Recruitment to clinical trials that lead to the licensing of antiretroviral drugs is not representative of the global HIV pandemic, an international group of researchers report in the Journal of Virus Eradication. Licensing studies were overwhelmingly conducted in richer countries and white men were massively over-recruited.
Failure to recruit a representative population could mean that important information about the pharmacokinetics of drugs is missed and that potentially dangerous side effects go unnoticed in this key stage in the drug approval process.
“Our analysis indicates that regulatory randomised controlled trials for novel antiretrovirals are vastly unrepresentative of people living with HIV globally,” write the authors. “Groups at highest risk of serious safety issues are under-recruited. This could impact drug safety profiles.”
Pharmaceutical companies test the safety and efficacy of experimental anti-HIV drugs before submitting them for approval by regulatory approval. The final stage in this process involves what are called phase III trials. These compare the investigational drug against the standard of care. They are randomised and double blind (neither the person with HIV nor their doctor know which study arm they have been assigned to). Phase III studies usually last for 48 weeks and recruit thousands of people. However, there are often strict inclusion and exclusion criteria, which usually exclude women who are pregnant or who are planning pregnancy.
There are several instances of serious side effects only being discovered after drugs received approval. These include lipodystrophy and stavudine, increased risk of suicide with efavirenz, and most recently, weight gain associated with integrase inhibitors (especially when taken in combination with tenofovir alafenamide (TAF)).
Although it is inevitable that some rare side effects will only be detected once a drug is being taken by several thousand individuals, it is now well known that the safety of some antiretrovirals differs according to sex and race (for instance, the connection between integrase inhibitors and obesity is especially prevalent in black females). The ability to detect potentially harmful side effects would possibly be improved if phase III studies recruited study populations that were more representative of the demographics of the global HIV pandemic.
A team of investigators led by Dr Toby Pepperrell of Imperial College, London therefore designed a study comparing the demographic characteristics of people living with HIV globally to those of people who were recruited to the phase III studies leading to the approval of four modern anti-HIV drugs.
Twenty four phase III studies were included in the analysis: ten for dolutegravir (7714 participants), four for bictegravir (2307), eight for TAF (7573) and two for doravirine (1407).
“Regulatory randomised controlled trials should aim for at least 50% female and 50% non-white participants to provide sufficient safety data."
Of the global population of people living with HIV in 2018, 42% were black women, 30% were black men, 3% were white women, 6% were white men, 7% were women of another race and 12% were men of another race.
This was not reflected in the demographics of the people recruited to the phase III studies. Overall, 7% of participants were black women, 17% were black men, 13% were white women and 50% were white men. These figures were consistent across all four drugs.
Recruitment was also unrepresentative in terms of study setting. Globally, over 60% of people with HIV live in low- or low middle-income countries, of whom 91% are non-white (68% black and 23% Asian). However, 76% of dolutegravir study sites were in high-income countries (which have only 5% of global HIV cases) and 23% were in upper middle-income countries.
Moreover, even in high-income countries, the studies were not representative of local demographics. Whereas 50% of study participants there were white men, only 31% of people with HIV in these countries are white men.
“The present study indicates that changes to randomised controlled trial recruitment practices are needed to gather an appropriate level of safety data for novel drugs,” conclude Dr Pepperrell and his colleagues. “Regulatory randomised controlled trials should aim for at least 50% female and 50% non-white participants to provide sufficient safety data."
Pepperrell T et al. Phase 3 trials of new antiretrovirals are not representative of the global HIV epidemic. Journal of Virus Eradication 6: 70-73, 2020 (open-access).
Correction: This article was amended on 27 May 2020. An earlier version said that ten studies were included in the analysis, whereas the correct figure is 24.