NIAID Celebrates Pivotal Step Toward Expanding HIV Prevention Choices for Women
July 24, 2020
Today the European Medicines Agency (EMA) announced it has adopted a positive scientific opinion on the dapivirine vaginal ring for use by cisgender women ages 18 and older in developing countries to reduce their risk of HIV infection. This milestone marks an important step toward expanding the number of biomedical HIV prevention options available to women in sub-Saharan Africa, who are among those most affected by the HIV epidemic. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, thanks and congratulates everyone who led, conducted and participated in the research that led to the positive opinion.
The dapivirine ring is made of flexible silicone and continuously releases the anti-HIV drug dapivirine in the vagina. The user replaces the long-acting product herself once a month.
More than a third of the 1.5 million new cases of HIV worldwide among adults ages 15 and older in 2019 were in women in sub-Saharan Africa, according to UNAIDS. Women currently have limited HIV prevention options, and many women are unable to negotiate condom use with male sexual partners. Women need choices of discreet HIV prevention tools that they can initiate, and the dapivirine ring is one such tool.
Two large clinical trials of the dapivirine ring, one of which was funded in part by NIAID, found the product reduced the risk of HIV infection by roughly 30 percent overall in cisgender women ages 18 to 45 years in east and southern Africa. However, the NIAID trial found the ring provided no statistically significant protection in cisgender women younger than 25 years, likely due to low product use. These trials were conducted by NIAID’s partners in research on the dapivirine ring: the NIH-funded Microbicide Trials Network (MTN) and the nonprofit International Partnership for Microbicides (IPM). The NIAID trial was also funded by the Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) and the National Institute on Mental Health (NIMH), both part of NIH.
The dapivirine ring was designed and developed by IPM, which is the regulatory sponsor of the product. IPM applied for a scientific opinion on the dapivirine ring from EMA through a procedure called Article 58. In cooperation with the World Health Organization (WHO), this procedure is designed to facilitate access to medicines intended to treat or prevent diseases of major public health interest in low- and middle-income countries outside the European Union.
The positive scientific opinion from EMA reflects its assessment of the quality, safety, efficacy and benefit-risk balance of the dapivirine ring. As stated on its website, EMA applies the same rigorous standards to its assessment of medicines reviewed through Article 58 as it does for medicines to be marketed within the European Union.
WHO may now include the dapivirine ring in its recommendations and guidelines for HIV prevention. WHO also will consider the product for prequalification, a global quality assurance designation for medicines. In addition, in collaboration with WHO, IPM will seek approval for the ring from African national regulatory authorities so it can be offered in countries where women face a very high risk for HIV.
As the EMA has requested, IPM will conduct additional research among cisgender women ages 18 to 25 years to better understand the ring’s efficacy and to collect additional data on safety and potential resistance to anti-HIV drugs. Results from this study could also inform strategies to support young women to use the ring consistently.
NIAID, NICHD and NIMH support three ongoing and planned studies—REACH, DELIVER and B-PROTECTED—to examine the safety of the dapivirine ring during adolescence and pregnancy, when the risk of HIV acquisition is heightened, and during periods of breastfeeding, when transmission to infants may occur. These essential MTN-conducted studies could inform next steps on potentially expanding the indication for the ring to women throughout their lives.
NIAID supports research on a wide variety of HIV prevention tools with the aim of making multiple options available to suit the varying needs of diverse populations. The institute will continue to invest in developing safe and effective HIV prevention technologies to expand choices for all.
More information about the EMA opinion on the dapivirine ring is available in a set of questions and answers below.
The EMA Opinion on the Dapivirine Ring
The European Medicines Agency (EMA) is the organization responsible for the scientific evaluation, supervision and safety monitoring of medicines in the European Union.
As stated on its website, Article 58 is a procedure created by EMA to help give people in low- and middle-income countries outside the European Union access to medicines intended to treat or prevent diseases of major public health interest. Through this procedure, EMA assesses medicines in cooperation with the World Health Organization (WHO) using standards as rigorous as those used to evaluate medicines intended for use in Europe. Once the assessment is complete, EMA publishes its scientific opinion of the risk-benefit balance of the medicine. The goal of this procedure is to facilitate WHO prequalification of the medicine and its subsequent registration in target countries.
As part of its assessment, the EMA examined the full set of data on the dapivirine ring, including both Phase 3 studies, The Ring Study (IPM 027) and ASPIRE (MTN-020). The EMA decided to exclude ASPIRE efficacy data from its assessment due to non-compliance with Good Clinical Practice, known as GCP. The EMA’s decision arose from gaps in documentation for certain processes and decisions related to how the efficacy data analysis for ASPIRE was performed.
As soon as NIAID learned that the EMA had these concerns, it took steps to address the issues with its partners. NIAID and its partners have also taken steps to strengthen processes across their organizations to improve documentation and oversight and ensure GCP compliance in all ongoing and future clinical trials. The ASPIRE trial was conducted by NIAID-funded sites in Malawi, South Africa, Uganda and Zimbabwe, and importantly, the EMA found that these sites followed international standards for good clinical conduct and were GCP compliant. Moreover, the safety data from ASPIRE, which the EMA did consider in its review, was critical for demonstrating the ring’s strong safety profile and contributed to the EMA’s positive opinion.
Each country where the ring would be used must first conduct its own regulatory review of the product, and then incorporate it into national policies once approved. IPM has indicated that it will be working with WHO and African national regulatory agencies to submit the ring for country review through WHO’s collaborative registration procedure. IPM hopes to begin these submissions by the end of 2020 and will post updated timelines in the coming months. IPM plans to submit the first applications at the end of 2020 to countries in eastern and southern Africa where studies of the ring took place and where oral PrEP is being implemented (South Africa, Zimbabwe, Kenya, Malawi, Uganda, Tanzania, and Rwanda).
ASPIRE and The Ring Study found the dapivirine ring reduced HIV risk by roughly 30 percent. Subsequent open-label studies showed greater ring use. In comparison, the first clinical trial to establish the efficacy of daily oral PrEP—the iPrEx study, which NIAID co-funded and helped oversee—found in 2010 that daily oral PrEP reduced the risk of HIV infection by 44 percent in men who have sex with men. Two years later, the Partners PrEP study reported that in heterosexual couples where one partner had HIV and the other did not, daily oral PrEP reduced the risk of HIV acquisition by 75 percent for men and women. A combination of two anti-HIV drugs taken orally once daily, PrEP has proven over time to be more than 90 percent effective at preventing HIV infection in men and women when used as directed. As the EMA stated in its opinion, the ring could be a valuable option for women who cannot or choose not to use daily oral PrEP.