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Understanding the EMA Opinion and Next Steps for the Dapivirine Vaginal Ring

On July 24, 2020, the European Medicines Agency (EMA) announced a positive regulatory opinion from on the Dapivirine Vaginal Ring as an HIV prevention option for cisgender women age 18 and older. The Ring is a new HIV prevention tool developed by the International Partnership for Microbicides (IPM).

The EMA is a regulatory body whose reviews and guidance are used within the EU. The Human Medicines Committee, which issued this opinion, also reviews products that are intended for use outside of Europe. The ring review came from this mechanism, which is referred to as Article 58. A “positive opinion” is the official term the EMA uses for its conclusion that a product should be authorized or approved for use in some contexts. This opinion means that a much-needed, woman-initiated HIV prevention option is one step closer to being made available. It is a choice that many women, including those in East and Southern Africa, need with urgency.

The EMA’s positive opinion states that the Dapivirine Vaginal Ring can be “used to reduce the risk of infection with the human immunodeficiency virus (HIV-1), in combination with safer sex practices when oral pre-exposure prophylaxes (PrEP) is not used, cannot be used or is not available.” It also calls for additional safety and efficacy data to be gathered among younger women aged 18-25, and for resistance monitoring among women who acquire HIV while using the ring.

This document helps advocates to understand the steps that can and must be taken now that the EMA has provided its opinion. It describes research to date on the ring, the regulatory process and additional steps for the ring to reach markets and users. It will be periodically updated to reflect new developments. Information is organized into the following sections:

Dapiviring Vaginal Ring Research and Development

What is the monthly Dapiviring Vaginal Ring?
The Dapiviring Vaginal Ring is a flexible silicone ring that can be inserted into the vagina for monthly protection against HIV. It’s designed to provide cisgender women with a discreet and long-acting option for HIV prevention. The ring contains the antiretroviral drug dapivirine, which is released steadily over the period of a month to reduce the risk of acquiring HIV via vaginal sex. The drug remains localized and has low absorption elsewhere in the body.

Over the last decade, a number of studies in different settings have tested the ring’s safety, efficacy and acceptability; these studies and the current research status of the ring are described below. The ring was developed by the International Partnership for Microbicides (IPM), a non-profit organization formed to develop HIV prevention products and other sexual and reproductive health technologies for women. The pharmaceutical company Johnson & Johnson donated rights to dapivirine to IPM and is lending IPM expertise and resources to assess critical issues for rollout, such as user needs and pricing.

What are the available data on the Dapiviring Vaginal Ring?
A portfolio of research conducted by IPM and the Microbicides Trials Network (MTN) has demonstrated that the dapivirine ring can reduce women’s HIV risk via vaginal sex. This research includes large clinical efficacy trials, studies of safety and acceptability, and qualitative work with women to understand preferences and concerns. See the table for a summary of key information.

large scale dapivirine ring trial details and key outcomes

Safety:
Starting in 2004, safety studies were conducted first in Belgium and the United States and then in Kenya, Malawi, South Africa and Tanzania. Extensive information on the safety of the ring for women was also collected in the large efficacy studies described in the table above. The initial research included women ages 18-45, with additional studies among post-menopausal women and adolescent girls ages 15-17 in the United States. All showed that the ring was well-tolerated and acceptable.

Young women ages 16-21 in South Africa, Uganda and Zimbabwe are currently participating in REACH, a two-year study of the ring and oral PrEP to collect additional safety information among this age group and investigate their needs and preferences related to these two products. In addition, a study called DELIVER is underway to explore the ring’s safety among pregnant women, and another study in development will investigate the ring’s safety in breastfeeding women.

Efficacy:
In 2016, two Phase III studies–The Ring Study and ASPIRE–showed that the monthly Dapiviring Vaginal Ring reduced women’s risk of HIV-1 infection via vaginal sex by approximately 31 percent overall. Some women reported receptive anal intercourse; no impact on HIV risk was associated with these participants; but it’s also not clear whether the ring provides protection for women having anal sex. Further analyses indicated that higher levels of protection were seen in women who used the ring most regularly. However, no reduction in HIV acquisition was seen in women under 21, likely due to low product use among this age group. These studies, which involved more than 4,500 women ages 18-45 in Malawi, South Africa, Uganda and Zimbabwe, also found no safety concerns with long-term use.

