Bioethics in the Oversight of Clinical Research: Institutional Review Boards and Data and Safety Monitoring Boards.

This article describes oversight mechanisms for clinical research that have developed substantially over the last few decades, including institutional review boards and data safety and monitoring boards. LeRoy Walters and others in the 1970s in the US thoughtfully described the importance of fundamental ethical principles and the application of bioethics to clinical research. Dr. Walters's important essay and work with the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research helped identify and explain ethical principles that guide research. These principles, subsequently enunciated by the Commission in the Belmont Report, remain central to our understanding of the ethics of clinical research and are the foundation of our regulations. In this article, I review some history, successes, and challenges of IRBs and DSMBs to exemplify the significance of understanding and applying ethical principles to the design and conduct of clinical research, and to honor Dr. Walters's contributions.

The changing landscape of data monitoring committees-Perspectives from regulators, members, and sponsors.

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN-ISBS conference held in Vienna, Austria, 2017.

New clinical trials regulation in Spain: analysis of royal decree 1090/2015

The coming into force of Directive 2001/20/EC represented a step forward in harmonising clinical trial regulation in European countries, guaranteeing a uniform protection of subjects participating in clinical research across Europe. However, it led to a disproportionate increase in the bureaucratization, and thus, it became evident that procedures needed to be simplified without detriment to patient’s safety. Thus, Regulation 536/2014, that repealed Directive 2001/20/EC, with the aim of decreasing the growing bureaucratization and stimulating clinical research in Europe, established simplified procedures, such as regulating a common procedure for authorising trials in Europe, the institution of strict assessment timelines, or the definition of new concepts, such as «low-intervention clinical trial». The legal form of a Regulation allowed the norm to be directly applied to Member States without the need for transposition. By means of the new Royal Decree, the national legislation is adapted to make the application of the regulation feasible and it allows the development of the aspects that the Regulation leaves to national legislation. Both documents seek to stimulate clinical research with medicinal products to foster knowledge, facilitate transparency, and reinforce subjects’ safety. This will surely be the case, but with this revision, we will look at the novelties and key aspects that are most relevant to investigators and we will analyse the consequences for all parties involved in clinical research (AU)

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Transparencia en los ensayos clínicos y el acceso a los datos individuales anonimizados de los participantes / Clinical trials transparency and access to anonymized individual participant data

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[Legal characteristics of expert opinions of anaesthetic cases of the North German Arbitration Board]. / Gutachtenfälle - Juristische Besonderheiten bei der Begutachtung anästhesiologischer Fälle der Norddeutschen Schlichtungsstelle.

The Arbitration Board for Medical Liability Issues of the State Medical Councils of Northern Germany in Hannover (North German Arbitration Board, NGAB) settles about 100 cases in the area of anaesthesiology per year. In these proceedings the patient carries the burden of proof. I. e. the patient has to prove that its health damage was caused by a medical error. Nevertheless, for individual cases the NGAB examines also whether facilitation of the burden of proof can be granted to the patient. This article exemplifies cases, for which the NGAB recognized such facilitation of the burden of proof. In each of these cases, the NGAB asserted the damage claim.

Enhancing trial integrity by protecting the independence of data monitoring committees in clinical trials.

Data monitoring committees (DMCs) have important roles in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill their responsibilities, DMCs should be independent of study sponsors, study investigators, and caregivers managing study participants. Unfortunately, in real-world settings where DMCs are in place, there are some practices that threaten to diminish the level of independence of these committees. To address this, some important approaches should be considered: A DMC charter should outline the roles and responsibilities of the DMC without appearing to be a legal contract; the meetings of the DMC should be led by its chair, ideally with a meeting format that ensures independence from the investigators and sponsor; the DMC and those having leadership roles in the monitoring process should have adequate training and experience; procedures should be in place to enable the DMC to have access to interim safety and efficacy data that are accurate, current, and comprehensive; these data should be presented to the DMC unblinded by treatment group, while being kept confidential from all others; DMC recommendations should be developed through consensus development rather than by casting votes; creative approaches are needed for the engagement of DMC members to increase the transparency such that they are neither employees of nor consultants to the sponsor of the trial; meaningful conflicts of interest should be identified and addressed; and finally, members of DMCs should have adequate indemnification that provides effective protection.

How to ascertain drug related deaths during clinical trials ?

