Approaches to accelerating the study of new antiretrovirals in pregnancy

Introduction: Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available. Discussion: The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year-long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre- and post-licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non-pregnant adults, provided that drug levels in pregnancy are similar. However, short-term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre-clinical studies is essential for pregnancy short-term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post-marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two-drug regimens, long-acting ARVs and ARVs administered through novel delivery systems. Conclusions: Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.</p

Accelerating investigation of new HIV drugs in pregnancy : advancing the research agenda from theory to action

Introduction: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. Discussion: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved. Conclusions: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV.</p

A living WHO guideline on drugs for covid-19

Clinical question What is the role of drug interventions in the treatment of patients with covid-19? New recommendation Increased attention on ivermectin as a potential treatment for covid-19 triggered this recommendation. The panel made a recommendation against ivermectin in patients with covid-19 regardless of disease severity, except in the context of a clinical trial. Prior recommendations (a) a strong recommendation against the use of hydroxychloroquine in patients with covid-19, regardless of disease severity; (b) a strong recommendation against the use of lopinavir-ritonavir in patients with covid-19, regardless of disease severity; (c) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19; (d) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, and (e) a conditional recommendation against remdesivir in hospitalised patients with covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation There is insufficient evidence to be clear to what extent, if any, ivermectin is helpful or harmful in treating covid-19. There was a large degree of uncertainty in the evidence about ivermectin on mortality, need for mechanical ventilation, need for hospital admission, time to clinical improvement, and other patient-important outcomes. There is potential for harm with an increased risk of adverse events leading to study drug discontinuation. Applying pre-determined values and preferences, the panel inferred that almost all well informed patients would want to receive ivermectin only in the context of a randomised trial, given that the evidence left a very high degree of uncertainty on important effects. Updates This is a living guideline. It replaces earlier versions (4 September, 20 November, and 17 December 2020) and supersedes the BMJ Rapid Recommendations on remdesivir published on 2 July 2020. The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline. Readers note This is the fourth version (update 3) of the living guideline (BMJ 2020;370:m3379). When citing this article, please consider adding the update number and date of access for clarity.Medicine, Faculty ofNon UBCEmergency Medicine, Department ofPediatrics, Department ofReviewedFacultyResearcherPostdoctoralGraduat