IntroductionIn 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource‐constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource‐constrained settings. Although the tFDA was originally intended to support the United States’ President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in‐depth review of the relevant legal and regulatory processes.Discussion USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use.ConclusionsIn this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource‐constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example.

BackgroundSince 2004, the US Food and Drug Administration’s (USFDA) dedicated drug review process in support of President’s Emergency Plan for AIDS Relief (PEPFAR) has made safe, effective and quality antiretrovirals (ARVs) available for millions of patients. Furthermore, the WHO and Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) can add the USFDA-reviewed products to their respective formularies, through a novel process of ‘one-way reliance’. We assessed the number of ARVs made available through WHO and Global Fund based on the USFDA review.MethodsWe conducted a cross-sectional study of all the USFDA-reviewed PEPFAR drugs between 1 December 2014 and 20 March 2017 to determine 1) the percentage that are included on the WHO and Global Fund formularies; 2) the number of the USFDA ARVs supporting the WHO HIV treatment guidelines, and their uptake by WHO and Global Fund and 3) time between the USFDA review and WHO review of the same ARVs.FindingsOverall, 91% (204/224) of the USFDA products appeared on either the WHO/Prequalification of Medicines Programme (PQP) or the Global Fund ARV lists. Forty-five per cent (100/224) and 83% (184/224) appear on WHO/PQP and Global Fund formularies through one-way reliance, respectively. Forty-one per cent (91/224) of the USFDA products support the WHO-preferred first-line HIV treatment options. Of these 91 products, 38% and 85% of products were adopted by WHO/PQP and Global Fund through one-way reliance, respectively. Sixty-six products that were fully reviewed and registered by WHO (vs one-way reliance) had also undergone the USFDA review; 46 of these were registered by WHO after the USFDA review was complete (median delay of 559 days (IQR 233–798 days)).ConclusionsThe USFDA’s PEPFAR process is making safe and effective ARVs available worldwide, in part because the major global ARV procurement organisations rely on the USFDA registration as proof of quality. There is room for improved information sharing and collaboration to reduce duplication of effort, save resources and further expedite access to ARVs.

Key PointsQuestionWhat has the US Food and Drug Administration (FDA) program to review antiretroviral drugs for use in low-resource settings via the US President’s Emergency Plan for AIDS Relief (PEPFAR) achieved since its inception in 2004, and how could the program be more effective?FindingsThis cross-sectional study found that under PEPFAR, the FDA has authorized 216 applications for 272 antiretroviral drugs, including 26% for pediatric use. Ninety-five of 260 applications (37%) received 172 rejection letters, primarily for deficiencies in manufacturing processes (44%).MeaningThe FDA’s efforts have made many HIV drugs available for use globally; however, more pediatric-specific therapies are needed, and the quality of applications needs to improve.