Ethical Research Issues: Going Beyond the Declaration of Helsinki

La Vaque and Rossiter made a strong, supported argument that it is unethical to use a no treatment control group in a research study if a known, effective treatment is available. Their argument is based on the supposition that the Declaration of Helsinki is the ethical world standard for research with humans. Their argument appears to be straightforward, but is not simple to apply. The issues are very complex, include issues not discussed in their argument, and can lead to a different conclusion as pointed out in this paper. The World Medical Association developed the Declaration of Helsinki as one of their official policies. The Declaration of Helsinki, however, is not accepted as the world ethical standard, as demonstrated by its lack of adoption by many professional associations or even by the United States Federal Government. Perhaps it is not mentioned because its ethical provisions are aspirational rather than mandatory as implied by La Vaque and Rossiter. Researchers and clinicians should also be aware of other ethical issues not directly discussed in the La Vaque and Rossiter paper. The Belmont Report is the basis for the ethical protection of human research subjects for at least 17 federal agencies and does not mention the Declaration of Helsinki. The Belmont Report mentions several ethical principles that form the basis for informed consent, risk/benefit assessment, confidentiality of data, subject selection, Institutional Review Boards, and other protections needed when doing research with human subjects. At least 2 of these core principles have direct implications to the discussion related to the use of placebo controls. The ethical principle of fidelity is also important in guiding research activities with human subjects. Researchers should be familiar with the La Vaque and Rossiter argument, the Belmont Report, and the federal policies developed to implement the provisions of that report, for example, Regulation 45 CFR 46.     

Ethical analysis of cadaver supply and usage processes for research within the scope of the Helsinki Declaration

Recent technological developments have considerably transformed the supply, storage, and transportation processes of cadavers, creating new and previously unforeseen ethical challenges regarding cadaver usage. In this study, we analyzed two aspects of the cadaver processing system—cadaver supply and its use in research. Thereafter, we highlighted the major ethical concerns underlying these stages and correlated our search results with the ethical principles outlined in the Declaration of Helsinki (DoH), or Helsinki Declaration. To ensure the reliability and continuity of medical progress, human—especially cadaver—research depends on the ethical priorities as outlined in the DoH: respect for autonomy, privacy/confidentiality, risks/burdens/benefits, and the protection of vulnerable groups. According to our ethics analysis, which also corresponds with the ethics guidelines of the Consensus Panel on Research with the Recently Dead, the most ignored values were respect for autonomy and privacy/confidentiality issues. Based on these ethical concerns, we provide recommendations to address these challenges in anatomy research.     

Illegitimate authorship and flawed procedures: Fundamental,formal criticisms of the Declaration of Helsinki

Some of the recent criticisms published during and after the last revision process of the Declaration of Helsinki are directed at its basic legitimacy. In this article we want to have a closer look at the two criticisms we consider to be the most fundamental. The first criticism questions the legitimate authorship of the World Medical Association to publish a document such as the Declaration. The second fundamental criticism we want to examine argues that the last revision process failed to meet the standards for fair, democratic procedures. Although both criticisms deny the formal legitimacy of the Declaration in the most fundamental way, they have never been addressed in detail in a single article. We refute most of the related arguments. However, acknowledging some of the points made, improvements for future revision processes and versions of the Declaration of Helsinki are outlined.     

Post‐trial obligations in the Declaration of Helsinki 2013: classification,reconstruction and interpretation

The general aim of this article is to give a critical interpretation of post‐trial obligations towards individual research participants in the Declaration of Helsinki 2013. Transitioning research participants to the appropriate health care when a research study ends is a global problem. The publication of a new version of the Declaration of Helsinki is a great opportunity to discuss it. In my view, the Declaration of Helsinki 2013 identifies at least two clearly different types of post‐trial obligations, specifically, access to care after research and access to information after research. The agents entitled to receive post‐trial access are the individual participants in research studies. The Declaration identifies the sponsors, researchers and host country governments as the main agents responsible for complying with the post‐trial obligations mentioned above. To justify this interpretation of post‐trial obligations, I first introduce a classification of post‐trial obligations and illustrate its application with examples from post‐trial ethics literature. I then make a brief reconstruction of the formulations of post‐trial obligations of the Declaration of Helsinki from 2000 to 2008 to correlate the changes with some of the most salient ethical arguments. Finally I advance a critical interpretation of the latest formulation of post‐trial obligations. I defend the view that paragraph 34 of ‘Post‐trial provisions’ is an improved formulation by comparison with earlier versions, especially for identifying responsible agents and abandoning ambiguous ‘fair benefit’ language. However, I criticize the disappearance of ‘access to other appropriate care’ present in the Declaration since 2004 and the narrow scope given to obligations of access to information after research.     

