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What’s Up with The Dapivirine Vaginal Ring: Understanding the regulatory process

This document is designed to help advocates understand the status of the monthly dapivirine vaginal ring, and the ongoing and planned regulatory submissions that are part of the process to reach markets and users. It also includes links and resources to learn more and stay engaged. It is organized into the following sections:

Dapivirine Ring Research and Development

What is the monthly dapivirine ring?

dapivirine ring

The dapivirine vaginal ring is a flexible, silicone ring that a woman can insert in the vagina for monthly protection against HIV. The ring is designed to provide women with a discreet and long-acting option for HIV prevention. It contains the anti-retroviral drug dapivirine, which is released slowly to reduce the risk of HIV infection locally in the vagina with few effects elsewhere in the body.

Over the last decade, a number of studies in different settings have tested the ring’s safety, effectiveness 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 such as user needs and pricing.

What do we know about the dapivirine ring?

A portfolio of research has assessed that the dapivirine ring is safe, effective and that some women will want and be able to use it. See table for summary of key information.

Safety: 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 effectiveness studies described below. The initial research included women aged 18-45, with additional safety studies among post-menopausal women and adolescent girls aged 15-17 in the United States.

Young women aged 16-21 in South Africa, Uganda and Zimbabwe are currently participating in REACH, a study of the ring and oral PrEP that is designed to collect additional safety information among this age group, and to understand their HIV prevention needs and preferences related to these two products. In addition, there are studies ongoing or in development right now to explore the ring’s safety among pregnant and breastfeeding women.

Effectiveness: In 2016 two Phase 3 studies – The Ring Study and ASPIRE – showed that the monthly dapivirine ring reduced women’s risk of HIV-1 infection by approximately 30 percent overall. 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 aged 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 effectiveness trials. OLE studies do not have a placebo group. DREAM and HOPE collected additional safety data and information about use when women know they are using a product proven to reduce their risk of acquiring HIV. OLE studies are also designed to more closely mirror service delivery settings and conditions. DREAM and HOPE showed an increase in ring use over the Phase 3 trials, and together with modeling data, suggested a higher HIV risk reduction of about 63 percent in DREAM and 39 percent in HOPE.

Perspectives from Users, Providers and Policymakers: Stakeholder perspectives on the ring have been an important part of the research agenda, and studies have shown a range of perspectives. 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 adherence increases with experience of using it.

Similarly, recent research among policymakers and health care providers shows interest in the ring. One reason for this: the distribution of active drug from the ring results in a localized rather than systemic effect which is thought to minimize side effects. In other words, the ring acts in the vagina, the site of potential exposure to HIV during vaginal sex. The ring’s active drug doesn’t linger in the body long after someone discontinues use, which may reduce the risk of developing HIV drug resistance. Some persistent questions will need to be addressed in the future, for example: stakeholders raised questions about the impact and effectiveness of typical use; how to explain modest efficacy; and about how to improve adherence, especially among young women.

What is the potential public health impact of the dapivirine ring? Modeling studies show that multiple prevention options are needed to end the HIV epidemic, and that even a product with modest efficacy like the dapivirine ring could have a meaningful public health impact as part of a comprehensive prevention strategy. If approved and successfully rolled out, the dapivirine 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. New woman-centered options will be crucial to achieving epidemic control.

Preparing for introduction: To make the ring available to women as quickly as possible, IPM has worked with a range of partners to inform and prepare for introduction of the ring. IPM and the OPTIONS consortium have prepared a Common Agenda to share information, streamline and accelerate efforts in this regard.

Where has the dapivirine ring been studied?

Dapivirine ring studies have been conducted with partners in Belgium, Kenya, Malawi, South Africa, Tanzania, Uganda, the United States and Zimbabwe. Women in Rwanda also participated in early studies of a gel-based form of dapivirine.

Why do women need additional HIV prevention options, such as the dapivirine ring?

Despite progress in HIV prevention and treatment, women remain at high risk in many settings, especially in sub-Saharan Africa. Adolescent girls and young women are especially at risk due to biological, social, economic and gender equity factors. No single HIV prevention method will meet the needs of all people at risk, so a range of options is needed for individuals to protect themselves and to curb the HIV epidemic.

The ring is a woman-controlled prevention option that could be used discreetly by women at times in their lives when they may be unable to negotiate condom use or unable to discreetly or consistently use daily oral PrEP. Choice is key: along with daily oral PrEP, and male and female condoms, the ring could fill a gap for a long-acting method that can be used discreetly when people at risk can’t or won’t use oral PrEP or condoms consistently.