Recent guidelines by the Drug Controller General of India require extra care by Investigators & Sponsors of Clinical Trials in India. The author, an eminent member & Chairman of various Independent Ethics Committees in Mumbai, proposes various concrete solutions for adherence to these guidelines. Insurance cover to the subjects, use of Internet databanks for drug interactions, active involvement by the pharmacologists in Ethics Committee, review of data from animal studies, being amongst them. In case of death due to trial, autopsies, or at least verbal autopsies, are essential in the interest of Science and Law. More importantly Anticipation and prevention of ADEs can be done by exclusion of subjects from trials by using newer technologies like cDNA in microarrays to determine several polygenic quantitative trait loci (QTLs) and tests for Single Nucleotide Polymorphisms (SNPs). Drug manufacturers must provide prototypes of Affymetrix chips to clinicians and bear the cost in their own enlightened self-interest.

Ethical considerations in conducting pediatric research.

The critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. In this chapter, we review key ethical considerations concerning the participation of children in clinical research. We propose a basic ethical framework to guide pediatric research, and suggest how this framework might be operationalized in linking science and ethics. Topics examined include: the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; ethical considerations underlying study design, including clinical equipoise, placebo controls, and non-inferiority designs; the use of data monitoring committees; compensation; and parental permission and child assent to participate in research. We incorporate selected national (USA) and international guidelines, as well as regulatory approaches to pediatric studies that have been adopted in the USA, Canada, and Europe.

Data safety monitoring boards: legal and ethical considerations for research accountability.

Those charged with assuring research accountability have little guidance as to how to best structure and manage data safety monitoring boards (DSMBs). One major concern is increased litigation surrounding human subject research which has led research institutions and those asked to serve on DSMBs to seek legal counsel regarding their risk of liability for DSMB activities. A major challenge is assessing the risk of potential liability. Yet, potential liability for DSMBs and their members has not been adequately addressed in the literature. The purpose of this article is to provide a legal and accountability analysis to begin to fill this gap. This article undertakes an analysis and exploration of the potential liability that exists for DSMBs and their members under negligence theory and discusses the means by which DSMBs and their members may avoid litigation or defend themselves in the face of a lawsuit. Research accountability implications of imposing liability, or not, on DSMBs are also considered. It is suggested that legislation be contemplated requiring sponsors to indemnify DSMBs and their members in the face of litigation.

International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009.

OBJECTIVE: Many definitions used in medically assisted reproduction (MAR) vary in different settings, making it difficult to standardize and compare procedures in different countries and regions. With the expansion of infertility interventions worldwide, including lower resource settings, the importance and value of a common nomenclature is critical. The objective is to develop an internationally accepted and continually updated set of definitions, which would be utilized to standardize and harmonize international data collection, and to assist in monitoring the availability, efficacy, and safety of assisted reproductive technology (ART) being practiced worldwide. METHOD: Seventy-two clinicians, basic scientists, epidemiologists and social scientists gathered together at the World Health Organization headquarters in Geneva, Switzerland, in December 2008. Several months before, three working groups were established as responsible for terminology in three specific areas: clinical conditions and procedures, laboratory procedures, and outcome measures. Each group reviewed the existing International Committee for Monitoring Assisted Reproductive Technology glossary, made recommendations for revisions and introduced new terms to be considered for glossary expansion. RESULT(S): A consensus was reached on 87 terms, expanding the original glossary by 34 terms, which included definitions for numerous clinical and laboratory procedures. Special emphasis was placed in describing outcome measures, such as cumulative delivery rates and other markers of safety and efficacy in ART. CONCLUSION(S): Standardized terminology should assist in analysis of worldwide trends in MAR interventions and in the comparison of ART outcomes across countries and regions. This glossary will contribute to a more standardized communication among professionals responsible for ART practice, as well as those responsible for national, regional, and international registries.

[The German Clinical Trials Register: reasons, general and technical aspects, international integration]. / Das Deutsche Register Klinischer Studien: Begründung, technische und inhaltliche Aspekte, internationale Einbindung.

In order to provide a central portal for information on clinical research in Germany and thus to facilitate the search of planned, ongoing and completed clinical trials, the German Clinical Trials Register (GermanCTR) was implemented in cooperation with the WHO's registries network. It is an open access online register of clinical trials conducted in Germany, which allows all users to search for, register and share information on clinical trials. The project is funded by the Federal Ministry of Education and Research and is implemented at the Institute for Medical Biometry and Medical Informatics of the University Medical Center Freiburg as a joint project of the Clinical Trials Center Freiburg and the German Cochrane Center. Since October 2008 the GermanCTR is an approved WHO Primary Registry and allows clinical trial registration in Germany according to the requirements of the International Committee of Medical Journal Editors (ICMJE). Reasons for a national trials register, general and technical aspects of implementing the GermanCTR as well as the national and international integration are described here.