Not Fit for Purpose: The Ethical Guidelines of the Indian Council of Medical Research

In 2006, the Indian Council of Medical Research (ICMR) published its ‘Ethical guidelines for Biomedical Research on human participants’. The intention was to translate international ethical standards into locally and culturally appropriate norms and values to help biomedical researchers in India to conduct ethical research and thereby safeguard the interest of human subjects. Unfortunately, it is apparent that the guideline is not fit for purpose. In addition to problems with the structure and clarity of the guidelines, there are several serious omissions and contradictions in the recommendations. In this paper, we take a close look at the two key chapters and highlight some of the striking flaws in this important document. We conclude that ethics committees and national authorities should not lose sight of international ethical standards while incorporating local reality and cultural and social values, as focusing too much on the local context could compromise the safety of human subjects in biomedical research, particularly in India.     

Ethical Considerations in Clinical Trials: A Critique of the ICH‐GCP Guideline

This article examines issues relating to ethics decision‐making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of the ICH‐GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existing ICH‐GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and responsibilities in line with the principles outlined in the ICH‐GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of the ICH‐GCP Guideline in its present form.     

The Effectiveness of Neurofeedback and Stimulant Drugs in Treating AD/HD: Part II. Replication

This study replicated T. R. Rossiter and T. J. La Vaque (1995) with a larger sample, expanded age range, and improved statistical analysis. Thirty-one AD/HD patients who chose stimulant drug (MED) treatment were matched with 31 patients who chose a neurofeedback (EEG) treatment program. EEG patients received either office (n = 14) or home (n = 17) neurofeedback. Stimulants for MED patients were titrated using the Test of Variables of Attention (TOVA). EEG (effect size [ES] = 1.01–1.71) and MED (ES = 0.80–1.80) groups showed statistically and clinically significant improvement on TOVA measures of attention, impulse control, processing speed, and variability in attention. The EEG group demonstrated statistically and clinically significant improvement on behavioral measures (Behavior Assessment System for Children, ES = 1.16–1.78, and Brown Attention Deficit Disorder Scales, ES = 1.59). TOVA gain scores for the EEG and MED groups were not significantly different. More importantly, confidence interval and nonequivalence null hypothesis testing confirmed that the neurofeedback program produced patient outcomes equivalent to those obtained with stimulant drugs. An effectiveness research design places some limitations on the conclusions that can be drawn.     

Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative ‘Pre‐Review’ Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis

Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel ‘pre‐review’ process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process.     

A Critical Analysis and Discussion of Clinical Research Ethics in the Russian Federation and Their Implications for Western Sponsored Trials

Globalization, political upheavals, and Western economic struggles have caused a geographical reprioritization in the realm of drug development and human clinical research. Regulatory and cost hurdles as well as a saturation of research sites and subjects in Western countries have forced the pharmaceutical industry to place an unprecedented level of importance on emerging markets, injecting Western corporate initiatives into cultures historically and socially isolated from Western‐centric value systems. One of the greatest recipients of this onslaught of Western business and research practices is the Russian Federation. Namely, market forces are dictating a focused research initiative in the traditional emerging markets, but this focus may be at the expense of individual and societal dignity.     

The Social Value of Knowledge and International Clinical Research

In light of the growth in the conduct of international clinical research in developing populations, this paper seeks to explore what is owed to developing world communities who host international clinical research. Although existing paradigms for assigning and assessing benefits to host communities offer valuable insight, I criticize their failure to distinguish between those benefits which can justify the conduct of research in a developing world setting and those which cannot. I argue that the justification for human subjects research is fundamentally grounded in the social value of knowledge, and that this value is context‐dependent in a manner which should inform our ethical evaluation of the conduct of research in specific settings. I propose a new framework for the assessment of research benefits assigned to developing world host communities, a natural implication of which is to limit the types of research projects which may permissibly be conducted in developing world settings.     

