Off-label Paediatric Drug Use for Juvenile Depression and the Clinical Trial Regulations 2004: The Impact of Available Protective Mechanisms

Across Europe, around one in four adults experience a mental health problem in any 1 year. It is estimated that 2–6% of children and adolescents suffer from depression and suicide is now the third leading cause of death in 10–19 year olds. Despite traditional Freudian teachings that children rarely suffer from clinically diagnosed depression, treatment figures for juvenile depression have soared in recent years. For adults, the current treatment trend, as advocated by the National Institute for Health and Clinical Excellence (NICE), is the use of Selective Serotonin Reuptake Inhibitors (SSRIs), such as Prozac. For children, efficacy of such treatment remains difficult to judge as all SSRI use in paediatric care remains ‘off-label’ or unlicensed. Notwithstanding this, in 2006 the European Medicines Agency (EMEA) advocated the use of Prozac within the EU for children from the age of eight, a position that reinforced the stance adopted by NICE in 2005. These recommendations have been made despite growing concern that many SSRIs have some serious side effects. In new legislation for paediatric medicines, that came into effect on 26th January 2007, the European Union (EU) has attempted to address several unresolved issues relating to children’s needs for medicines in Europe. This paper considers the position of off-label drug-therapy for juvenile depression, and assesses the effectiveness of available legal mechanisms that can protect juveniles from harm when involved in clinical drug trials, most notably the Clinical Trial Regulations 2004. It further reviews the new EU legislation and evaluates its likely impact.

The 2008 Declaration of Helsinki — First among Equals in Research Ethics?

The World Medical Association's (WMA) Declaration of Helsinki is one of the most important and influential international research ethics documents. Its most recent 2008 version declares unprecedented universal primacy over all existing national or international ethical, legal, or regulatory requirements. This self-proclaimed status as a set of minimal ethical standards raises important questions about the Declaration's appropriate normative status. The present paper argues that the new claim of ethical primacy is problematic and makes the Declaration unnecessarily vulnerable to criticism. Future revisions of the Declaration should therefore remove this claim and strengthen the document, first, by clarifying its normative status as a set of strong default recommendations, to be followed unless there is compelling ethical reason to do otherwise; and second, by improving the substance of the Declaration through further precision, specification, and argument.     

Clinical studies in the intensive care unit: ethical and legal aspects

This article draws on international experience to explore the ethical and legal aspects of performing clinical studies on patients in intensive care units. It discusses aspects of consent relevant to clinical studies in this medical environment, it considers the involvement of ethical committees, and the role and appropriate level of intensive cover.     

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.     

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.     

Legal skills and the SQE: confronting the challenge head on

Whether the teaching and assessment of practical legal skills and professional conduct should be focused at the academic or vocational stage of legal education has been considered numerous times, with recommendations made and varying degrees of implementation carried out. With the approval of the Solicitors Qualifying Examination being granted by the Legal Services Board this issue is once again being brought into focus. The end of the Legal Practice Course will result in the required compulsory teaching and assessment of core practical legal skills and professional conduct being removed from legal education. The question therefore is whether legal education should incorporate practical legal skills and professional conduct into teaching and assessment at the academic stage and, if so, how can this be achieved in a way that complements rather than distracts from the study of academic law. This study will consider the recommendations made in relation to practical legal skills and professional conduct over the last five decades and identify possible options for the embedding of practical legal skills and professional conduct in the law curriculum at undergraduate level.     

The Swiss regulatory framework for paediatric health research

Medical research on minors entails both risks and benefits. Under Swiss law, clinical trials on children, including nontherapeutic drug trials, are permissible. However, ethics committees must systematically verify that all clinical studies have a favorable risk-benefit profile. Additional safeguards are designed to ensure that children are not unnecessarily involved in research and that proper consent is always obtained. Federal Swiss law is undergoing revision to extend these protections beyond clinical trials to a broad array of health research. The Swiss drug agency also seeks to improve the incentives for pharmaceutical firms to develop new paediatric drugs and relevant paediatric drug labels.     

Research on medical records without informed consent

Observational research involving access to personally identifiable data in medical records has often been conducted without informed consent, owing to practical barriers to soliciting consent and concerns about selection bias. Nevertheless, medical records research without informed consent appears to conflict with basic ethical norms relating to clinical research and personal privacy. This article analyzes the scope of these norms and provides an ethical justification for research using personally identifiable medical information without consent.     

