European Union. Ethical considerations for clinical trials on medicinal products conducted with the paediatric population

This document has been developed by the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the European Commission. The document provides recommendations on various ethical aspects of clinical trials performed in children from birth up to the legal age of adulthood. This will contribute to the protection of all children who are the subject of clinical trials. As the approval of clinical trials, including ethical approval, is performed by the Member States, any recommendations on ethical aspects of clinical trials in children will also facilitate a harmonised approach to the application of the clinical trials directive across the EU, thereby facilitating the conduct of clinical trials in the EU and in whichever country the paediatric trial occurs. The protection against the risks of research in such a vulnerable population is paramount whilst this should not lead to denying them the benefits of research. Children are not small adults and there is a need to carry out specific trials that cannot be performed in adults. In general, children (minors) are unable to consent (in the legal sense) but their assent should be sought using age appropriate information. Ethics Committees need paediatric expertise to balance the benefits and risks of research in children. The lack of legal ability to consent has implications on the design, analysis and the choice of comparators used in trials, which should only be performed by trained investigators with paediatric experience. Pain, fear, distress and parental separation should be prevented and minimised when unavoidable. The neonate represents the most vulnerable of all paediatric age groups and requires even more careful review. Finally, various other aspects relating to the performance of trials in children are discussed.     

Revising the declaration of Helsinki: ethics vs economics or the fallacy of urgency

Constant vigilance is required to ensure that the rights of volunteers in clinical trials are protected, particularly in developing countries. In this presentation to the XIII International AIDS Conference (abstract ThOrE651), Dirceu B Greco, of the Federal University of Minas Gerais in Brazil, describes the debate that has raged over the proposed changes to the Declaration of Helsinki, particularly with respect to access to medical care for trial volunteers and to the use of placebos in the control arms of the trials. The presentation argues: (1) that all trial volunteers should have access to the best diagnostic, preventive, and therapeutic methods, regardless of the standard of care in the countries where the trials are taking place; (2) that large efficacy trials of vaccines and drugs should be done first in countries where the best diagnostic, preventive, and therapeutic methods are available; and (3) that the costs of providing care and prevention services should be considered an integral part of the cost of the trials. The presentation explains how a partnership between activists, scientists, ethicists, and medical associations was effective in resisting pressures to lower the ethical standards for clinic trials. The presentation concludes that the gains made by this partnership constitute an important step in the struggle to provide universal access to education and health.     

Regulating developments in embryonic stem cell research in Africa: a third person's perspective

Among the many advances in modern biotechnology, embryonic stem (ES) cell research has raised perhaps the most intense debate over the ethical, legal and policy issues involved. This debate has centred inter alia on the lives and well-being of the donors or participants in clinical trials, the presumed lives of embryos, the possibility of reproductive cloning, and government funding, among others. These ethical, legal and policy issues tend to overlap and cut across all strata of society, with opponents of the research calling for prohibition and proponents calling for promotion. One important question is whether African countries should regulate to limit or promote developments in ES cell research. This article argues that, in view of the dynamism of modern biotechnology, African countries should regulate in such a way as to maximise the benefits while minimising the disadvantages associated with the research.     

Ethics at Phase 0: Clarifying the Issues

The Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) recently issued documents encouraging sponsors to consider microdose testing before launching Phase I trials, and many commentators predict that such methodologies will be applied more routinely in drug development. However, exploratory testing has provoked several ethical criticisms. Skeptics question the value and validity of microdose trials, and whether they present a reasonable balance of risks and benefits for subjects. Another major criticism is that such studies serve mainly commercial ends. The present article explores these and other ethical concerns for studies conducted in the oncology setting. It concludes that microdosing is not inconsistent with prevailing practices in Phase I research, and that in principle, such studies could strengthen the ethical basis for Phase I trials by providing them better evidentiary justification.     

The emergence of biobanks in the legal landscape: towards a new model of governance

Biobanks are increasingly seen as new tools for medical research. Their main purpose is to collect, store, and distribute human body materials. These activities are regulated by legal instruments which are heterogeneous in source (national and international), and in form (binding and non-binding). We analyse these to underline the need for a new model of governance for modern biobanks. The protection initially ensured by respect for fundamental rights will need to focus on more interactions with society in order to ensure biobanks' sustainability. International regulation is more oriented on ethical principles and traces the limits of the uses of genetics, while European regulation is more concerned with the protection of fundamental rights and the elaboration of standards for biobanks' quality assurance. But is this protection adequate and sufficient? Do we need to move from the biomedical research analogy to new forms of legal protection, and governance systems which involve citizens?     

