The utility of real-world evidence for benefit-risk assessment, communication, and evaluation of pharmaceuticals: Case studies.

PURPOSE: In recent years, novel types of real-world evidence (RWE) have played a role in various decision-making processes relating to medicinal products, including regulatory approval, patient access, health technology assessment, safety monitoring, clinical use, and post-approval lifecycle management. We therefore reviewed the potential utility of RWE in the cycle of medicinal product benefit-risk (BR) assessment, communication/risk minimization and evaluation ("BRACE"). METHODS: A convenience sample of illustrative studies was drawn from the published literature and examined. Specifically, we examined the purpose for using RWE, the type of RWE used, its novelty and how it might be integrated with other data and activities of the BRACE cycle, and how it contributed to regulatory decision-making. RESULTS: Eight studies were selected with each illustrating a different activity in the BRACE cycle ranging from BR assessment in the preapproval setting, post-approval assessment of safety or effectiveness, communicating BR information to patients and healthcare professionals, and evaluating the effectiveness of risk minimization initiatives to support a positive BR balance. CONCLUSIONS: RWE has an important role in informing regulatory decision-making regarding the BR management of medicines. With increasing digitalization, facilitating data collection and stakeholder engagement in health, this role is only expected to expand in the future. To reach the full potential of RWE, both regulators and sponsors will need to be familiar with a range of existing and emerging methods for generating and analyzing such evidence appropriately and achieve convergence regarding how different types of RWE can best be used to inform BR management and decision-making.

'Engagement' of patients and healthcare professionals in regulatory pharmacovigilance: establishing a conceptual and methodological framework.

BACKGROUND: Engagement of patients and healthcare professionals is increasingly considered as fundamental to pharmacovigilance and risk minimisation activities. Few empirical studies of engagement exist and a lack of explicit conceptualisations impedes effective measurement, research and the development of evidence-based engagement interventions. AIMS: This article (1) develops a widely applicable conceptualisation, (2) considers various methodological challenges to researching engagement, proposing some solutions, and (3) outlines a basis for converting the conceptualisation into specific measures and indicators of engagement among stakeholders. METHOD: We synthesise social science work on risk governance and public understandings of science with insights from studies in the pharmacovigilance field. FINDINGS: This leads us to define engagement as an ongoing process of knowledge exchange among stakeholders, with the adoption of this knowledge as the outcome which may feed back into engagement processes over time. We conceptualise this process via three dimensions; breadth, depth and texture. In addressing challenges to capturing each dimension, we emphasise the importance of combining survey approaches with qualitative studies and secondary data on medicines use, prescribing, adverse reaction reporting and health outcomes. A framework for evaluating engagement intervention processes and outcomes is proposed. Alongside measuring engagement via breadth and depth, we highlight the need to research the engagement process through attentiveness to texture-what engagement feels like, what it means to people, and how this shapes motivations based on values, emotions, trust and rationales. CONCLUSION: Capturing all three dimensions of engagement is vital to develop valid understandings of what works and why, thus informing engagement interventions of patients and healthcare professionals to given regulatory pharmacovigilance scenarios.

Listen to the public and fulfil their information interests - translating vaccine communication research findings into guidance for regulators.

Regulatory authorities have a crucial role in communicating about the vaccines they license. In terms of content and timing, their communication to the public is usually driven by data on quality, safety and efficacy. However, concerns over safety and vaccine hesitancy have emerged in some communities in various countries, and this demands a new approach to communication, starting with listening to the public debate. Reviewing communication research findings, coming in particular from the cognitive, decision-making and media sciences, constitutes one mechanism of listening and has led the European Union (EU) regulatory network to developing guidance about which common concerns and information needs of the public to address through proactive and prepared communication. The guidance has been welcomed by EU and international fora. The current article summarizes the recommendations and shares the underlying research findings, as well as a proof of concept that communication research can be valuable for regulators. It is critical that regulators integrate the communication process with product risk assessment in the framework of pharmacovigilance, to ensure that public concerns are addressed in the assessments and that information about evidence and uncertainty relating to safety is provided to the public and vaccination policy makers in a specific, clear and accurate manner. Additionally, information from regulatory authorities should support healthcare professionals in their communication with patients. Meeting the information interests of the public is the principal prerequisite for informed decisions as well as safe and effective use of vaccines and medicines overall. This is also fundamental for trust in the authorities' commitment to patient and population health.

Application of real-time global media monitoring and 'derived questions' for enhancing communication by regulatory bodies: the case of human papillomavirus vaccines.