Towards the development of ethical practices in paediatric clinical trials: the special position of the terminally ill child

This article examines the emotive and vexing issue of the involvement of terminally children in paediatric clinical trials. Particular emphasis is placed on the participation of such children in Phase I clinical studies, as such studies do not yield any benefit to the individual child. It provides an historical overview of medical research involving children and examines the moral arguments surrounding the participation of children in clinical trials. The article examines the conflict between doctor-as-researcher and doctor-as-treater as well as the problems presented by proxy consent providers. The role played by the human research ethics committee in this area is examined, as is the regulatory framework established by the National Health and Medical Research Council. The article argues that the participation of terminally ill children in Phase I clinical trials is not morally repugnant provided that there is a total commitment to the protection of the child participant's well-being during the dying process. It is argued that the moral justification for such position derives from the utilitarian notion that participation in such studies aims to benefit future generations of ill children.     

Using EHRs to design drug repositioning trials: A devolved approach to data protection

One area where the application of data protection law has proven complex is in relation to the secondary usage of health data in EHRs for medical research. Here the tension between the privacy interests of patients and the risk of harm if such sensitive data are compromised, and on the other side, the potential societal value of utilizing the data for the benefit of medical science, is especially striking. In this paper, we consider the applicable provisions of the EU Data Protection Directive, and outline a general approach to patient data handling for research, which we believe to be compatible with relevant legal and ethical requirements. We then illustrate and apply this by reference to a specific EU FP7 project, involving EHR data processing to select patients for clinical pharmaceutical trials. After introducing the project (PONTE), we explain the ‘devolved’ data protection architecture it employs and provide a legal evaluation.     

Age determination of unaccompanied asylum seeking minors in the European Union: a health law perspective

In the European Union, unaccompanied asylum seekers below 18 years of age are entitled to specific treatment. Age assessment practices to verify the age-statement by the asylum seeker differ between EU Member States. Medical methods in use raise questions about accuracy, reliability and safety. The medical, legal and ethical acceptability of invasive methods (notably X-rays) in particular is controversial. Human rights are at stake. The lack of common practices results in different levels of protection (discrimination). The absence ofstandardisation is an obstacle for the functioning of the Common European Asylum System. EU Best Practice Guidelines should remedy the situation; such guidelines should reflect the best interest of the child.     

Screening by Healthcare Staff for Domestic Violence Against Women in Israel - Ethical and Legal Aspects

This paper describes the ethical and legal aspects involved in healthcare Staff screening women for domestic violence in Israel. The primary aim of this article is to present the legal and ethical aspects of domestic violence in general, and of screening for violence, in particular. This article describes tools that play a crucial role in helping care for women who have been subjected to domestic violence, with an emphasis on the ethical dilemma stemming from the conflict between upholding moral conduct and individual autonomy versus ensuring the safety of patients who have been subjected to domestic violence and the need to provide high quality professional care.     

Data and Safety Monitoring Boards: Some Enduring Questions

Data Safety and Monitoring Boards (DSMBs) have been referred to as a "growth industry," and this trend continues to be fueled by recent FDA guidance and the NIH's requirement that DSMBs be employed in virtually all phase III clinical trials. The widening role of DSMBs has been sporadically questioned on ethical grounds, but growth has continued, despite the fact that many of the questions endure, unanswered, save for repeated references to safeguarding the scientific integrity of trials. This may be about to change. The recently appointed director of the Office for Human Research Protections (OHRP), Jerry Menikoff, is on record as regarding current practices — where consent forms often promise what the DSMB has been assembled to specifically not provide — as constituting fraudulent behavior. That is, a subject may inherently rely on, to their detriment, information that has been misrepresented in the consent document. In this paper, we assemble some of the enduring questions and top them off with Menikoff's tour de force to present what we hope will be a compelling argument to require that consent forms fairly represent what the DSMB will do — and not do — with trial data as they accumulate. We argue that DSMBs should be used only in rare circumstances, and question the practice of precluding principal investigators from DSMB membership, but our main thrust is to ensure that DSMBs, when used at all, are properly described in trial consent forms.     