New Malaise: Bioethics and Human Rights in the Global Era

Recent transnational HIV research projects have raised questions about the ethics of research in developing countries, and with good reason. Lower ethical standards are often applied in these settings, yet the field of bioethics has remained relatively quiet on the subject, concerning itself primarily with issues that only affect affluent countries. Here we call for a new focus on equity and human rights in bioethics.     

对法定证据制度的再认识与证据采信标准的规范化

大陆法系国家在16世纪实行的法定证据制度具有一定的科学性与合理性。与自由证明模式相比,法定证明模式有助于提高司法的公正性、可预见性和权威性。中国证据制度改革的方向应该是走向法定证明,而实现证据采信标准的规范化则是当前的首要任务之一。     

Participation of children in clinical trials: UK, European and international legal perspectives on consent

The Declaration of Helsinki was, until recently, the leading international code on the conduct of clinical trials on human subjects. The Council of Europe's Convention on Human Rights and Biomedicine (1997) and the ICH guidelines for Good Clinical Practice (1996) represent a significant step towards increased harmonization of standards in the conduct of medical experiments on human subjects. But in spite of emerging areas of consensus, there remain important areas of unclarity and divergence. Medical practitioners involved in paediatric research in the UK are concerned about the lack of certainty in the law, particularly on the application of consent rules to emergency research. This paper examines UK, European and International norms on the participation of children in medical research and compares the circumstances under which consent rules may be waived under each normative regime.     

Are ethics promulgations self-defeating?

Alan Wertheimer argues that promulgating some ethical standards of international clinical research may be self-defeating: the intended purpose of these standards is to promote the interests of subjects and communities in LMICs, while the outcome of promulgation could be to undermine these very same interests. If enforced, such standards would increase the costs of performing beneficial research in LMICs, potentially diverting opportunities to participate in this research away from those who have no other access to the care participation allows. I argue that these standards are really intended as deontological constraints protecting subjects from being exploited by research sponsors. First, I show that Wertheimer begs the question against this deontological interpretation of ethics promulgations, rejecting it on non-deontological grounds. I go on to show that non-exploitation is an important goal on its own, sometimes independent from—and sometimes even outweighing—the goal of promoting the interests of subjects and communities in LMICs. I conclude by suggesting that those who criticize the promulgation of non-exploitation on the grounds that exploitative practices help those badly off might do best to reconsider the background assumption that sponsors in wealthier countries have no pre-existing obligation to promote the interests of the world''s poor.     

Ensuring safety, implementation and scientific integrity of clinical trials: lessons from the Criminal Justice–Drug Abuse Treatment Studies Data and Safety Monitoring Board

Data and safety monitoring boards (DSMBs) provide independent oversight to bio-medical clinical trials, ensuring safe and ethical treatment of research participants, data quality, and credibility of study findings. Recently, the type of research monitored by DSMBs has been expanded to include randomized clinical trials of behavioral and psychosocial interventions in community and justice based settings. This paper focuses on the development and role of a DSMB created by the National Institute on Drug Abuse (NIDA) to monitor six multi-site clinical trials conducted within the Criminal Justice–Drug Abuse Treatment Studies (CJ-DATS). We believe this is one of the first such applications of formal DSMBs in justice settings. Special attention is given to developing processes for measuring and monitoring a range of implementation issues for research conducted within criminal justice settings. Lessons learned and recommendations to enhance future DSMB work within this area are discussed.     

Clinical research with children: the European legal framework and its implementation in French and Italian law

According to the International Convention of the Rights of the Child, an improvement of the protection of the rights of children in Europe should be accomplished by inserting the principle of best interests and evolving capacities in the legal framework related to paediatric clinical research. In this article, an overview is given of the European legal framework governing clinical research on minors in a comparative approach. The lack of coordination between different International and European ethical/ legal statements and its impact on national legislations is evaluated by analyzing provisions that have been foreseen in Italy and in France as a result of the ratification/implementation process. A presentation of the perspectives of paediatric research in Europe is provided.     

The ethics of promulgating principles of research ethics: the problem of diversion effects

There is an important distinction between ethical standards for the conduct of research with human subjects and the ethics of promulgating principles of research ethics. Those who promulgate ethical standards for the conduct of research have an ethical responsibility to consider the consequences to which those promulgations give rise. In particular, they must consider whether their promulgations will give researchers incentives not to conduct research or not to conduct research in locales in which participants would benefit from participation. I first show how such ‘diversion effects’ are possible and then examine four principles of research ethics in that light. I then consider several objections to the argument that those who promulgate principles of research ethics should consider diversion effects.     

