The US Food and Drug Administration's tentative approval process and the global fight against HIV

Abstract

Introduction: In 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.

Conclusions: In 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.

Keywords: AIDS; FDA; HIV; PEPFAR; TAF; USFDA; Global Health; tentative approval.

Figure 1

High‐level overview of how the USFDA registrations of ARVs for PEPFAR are used by global actors. The figure shows how USFDA registrations for PEPFAR both directly and indirectly support procurement of ARVs by various global actors. The process starts when USFDA receives a product application for review under the tFDA process (blue box). If the product meets USFDA standards for safety, efficacy and quality, it is added to the list of quality‐assured ARVs that can be purchased utilizing the United States’ PEPFAR funds by USAID and its partners (green box). In addition, the WHO selectively places some of the USFDA registered ARVs on its quality‐assured prequalification of medicines list (orange box). ARVs on the United States tFDA list and/or the WHO list may be procured by various international agencies (e.g. the Global Fund, UNICEF, UNAIDS, UNITAID) that purchase medicines for HIV treatment programmes (purple boxes). In addition to USFDA, The Global Fund, WHO, and United Nations entities may rely on other stringent regulatory authorities for quality assurance and the Global Fund may, in limited circumstances, use WHO's Expert Review Panel (grey boxes). USFDA, US Food and Drug Administration; PEPFAR, President's Emergency Plan for AIDS Relief; ARV, antiretroviral; USAID, US Agency for International Development; WHO, World Health Organization.

Figure 2

Infographic of USFDA's tentative approval regulatory pathways for drugs used by PEPFAR, as well as, legal restrictions, and timelines. The infographic depicts (from top to bottom) the overall process for receiving and reviewing an application for PEPFAR. The process is divided horizontally into four distinct processes: Process 1 – initial drug registration for the innovator product(s) that serve as the reference for drugs used by PEPFAR; Process 2 – the various regulatory pathways available for drugs used by PEPFAR; Process 3 – legal restrictions and considerations for tFDA application submission for PEPFAR programme; and Process 4 – determination of priority versus standard reviews and related review timelines. USFDA, US Food and Drug Administration; PEPFAR, President's Emergency Plan for AIDS Relief.

Figure 3

The simplified administrative process of drug review and dissemination of information related to drugs for the PEPFAR programme. The diagram flows from left to right, representing key distinct functions across two offices at the USFDA; and from top to bottom, displaying the various processes involved in fulfilling each function. USFDA, US Food and Drug Administration; PEPFAR, President's Emergency Plan for AIDS Relief; NDA, New Drug Application; ANDA, Abbreviated New Drug Application; TA, Tentative Approval; OIP, Office of International Programs; WHO, World Health Organization; PQP, Prequalification of Medicines Programme; USAID, US Agency for International Development.