Looking for needles in a haystack: Key issues affecting children's rights in the General Data Protection Regulation

The EU General Data Protection Regulation (GDPR) devotes particular attention to the protection of personal data of children. The rationale is that children are less aware of the risks and the potential consequences of the processing of their personal data on their rights. Yet, the text of the GDPR offers little clarity as to the actual implementation and impact of a number of provisions that may significantly affect children and their rights, leading to legal uncertainty for data controllers, parents and children. This uncertainty relates for instance to the age of consent for processing children's data in relation to information society services, the technical requirements regarding parental consent in that regard, the interpretation of the extent to which profiling of children is allowed and the level of transparency that is required vis-à-vis children. This article aims to identify a number of key issues and questions – both theoretical and practical – that raise concerns from a multi-dimensional children's rights perspective, and to clarify remaining ambiguities in the run-up to the actual application of the GDPR from 25 May 2018 onwards.     

Educational Research and the Protection of Human Subjects

Educational research is increasingly subject to legal restrictions designed for the protection of human subjects of research. In this article the author discusses legal restrictions–both in the courts and under HEW regulations–on educational research, comparing these restrictions with those on biomedical research. He finds that although educational research in particular instances may give rise to suits for damages for invasion of privacy or intentional infliction of psychological distress, the legal issues relating to educational research will most often be resolved in proceedings before institutional review boards charged by HEW with the responsibility for passing upon proposals to conduct research on human subjects. He argues that the interests protected in proceedings before institutional review boards are not limited to those that have received judicial recognition in suits for damages. The author finds that the requirement that the informed consent of subjects be obtained presents difficult issues for educational research. He notes in particular the problems presented by research proposals that as an element of the research design contemplate the observation of subjects without their knowledge and the use of children as research subjects.     

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.     

The legal basis for ethical withholding and withdrawing of life-sustaining medical treatment in children

Withholding and withdrawing life-sustaining medical treatment are common in paediatric practice, especially in intensive care units. However, not all clinicians apparently adhere to principles in ethical guidelines or to the principles which are to be found in judgments from common law cases arising when doctors and parents dispute treatment. This article examines selected ethical guidelines and compares them to judgments in leading cases. The rationale to forgo treatment is usually the child's "best interests" in both clinical practice guidelines and legal cases but in the former "best interests" may remain ill defined. Although "best interests" must essentially pertain to the individual child, the interests of others are not irrelevant. In legal cases "best interests" of the child are defined in terms such as "burden versus benefit", "futility", "indignity", "intolerability", "prolonging death rather than saving life" and "quality of life". These or like terms should form the basis of ethical decisions in discussions with parents when contemplating withholding or withdrawing life-sustaining treatment.     

Age estimation

While age estimation of unidentified corpses and skeletons for identification purposes has a long tradition in forensic sciences, age estimation of living persons has formed a relatively recent area of forensic research which is becoming increasingly important. The international interdisciplinary Study Group on Forensic Age Diagnostics (AGFAD) issued recommendations for age estimation of living persons for the purpose of criminal, civil, asylum and old-age pension procedures as well as for determining the sex and age of skeletons. In the present work, the authors set out state-of-the art age estimation methods for specific case groups, define minimum requirements for reference studies and specify the need for further research. In addition, ethical and medico-legal aspects as well as issues relating to quality assurance are discussed.     

Breaking through the silence: illegality of performing resuscitation procedures on the "newly-dead"

Israeli author Daniel Sperling brings to a light a disturbing practice that is taking place in some teaching hospitals throughout the world--the practice of resuscitation procedures on newly dead patients without the consent of the next-of-kin. Mr. Sperling examines some of the policies and procedures in place to prevent such practice and also looks at the ethical principles that should guide such procedures. The paper also reviews the general issue of consent in the context of medical decision-making and discusses potential legal claims that might be available to persons who have not been consulted or informed before such procedures are performed. The evolving jurisprudence surrounding the treatment of the newly dead is analyzed and Mr. Sperling concludes by suggesting ways to improve upon the procedures currently in place at some teaching facilities.     

德国人工智能创造物的知识产权法保护及其启示

人工智能时代的到来,有关其创造物的知识产权法保护问题给现有的法律理念与规则带来了巨大挑战。因而比较法视阈欧盟背景下的德国经验或许有一定参考意义;即先通过评介欧盟层面与人工智能相关的法政策与伦理准则,再从德国层面整理其创造物知识产权法保护上的实务经验与理论讨论。进而从中获得对我国的启示:一方面,呼吁今后在我国人工智能创造物知识产权法保护的外部,进一步细化相关的法政策,并着手制定相适应的伦理准则;另一方面,在其内部,基于当前现行法修改实际,分别从专利法、著作权法二个主要维度提出具体的完善建议。并强调内外规制体系间的协调配合,以期塑造既具体可行又灵活完整的我国人工智能创造物的知识产权法保护体系。