Open-label extension studies:
Two open-label extension (OLE) studies—DREAM and HOPE—offered the ring to former participants in the two efficacy trials. OLE studies collect data in unblinded trials without a placebo group and more closely mirror service delivery settings. The DREAM and HOPE studies collected more safety data and information on use; as OLE studies, the data reflected the use of the ring by participants who knew the product was proven to reduce the risk of acquiring HIV. Participants in the OLE studies increased ring use compared to those in Phase III trials. Together with statistical modeling data called “bootstrap sampling”, the OLEs suggest that the ring provides a greater degree of protection against HIV than what was seen in the efficacy trials. It appears that women who used the ring in DREAM had a 63 percent reduction in HIV risk, and women in HOPE had a 39 percent reduction, compared to non-ring users.

Perspectives from potential users, providers, advocates and policy makers:
Stakeholder perspectives on the ring have been an important part of the research agenda, and studies have shown that there is a range of views to factor into implementation and further research.

Potential ring users:
While some women are unable or unwilling to try the ring, a number of studies show that many women like and can use the ring, and that comfort with the product increases over time. Women who have tried the ring generally like it, citing its ease of use, that it is long-acting, does not interfere with sexual pleasure and is discreet. Information, support and experience allow women to become more comfortable and knowledgeable about the ring, and better able to use it.

Policy makers and health care providers:
Recent research conducted by the OPTIONS Consortium among policy makers and health care providers in seven African countries also shows significant interest in the ring as part of a combination HIV prevention approach. In particular, providers appreciate that the ring acts locally, in the vagina, rather than systemically (e.g. oral or injectable PrEP). The ring’s active drug doesn’t linger in the body long after someone discontinues use, a feature which may reduce the risk of developing HIV drug resistance and help minimize side effects. Country stakeholders are keen to determine how to improve adherence and to understand the impact and effectiveness of typical use. They will draw on experience with oral PrEP introduction to identify how to build the ring into a comprehensive prevention package.

Women’s health and prevention advocates:
In many of the same countries, advocates have long highlighted the need for choice in prevention options, emphasizing the need for both systemic and locally-acting options. Women’s health advocates insist that women's prevention be integrated into sexual and reproductive health and rights (SRHR) and that the development of multipurpose prevention technologies be prioritized. Many see the ring as a welcome new intervention and a platform to build on for future interventions.

What is the potential public health impact of the Dapiviring Vaginal Ring?
Modeling studies show that multiple prevention options are needed to end the HIV epidemic, and even a product with modest efficacy like the dapivirine vaginal ring could have a meaningful public health impact as part of a comprehensive prevention strategy. If approved and successfully rolled out, the ring would increase the number of women successfully using an HIV prevention method and could prevent infections that would not be averted by another method. Studies emphasize that cost-effectiveness will improve with targeted rollout. Therefore, it will be important to identify and reach the women who most need and want the ring.

Why do women need additional HIV prevention options, such as the Dapiviring Vaginal Ring?
Despite progress in HIV prevention and treatment, women remain at high risk in many settings, especially in some areas of sub-Saharan Africa. Clinical trials completed over more than a decade, from 2007 (MIRA) to 2019-20 (ECHO and HVTN 702), show an alarmingly persistent four percent HIV incidence rate among women participants. Adolescent girls and young women are especially at risk due to gender inequity and biological, social and economic factors. A range of options is needed for individuals to protect themselves and to curb the HIV epidemic; no single intervention can work for everyone.

The ring joins daily oral PrEP and the female condom as biomedical woman-initiated prevention options that can be used discreetly by women who choose it. It is the first long-acting option that can be used vaginally, providing protection over a longer period without daily or coitally-dependent adherence requirements. Vaginal rings are also a critical platform for a “multi-purpose” prevention technology that reduces HIV risk and also potentially protects against other STIs and/or serves as a form of contraception. Ring-based MPTs are in development today—and moving forward with the vaginal dapivirine ring as part of a woman-centered, choice-oriented platform of options will prepare for these urgently needed products in the future.

Preparing for introduction:
To make the ring available to women as quickly as possible, IPM has worked with a range of partners and prepared a Common Agenda with the OPTIONS Consortium to coordinate and accelerate introduction efforts. This guide reflects considerations identified by national policy makers, priorities for donor support, and other critical needs, such as normative guidance development, design for pilot introduction, creating demand, and advocacy to support all of it.