BACKGROUND: The benefit-risk balance of vaccines is regularly debated by the public, but the utility of media monitoring for regulatory bodies is unclear. A media monitoring study was conducted at the European Medicines Agency (EMA) concerning human papillomavirus (HPV) vaccines during a European Union (EU) referral procedure assessing the potential causality of complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) reported to the authorities as suspected adverse reactions. METHODS: To evaluate the utility of media monitoring in real life, prospective real-time monitoring of worldwide online news was conducted from September to December 2015 with inductive content analysis, generating 'derived questions'. The evaluation was performed through the validation of the predictive capacity of these questions against journalists' queries, review of the EMA's public statement and feedback from EU regulators. RESULTS: A total of 4230 news items were identified, containing personal stories, scientific and policy/process-related topics. Explicit and implicit concerns were identified, including those raised due to lack of knowledge or anticipated once more information would be published. Fifty derived questions were generated and categorised into 12 themes. The evaluation demonstrated that providing the media monitoring findings to assessors and communicators resulted in (1) confirming that public concerns regarding CRPS and POTS would be covered by the assessment; (2) meeting specific information needs proactively in the public statement; (3) predicting all queries from journalists; and (4) altering the tone of the public statement with respectful acknowledgement of the health status of patients with CRSP or POTS. CONCLUSIONS: The study demonstrated the potential utility of media monitoring for regulatory bodies to support communication proactivity and preparedness, intended to support trusted safe and effective vaccine use. Derived questions seem to be a familiar and effective format for presenting media monitoring results in the scientific-regulatory environment. It is suggested that media monitoring could form part of regular surveillance for medicines of high public interest. Future work is recommended to develop efficient monitoring strategies for that purpose.

Benefit-Risk Assessment, Communication, and Evaluation (BRACE) throughout the life cycle of therapeutic products: overall perspective and role of the pharmacoepidemiologist.

PURPOSE: Optimizing a therapeutic product's benefit-risk profile is an on-going process throughout the product's life cycle. Different, yet related, benefit-risk assessment strategies and frameworks are being developed by various regulatory agencies, industry groups, and stakeholders. This paper summarizes current best practices and discusses the role of the pharmacoepidemiologist in these activities, taking a life-cycle approach to integrated Benefit-Risk Assessment, Communication, and Evaluation (BRACE). METHODS: A review of the medical and regulatory literature was performed for the following steps involved in therapeutic benefit-risk optimization: benefit-risk evidence generation; data integration and analysis; decision making; regulatory and policy decision making; benefit-risk communication and risk minimization; and evaluation. Feedback from International Society for Pharmacoepidemiology members was solicited on the role of the pharmacoepidemiologist. The case example of natalizumab is provided to illustrate the cyclic nature of the benefit-risk optimization process. RESULTS: No single, globally adopted benefit-risk assessment process exists. The BRACE heuristic offers a way to clarify research needs and to promote best practices in a cyclic and integrated manner and highlight the critical importance of cross-disciplinary input. Its approach focuses on the integration of BRACE activities for risk minimization and optimization of the benefit-risk profile. CONCLUSION: The activities defined in the BRACE heuristic contribute to the optimization of the benefit-risk profile of therapeutic products in the clinical world at both the patient and population health level. With interdisciplinary collaboration, pharmacoepidemiologists are well suited for bringing in methodology expertise, relevant research, and public health perspectives into the BRACE process.

Medicines for an aging population: The EMA perspective and policies.

The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre- and post-approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment.

What Factors Make EU Regulators Want to Communicate Drug Safety Issues Related to SGLT2 Inhibitors? An Online Survey Study.