Research versus practice: The dilemmas of research ethics in the era of learning health‐care systems

In this article we attempt to answer the question of how the ethical and conceptual framework (ECF) for a learning health‐care system (LHS) affects some of the main controversies in research ethics by addressing five key problems of research ethics: (a) What is the difference between practice and research? (b) What is the relationship between research ethics and clinical ethics? (c) What is the ethical relevance of the principle of clinical equipoise? (d) Does participation in research require a higher standard of informed consent than the practice of medicine? and (e) What ethical principle should take precedence in medicine? These questions allow us to construct two opposite idealized positions on the distinction between research and practice: the integration model and the segregation model of research and practice. We then compare the ECF for an LHS with these two idealized positions. We argue that the ECF for a LHS does not, in fact, solve these problems, but that it is a third, separate position in the relationship between research ethics and clinical ethics. Moreover, we suggest that the ECF for a LHS raises new ethical problems that require additional ethical analysis and justification. Our article contributes to the discussion on the relationship between research ethics and clinical ethics, revealing that although a learning health‐care system may significantly change the landscape of health care, some ethical dilemmas still require resolving on both theoretical and policy‐making levels.     

滋肾骨康丸治疗骨质疏松症的临床研究

目的：观察滋肾骨康丸治疗骨质疏松症的临床疗效,并对该药的作用机理进行探讨。方法：将60例病人随机分为治疗组（滋肾骨康丸组）及对照组（西药组）,根据2组骨密度、骨痛、中医证候结果及临床总体疗效为指标进行比较。结果：治疗组治疗后总有效率为95．8％,对照组治疗后总有效率为75．3％,差异有统计学意义（P〈0．01）;2组治疗前后骨密度无显著性差异（P〉0．05）;治疗组治疗后骨痛有效率为92．5％。优于对照组的7313％（P〈0．05）;治疗后治疗组中医证候有效率为100％,明显优于对照组的53.3％（P〈0．01）。结论：滋肾骨康丸能显著改善骨痛、肾虚证候,总体改善临床症状,具有较好的治疗作用,值得进一步推广。     

Application of Ethical Principles to Research using Public Health Data in The Global South: Perspectives from Africa

Existing ethics guidelines, influential literature and policies on ethical research generally focus on real‐time data collection from humans. They enforce individual rights and liberties, thereby lowering need for aggregate protections. Although dependable, emerging public health research paradigms like research using public health data (RUPD) raise new challenges to their application. Unlike traditional research, RUPD is population‐based, aligned to public health activities, and often reliant on pre‐collected longitudinal data. These characteristics, when considered in relation to the generally lower protective ethico‐legal frameworks of the Global South, including Africa, highlight ethical gaps. Health and demographic surveillance systems are examples of public health programs that accommodate RUPD in these contexts. We set out to explore the perspectives of professionals with a working knowledge of these systems to determine practical ways of appropriating the foundational principles of health research to advance the ever growing opportunities in RUPD. We present their perspectives and in relation to the literature and our ethical analysis, make context relevant recommendations. We further argue for the development of a framework founded on the discussions and recommendations as a minimum base for achieving optimal ethics for optimal RUPD in the Global South.     

A Framework to Link International Clinical Research to the Promotion of Justice in Global Health

How international research might contribute to justice in global health has not been substantively addressed by bioethics. Theories of justice from political philosophy establish obligations for parties from high‐income countries owed to parties from low and middle‐income countries. We have developed a new framework that is based on Jennifer Ruger's health capability paradigm to strengthen the link between international clinical research and justice in global health. The ‘research for health justice’ framework provides direction on three aspects of international clinical research: the research target, research capacity strengthening, and post‐trial benefits. It identifies the obligations of justice owed by national governments, research funders, research sponsors, and investigators to trial participants and host communities. These obligations vary from those currently articulated in international research ethics guidelines. Ethical requirements of a different kind are needed if international clinical research is to advance global health equity.     