Next Steps in the Path to Access

IPM applied to the European Medicines Agency (EMA) to review the dapivirine vaginal ring under Article 58 in June 2017. The EMA, along with the World Health Organization (WHO), implements Article 58 to provide scientific opinions on products that will be marketed outside of the European Union in low- and middle-income countries [see box]. IPM’s regulatory strategy reflects its mission: focus on the fastest possible route to approval in African countries that have participated in research on the ring, and on places where the ring can have the greatest public health impact. Now that the EMA has issued its opinion, several related processes are needed to move the ring forward and make it available to women who want and can use it. Advocates and partners will play an important role in advancing this work, including securing resources and political commitment and putting women’s voices at the center.

potential regulatory procedure and timeline post-EMA scientific opinion

Source: IPM

National regulatory reviews:
IPM will work with WHO through its Collaborative Procedure for Accelerated Registration to submit applications for regulatory review to countries in Africa that participated in research, have indicated an interest in rolling out the ring and where public health need is high. These include Kenya, Malawi, Rwanda, South Africa, Tanzania, Uganda and Zimbabwe. This is a relatively new mechanism in which a country’s regulatory authority and WHO work to conduct an accelerated review of a product that has received a positive opinion from a stringent regulatory authority such as the EMA.

WHO guidelines:
In parallel, WHO will convene a guideline development committee to review the evidence and revise the HIV treatment and prevention guidelines to include recommendations on the use of the ring in national programs. WHO expects this review to begin before the end of 2020.

WHO prequalification:
With the EMA opinion and updated guidelines, WHO will then review the ring for prequalification, a process to evaluate whether a medicine meets global standards for quality, safety and efficacy. WHO prequalification can facilitate national regulatory review and guideline development, and many African national regulatory agencies consider WHO prequalification as they review new products.

United States Food and Drug Administration (FDA):
IPM will also submit an application to the US FDA later in 2020. An FDA approval of the ring can enable potential use in the US and also pave the way for the regulatory process for future dapivirine-based products.

Implementation research and policy development:
Given public health need, the location of previous trials of the ring, and the results of national and community engagement, IPM is prioritizing Kenya, Malawi, Rwanda, South Africa, Tanzania, Uganda and Zimbabwe for the first phase of ring introduction. As the regulatory process moves forward, discussion and planning with regulatory authorities, policy makers, program implementers and advocates in those countries will determine specific next steps that may include: implementation research, policy development, provider training, market research, demand creation and other activities.

Ongoing Dapiviring Vaginal Ring studies:
Studies will continue to further knowledge about ring safety and use in different populations and to inform introduction and rollout of the ring. Research is underway on a three-month Dapiviring Vaginal Ring, as well as a phase I study that includes both dapivirine for HIV prevention and levonorgestrel for contraception. With the ongoing, urgent need for additional options that prevent both unintended pregnancy and HIV acquisition, developing and testing a range of multipurpose products—including those based on the monthly Dapiviring Vaginal Ring—must continue. Companies and organizations working on these products will assess the scientific and practical considerations and decide on next steps.

What Can Advocates Do?

The need for additional HIV prevention options for women is urgent. The Dapiviring Vaginal Ring must be brought to market as soon as possible for women who need, want and can use it. Even in the changed landscape of COVID-19, it’s important for implementation plans and ongoing research on the ring among adolescents, pregnant and breastfeeding women to keep moving forward. Advancing these priorities will require applying pressure to country and global funders, scientists and other decision-makers to keep women at the center of the effort to expand HIV prevention. Women, advocates and community experts—and especially young women and previous ring users—must continue to play a leading role in setting priorities and decision-making in WHO guideline development, country planning for rollout, trial design for implementation research and getting resources allocated where they’re needed.

There are critical next steps that must move forward now on a number of fronts. Advocacy around the regulatory process is key.

ACTIONS

  • Advocate for WHO to swiftly convene the guideline development group to update the HIV treatment and prevention guidelines and to expedite the prequalification process.
  • Insist that women’s expertise and perspectives—especially young women’s—determine priorities and lead decision-making, and that they are involved in updating WHO guidelines.
  • Track national processes. Even with the EMA opinion, countries still need to review and approve the product themselves, a process that starts with submission from IPM. As this moves forward, advocates can watchdog the review process, and call for timely submission and consideration in their own countries.

A research agenda must inform implementation planning.