INTRODUCTION: Previous studies have found differences in the communication of safety issues among medicines regulatory agencies. OBJECTIVES: To explore (1) to what extent regulators' opinions regarding the need to communicate safety issues related to sodium-glucose cotransporter-2 (SGLT2) inhibitors might be influenced by their concern about the safety issue, and (2) whether regulators' concerns might be influenced by certain characteristics of the safety issue or by the demographic and professional characteristics and attitudes of the regulators. METHODS: An online cross-sectional survey study with a rating-based conjoint analysis among clinical and pharmacovigilance assessors from the EU regulatory network was performed between April and June 2021. Regulators were invited by email, and participants were asked about their level of concern and their opinion regarding the need to communicate about 12 scenarios defined by four characteristics: adverse drug reaction, source of information, causality, and frequency. The outcomes for the first objective were to update the summary of product characteristics (SmPC; yes/no) and to send direct healthcare professional communications (DHPC; yes/no). The determinant was regulators' level of concern (range 0-100%). The outcome of the second objective was regulators' level of concern, and the determinants were the characteristics of the safety issue, demographic and professional characteristics, and attitudes of the regulators (beliefs about medicines and risk perception). RESULTS: A total of 222 regulators completed the survey (64% women; mean age 46 ± 10 years). Depending on the scenario, 54-94% and 25-74% of the participants would update the SmPC or send a DHPC, respectively. The participants' level of concern influenced their opinions regarding the need to update the SmPC and send a DHPC (odds ratio (OR) 13.0; 95% confidence interval (CI) 7.8-21.7 and OR 13.6; 95% CI 9.5-19.2, respectively, for every 10% increase in the level of concern). All characteristics of the safety issue influenced the level of concern. Younger participants, women, and those working for Eastern European agencies had a higher level of concern than older participants, men, and those working in other regions. Beliefs about medicines and general risk perception also influenced their concern. CONCLUSIONS: The opinion regarding the need to communicate safety issues was influenced by the concern of regulators. Regulators' concern was influenced by the characteristics of the safety issue, demographic characteristics, and attitudes. Diverse groups of experts regarding such factors would ensure that various views are incorporated in risk communication decisions.

How do safety warnings on medicines affect prescribing?

INTRODUCTION: Many adverse effects of medicines only become known after approval, prompting regulatory agencies to issue post-market safety advisories to support safer care. Our team evaluated advisories issued by national regulators in Australia, Canada, Denmark, the United Kingdom, and the United States from 2007 to 2016 inclusive, comparing regulators' decisions to warn, effects on prescribing, doctors' awareness and responses to warnings, relevant regulatory policies, and specific case studies. AREAS COVERED: Based mainly on our research program and a narrative review, this commentary describes how often regulators issue safety advisories and effects on clinical practice. We found extensive differences in decisions to warn, timing and content of warnings. Monitoring advice is often inadequate. The most systematic estimate suggests an average reduction in prescribing of around 6% compared with settings with no advisory. Interviews with doctors suggest limited awareness, uptake, and at times belief in these warnings. EXPERT OPINION: Post-market safety advisories are an important intervention aiming to improve prescribing and use of medicines. However, differing warnings mean that some patients may be exposed to riskier prescribing than others. Better integration of safety information into clinical practice is needed, as well as improved transparency, independence, and public engagement in regulatory decision-making.

Systematising Pharmacovigilance Engagement of Patients, Healthcare Professionals and Regulators: A Practical Decision Guide Derived from the International Risk Governance Framework for Engagement Events and Discourse.

INTRODUCTION: Input from patients and healthcare professionals to regulatory assessments is essential for benefit-risk management of medicines. How to best obtain input in different risk scenarios is uncertain. OBJECTIVES: The objective of this study was to investigate whether the International Risk Governance Council (IRGC) Framework is applicable to pharmacovigilance and can guide selecting engagement mechanisms for optimising stakeholder input. METHODS: For proof-of-concept, classify 'iconic' cases of pharmacovigilance engagement at the European Medicines Agency (EMA) by IRGC risk scenario types and compare the engagement that happened with the engagement discourse recommended by the IRGC Framework for different risk scenarios. If the concept is proven, derive proposals for strengthening engagement. RESULTS: Six iconic cases were classified by risk scenario type at the respective time points when deciding on engagement: venous thromboembolism with combined hormonal contraceptives (complex risk); lipodystrophy with highly active antiretroviral therapy medicines, carcinogenicity with contaminated nelfinavir products (uncertain risks); teratogenicity with thalidomide, progressive multifocal leukoencephalopathy with natalizumab, teratogenicity and developmental disorders with valproate (ambiguous risks). The comparison of the engagement events with IRGC recommendations showed correspondence between the scope/outcomes of the events and the features of the recommended discourse. CONCLUSIONS: The IRGC Framework appears applicable to pharmacovigilance. Proposals derived from the IRGC recommendations may be valuable for guiding regulators when selecting mechanisms for engagement with patients and healthcare professionals in given risk scenarios. The proposed decision guide aims at ensuring systematic and consistent engagement across regulatory assessments and providing for the most purposeful discourse, to effectively obtain real-world input for regulatory risk assessment, evaluation of risk minimisation measures and decision making.

Proposals for Engaging Patients and Healthcare Professionals in Risk Minimisation from an Analysis of Stakeholder Input to the EU Valproate Assessment Using the Novel Analysing Stakeholder Safety Engagement Tool (ASSET).

