Strategies for early prediction and timely recognition of drug-induced liver injury: The case of cyclin-dependent kinase 4/6 inhibitors

The idiosyncratic nature of drug-induced liver injury (Dili) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized Dili potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of Dili, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of Dili and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of Dili signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences

Analyzing Adverse Events from Publicly Available Web Sources

Data mining for drug-reaction associations is a major topic in the pharmaceutical industry. Historically the focus has been on using privately owned and maintained datasets consisting of information that has been transformed via the FDA Adverse Event Reporting System (FAERS) and privatized reporting systems that house the data from clinical trials. Our focus will be on building a pipeline that demonstrates an open source solution for building a drug’s safety profile from data collection through signal detection. In contrast this pipeline primarily uses the openFDA and social media data available through Reddit with all analysis being done in the R statistical programming language. The aim was to collect the information available in these public sources and apply popular data mining methodologies used to identify and predict the occurrence of adverse events. The results show the ability of the openFDA and social media sites to create real-time drug safety occurrence profiles by applying the same statistical methods applied in clinical trials. Social media will be shown to provide the best results when applied to prescribed daily use medications compared to common over-the-counter drugs or last line of defense medications. The information and results reported in this paper are not intended or implied to be a substitute for professional medical advice, diagnosis, or treatment. Do not delay seeking medical treatment or advice because of something you have read in this paper

Distributed Governance of Medical AI

Artificial intelligence (AI) promises to bring substantial benefits to medicine. In addition to pushing the frontiers of what is humanly possible, like predicting kidney failure or sepsis before any human can notice, it can democratize expertise beyond the circle of highly specialized practitioners, like letting generalists diagnose diabetic degeneration of the retina. But AI doesn’t always work, and it doesn’t always work for everyone, and it doesn’t always work in every context. AI is likely to behave differently in well-resourced hospitals where it is developed than in poorly resourced frontline health environments where it might well make the biggest difference for patient care. To make the situation even more complicated, AI is unlikely to go through the centralized review and validation process that other medical technologies undergo, like drugs and most medical devices. Even if it did go through those centralized processes, ensuring high-quality performance across a wide variety of settings, including poorly resourced settings, is especially challenging for such centralized mechanisms. What are policymakers to do? This short Essay argues that the diffusion of medical AI, with its many potential benefits, will require policy support for a process of distributed governance, where quality evaluation and oversight take place in the settings of application—but with policy assistance in developing capacities and making that oversight more straightforward to undertake. Getting governance right will not be easy (it never is), but ignoring the issue is likely to leave benefits on the table and patients at risk

Regulatory Reliance and Post-Marketing Surveillance Systems for Safe and Accelerated Introduction of New Medical Products in Low- and Middle-Income Countries

Though delayed access to medicines is still common, disease outbreaks in the past three decades has driven speedier introduction of innovative medical products. Yet, successful models for safe and accelerated introduction of new medical products in low- and middle-income countries are scarcely documented. Recent viral diseases outbreaks like Ebola, COVID-19, and Monkeypox has further highlighted the need for regulatory preparedness for health emergencies. Well-resourced countries have developed expedited regulatory pathways for such situations, while LMICs are not as prepared. They lack models for adopting best practices for implementing regulatory reliance and integrated post marketing surveillance (PMS). Experiences gained from our work strengthening regulatory systems for HIV/AIDS, Tb, and malaria may inform the development of best practices and models for accelerated introduction of future medical products. Chapter 1 of this thesis provides summary of research outputs which documents my published work on introduction of new medical products in global health. Chapter 2 is an integrative literature review of pharmaceutical access, regulatory reliance, and PMS, concluding that regulatory reliance and PMS are critical for safe and accelerated introduction of new medical products in LMICs. However, gaps and challenges exist, and they lead to delayed access which costs lives. To address those gaps, in Chapter 3 we developed Model Integrated Quality and Safety Review (IQSR) checklist, reliance-based review, and tools for integrated surveillance. Evolution in medicines regulation is typically predicated by access campaigns or mishaps. Stronger regulatory systems with well-established approaches for implementing reliance and post market surveillance have the capability to ensure safe and accelerated introduction of new medical products. To ensure that best practices are implemented, we recommended practical tools for the operationalization of reliance practices and post marketing surveillance systems. The tools identified will help regulators, industry, global health experts in advancing timely access to address unmet medical needs

PHARMACOVIGILANCE AND ADVERSE DRUG REACTION REPORTING PRACTICES AMONG GHANAIAN HEALTHCARE PROFESSIONALS

Background - Under-reporting of adverse drug reactions (ADRs) is a challenging medication safety problem globally. Even though ADRs are associated with significant morbidity and mortality, poor reporting among healthcare professionals (HCPs) persists, particularly in resource-limited settings. This study aimed to explore HCP experiences and factors influencing ADR reporting in the Ghanaian hospital setting. Methods - A concurrent mixed methods design was undertaken using face-to-face semi-structured qualitative interviews, focus groups and a survey. Nursing, pharmacy and medical staff were sampled using a stratified random sample from five hospitals in Tamale, Ghana coupled with purposive sampling for interviews. Survey data were analysed descriptively using SPSS and in-depth interviews and focus group discussions analysed using a six-stage thematic analysis using NVivo. Findings - 386 HCPs (86% response rate) participated in the survey. Pharmacovigilance (PV) knowledge was low (19%) with the majority being unaware of the national PV centre (68%) and basic information on reporting forms (65%). Pharmacy staff were however more knowledgeable compared to nursing and medical staff. Only 13% of HCPs reported to have observed an ADR at least once in a year and another 14% had completed a form. The majority (92%) of HCPs agreed that patient safety could improve if they reported ADRs and disagreed that litigation (82%) and lethargy (81%) were a hindrance. Pharmacists were perceived to have a key ADR reporting role. Use of verbal reporting was perceived to reduce ADR reporting formally along with complex interrelated system and human factors, such as lack of forms, inadequate infrastructure, stakeholder issues, uncertainty about reporting responsibilities, poor interpersonal relations, perceive patient attitudes, bureaucracies, fear of wrongdoing and blame. Conclusions – This study suggests that ADR reporting is low and often informal in the Ghanaian hospital setting but enhancing the role of pharmacists may be important in improving ADR reporting, as well as increasing HCP awareness through training – particularly for non-pharmacy staff - and logistical changes such as electronic ADR reporting