US regulator’s decision on vaginal ring denies choice to women who need HIV prevention

NIAID. Creative Commons licence.

The Food and Drug Administration’s rejection of the dapivirine vaginal ring sets a dangerous precedent, Professor Erica Gollub and Raven Vaughan of Pace University argue in a commentary published in the journal AIDS Education and Prevention. “Absence of the dapivrine ring as an HIV risk reduction method for US women will result in a narrower set of choices for women, resulting in additional, preventable HIV infections,” they say.

The dapivirine ring is a small, flexible device similar to a contraceptive ring. It is inserted into the vagina and slowly releases the anti-HIV drug dapivirine over the course of a month. Whereas PrEP tablets and injections are systemic drugs – the medication spreads throughout the body – the vaginal ring is a form of topical PrEP in which the medication is concentrated in genital tissues.

Two phase III studies, in which African women were randomly assigned to receive either a vaginal ring containing dapivirine or a placebo, announced their results in 2016. The RING and ASPIRE studies reported lower efficacy rates for the vaginal ring when compared with oral PrEP: 31% and 27%, respectively. In other words, the ring prevented a quarter to a third of HIV infections that would otherwise have happened. Efficacy was higher among older women and when the rings were used consistently. In subsequent open-label extension studies (in which participants knew that the ring they had been given could help prevent HIV), estimated efficacy rose to 62% and 39% respectively.

Glossary

efficacy

How well something works (in a research study). See also ‘effectiveness’.

vaginal ring

A device that is worn inside the vagina for a month at a time, which women can insert and remove themselves. A vaginal ring for HIV prevention that slowly releases the antiretroviral drug dapivirine is being developed.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

oral

Refers to the mouth, for example a medicine taken by mouth.

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.

In 2020 the European Medicines Agency (EMA) gave regulatory approval to the ring, though in an unusual way: it was done under a measure called Article 58, which enabled the regulatory expertise of the EMA to be used to grant a licence for a device intended to be used in lower-income countries. Soon afterwards, the World Health Organization confirmed that the ring met global standards for quality, safety and efficacy (this is known as WHO prequalification). It also recommended that the ring “may be offered as an additional prevention choice for women at substantial risk of HIV infection as part of combination prevention approaches.”

These steps have allowed regulatory agencies in Kenya, South Africa, Uganda, Zambia and Zimbabwe to approve the ring, while applications have been submitted in several other African countries. Guidelines in Kenya, Lesotho, Namibia and Uganda already support use of the ring.

But the ring is not yet licensed in high-income countries. In December 2021, the Food and Drug Administration (FDA) advised the ring’s developer that it would be unlikely to give approval to the ring in the United States, “given the context of the current HIV prevention landscape for women in the United States”.

This appears to be a reference to the current availability of oral PrEP and injectable PrEP, both of which had higher efficacy than the vaginal ring in clinical trials. However, Gollub and Vaughan argue that basing approval primarily on comparative efficacy in randomised trials is inadequate, given other factors that contribute to women’s ability and preferences when choosing protection. These include cost, convenience, sexual pleasure, side effects, health risks, and user control.

They believe a product of high efficacy which is not being used is worse than a product of moderate efficacy that is used widely and continuously. The history of contraception suggests that giving women a choice of methods results in greater numbers using some protection instead of none, greater satisfaction for women and couples, and an overall public health gain.

Another lesson from contraception concerns the harm caused by policies which undermine women’s agency. In some settings, clinicians have steered women seeking contraception to long-acting methods (such as injectables, implants and intrauterine devices) as their ‘best’ options, based on a hierarchy of efficacy. Especially when these policies have been implemented amongst adolescents, racially minoritised women and in disadvantaged communities, this has deepened medical mistrust and women’s sense of not being heard.

Gollub and Vaughan point to the considerable unmet need for HIV prevention for women. Each year, around 7000 American women a year acquire HIV, with a disproportionate burden among Black and Latina women. The uptake of oral PrEP is low and 78% of women prescribed PrEP discontinue it within a year, with higher rates of discontinuation among poorer women who do not have private insurance.

Some women may feel that the vaginal ring has advantages over daily pills and injectable PrEP. Like the injections, it is more discreet than oral PrEP and does not require daily adherence. Whereas PrEP injections can only be administered by a healthcare professional, women can insert and remove the ring themselves. While all forms of PrEP require regular HIV testing, ring users do not need the assessment of kidney, bone health and hepatitis B status that oral PrEP involves.

"A product of high efficacy which is not being used is worse than a product of moderate efficacy that is used widely."

“Presently, the landscape of approved HIV prevention methods does not offer other options to women who do not wish to use drugs with systemic effects, cannot afford the injection, do not find pills discreet enough, and do not wish to – or cannot – adhere to a daily dosing,” Gollub and Vaughan say.

The FDA decision has also had an impact in the global South. It may send a message of double standards for American and African women, and undermine confidence in the ring among women in African countries. There are questions about whether funding from the US President’s Emergency Plan for AIDS Relief (PEPFAR) will be available for a product that is not approved by the FDA. Moreover, US agencies have already scaled back their support for research and development of prevention methods that do not provide long-acting, systemic protection – including improvements to the current product such as rings that simultaneously prevent HIV and pregnancy.

The authors recommend that the FDA should invite the ring developers to resubmit their application for approval of the dapivirine ring, without the need for additional data, and convene a review that includes wider stakeholder input.

References

Gollub EL & Vaughan R. U.S. Women Need the Dapivirine Ring, Too: FDA as Structural Barrier to HIV Prevention for Women. AIDS Education and Prevention, 34: 311–324, 2022.

Update: This article was corrected on 22 September 2022 to mention additional countries has received regulatory approval.