The ENCePP Code of Conduct: A best practise for scientific independence and transparency in noninterventional postauthorisation studies.

PURPOSE: The ENCePP Code of Conduct provides a framework for scientifically independent and transparent pharmacoepidemiological research. Despite becoming a landmark reference, practical implementation of key provisions was still limited. The fourth revision defines scientific independence and clarifies uncertainties on the applicability to postauthorisation safety studies requested by regulators. To separate the influence of the funder from the investigator's scientific responsibility, the Code now requires that the lead investigator is not employed by the funding institution. METHOD: To assess how the revised Code fits the ecosystem of noninterventional pharmacoepidemiology research in Europe, we first mapped key recommendations of the revised Code against ISPE Good Pharmacoepidemiology Practices and the ADVANCE Code of Conduct. We surveyed stakeholders to understand perceptions on its value and practical applicability. Representatives from the different stakeholders' groups described their experience and expectations. RESULTS: Unmet needs in pharmacoepidemiological research are fulfilled by providing unique guidance on roles and responsibilities to support scientific independence. The principles of scientific independence and transparency are well understood and reinforce trust in study results; however, around 70% of survey respondents still found some provisions difficult to apply. Representatives from stakeholders' groups found the new version promising, although limitations still exist. CONCLUSION: By clarifying definitions and roles, the latest revision of the Code sets a new standard in the relationship between investigators and funders to support scientific independence of pharmacoepidemiological research. Disseminating and training on the provisions of the Code would help stakeholders to better understand its advantages and promote its adoption in noninterventional research.

Recommendations for benefit-risk assessment methodologies and visual representations.

PURPOSE: The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. METHODS: Eight case studies based on the benefit-risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit-risk assessment. Recommendations were drawn up based on the results of the case studies. RESULTS: A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. CONCLUSIONS: Adopting formal, structured approaches to benefit-risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit-risk assessment from multiple perspectives.

Epidemiological evidence in forensic pharmacovigilance.

Until recently epidemiological evidence was not regarded as helpful in determining cause and effect. It generated associations that then had to be explained in terms of bio-mechanisms and applied to individual patients. A series of legal cases surrounding possible birth defects triggered by doxylamine (Bendectin) and connective tissue disorders linked to breast implants made it clear that in some instances epidemiological evidence might have a more important role, but the pendulum swung too far so that epidemiological evidence has in recent decades been given an unwarranted primacy, partly perhaps because it suits the interests of certain stakeholders. Older and more recent epidemiological studies on doxylamine and other antihistamines are reviewed to bring out the ambiguities and pitfalls of an undue reliance on epidemiological studies.

[Pharmacoepidemiolgy: regulatory basis, methodological approaches and scope]. / La pharmacoépidémiologie: bases réglementaires, approches méthodologiques et champ d'application.

Pharmacoepidemiology is a discipline that studies the use of drugs and evaluation of their beneficial or adverse effects on large populations. It requires compliance with laws and maintaining a regulatory approach in order to ensure confidentiality and protection of personal data. It also requires good knowledge of drugs and diseases and the use of the different available data sources. Pharmacoepidemiology incorporates epidemiological methods (cohort, case-control and cross-sectional studies) where the exposure is drug intake. These methods must be applied at the conception of the pharmacoepidemiological study in order to minimize the effect of bias hich can lead to false conclusions. This paper reviews the regulatory basis, methodological approaches and scope of pharmacoepidemiology.

A regulatory overview about rare diseases.

Rare diseases attract very little interest for drug development. To create more favourable conditions, incentives for development (scientific advice, research grants) and marketing of medicines (market exclusivity, regulatory fee reductions) are offered by several orphan legislations. These incentives have proven to be a valuable stimulus for research and development for new products for treatment, prevention and diagnosis of rare diseases. In the US almost 2000 products have been designated as orphan medicines and about 340 have received marketing authorisation. Rare diseases have also gained attention from regulators in the last years. Nowadays it is acknowledged that rare diseases deserve specific attention and individual regulatory guidance. Also, regulatory authorities have developed different mechanisms to put products on the market considering specific limitations of data availability (conditional marketing authorisation, exceptional circumstances authorisation). In the future more initiatives will have to address the need for networking scientific knowledge and research capabilities to address the difficulties to generate data in rare diseases.

