Dapivirine vaginal ring and long-acting cabotegravir PrEP each approved in less than six months
Zimbabwe has been able to approve two new HIV prevention products within six months and did so before any other African nation. How did it achieve this and what are the lessons for other countries that have urgent needs for new HIV prevention options?
Oral PrEP, consisting of tenofovir disoproxil and emtricitabine, has become increasingly available in countries with high HIV prevalence and high levels of HIV transmission. But oral PrEP may not be suitable for everyone and more choice in antiretroviral prevention products is needed, especially for people who have difficulties in taking pills every day.
he dapivirine vaginal ring and long-acting injectable cabotegravir have been approved by regulatory agencies in Europe and North America over the past three years after clinical trials showed that both are effective when used regularly. However, the two products are still unavailable in many countries. So far, 11 African countries have approved the ring and eight have approved cabotegravir.
The dapivirine vaginal ring is a flexible silicone ring that is inserted in the vagina and releases the antiretroviral dapivirine for one month. The MTN-020/ASPIRE clinical trial showed that using the ring every day reduced the risk of acquiring HIV by at least 75%. It offers an attractive alternative to condom use or oral PrEP as it is discreet, can provide protection throughout a month and its use is controlled by women.
The dapivirine vaginal ring was approved by the European Medicines Agency in July 2020, under a measure called Article 58, which enabled the agency’s regulatory expertise to be used to grant a licence for a device intended to be used in lower-income countries (the ring is not licensed in Europe or other high-income countries). In November 2020, the World Health Organization granted prequalification of the dapivirine vaginal ring, which guarantees that the product has passed adequate quality checks, that it is manufactured to internationally recognised standards and that safety and efficacy data are sufficient for approval by national regulatory agencies.
For antiretroviral products, the interval between WHO prequalification and availability in countries depends on the capacity of national regulatory agencies, the commitment of product manufacturers to get the product approved and pricing. Some national agencies, notably South Africa, have been criticised in the past by doctors and activists for delays in approval of WHO prequalified products.
Despite approvals in other parts of the world, national regulatory agencies have tended to require a full registration submission, comprising hundreds of pages detailing everything from adverse events in clinical trials to how the quality of drug ingredients is ensured and the shelf-life of the product at different temperatures. All this information takes months to review and the WHO prequalification process is designed to spare under-resourced regulatory agencies from having to repeat this process.
In Zimbabwe, the International Partnerships for Microbicides moved quickly to seek approval for the dapivirine vaginal ring after WHO prequalification, submitting its registration dossier in February 2021. As clinical trials leading to the approval of the dapivirine vaginal ring had taken place in Zimbabwe, the Medicines Control Agency of Zimbabwe was already familiar with the product. They decided to use the European Medicines Agency approval and WHO prequalification as the basis for an “abridged review”, a fast-track process that enabled approval on 6 July 2021, the first national approval of the dapivirine vaginal ring in the world.
Long-acting cabotegravir (also known as CAB-LA) is an injectable formulation of an HIV integrase inhibitor. Two clinical trials have shown that it is more effective than oral PrEP consisting of tenofovir disoproxil and emtricitabine in preventing HIV acquisition, probably because of improved adherence. Cabotegravir is injected every two months.
The US Food and Drug Administration approved cabotegravir for PrEP in December 2021 and the World Health Organization recommended it as an additional HIV prevention option in March 2022. It was submitted for registration in Zimbabwe in January 2022. The Medicines Control Agency of Zimbabwe decided that because cabotegravir had already been approved by the US FDA, it could undergo expedited review in Zimbabwe, and it was approved on 6 July 2022.
Whereas it took 1045 days to grant approval of tenofovir disoproxil/emtricitabine in Zimbabwe in 2009, the dapivirine vaginal ring took 133 days and long-acting cabotegravir took 159 days to receive approval.
Zimbabwean regulators say that several strategies enabled them to move quickly:
- An existing policy of using regulatory approval by a stringent authority such as the US FDA or EMA to trigger an expedited review pathway
- Close collaboration between clinical trials review and product review divisions of the Medicines Control Agency promoted familiarity with the products under review
- WHO prequalification was a guarantee of product quality and avoided the need for time-consuming manufacturing and product inspections
- Taking part in a project to strengthen pharmacovigilance and regulatory capacity with agencies in other nations in southern Africa and an initiative to promote collaborative medicines registration among nations in the region.
Other countries, especially African nations, could benefit from greater collaboration and pooling of regulatory resources to speed up approvals, as well as making use of reviews by stringent regulatory agencies to streamline their own processes, they conclude.