Regulatory pathways for the Dapivirine Ring

IPM’s regulatory strategy reflects its mission — focused on the fastest possible route to approval in key African countries that have participated in research on the ring, and where the ring can have the greatest public health impact. IPM, therefore, submitted the dapivirine ring first to the European Medicines Agency (EMA) in June 2017 where it is being reviewed under Article 58. This is a mechanism implemented by the EMA with the World Health Organization (WHO), which provides scientific opinions on products that will be marketed outside of the European Union in low- and middle-income countries (see below).

IPM will also seek WHO prequalification for the ring, which regulatory agencies in many African countries use to determine which new products they approve. IPM also plans to submit applications to the US Food and Drug Administration (FDA) and the South African Health Products Regulatory Authority (SAPHRA). Following WHO prequalification, IPM would submit applications to additional key countries in Africa that participated in research and have indicated an interest in rolling out the ring. These include Kenya, Malawi, Rwanda, Tanzania, Uganda and Zimbabwe.

For what populations is the ring’s approval being sought?

IPM is seeking an opinion on the dapivirine ring for women ages 18 and older, which is the group represented in the Phase 3 clinical effectiveness trials, and in an additional safety study in postmenopausal women.

IPM is not currently seeking regulatory approvals for dapivirine ring use in women below the age of 18. However, results from two safety studies will inform whether IPM will seek approval for adolescents in the future. A completed study in the US showed that the ring was well-tolerated and acceptable among adolescents ages 15-17. An ongoing two-year study, REACH, is assessing the safety, adherence and acceptability of the ring and oral PrEP among adolescent girls and young women ages 16-21 in South Africa, Uganda and Zimbabwe.

Safety studies planned for 2020 will inform whether IPM will seek expanded regulatory approvals in the future for the ring’s use among pregnant and breastfeeding women.

EMA’s Article 58

What is the European Medicines Agency (EMA)?

The European Medicines Agency (EMA) is an agency of the European Union (EU) responsible for the scientific evaluation, supervision and safety monitoring of medicines in the EU. It convenes scientific committees made up of staff and external scientific experts. 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).

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 intended end-users. It involves experts from WHO and observers from national regulatory authorities in relevant countries. The dapivirine ring review process will include observers from some of the African regulatory agencies where IPM would apply for ring licensure.

A positive opinion from the EMA can facilitate registration in priority African countries. An Article 58 review 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.

What is included in the EMA application?

The EMA application is a comprehensive package of data from pre-clinical and clinical studies on safety, effectiveness and acceptability. It also includes information on the manufacturing process. IPM is seeking an opinion on the dapivirine ring for women ages 18 and older, which is the group represented in the Phase 3 clinical effectiveness trials, and in an additional safety study in postmenopausal women.

Have any similar products gone through the Article 58 process and moved on to the next stage?

As of February 2019, ten scientific opinions have led to 105 approvals world wide through the Article 58 process, and 72 non-EU countries have authorized medicines evaluated through this mechanism. These have included a preventive malaria vaccine, combination childhood vaccines, as well as treatments for umbilical cord infection, post-partum hemorrhage, malaria, HIV and sleeping sickness. A 2015 review found some limitations with the process, noting that products to date had mixed success due to limited commercial viability and, in some cases, poor recognition of Article 58 opinions by national regulatory authorities.

Mosquirix, the malaria vaccine, was reviewed under Article 58 and is helpful when considering the dapivirine application. The EMA issued a positive scientific opinion on the vaccine in July 2015 concluding that, despite efficacy of about 30 percent, the benefits of the vaccine outweigh the risks. Used in conjunction with ongoing interventions such as bed nets and treatment, the vaccine could reduce deaths and have a meaningful public health benefit. Following an expert review process led by WHO, Mosquirix is currently being pilot tested in select districts in Ghana, Kenya and Malawi. This pilot test is designed to generate evidence and experience to inform WHO policy recommendations on the broader use of the malaria vaccine, and will examine reductions in child deaths; feasibility; vaccine uptake, including whether parents bring their children on time for the four required doses; and vaccine safety in the context of routine use.

When can we expect EMA to have an opinion?

The EMA may issue an opinion mid 2020, or may request additional information before deliberating.

What happens next and what can advocates do?

Scenario 1: If the EMA Opinion is Positive

In the event of a positive opinion, several related processes move the ring forward to make it available to women who want and can use the ring. Advocates and partners can play an important role.

WHO Guidelines: WHO will convene a guideline development committee to review the evidence and issue guidance on incorporating the ring into national programs.

