Anjan K. Banerjee

Patient-Reported Outcome Measures in Safety Event Reporting: PROSPER Consortium Guidance

The Patient-Reported Outcomes Safety Event Reporting (PROSPER) Consortium was convened to improve safety reporting by better incorporating the perspective of the patient. PROSPER comprises industry, regulatory authority, academic, private sector and patient representatives who are interested in the area of patient-reported outcomes of adverse events (PRO-AEs). It has developed guidance on PRO-AE data, including the benefits of wider use and approaches for data capture and analysis. Patient-reported outcomes (PROs) encompass the full range of self-reporting, rather than only patient reports collected by clinicians using validated instruments. In recent years, PROs have become increasingly important across the spectrum of healthcare and life sciences. Patient-centred models of care are integrating shared decision making and PROs at the point of care; comparative effectiveness research seeks to include patients as participatory stakeholders; and industry is expanding its involvement with patients and patient groups as part of the drug development process and safety monitoring. Additionally, recent pharmacovigilance legislation from regulatory authorities in the EU and the USA calls for the inclusion of patient-reported information in benefit–risk assessment of pharmaceutical products. For patients, technological advancements have made it easier to be an active participant in one’s healthcare. Simplified internet search capabilities, electronic and personal health records, digital mobile devices, and PRO-enabled patient online communities are just a few examples of tools that allow patients to gain increased knowledge about conditions, symptoms, treatment options and side effects. Despite these changes and increased attention on the perceived value of PROs, their full potential has yet to be realised in pharmacovigilance. Current safety reporting and risk assessment processes remain heavily dependent on healthcare professionals, though there are known limitations such as under-reporting and discordant perspectives between patient reports and clinician perceptions of adverse outcomes. PROSPER seeks to support the wider use of PRO-AEs. The scope of this guidance document, which was completed between July 2011 and March 2013, considered a host of domains related to PRO-AEs, including definitions and suitable taxonomies, the range of datasets that could be used, data collection mechanisms, and suitable analytical methodologies. PROSPER offers an innovative framework to differentiate patient populations. This framework considers populations that are prespecified (such as those in clinical trials, prospective observational studies and some registries) and non-prespecified populations (such as those in claims databases, PRO-enabled online patient networks, and social websites in general). While the main focus of this guidance is on post-approval PRO-AEs from both prespecified and non-prespecified population groups, PROSPER has also considered pre-approval, prespecified populations. The ultimate aim of this guidance is to ensure that the patient ‘voice’ and perspective feed appropriately into collection of safety data. The guidance also covers a minimum core dataset for use by industry or regulators to structure PRO-AEs (accessible in the online appendix) and how data, once collected, might be evaluated to better inform on the safe and effective use of medicinal products. Structured collection of such patient data can be considered both a means to an end (improving patient safety) as well as an end in itself (expressing the patient viewpoint). The members of the PROSPER Consortium therefore direct this PRO-AE guidance to multiple stakeholders in drug safety, including industry, regulators, prescribers and patients. The use of this document across the entirety of the drug development life cycle will help to better define the benefit–risk profile of new and existing medicines. Because of the clinical relevance of ‘real-world’ data, PROs have the potential to contribute important new knowledge about the benefits and risks of medicinal products, communicated through the voice of the patient.

Web-Based Patient-Reported Outcomes in Drug Safety and Risk Management

Patient-reported outcomes (PROs) from web-based sources are becoming increasingly important, providing opportunities for industry and regulators to understand the benefits and risks of medicines in a real-world context. Although some guidance exists for the use of adverse event (AE) reports from company-sponsored social network sites, this does not cover non-company-sponsored sites. Additionally, there are concerns about the validity of data from social media sources. Techniques for the collection, analysis and reporting of safety data from patients should be defined, and guidelines agreed, to cover PROs and patient-reported adverse drug-related events from more organized sources of patient outcomes.This review considers drivers for web-based PRO adoption in drug safety, the current regulatory framework and potential methodologies, and concludes that there is an urgent unmet need for guidelines on web-based PRO AEs. Stakeholders for the development of any such guidance should include industry, patients, regulators, academic groups and prescribers.

Post-Approval Evaluation of Effectiveness of Risk Minimisation: Methods, Challenges and Interpretation

Evaluation of the effectiveness of drug risk-minimisation measures is mandatory for both risk evaluation and mitigation strategies (REMS) in the United States and risk management plans in the European Union (EU-RMPs). Such evaluations aim to assess the impact of risk-minimisation measures on the knowledge, attitudes or behaviours of healthcare professionals or patients, the incidence of safety concerns, and their impact on the overall benefit-risk balance. Although many effectiveness evaluation models and methods are available, regulatory guidance and policy are still evolving. This paper considers evaluation strategies, challenges in evaluating risk minimisation post-authorisation, possible outcome measures and their interpretation, and potential emerging regulatory policy issues. Particular challenges include appropriate data collection, perceived and real burdens of performing evaluation on clinical practice, lack of comparators and benchmarking, and uncertainty about the best outcome measures.

