria in pregnancy is responsible for around 20% of stillbirths and 11% of all newborn deaths in sub‑Saharan Africa, as well as some 10,000 maternal deaths globally each year. It can also cause severe maternal anaemia, miscarriage, stillbirth, preterm delivery and low birthweight. 

Back in 1998, the World Health Organization (WHO) recommended artemisinin-based combination therapy (ACT) as the standard of care for malaria – but it only updated its guidelines for malaria to include pregnant women in their first trimester in 2022, according to Dr Myriam El Gaaloul, head of clinical and regulatory sciences at Medicines for Malaria Venture.

“With the threat of emerging resistance to malaria drugs, alternatives are needed, and I think we all agree that we cannot afford to wait for another quarter of century [for treatment for pregnant women],” El Gaaloul told a webinar on under-represented populations in clinical trials, hosted by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) as part of its African Regulatory Conference.  

The trial, which will also run in Kenya and Burkina Faso, is an initiative of the Safety of Anti-malarials in the First Trimester (SAFIRE) Consortium, with El Ghaloul as its principal investigator.

Preparation for the trial started in 2023 and involved getting ethical clearance in all three countries and holding meetings with regulators, said El Ghaloul.

Ethical considerations

Dr Jacqueline Kitulu, the incoming president of the World Medical Association (WMA), told the webinar that excluding under-represented groups “generates several ethical harms”, including the risk that “clinical decisions are built on non-generalisable data”. 

She defined these groups as “women, including the pregnant ones, older adults, children, people with disabilities, indigenous and marginalised populations and those in conflict settings”.

“Exclusion can cause harm when interventions are later rolled out without safety or dosage data for larger segments of the population who are really excluded or under-represented groups,” Kitulu explained.

The WMA developed the Helsinki Declaration 61 years ago to guide research on human subjects, and this remains the cornerstone for researchers.

Mercury Shitindo, executive director of the Africa Bioethics Network, said there needs to be a shift in thinking: “We are not protecting people from research, but we are working on ways to protect people through research.”

“This particular shift requires not only including under-represented populations in trials, but also ensuring that our regulatory systems and community policies are at the centre of how research is designed, conducted and shared.”

Runcie Chidebe, founder of Project PINK BLUE, a Nigerian cancer awareness and patient advocacy organisation, said that Africa only hosts 4% of global clinical trials, although it makes up almost 19% of the world’s population.

He knew of only one oncology clinical trial in Africa at present, and said that clinical trials for treatments for metastatic cerebral and cervical cancer mental had involved “95% white people”.

Evolving international policy

On 7 October, the WHO launched the Global Clinical Trial Forum (GCTF) to strengthen the clinical trial ecosystem, Martina Penazzato, WHO lead of Global Accelerator for Paediatric Formulations (GAP-f), told the webinar.

The forum is in response to a resolution from the World Health Assembly (WHA75.8), which called on WHO member states to improve the quality and coordination of clinical trials to generate high-quality evidence for health decision-making. 

“The WHO has also released a global action plan, with action three [of nine actions] emphasising the inclusion of under-represented populations,” said Penazzato, adding  

Research is underway to better define under-represented populations and the policy landscape. 

“The WHO has identified key barriers to paediatric clinical trial inclusion, such as ethical and regulatory frameworks, and has advocated for a more coordinated, transparent process to prioritise research in this area,” she added.

Mariana Widmer, a WHO scientist in maternal and perinatal health, said that medicines need to be tested on pregnant women as “pregnancy introduces significant physiological changes”. 

“For example, the blood volume increases by about 40% and this affects how medicines are absorbed and processed,” said Widmer, “So medicines should be tested in pregnant women to ensure safe treatment, yet pregnant women are often excluded from trials. 

“Around 70% of pregnant women take prescription medicines, and most of them are off-label; therefore, excluding pregnant women poses greater risks than including them.”

Meanwhile, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is considering guidelines to include pregnant and breastfeeding women in research, said Theresa Wang, director of Clinical Quality and Compliance Management at AstraZeneca, who spoke on behalf of IFPMA

The ICH brings regulatory authorities and the pharmaceutical industry together to discuss scientific and technical aspects of pharmaceuticals.

The ICH resolved to include pregnant and breastfeeding women in clinical trials in 2023, said Theresa Wang, director of Clinical Quality and Compliance Management at AstraZeneca, speaking on behalf of IFPMA. 

This was the second of a  four-part virtual Africa Regulatory Conference webinar series hosted by the IFPMA that is open to all who are interested. The third webinar, ‘Innovative clinical trial designs and digital technologies, is on Tuesday, 21 October.

Image Credits: Medicines for Malaria Venture.