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Ensuring the safety of drugs is a critical aspect of healthcare. Accurate interpretation of drug safety evidence is vital to understand the safety profile and to evaluate the benefits and risks of the medicinal product. However, validity of this evidence has numerous challenges that must be carefully considered, highlighting the need for a heightened appreciation of data interpretation pitfalls. This paper aims to delve into the intricacies of analytic considerations in drug safety data interpretation aiming at providing insights into the safety profile of pharmaceutical interventions. The applicability of these analytic considerations extends to controlled and observational data as well as spontaneously reported individual case reports. Increasing the understanding of scientific underpinnings of evidence interpretation empowers Pharmacovigilance professionals to grasp fundamental concepts, use appropriate terminology, engage in meaningful discussions with colleagues conducting analyses, and critically evaluate evidence. These skills and knowledge enable them to make informed decisions and enhance their expertise in drug safety. By correct utilization of analytic approaches while appreciating their strengths and limitations, one can advance drug safety and benefit-risk research using evidence-based decision-making and ultimately ensure better healthcare outcomes for patients.

Contrary to the famous quote from Voltaire, “The art of medicine consists in amusing the patient, while nature cures the disease”, medicine has evolved since the 17th century into a multi-faceted scientific field facilitating healing and improving overall wellbeing. One rapidly evolving area within this field is drug safety, also known as pharmacovigilance (PV). PV identifies and evaluates potential risks throughout the life cycle of the drug, minimizing patient exposure to harmful effects and guiding appropriate risk mitigation and management strategies. Timely identification and mitigation of risks not only contribute to patient safety but also allows maximum therapeutic benefits while curtailing economic burden associated with adverse events. In the evolving landscape of drug safety, the role of the PV physicians has emerged as an integral component of drug development. This paper aims to explore the evolving nature of PV physicians’ roles in drug development, highlighting changing landscape in drug development and safety monitoring and attendant changes and advancements in responsibilities, scope, and training implications. To be well-rounded, PV physicians are encouraged to strive to undergo relevant training and education. This would enable them to leverage pertinent complementary fields of science by developing the proficiency to ask the right questions, acknowledge multidisciplinary perspectives, and interpret the overall evidence. While on-the-job training is valuable for gaining experience, building a future safety workforce necessitates more targeted efforts, especially considering that medical school curricula may not readily emphasize the development of skills required for successful PV physician roles. Therefore, academic centers, pharmaceutical companies, and regulatory agencies should increase collaboration to establish hands-on training opportunities through post-doctoral, internship, and fellowship programs, in order to meet the growing demand for well-trained PV physicians.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making.Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022.Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators’ understanding of patients’ unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions.Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators’ experience with PPS implementation and communication in regulatory evaluations.

In the field of drug safety, causality assessment aims to determine the level of plausibility of the relationship between an adverse event and exposure to a particular product. It is after the causality assessment process that we will be able to point out a product adverse reaction. While regulators often require pharmaceutical companies to use a structured approach for assessing the causality of their products, the available methods are challenged by a number of procedural differences, even when drawing from the same domain of elements. To mitigate these inconsistencies, as well as the additional challenges associated with incomplete information and differences in the application of clinical judgments at the individual case level, this paper proposes a holistic framework for causality assessment that utilizes a combination of expert judgment/global introspection, evidence-based medicine, and probabilistic method. The goal of the presented approach is to provide a guide of clues to causality reminding medical safety assessors to seek and examine all available streams of evidence in totality and to assess this evidence in a qualitative, structured way.