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.     

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.     

Ethical issues in the diagnostic genetic testing process

The diagnostic genetic testing process has certain unique ethical features and deserves special consideration. The purpose of this study was to determine through empirical research, using focussed interview, what ethical issues are involved in the diagnostic genetic testing process. This article describes views and perceptions of adult patients, parents of child patients and various personnel groups (n = 30). The ethical issues were analysed classified into three main categories: a) personnel characteristics, including personality, professional skills, morals and values; b) realization of ethical principles in the examination process, with subcategories of knowledge, autonomy, data protection and equity; and c) consequences of genetic testing, including patients' control over their own lives, manifestation of heterogeneity and outlook on the world. Problematic ethical issues in all three main categories were described in a more many‐sided way by parents and personnel than by adult patients. In the future, attention should be paid to the content areas highlighted by the study, in both clinical practice and further studies.     

Ethical issues in the diagnostic genetic testing process

The diagnostic genetic testing process has certain unique ethical features and deserves special consideration. The purpose of this study was to determine through empirical research, using focussed interview, what ethical issues are involved in the diagnostic genetic testing process. This article describes views and perceptions of adult patients, parents of child patients and various personnel groups (n=30). The ethical issues were analysed classified into three main categories: a) personnel characteristics, including personality, professional skills, morals and values; b) realization of ethical principles in the examination process, with subcategories of knowledge, autonomy, data protection and equity; and c) consequences of genetic testing, including patients' control over their own lives, manifestation of heterogeneity and outlook on the world. Problematic ethical issues in all three main categories were described in a more many-sided way by parents and personnel than by adult patients. In the future, attention should be paid to the content areas highlighted by the study, in both clinical practice and further studies.     

The Vulnerability of Study Participants in the Context of Transnational Biomedical Research: From Conceptual Considerations to Practical Implications

Outsourcing clinical trials sponsored by pharmaceutical companies from industrialized countries to low‐ (middle)‐income countries – summarized as transnational biomedical research (TBR) – has lead to many concerns about ethical standards. Whether study participants are particularly vulnerable is one of those concerns. However, the concept of vulnerability is still vague and varies in its definition. Despite the fact that important international ethical guidelines such as the Declaration of Helsinki by the World Medical Association or the Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council of International Organizations of Medical Sciences refer to vulnerability as ethical principle, each of their approaches are different. To overcome these shortcomings, we analyze and unite different approaches of vulnerability and develop practical criteria in order to operationalize the concept especially for the context of TBR. These criteria refer to the context of a study as well as the characteristics and the current living situation of study participants. Based on a case study of an HIV‐vaccine‐trial conducted in India we demonstrate how those criteria can be applied in a retrospective way to identify potential ethical conflicts. The criteria can also indicate a prospective function for ethical pre‐assessment. For this, we provide an outlook for three major topics: 1. Vulnerability as a normative concept: Different ways of protection; 2. The relevance of transparency and 3. Vulnerability as an instrument to increase decision participation of human subjects.     

[Re]considering Respect for Persons in a Globalizing World

Contemporary clinical ethics was founded on principlism, and the four principles: respect for autonomy, nonmaleficence, beneficence and justice, remain dominant in medical ethics discourse and practice. These principles are held to be expansive enough to provide the basis for the ethical practice of medicine across cultures. Although principlism remains subject to critique and revision, the four‐principle model continues to be taught and applied across the world. As the practice of medicine globalizes, it remains critical to examine the extent to which both the four‐principle framework, and individual principles among the four, suffice patients and practitioners in different social and cultural contexts. Using the four‐principle model we analyze two accounts of surrogate decision making – one from the developed and one from the developing world – in which the clinician undertakes medical decision‐making with apparently little input from the patient and/or family. The purpose of this analysis is to highlight challenges in assessing ethical behaviour according to the principlist model. We next describe cultural expectations and mores that inform both patient and clinician behaviors in these scenarios in order to argue that the principle of respect for persons informed by culture‐specific ideas of personhood may offer an improved ethical construct for analyzing and guiding medical practice in a globalized and plural world.     

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries

Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro-organisms. There have been increased calls for more CHIs to be conducted in low- and middle-income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third-party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well-designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.     

Informed Consent in Health Research: Challenges and Barriers in Low‐and Middle‐Income Countries with Specific Reference to Nepal

Obtaining ‘informed consent’ from every individual participant involved in health research is a mandatory ethical practice. Informed consent is a process whereby potential participants are genuinely informed about their role, risk and rights before they are enrolled in the study. Thus, ethics committees in most countries require ‘informed consent form’ as part of an ethics application which is reviewed before granting research ethics approval. Despite a significant increase in health research activity in low‐and middle‐income countries (LMICs) in recent years, only limited work has been done to address ethical concerns. Most ethics committees in LMICs lack the authority and/or the capacity to monitor research in the field. This is important since not all research, particularly in LMICs region, complies with ethical principles, sometimes this is inadvertently or due to a lack of awareness of their importance in assuring proper research governance. With several examples from Nepal, this paper reflects on the steps required to obtain informed consents and highlights some of the major challenges and barriers to seeking informed consent from research participants. At the end of this paper, we also offer some recommendations around how can we can promote and implement optimal informed consent taking process. We believe that paper is useful for researchers and members of ethical review boards in highlighting key issues around informed consent.     