The Challenges of Research Informed Consent in Socio‐Economically Vulnerable Populations: A Viewpoint From the Democratic Republic of Congo

In medical research, the ethical principle of respect for persons is operationalized into the process of informed consent. The consent tools should be contextualized and adapted to the different socio‐cultural environment, especially when research crosses the traditional boundaries and reaches poor communities. We look at the challenges experienced in the malaria Quinact trial, conducted in the Democratic Republic of Congo, and describe some lessons learned, related to the definition of acceptable representative, the role of independent witness and the impact of socio‐economic vulnerability. To ensure children's protection, consent is required by the parents or, in their absence, by a legally mandated representative. In our setting, children's responsibility is often entrusted permanently or temporarily to relatives or friends without a tribunal mandate. Hence, a notion of ‘culturally acceptable representative’ under supervision of the local Ethics Committee may be more suitable. To ensure protection of illiterate subjects, an independent witness is required to confirm that the consent was freely given. However, in low‐literacy contexts, potential witnesses often don't have any previous relationship with patient and there may be power‐unbalance in their relationship, rather than genuine dialogue. In poor communities, trial participation may be seen as an opportunity to secure access to healthcare. Poverty may also lead to ‘competition’ to access the research‐related benefits, with a risk of disturbance at societal or household level. Adjusting consent procedures to sociocultural and socioeconomic realities is essential for fulfilling the underlying ethical principles. This requires a collaborative dialogue between researchers, regulators and ethics committees.     

Enhancing Research Ethics Review Systems in Egypt: The Focus of an International Training Program Informed by an Ecological Developmental Approach to Enhancing Research Ethics Capacity

Recently, training programs in research ethics have been established to enhance individual and institutional capacity in research ethics in the developing world. However, commentators have expressed concern that the efforts of these training programs have placed ‘too great an emphasis on guidelines and research ethics review’, which will have limited effect on ensuring ethical conduct in research. What is needed instead is a culture of ethical conduct supported by national and institutional commitment to ethical practices that are reinforced by upstream enabling conditions (strong civil society, public accountability, and trust in basic transactional processes), which are in turn influenced by developmental conditions (basic freedoms of political freedoms, economic facilities, social opportunities, transparency guarantees, and protective security). Examining this more inclusive understanding of the determinants of ethical conduct enhances at once both an appreciation of the limitations of current efforts of training programs in research ethics and an understanding of what additional training elements are needed to enable trainees to facilitate national and institutional policy changes that enhance research practices. We apply this developmental model to a training program focused in Egypt to describe examples of such additional training activities.     

临床蛋白质组学———蛋白质组学在临床研究中的应用

临床蛋白质组学是将蛋白质组学技术应用于临床医学研究,它主要围绕疾病的预防、早期诊断和治疗等方面开展研究,其中,恶性肿瘤是临床蛋白质组学研究的一个重点研究对象.由于肿瘤生物标志物对早期诊断具有重要价值,所以临床蛋白质组学的主要目标之一是寻找合适的肿瘤生物标志物,多分子生物标志物已成为寻找肿瘤生物标志物的一个研究趋势.简要介绍了临床蛋白质组学的基本概念,实验设计,临床样本收集与预处理以及蛋白质组学技术在临床研究中的应用与进展.     

The experiences of pregnant women in an interventional clinical trial: Research In Pregnancy Ethics (RIPE) study

There is increasing global pressure to ensure that pregnant women are responsibly and safely included in clinical research in order to improve the evidence base that underpins healthcare delivery during pregnancy. One supposed barrier to inclusion is the assumption that pregnant women will be reluctant to participate in research. There is however very little empirical research investigating the views of pregnant women. Their perspective on the benefits, burdens and risks of research is a crucial component to ensuring effective recruitment. The Research In Pregnancy Ethics (RIPE) study set out to ascertain the views of pregnant women about research participation using an inductive thematic analysis. We conducted semi‐structured interviews with 20 women who had participated in a double‐blind randomised placebo controlled trial in Wellington (New Zealand) while pregnant. Our results show that at least some pregnant women recognise the value and importance of research during pregnancy. The women we interviewed were deeply invested in the research process and outcomes. Key motivations for participating were altruism, playing a valuable civic role and the importance of research. The main perceived burdens related to inconvenience and time commitment. For some women, possible randomization to the placebo arm was regarded as a burden or disadvantage.