Sir Samuel Wilks: a founding father of clinical science.

The Victorian era was a remarkable epoch in many ways for medicine in England. It marked a transition from ephemeral, descriptive practice into a more sound clinical tradition built on the foundations of applied science. This metamorphosis occurred within the general background of an increasing appreciation of physiology and pathology in no institution was this more apparent than in Guys Hospital. When one considers celebrated physicians from this most famous of institutions, the names ofHodgkin, Addison, Bright and Gull easily come to mind. This essay ai-ms to trace the record of a man equally worthy of such recognition, but who, despite his presidency of the Royal College of Physicians of London, has largely been consigned to obscurity. Samuel Wilks (Figure 1) was born in Camberwell; the second of Joseph Barber Wilks (a cashier in the East India Company) by his wife Susannah Edwards, daughter of William Bennett of Southborough, Kent. After attending Aldenham School and University College School, he was apprenticed to a general practitioner in Newington and then, in 1842, began his long association with Guys. He qualified as a Licentiate of the Society of Apothecaries (LSA) and

The evolution of therapeutic risk management

This chapter explains why and how therapeutic risk management has emerged as an important discipline. Seminal events in the history of drug safety are described, highlighting how the need to manage risks of medicinal products evolved. There have been a number of high-profile incidences involving withdrawals of medicines after they were launched, due to serious safety issues, and with a substantial public health impact. The most important ones are summarised here. These key incidences led to pressure for a more effective and regulated approach to control risks. In parallel with these, there was a growing impetus to allow suitable patients safe access to effective – but potentially risky – therapies in areas of high unmet medical need; previously they would have been unable to gain market approval. Some formative examples of the resulting risk minimisation programmes are given below. The emergence of the modern risk management era is then discussed, which has seen rapid progress and widespread adoption over the past decade.

Effective interactions with health authorities

This chapter places risk management in the context of the regulatory system. It summarises the different regulatory agencies and processes that impact risk management in the EU and the US. Companies and health authorities can most effectively engage together when each party understands the perspective of the other. A company should plan for potential scenarios in case its risk management approach is not accepted, which includes the development of back-up strategies to maximise the probability of a desirable and productive outcome during regulatory discussions.

Basic principles of therapeutic risk management

This chapter initially defines therapeutic risk management, which comprises an ongoing cycle of risk detection, risk assessment, risk characterisation, risk minimisation (mitigation), effectiveness evaluation and improvement. It then explains how the risks of a medicinal product should be placed in the context of its benefits, and factors to consider when assessing the benefit–risk balance. The various stakeholders involved in risk management are detailed, with the most important being the pharmaceutical industry, regulatory authorities, healthcare professionals, and patients and their carers (caregivers). The final section describes key risk management activities at different stages of the product life-cycle.

17 – Learnings from other types of risk management

This chapter highlights some other relevant types of risk management, both within the pharmaceutical sector and from other industries. An example is quality risk management concerning the manufacture of medicinal products, which has some limited overlap with therapeutic risk management. Sectors dealing with a high degree of risk, such as the aviation, space and nuclear industries, have innovated risk management techniques and have used a systematic approach for far longer than the healthcare industry. There have been some useful parallels and transferable learnings from these sectors, with an opportunity still to do more.

Developing a safety specification and selecting risks

This chapter describes the structure and contents of a safety specification, as well as how to select and classify safety concerns. A safety specification describes what is known (and what is not known) about the safety profile of the product(s) in an RMP. It is divided into eight modules within an EU-RMP that address different topics with risk implications. These encompass relevant non-clinical, clinical and (where appropriate) post-authorisation experience, as well as the target population and potentially higher-risk subpopulations. The characterised safety concerns form the major output of a safety specification and are classified as important identified risks, important potential risks, or missing information. Later parts of the RMP then consider whether additional activities are needed to address each safety concern.

Overview of risk management around the world

This chapter describes risk management approaches taken around the world. A globally consistent approach would help to optimise both patient safety and overall efficiency. However, differing regulatory requirements have arisen, despite some underlying commonalities. The varying approaches taken by the EU and the US have been the most influential and are briefly compared. Descriptions of risk management in several other advanced and emerging countries are then provided. Regulatory authorities in many countries follow either the EU or US approach, with minor modifications, but others have developed their own system of requirements; some still have no defined process for therapeutic risk management.