WHO Prequalification: WHO may also begin to “prequalify” the ring, 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. Many African national regulatory agencies use WHO prequalification to determine which new products they approve.

National Regulatory Reviews: Following a positive opinion from EMA, IPM has indicated it will submit dossiers to national regulatory authorities in select countries in Africa: Kenya, Malawi, Rwanda, South Africa, Tanzania, Uganda and Zimbabwe.

United States Food and Drug Administration: IPM also plans to apply to the US FDA for review. With FDA approval the ring can potentially be provided at scale through US government-supported programs and funding mechanisms such as PEPFAR.

Implementation Research and Policy Development: Given public health need, the location of trial sites on 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, policymakers, 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.

What can advocates do?

  • Stay informed about the latest developments with the ring through advocacy networks in your country and by checking in at PrEPWatch.
  • If the ring receives a favorable EMA opinion – advocate for further review, under the WHO pre-qualification process, by country regulatory agencies, and for investment in ring introduction from funders.
  • Call for including the ring in country HIV prevention guidelines so this proven option moves from research to a reality in women’s lives.
  • Make the case at the global level, and in countries and communities, for this new prevention option to be made available for women to use as soon as possible.
  • Demand women, advocates, and community experts — and especially young women — play a leading role in decision making and priority setting: including the process for WHO guideline development, country planning, implementation research design and resource allocation.
  • Write opinion pieces about the need for more prevention options, including the ring as well as multi-purpose prevention options, for women.
  • Continue to advocate and support scale-up of programs for women that deliver daily oral PrEP:
    • Daily oral PrEP is still not available to all women who would benefit from it.
    • Expanded access to PrEP can help pave the way for accelerated access to the monthly dapivirine ring.

Scenario 2: If the EMA opinion is negative

What does a negative opinion from EMA under Article 58 mean for the ring as an HIV prevention option?
While a negative opinion is disappointing and a setback for the dapivirine ring, it does not mean the end of the ring as a potential HIV prevention option for women. IPM is exploring the best way to continue regulatory review for the ring, including submission to the South African and US regulatory agencies.

Are there plans to submit the dapivirine ring to additional regulators?
IPM plans to submit applications to SAHPRA and the US FDA. Both are independent regulatory bodies that do not necessarily rely on the EMA opinion in their decision-making process.

What will happen to ongoing dapivirine ring studies?
Although it is not certain what sponsors and national regulatory authorities will choose to do about these studies, AVAC believes it is critical they continue to further knowledge about ring safety and use, and to inform introduction and roll-out of the ring if it is approved in the future. In addition, women participating in the ring studies count on the care and HIV prevention support they receive through participating in the studies.

What will happen to multipurpose prevention products that use the dapivirine ring?
There is an ongoing phase 1 study of a combination ring that includes both dapivirine for HIV prevention and levonorgestrel for contraception. There are also other combination rings in development. Given the ongoing urgent need for additional options that prevent both unintended pregnancy and HIV acquisition, AVAC believes developing and testing a range of multipurpose products, including those based on the dapivirine ring, must continue. Companies and organizations working on these products will assess the scientific and practical considerations and decide on next steps, but a negative EMA opinion should not stop the development of these urgently needed technologies.

What can advocates do?

  • Continue to advocate for investment in women-initiated methods of HIV prevention including multipurpose prevention technologies.
  • Stay informed about the latest developments with the ring through advocacy networks in your country and checking in at PrEPWatch.
  • Advocate for rapid regulatory review of the ring by other bodies including transparent decision making, and — if approved — providing access to the ring for women who want it and can use it.
  • Insist women’s expertise and perspectives — especially young women’s — determine priorities and lead decision-making.
  • Redouble efforts to advocate for and support scale-up of programs delivering daily oral PrEP to women:
    • Daily oral PrEP is still not available to all women who would benefit from it.
    • Expanded access to PrEP can help pave the way for eventual access to the monthly dapivirine ring if it is approved for use, as well as other next generation options.
  • Get informed and involved in planning and advocating for eventual access to other prevention options for women in the research pipeline, such as long-acting injectable PrEP.

No matter what the outcome of the EMA opinion and IPM’s next steps, advocates must continue to raise key priorities: new products and new programmatic approaches must meet women’s comprehensive sexual and reproductive health needs, and women must be at the center of these programs and decision-making.

Informed choice must offer an array of contraceptive options. HIV prevention and treatment services must be high quality, and they must be found at the same clinics where contraceptives are accessed and care is provided for diagnosis and treatment of sexually transmitted infections. 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.

Summary Results from Dapivirine Ring Trials

table summary of results from dapivirine ring trials