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The ICH S1B carcinogenicity global testing guideline has been recently revised with a novel addendum that describes a comprehensive integrated Weight of Evidence (WoE) approach to determine the need for a 2-year rat carcinogenicity study. In the present work, experts from different organizations have joined efforts to standardize as much as possible a procedural framework for the integration of evidence associated with the different ICH S1B(R1) WoE criteria. The framework uses a pragmatic consensus procedure for carcinogenicity hazard assessment to facilitate transparent, consistent, and documented decision-making and it discusses best-practices both for the organization of studies and presentation of data in a format suitable for regulatory review. First, it is acknowledged that the six WoE factors described in the addendum form an integrated network of evidence within a holistic assessment framework that is used synergistically to analyze and explain safety signals. Second, the proposed standardized procedure builds upon different considerations related to the primary sources of evidence, mechanistic analysis, alternative methodologies and novel investigative approaches, metabolites, and reliability of the data and other acquired information. Each of the six WoE factors is described highlighting how they can contribute evidence for the overall WoE assessment. A suggested reporting format to summarize the cross-integration of evidence from the different WoE factors is also presented. This work also notes that even if a 2-year rat study is ultimately required, creating a WoE assessment is valuable in understanding the specific factors and levels of human carcinogenic risk better than have been identified previously with the 2-year rat bioassay alone.

ABSTRACT The toxicity of tenofovir alafenamide (TAF) hemifumarate (HF) was evaluated when administered by continuous subcutaneous (s.c.) infusion via an external infusion pump for 28 days to rats and dogs. The toxicokinetics of TAF and two metabolites, tenofovir (TFV) and tenofovir diphosphate (TFV-DP) were also evaluated. After administration of TAF HF in rats and dogs, primary systemic findings supported an inflammatory response that was considered minimal to mild. Gross pathology and histopathologic evaluation of tissue surrounding the s.c. infusion site revealed signs of inflammation, including edema, mass formation, fibrosis, and mononuclear cell inflammation in groups receiving ≥300 μg/kg/day in rats and ≥25 μg/day in dogs. Although these changes were observed in animals receiving vehicle, the severity was greater in animals receiving TAF HF. Changes in the local tissue were considered a TAF HF-mediated exacerbation of an inflammatory response to the presence of the catheter. In rats, systemic and local findings were considered not adverse due to their low severity and reversibility; therefore, the “no observed adverse effect level” (NOAEL) was set at 1,000 μg/kg/day. Because none of the systemic findings were related to systemic exposure to TAF, the systemic NOAEL was set at 250 μg/kg/day in dogs. Due to the severity of the observations noted, a NOAEL for local toxicity could not be established. Although these results might allow for exploration of tolerability and pharmacokinetics of s.c. administered TAF HF in humans, data suggest a local reaction may develop in humans at doses below a clinically relevant dose. IMPORTANCE Human immunodeficiency virus (HIV) infection continues to be a serious global human health issue, with ∼38 million people living with HIV worldwide at the end of 2019. HIV preexposure prophylaxis (PrEP) has introduced the use of antiretroviral therapies as another helpful tool for slowing the spread of HIV worldwide. One possible solution to the problem of inconsistent access and poor adherence to HIV PrEP therapies is the development of subcutaneous (s.c.) depots or s.c. implantable devices that continuously administer protective levels of an HIV PrEP therapy for weeks, months, or even years at a time. We evaluate here the toxicity of tenofovir alafenamide, a potent inhibitor or HIV replication, after continuous s.c. infusion in rats and dogs for HIV PrEP.