Recruitment to clinical trials that lead to the licensing of antiretroviral drugs is not representative of the global HIV pandemic, Aidsmap reports an international group of researchers has found. Licensing studies were overwhelming 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, the report says.
“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.”
A team of investigators at Liverpool University, Wits Reproductive Health and HIV Institute and the University of the Witwatersrand 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.
Ten phase III studies were included in the analysis: three for dolutegravir (7,714 participants), four for bictegravir (2,307 people), eight for TAF (7,573 individuals) and two for doravirine (1,407 people with HIV).
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, 17% were women of another race and 7% 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.
“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 Pepperell and his colleagues. “Regulatory randomised controlled trials should aim for at least 50% female and 50% non-white participants to provide sufficient safety data."
Introduction: People living with HIV (PLWH) are mainly African or Asian, the majority female. In contrast, pharmaceutical companies typically conduct phase 3 regulatory randomised controlled trials (RCTs) in high-income countries (HICs), where PLWH are mainly white males. Regulatory authorities can be conservative about including pregnant women in trials, discouraging female participation. Some adverse events occur more frequently by sex or by race because of differing pharmacokinetics. Most drugs have insufficient safety data in pregnancy and non-white people even after regulatory approval. The present study compared race and sex demographics of phase 3 RCTs of dolutegravir (DTG), bictegravir (BIC) and tenofovir alafenamide (TAF) with global HIV epidemic demography.
Methods: National epidemic sizes by sex were extracted from UNAIDS 2018 data. National demographics were used to estimate prevalence by race. PLWH by national socio-economic status were calculated from World Bank data. Summary race and sex demographic data for 10 phase 3 trials of DTG (n = 7714), four of BIC (n = 2307), eight of TAF (n = 7573) and two of doravirine (DOR) (n = 1407) were extracted from ClinicalTrials.gov.
Results: Black females (42%) and black males (30%) have highest prevalence globally. White males comprise 6% of PLWH. Over 60% of PLWH live in low or low-middle-income countries, 68% of whom are black and 23% Asian. Seventysix per cent of DTG trial centres were in high-income countries (HICs) (5% global burden) and 23% in upper-middle-income countries (UMICs). DTG trials were not representative of PLWH even within the UMIC and HIC setting (49% white male vs 31% income band). White males were overrecruited by 44% to DTG, BIC, TAF and DOR trials in comparison with prevalence. Black females were underrepresented by 35%.
Conclusion: Phase 3 RCT populations for new antiretrovirals comprised 51% white males, vastly disproportionate to the global HIV epidemic (6%). Females and non-white people are underrepresented. Female safety data are insufficient despite drug approval in Europe and USA. HIV trials should be located in regions representing the global epidemic with no sex-based selection. Trials should aim for at least 50% female and 50% non-white recruitment to properly provide safety information.
Toby Pepperrell, Andrew Hill, Michelle Moorhouse, Polly Clayden, Kaitlyn McCann, Simiso Sokhela, Celicia Serenata, Willem Daniel Francois Venter