Resolving legal, ethical, and human rights challenges in HIV vaccine research

In the absence of a cure for AIDS, attention has turned to the possibility of developing a preventive vaccine for HIV infection. Yet many scientific, ethical, legal, and economic obstacles remain. At the current rate, the development and production of an effective vaccine could take 15 to 20 years or longer. If tens of millions more HIV infections and deaths are to be avoided in the coming decades, vaccine research needs to be greatly expedited. Furthermore, it must be undertaken ethically, and the products of this research must benefit people in developing countries. This article, an edited and updated version of a paper presented at "Putting Third First," addresses challenges arising in HIV preventive vaccine research in developing countries. It does not address clinical research in developing countries relating to treatments or therapeutic vaccines. Nor does it address legal and ethical issues relating to HIV vaccine research in industrialized countries, although similar issues arise in both contexts. The article concludes that while ethical codes are silent on the obligation to undertake research and development, international law provides strong legal obligations--particularly with regard to industrialized states--that should be invoked to accelerate HIV vaccine development, and distribution.     

Research with minors in Germany

The European GCP Directive has been implemented into German law in sect. 40 ff. AMG (German pharmaceutical law). Unlike the Directive, German pharmaceutical law basically differentiates between three constellations of clinical trials on minors: clinical trials on healthy minors, clinical trials on ill minors with an individual benefit for the individual participant, and clinical trials on ill minors without direct benefit for the individual participant, but with a so-called "group benefit". Particularly the latter possibility of conducting clinical trials on minors even if no individual benefit can be expected is not a matter of course in Germany since due to historical experiences a sceptical attitude towards clinical research on humans prevailed for a long time. German legislature has availed itself of the option granted by Article 3 of the GCP Directive to establish a higher level of protection of clinical trial subjects than the European level.     

First-in-Human Trial Participants: Not a Vulnerable Population, but Vulnerable Nonetheless

The 21st-century translational science campaign could lead to an increase in first-in-human (FIH) trials. As tests of investigational interventions move from the laboratory to human research, scientists, officials, and review committees should address ongoing concerns about the ethics of FIH trials. In this article, I describe three ethical considerations relevant to all FIH trials: (1) the requirement for adequate preclinical research; (2) study design safeguards; and (3) choice of subject population. I also examine specific ethical considerations relevant to the three subject populations (healthy volunteers, seriously ill patients lacking standard treatment options, and stable patients) involved in FIH research. I recommend a variety of actions that could increase subject protection and the value of the information generated in FIH trials.     

"Who is first on the scene?"

Forensic specialists are well standardised throughout the world and their opinions are respected by the courts. Doctors involved in the immediate clinical forensic assessment of persons in police custody are not, however, so well standardised. Some countries employ trained police surgeons or police medical officers, other countries rely on hospital interns, others simply accept the first doctor available. Can courts rely on their testimony? Can specialists depend on their skills? A call is made for such generalists to meet on an international basis to establish standards.     

Judicial Exceptions to the Free Provision of Services

Abstract: Recent case-law of the Court of Justice on general interest exceptions to the free provision of services has indicated a flexible approach to general interest exceptions involving moral or ethical issues. In contrast, where the general interest exception is relied on in a case which demonstrates predominantly economic issues, it is subject to strict scrutiny, in particular, with reference to the principle of proportionality. The article analyses the Court's case-law and tries to deduce the criteria which now govern the Court's position. It also highlights difficulties which this two-tier approach may excite. The position of the Court of Justice reflects the lack of homogeneous European ethical and moral standards, but it also underlines the predominantly economic character of European integration to date. It is submitted, nevertheless, that divorcing the economic criteria for integration from general ethical considerations will prove an extremely difficult, if not fruitless, task.     

Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme

Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.     

The contribution of the right to information laws in Europe to local government transparency on sustainability

The aim of this paper is to examine the influence of the right to information laws on sustainability transparency in European local governments. This goal is novel, in that previous studies have examined the effects of various factors on the dissemination of government information (demographic, socioeconomic, political and financial) but not the contribution of legal factors to online transparency on environmental, social and economic sustainability. Our research question is this: Do information laws contribute to transparency on sustainability? Using the Global Reporting Initiative guidelines and a statistical regression analysis, we studied the websites of 106 local governments in ten European countries. The results obtained show that when transparency laws clearly stipulate the rules applicable and the procedures established for appeals, exceptions, refusals and requests, this can favour transparency on environmental, social and economic sustainability. Our findings advance understanding of this field and reinforce the basis for legal reforms to enhance sustainability transparency.