ACTIONS

  • Demand a rational post-authorization research agenda –including the PAES—that will provide answers to the most pressing questions about how best to integrate the ring into programs. This includes full and timely funding to ensure its implementation.
  • Advocate to IPM that any study designed for the collection of additional efficacy and safety data in young women, as requested by the EMA, should be conducted in a ‘real world’ situation where participants will access the ring from family-planning clinics, youth centers and other places where they already go for services. This will provide an opportunity to learn about implementation at the same time. Insist that community voices help to determine the design of the study in accordance with Good Participatory Practice (GPP).
  • Advocate for swift development of product introduction plans and funding for them. Introduction must be at a sufficient scale to address the priorities of local stakeholders. Introduction initiatives should assess health system needs for the most effective delivery of the ring, deepen understanding of women’s real-life experiences and what women need to use the ring, and how to market and promote the ring within the context of informed choice among a range of options.
  • Build on the Common Agenda developed by the OPTIONS Consortium as well as current introduction investments—including the USAID-funded PROMISE and CHOICE projects—to accelerate the design and implementation of pilot initiatives for product introduction. Draw on lessons learned from oral PrEP implementation and adequately invest in demand creation strategies in consultation with women who may need and want to use the ring.

Access to the oral PrEP and monthly dapivirine vaginal could be life-saving options for some women.

ACTIONS

  • Prioritize access! Women can only choose the ring as an option if it is made available. Demand that policy makers, regulators, funders and implementers move quickly to integrate the ring into country HIV prevention guidelines and prevention programs.
  • Funding is critical to access. As soon as WHO and national guidance documents support ring introduction, PEPFAR Country Operational Plan guidance and GFATM technical review committees must encourage proposals for ring introduction as part of broader packages of services for women.
  • Continue to advocate and support scale-up and improvement of programs for women–including young women–that deliver daily oral PrEP. This includes adding innovative approaches to oral PrEP delivery such as self-testing, multi-month dispensing and telehealth. This may also be relevant to the Dapiviring Vaginal Ring.
  • Ensure that we are applying lessons learned from oral PrEP rollout, including moving faster and engaging user voices early in designing programs.

Women need integrated HIV prevention and sexual and reproductive health (SRH). Women should find access to the Dapiviring Vaginal Ring in the same place that they access contraception.

ACTIONS

  • Intensify advocacy for integration of HIV prevention and SRH services and messages. This means targeted funds, reenvisioning programs and developing customized training.
  • As COVID-19 shrinks resources for other global health priorities, look for opportunities to explain the benefits of integrated services as an efficient and safer way to deliver products for women.
  • Advocate for innovative ways to deliver HIV prevention, SRH and other health services that keep women safe during COVID-19 outbreaks and lockdowns.

Women want, need and deserve choices for HIV prevention.

ACTIONS

  • Even in the changed landscape of COVID-19, ongoing research on the Dapiviring Vaginal Ring among adolescents, pregnant and breastfeeding women must keep moving forward so that future approvals and access could potentially be expanded to these populations (if the studies show the ring to be safe and effective for them).
  • Platforms and systems built to deliver the ring should also be designed with an eye toward rollout of potential future products, such as long-acting injectable (LAI) PrEP, oral F/TAF for cisgender women, the 90-day Dapiviring Vaginal Ring, the Dual Prevention Pill and other multipurpose prevention options.
  • Continue to advocate for investment in the development of a diverse pipeline of women-initiated methods for HIV prevention, including multipurpose prevention technologies.

Understanding EMA’s Article 58

What is the European Medicines Agency (EMA)?

The European Medicines Agency (EMA), an agency of the European Union (EU), is responsible for the evaluation, supervision and safety monitoring of medicines in the EU. The EMA’s mission is to foster scientific excellence in the evaluation and supervision of medicines for the benefit of public and animal health in the European Union (EU). An EMA application is a comprehensive package of data from preclinical and clinical studies on safety, effectiveness and acceptability, and it also includes information on the manufacturing process.

What is “Article 58”?

The Article 58 procedure allows the EMA, in cooperation with the World Health Organization (WHO), to provide a scientific opinion on a product intended for use outside of the European Union, specifically to address diseases of major public health interest in low- and middle-income countries. Article 58 includes a rigorous scientific assessment to the same standards used for medicines intended for use in Europe, along with a risk-benefit assessment tailored to the product’s intended users. It involves experts from WHO and observers from national regulatory authorities in relevant countries. A positive opinion from the EMA can facilitate registration in African countries and can also shorten the timeline for possible WHO prequalification, a process through which WHO evaluates whether a medicine meets global standards for quality, safety and efficacy.

This is the eleventh medicine recommended by EMA under EU Medicines for all (EU-M4All), a mechanism that allows the CHMP to assess and give opinions on medicines that are intended for use in countries outside the European Union under Article 58 of Regulation (EC) No 726/2004.