Individual Trade-Offs Between Possible Benefits and Risks of Cancer Treatments: Results from a Stated Preference Study with Patients with Multiple Myeloma.

BACKGROUND: The objectives of this study were to elicit the preferences of patients with multiple myeloma regarding the possible benefits and risks of cancer treatments and to illustrate how such data may be used to estimate patients' acceptance of new treatments. PATIENTS AND METHODS: Patients with multiple myeloma from the cancer charity Myeloma UK were invited to participate in an online survey based on multicriteria decision analysis and swing weighting to elicit individual stated preferences for the following attributes: (a) 1-year progression-free survival (PFS, ranging from 50% to 90%), (b) mild or moderate toxicity for 2 months or longer (ranging from 85% to 45%), and (c) severe or life-threatening toxicity (ranging from 80% to 20%). RESULTS: A total of 560 participants completed the survey. The average weight given to PFS was 0.54, followed by 0.32 for severe or life-threatening toxicity and 0.14 for mild or moderate chronic toxicity. Participants who ranked severe or life-threatening toxicity above mild or moderate chronic toxicity (56%) were more frequently younger, working, and looking after dependent family members and had more frequently experienced severe or life-threatening side effects. The amount of weight given to PFS did not depend on any of the collected covariates. The feasibility of using the collected preference data to estimate the patients' acceptance of specific multiple myeloma treatments was demonstrated in a subsequent decision analysis example. CONCLUSION: Stated preference studies provide a systematic approach to gain knowledge about the distribution of preferences in the population and about what this implies for patients' acceptance of specific treatments. IMPLICATIONS FOR PRACTICE: This study demonstrated how quantitative preference statements from a large group of participants can be collected through an online survey and how such information may be used to explore the acceptability of specific treatments based on the attributes studied. Results from such studies have the potential to become an important new tool for gathering patient views and studying heterogeneity in preferences in a systematic way, along with other methods, such as focus groups and expert opinions.

A decade of collaboration in medicines regulation: healthcare professionals engaging with the European Medicines Agency.

The article shows that the input given by healthcare professionals (HCPs) adds value to the regulatory processes surrounding the development, authorisation, and monitoring of a medicine, but is also an instrument for accountability, trust, mutual exchange as well as an insight into the public health issues that matter most to one of the key stakeholder groups the Agency works with. We highlight the role of HCPs in the EU regulatory process and take stock of the first 10 years of the Framework for Interaction with HCPs to describe how practises have evolved over this time to meet the goals of informing, consulting and improving trust in the EU regulatory system. We will analyse what led European Medicines Agency (EMA) to develop this framework through to the next steps and where the interaction might lead in the future.

Clinical trials for registration in the European Union: the EMEA 5-year experience in oncology.

The evaluation of quality, safety and efficacy of medicinal products by regulatory agencies is a necessary step for obtaining marketing authorisation in the European Union (EU). The objective of this paper is to outline some key aspects of the EU regulatory system relevant to the field of oncology. Regulatory standards in oncology and the experience with anti-neoplastic and endocrine therapy agents in the centralised EU review system are presented. Also, the most common pitfalls encountered with oncology applications that were rejected are illustrated. The review is based on the first 5 years (1995-1999) of operation of the European Agency for the Evaluation of Medicinal Products (EMEA). Nineteen out of 30 different oncology drugs submitted during this period were approved, based on the recommendations of the Committee for Proprietary Medicinal Products (CPMP), which is the main scientific body within the EMEA responsible for evaluating medicines for human use. Although, in general, randomised trials to test the benefit of the new drug are a prerequisite for approval, this series showed that in strictly defined situations, approval could be obtained based on non-randomised trials measuring surrogate endpoints, provided the applicant agreed to the completion of a further programme of studies. These situations were the majority in our series and the CPMP has produced a guideline in oncology to address these specific requirements. Eleven out of the 30 oncology applications did not establish a positive benefit/risk profile of the drug in the proposed therapeutic indication, and were therefore rejected. Failure generally occurred because applications were based on too small series of patients or relied on the results of exploratory analyses after pre-defined analyses had failed to produce the expected results or, particularly for diagnostic agents, due to the fact that the effect of the agent had been measured only in terms of endpoints that were of unclear relevance.

EMEA and Gene Therapy Medicinal Products Development in the European Union.

The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products.

Overview of the European regulatory approval system.

The primary aim of European pharmaceutical law is to safeguard public health, while encouraging the development of the pharmaceutical industry and the creation of a single market for pharmaceuticals in the European Union (EU). Over the last 40 years, European law has established and harmonized many aspects of regulating the production, distribution, and use of medicines in the EU. A major step was taken in 1995 with the creation of the European agency for the evaluation of medicinal products (European Medicines Evaluation Agency, EMEA) and the establishment of a centralized procedure, leading to a single EU-wide evaluation and approval of new medicines. This article presents the available systems for drug approval in the EU together with the changes proposed for the future.

The patients' and consumers' working party at the European Medicines Agency: a model of interaction between patients, consumers, and medicines regulatory authorities.

Since the European Medicines Agency was created in 1995, it has engaged in dialogue with its various stakeholders, including patients and other representatives of civil society. The establishment of the Patients' and Consumers' Working Party represented a key step forward in the formalization of this interaction. The working party has played a crucial role in facilitating the integration of patients and consumers in various regulatory activities. This article describes how this group operates and gives a detailed overview of the interaction between the agency and the patients' and consumers' organizations focusing on the main achievements to date.

The review of drug applications submitted to the European Medicines Evaluation Agency: frequently raised objections, and outcome.

OBJECTIVE: To study the issues raised during the review of drug applications submitted to the European Medicines Evaluation Agency for approval in the European Union and to identify important predictors of outcome. METHODS: All consecutive applications submitted since September 1997 and which had reached an outcome by May 2001 were included. The factors considered in this exploratory analysis were: year of submission, anatomical therapeutic chemical classification (ATC code), type of medicinal product (biopharmaceuticals vs. new chemical entities), and common "major objections" raised during the review. Predictors were identified using multivariate logistic regression on outcome (positive opinion vs. negative opinion or withdrawal). Examples have been provided to illustrate some of the weaknesses of the applications received, the types of objections raised by the reviewers, and the strategies used to address them. RESULTS: This series consisted of 111 successive applications for which the review had started between September 1997 and April 2000. It included 73 (66%) new chemical entities and 38 (34%) biopharmaceuticals, the most represented agents being anti-neoplastic and immunomodulating agents, and anti-infectives for systemic use, with 25 (22%), and 19 (17%) applications, respectively. Overall the proportion of drug applications that failed to reach a positive outcome was 32/111 (29%). The most frequent major objections raised were those related to the safety database and to serious adverse events. These clinical safety objections were raised in 54 (48.6%) applications. Another frequent objection was the clinical efficacy objection on the lack of adequate randomised controlled trials, which was raised in 47 (42.3%) applications. This clinical efficacy objection was the only factor that was retained after multivariate selection (P<0.01). The odds of a positive outcome for an application lacking adequate randomised controlled trials were: 0.46 (95% confidence interval 0.29-0.71) times the odds of an application without this objection (P=0.0006). CONCLUSIONS: Despite the existence of various mechanisms that allow important deficiencies to be resolved, failure to establish clinical efficacy due to the lack of adequate randomised controlled trials remained problematic, leading to a high risk of rejection.