[The Coordinating Centres for Clinical Trials Network. Objectives and significance for research sites]. / Das KKS-Netzwerk. Ziele und Bedeutung für den Forschungsstandort.

In the late 1990s a funding program was set up by the federal German government to help keep stride with developments in the international research arena. Within this programme, Coordinating Centres for Clinical Trials ("Koordinierungszentren für Klinische Studien", KKS) were established at 12 German universities aiming at supporting all processes of academic clinical trials according to international standards. A close network infrastructure was chosen in order to reap maximum benefit from synergy effects and to promote the harmonisation of standards. Continuing to grow, the KKS Network currently has 16 research institutions as members. More than 400 employees within the KKS Network provide scientific services to clinical trials at universities, hospitals and in industry. In cooperation with study clinics, surgeries, study groups and competence networks in medicine within Europe and beyond, the KKS supports many different research projects covering all areas of medicine. The KKS Network contributes expertise to legislative processes within Germany and Europe through its work in professional committees and working groups. A wide range of education and training concepts supports clinical research as a scientific field in its own right. After nearly ten years the KKS Network has established itself as an indispensable partner in the field of clinical research.

[Mission and tasks of the Coordination Centres for Clinical Trials]. / Aufgaben der Koordinierungszentren für Klinische Studien.

Coordination Centres for Clinical Trials (Koordinierungszentren für Klinische Studien, KKS) were set up to increase the quality and number of clinical trials in Germany as well as to establish clinical trial training programs in order to improve international recognition of German clinical research. Over the past 6 years, 12 KKS have been set up at the respective universities with a public grant from the Federal Ministry of Education and Research (BMBF). Many non-clinical services have been established to ensure successful co-operation in clinical trials with clinical scientists and industry. KKS help researchers to efficiently conduct commercial and non-commercial clinical trials in various disease areas. Their expertise and infrastructure allow the university to assume sponsor responsibility in non-commercial drug trials. Because of their professional work and education activities KKS are well accepted by industry and the scientific community. Central professional trial organisations such as the KKS have been shown to be the pre-requisite for meeting the growing, manifold and complex requirements for clinical trials. Therefore they are considered essential for progress and success in clinical research.

[Requirements to a medical and biologic assessment and the hygienic control of the food production received from recombinant-DNA microorganisms].

In work the characteristic of the created in the Russian Federation system of an estimation of safety of the foodstuff received from/or with use of genetically modified microorganisms (GMM) is given, at their admission to realization and the hygienic control of given production over a revolution. It is shown, that strategy of a safety at a stage of registration GMM, the established order and accepted control measures of the foodstuff received from/or with use GMM, in Russia their large-scale commercial use, and the normative-legal and methodical base based on the federal legislation on state regulation in the field of genetically engineering activity, about quality and effectively outstrip safety of foodstuff about protection of the rights of consumers, is harmonized with approaches of the international organizations.

Monitoramento e avaliação de eventos adversos: a experiência do Hospital de Clínicas de Porto Alegre / Monitoring and evaluation of adverse events: the experience at Hospital de Clínicas de Porto Alegre

A proteção dos participantes nas pesquisas que envolvem seres humanos é uma das atribuições fundamentais dos Comitês de Ética em Pesquisa (CEPs), estando regulamentada em âmbito nacional e internacional. Segundo esses documentos, cabe aos CEPs não só revisar todos os protocolos de pesquisa submetidos a ele, mas também monitorar a ocorrência dos eventos adversos (EA) encaminhados pelo pesquisador no transcorrer da pesquisa. Esse monitoramento deve ser ágil e crítico, orientando sua ação em observância à relação dano/benefício de cada estudo, com o objetivo de proteger os participantes de pesquisa. O Grupo de Pesquisa e Pós-Graduação do Hospital de Clínicas de Porto Alegre (HCPA) implantou, em 2001, o Programa de Monitoramento de Riscos e Eventos Adversos, que atualmente é desenvolvido pelo Laboratório de Pesquisa em Bioética e Ética na Ciência

Based on national and international regulations, one of the the Research Ethics Committees (REC) have the attribution to protect human beings involved in research. According to these documents, REC should not only review all the research protocols, but also monitor adverse events (AE) reported by the investigator. This monitoring activities must be agile and critical, guiding its actions by evaluation of risk/benefit associated to each study. The Grupo de Pesquisa e Pós-Graduação of the Hospital de Clínicas de Porto Alegre (HCPA) introduced, in 2001, the Program of Monitoring of Risks and Adverse Events, developed by the Laboratório de Pesquisa em Bioética e Ética na Ciência