INTRODUCTION: Understanding the impact of regulatory actions for medicines and enablers/barriers for positive health outcomes is fundamental to effective risk minimisation measures (RMM). Therefore, the Impact Strategy of the European Union (EU) Pharmacovigilance Risk Assessment Committee (PRAC) includes engagement with patient communities and healthcare professional (HCP) bodies regarding RMM. However, there is uncertainty on how best to obtain stakeholder input. OBJECTIVES: The objectives of this study were to (1) analyse stakeholder input at a public hearing and dedicated meeting for the 2017-18 EU procedure on valproate teratogenicity and (2) draw proposals for enhancing PRAC engagement. METHODS: For the content analysis, the novel 'Analysing Stakeholder Safety Engagement Tool' (ASSET) was developed with 21 themes in six domains (appropriateness, access, audience, compatibility, integrability, time), based on implementation theories. RESULTS: Stakeholders provided a wide range of RMM proposals, some beyond the regulatory remit. Patients and most HCPs converged remarkably, but there was some divergence among HCPs on the informed choice objective, the therapeutic place of valproate, the RMM appropriateness, and RMM delivery to HCPs and patients. Ethical aspects emerged as relevant for regulatory decision making, and crucial input gaps were identified from an RMM implementation perspective. Nine pilotable proposals for PRAC were made regarding: (A) Agreeing on appropriate RMM with stakeholders and catalysing healthcare leadership for implementation; (B) Building-up stakeholder input on all elements critical to RMM implementation guided by the ASSET; and (C) Collaborating with all stakeholders for monitoring implementation and evaluating RMM. CONCLUSIONS: New implementation theory-based approaches are promising for enhancing the valuable dialogue between regulators, patients and HCPs and achieving patient safety. EU PAS REGISTER NUMBER: EUPAS35947.

Postmarket Safety Communication for Protection of Public Health: A Comparison of Regulatory Policy in Australia, Canada, the European Union, and the United States.

In the wake of the withdrawal of the nonsteroidal anti-inflammatory drug rofecoxib, regulators worldwide reconsidered their approach to postmarket safety. Many have since adopted a "life cycle" approach to regulation of medicines, facilitating faster approval of new medicines while planning for potential postmarket safety issues. A crucial aspect of postmarket safety is the effective and timely communication of emerging risk information using postmarket safety advisories, commonly issued as letters to healthcare professionals, drug safety bulletins, media alerts, and website announcements. Yet regulators differ in their use of postmarket safety advisories. We examined the capacity of regulators in the United States, Europe, Canada, and Australia to warn about postmarket safety issues through safety advisories by assessing their governance, legislative authority, risk communication capabilities, and transparency.

Why we need more collaboration in Europe to enhance post-marketing surveillance of vaccines.

The influenza A/H1N1 pandemic in 2009 taught us that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better (public health institutes (PHIs), regulatory authorities, research institutes, vaccine manufacturers). The Innovative Medicines Initiative (IMI) subsequently issued a competitive call to establish a public-private partnership to build and test a novel system for monitoring vaccine benefits and risks in Europe. The ADVANCE project (Accelerated Development of Vaccine benefit-risk Collaboration in Europe) was created as a result. The objective of this paper is to describe the perspectives of key stakeholder groups of the ADVANCE consortium for vaccine benefit-risk monitoring and their views on how to build a European system addressing the needs and challenges of such monitoring. These perspectives and needs were assessed at the start of the ADVANCE project by the European Medicines Agency together with representatives of the main stakeholders in the field of vaccines within and outside the ADVANCE consortium (i.e. research institutes, public health institutes, medicines regulatory authorities, vaccine manufacturers, patient associations). Although all stakeholder representatives stated they conduct vaccine benefit-risk monitoring according to their own remit, needs and obligations, they are faced with similar challenges and needs for improved collaboration. A robust, rapid system yielding high-quality information on the benefits and risks of vaccines would therefore support their decision making. ADVANCE has developed such a system and has tested its performance in a series of proof of concept (POC) studies. The system, how it was used and the results from the POC studies are described in the papers in this supplementary issue.

CIOMS Guide To Vaccine Safety Communication - Executive summary.