Drug epidemiology in Italy: methods and ethical issues. The example of psychiatry.

PURPOSE: These notes aim at analysing current methods, ethical issues and major legislation changes related to drug epidemiology in Italy. METHODS: The design and conduct of two pharmacoepidemiological surveys carried out in the context of recent law dispositions on psychiatric care and confidentiality are presented. RESULTS: In 1978 law 180 stated that no more patients had to be admitted to psychiatric hospitals, and no more psychiatric hospitals had to be built. Chronic long-stay patients were allowed to remain in hospitals. In 1994, however, financial law 724 established a deadline for the final closure of Italian psychiatric hospitals. A survey of more than 1000 patients living in eight state psychiatric hospitals was carried out to describe the social and clinical characteristics of the inpatient population and to monitor their community placement. In 1996 law 675 established that private and confidential information could not be used for any purpose without the patient's informed consent. However, this law was not implemented that year. A survey of benzodiazepine use among general practice patients was conducted without written informed consent. CONCLUSIONS: The Italian legislation has been changing for some years, and regulations might still be modified in the near future. To increase ethical practices in pharmacoepidemiology scientists and clinical researchers should guarantee high standards in terms of research objectives, design and analyses. Potential conflict of interest should always be declared.

Drug use investigation (DUI) and prescription-event monitoring in Japan (J-PEM).

OBJECTIVE: To present ethical issues and relevant problems in observational studies of drug safety in Japan. METHODS: The Pharmaceutical Affairs Law, associated ordinances, and notifications relevant to Drug Use Investigations (DUIs), and published documents for two pilot studies of prescription-event monitoring in Japan (J-PEM) were examined, particularly with regard to the protection of privacy. Information relevant to the proposed legislation intended to protect personal information and proposed guidelines on ethical issues in epidemiological studies were also collected. RESULTS AND CONCLUSION: The formal studies inaugurated as the 'side-effect investigations' in the late 1960s and replaced by those of the DUI in 1980 have been conducted by drug manufacturers, in accordance with the Pharmaceutical Affairs Law. The first pilot study of J-PEM was started in 1997 and the second one is currently operated under a Health Sciences Research grant, supported by the Ministry of Health and Welfare. Those observational studies have been conducted while maintaining the confidentiality of personal data, but without requiring either approval by institutional ethics boards or informed consent from patients. However, according to the Pharmaceutical Affairs Law, those involved in postmarketing surveillance studies must protect the privacy of study subjects and those who break this rule may be subject to penalties. Ethical issues associated with pharmacoepidemiological studies will be clearly determined in Japan before the end of 2001 when the law designed to protect personal information will be introduced and official guidelines on ethical issues in epidemiological studies will have come into effect.

Consideraciones basicas sobre la epidemiologia del medicamento / Basic considerations of the medicament epidemiology

En la presente decada se plantean grandes desafios para los profesionales y trabajadores de la salud. Uno de ellos es lograr la utilizacion racional de farmacos. Todo medicamentos presenta beneficios y riesgos. Necesitamos ser mas rigurosos no solo en cuanto a normas y regulaciones, sino tambien, en aspectos practicos como el control de calidad, la eficacia, efectividad, seguridad del arsenal terapeutico que usamos, el seguimiento y evaluacion de reacciones adversas, pues ningun medicamento es inocuo en su totalidad, con las implicaciones cientificas, sociales y de costo que ello implica. Cobra sentido por tanto el desarrollo mas aun el concepto de farmacoepidemiologia. el presente articulo repasa aspectos basicos a tener en cuenta en el campo de la epidemiologia del medicamento, como instrumento de motivacion y actualizacion de quiene aun creemos y confiamos en el postulado de salud accesible para todos sin discriminaciones y sin convertir la salud en un negocio saludable