BACKGROUND: In 2018, the Council for International Organizations of Medical Sciences (CIOMS) issued their Guide to Vaccine Safety Communication. This has been built upon existing guidance and a new review of research and compilation of latest experiences, in order to fill, for the first time at global level, a specific niche for regulatory authorities in the contexts of vaccine hesitancy and informed choice. The Guide was developed by the international multi-stakeholder CIOMS Working Group on Vaccine Safety, formed to assist the Global Vaccine Safety Initiative (GVSI) of the World Health Organization (WHO). SUMMARY: Besides the public health authorities responsible for immunization programmes, regulators have their own role in communicating about vaccine safety. As they are responsible for licensing vaccine products, they need to be transparent about their assessments of data on quality, safety and efficacy. Furthermore, they are responsible for continuous safety surveillance and keeping safe use advice to the public up-to-date. The Guide stresses the fundamental importance of regulatory bodies to have a system in place with defined functions and skilled persons who can efficiently run vaccine safety communication in collaboration with stakeholders. This system should take a strategic approach to communication, be integral to safety surveillance and risk assessment, and support vaccine safety communication plans (VacSCPs) adapted to vaccine types in local situations. The Guide provides recommendations and examples for the system components as well as a practical VacSCP template. CONCLUSIONS: While the Guide should help strengthening regulatory bodies worldwide with regard to vaccine safety communication, it is meant to help regulators in resource-limited countries in particular. It can also be of interest to other stakeholders and be leveraged to other medicinal products.

Correction to: Patient Registries: An Underused Resource for Medicines Evaluation : Operational proposals for increasing the use of patient registries in regulatory assessments.

The fourth sentence under the heading "1.1 Use of Patient Registries for Supporting Regulatory Assessments" in "1 Introduction" section should read as below.

Patient Registries: An Underused Resource for Medicines Evaluation : Operational proposals for increasing the use of patient registries in regulatory assessments.

INTRODUCTION: Patient registries, 'organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time', are potentially valuable sources of data for supporting regulatory decision-making, especially for products to treat rare diseases. Nevertheless, patient registries are greatly underused in regulatory assessments. Reasons include heterogeneity in registry design and in the data collected, even across registries for the same disease, as well as unreliable data quality and data sharing impediments. The Patient Registries Initiative was established by the European Medicines Agency in 2015 to support registries in collecting data suitable to contribute to regulatory assessments, especially post-authorisation safety and effectiveness studies. METHODS: We conducted a qualitative synthesis of the published observations and recommendations from an initiative-led multi-stakeholder consultation and four disease-specific patient registry workshops. We identified the primary factors facilitating the use of registry data in regulatory assessments. We generated proposals on operational measures needed from stakeholders including registry holders, patients, healthcare professionals, regulators, marketing authorisation applicants and holders, and health technology assessment bodies for implementing these. RESULTS: Ten factors were identified as facilitating registry use for supporting regulatory assessments of medicinal products. Proposals on operational measures needed for implementation were categorised according to three themes: (1) nature of the data collected and registry quality assurance processes; (2) registry governance, informed consent, data protection and sharing; and (3) stakeholder communication and planning of benefit-risk assessments. CONCLUSIONS: These are the first explicit proposals, from a regulatory perspective, on operational methods for increasing the use of patient registries in medicines regulation. They apply to registry holders, patients, regulators, marketing authorisation holders/applicants and healthcare stakeholders broadly, and their implementation would greatly facilitate the use of these valuable data sources in regulatory decision-making.

The RIMES Statement: A Checklist to Assess the Quality of Studies Evaluating Risk Minimization Programs for Medicinal Products.

INTRODUCTION: Pharmaceutical risk minimization programs involve interventions designed to support safe and appropriate use of medicines. Currently, information regarding the evaluation of these programs is not publicly reported in a standardized and transparent manner. To address this gap, we developed and piloted a quality reporting checklist entitled the Reporting recommendations Intended for pharmaceutical risk Minimization Evaluation Studies (RIMES). METHODS: Checklist development was guided by three sources: (1) a theoretical framework derived from program theory and process evaluation; (2) public health intervention design and evaluation principles; and (3) a review of existing quality reporting checklists. Two raters independently reviewed 10 recently published (2012-2016) risk minimization program evaluation studies using the proposed checklist. Inter-rater reliability of the checklist was assessed using Cohen's Kappa and Gwet's AC1. RESULTS: A 43-item checklist was generated. Results indicated substantial inter-rater reliability overall (κ = 0.65, AC1 = 0.65) and for three (key information, design and evaluation) of the four subscales (κ ≥ 0.64, AC1 ≥ 0.64). The fourth subscale (implementation) showed low reliability based on Cohen's Kappa, but substantial reliability based on the AC1 (κ = 0.17, AC1 = 0.61). CONCLUSIONS: The RIMES statement augments relevant elements from existing quality reporting guidelines with items that address aspects of intervention design, implementation and evaluation specific to pharmaceutical risk minimization programs. Our results show that the RIMES statement reliably measures key dimensions of reporting quality. This tailored checklist is an important first step in improving the reporting quality of risk minimization evaluation studies and may ultimately help to improve the quality of these interventions themselves.