Ethical and legal aspects of oncogenomics

The discovery of the genes and cellular pathways that play fundamental roles in several diseases, and the understanding of many diseases at a molecular level due to the advances in the field of genomics, have revolutionized the diagnosis, therapy and prevention of human diseases. Application of genetic testing in numerous medical fields, including pharmacogenomics and oncogenomics, raised numerous ethical questions and introduced legal instruments that are aimed at ensuring the appropriate protection of human research participants. For the effective development of human genomics and translation of novel, validated biomarkers into potentially useful clinical applications in personalized medicine, there is a need for clear ethical standards and principles in all phases of clinical research.     

NAVIGATING THE MURKY INTERSECTION BETWEEN CLINICAL AND ORGANIZATIONAL ETHICS: A HYBRID CASE TAXONOMY

Ethical challenges that arise within healthcare delivery institutions are currently categorized as either clinical or organizational, based on the type of issue. Despite this common binary issue‐based methodology, empirical study and increasing academic dialogue indicate that a clear line cannot easily be drawn between organizational and clinical ethics. Disagreement around end‐of‐life treatments, for example, often spawn value differences amongst parties at both organizational and clinical levels and requires a resolution to address both the case at hand and large‐scale underlying system‐level confounders. I refer to issues that contain elements of both clinical and organizational issues as hybrids and propose a new taxonomy to characterize hybrid cases. I contend that salient contextual features of an ethical issue, such as where it is identified, who it impacts and where it is ideally resolved in relation to its scope of impact, should inform procedure. Implementation of a Hybrid taxonomy viewing ethical issues as existing on a continuum furthers that end. The primary goals are to 1) systematize thinking about ethical issues that arise within healthcare delivery institutions and 2) allow the content of the ethical challenge to drive the process, rather than continuing to rely on the traditional binary issue‐based choice. Failure to capture the complexity of hybrid situations perpetuates incomplete information and ultimately an inchoate resolution that creates more questions than answers.     

The Disclosure of Genetic Information: A Human Research Ethics Perspective

Increasing emphasis on genetic research means that growing numbers of human research projects in Australia will involve complex issues related to genetic privacy, familial information and genetic epidemiology. The Office of Population Health Genomics (Department of Health, Western Australia) hosted an interactive workshop to explore the ethical issues involved in the disclosure of genetic information, where researchers and members of human research ethics committees (HRECs) were asked to consider several case studies from an ethical perspective. Workshop participants used a variety of approaches to examine the complex ethical issues encountered, but did not consistently refer to the values and principles outlined in the National Statement on Ethical Conduct in Human Research (NHMRC 2007) or apply rational ethical approaches. Overall, the data suggested that both researchers and HREC members may benefit from further education and support regarding the application of ethical frameworks to the issues encountered in genetic research.     

Trends in health research ethics in the Philippines during the American Colonial Period (1898‐1946)

Research involving human participants has been conducted in the Philippines since the beginning of the Spanish colonial period. Such studies are expected to adhere to internationally accepted ethical guidelines. This paper discusses trends in clinical research ethics in the Philippines during the American colonial period (1898‐1946). Specifically, studies were assessed on: 1) their observance of ethical protocols, including review; 2) identification of inclusion and exclusion criteria in the selection of participants; 3) use of vulnerable subjects; and 4) practice of the informed consent process. Only the informed consent process had a significant logistic correlation with progression of years. Recruitment of vulnerable groups was common during this period; children and prisoners were the most common participants. Trends in medical ethics in the Philippines reflected those in the United States prior to the publication of the Nuremberg Code, which served as a milestone in the protection of human welfare in clinical research.     

Ethics and biomedical research

Ethics in biomedical research took off from the 1947 Nuremberg Code to its own right in the wake of the Declaration of Helsinki in 1964. Since then, (inter)national regulations and guidelines providing a framework for clinical studies and protection for study participants have been drafted and implemented, while ethics committees and drug evaluation agencies have sprung up throughout the world. These two developments were crucial in bringing about the protection of rights and safety of the participants and harmonization of the conduct of biomedical research. Ethics committees and drug evaluation agencies deliver ethical and scientific assessments on the quality and safety of the projects submitted to them and issue respectively approvals and authorizations to carry out clinical trials, while ensuring that they comply with regulatory requirements, ethical principles, and scientific guidelines. The advent of biomedical ethics, together with the responsible commitment of clinical investigators and of the pharmaceutical industry, has guaranteed respect for the patient, for whom and with whom research is conducted. Just as importantly, it has also ensured that patients reap the benefit of what is the primary objective of biomedical research: greater life expectancy, well-being, and quality of life.     

Society and ethics - the genetics of disease

Established guidance for the protection of human subjects in research has provided the framework for research and clinical practice in genetics. Three key principles to emerge are the requirements for consent, privacy and confidentiality. However, recent research on genetic susceptibility to common diseases indicates that it may be more difficult to decide if and when genetic testing will be appropriate. Risks of disease may be low and interventions may not be available. Today, debate is primarily focussed on ethical issues raised by the use and storage of genetic information. One of the earliest experiences of genetic testing for some people is likely to be in the area of pharmacogenetics. Debate about ethical issues has been focused on the implications of patient stratification, particularly with regard to the availability of medicines for small groups and the significance of racial variation in response to medicines. The possible use of personal genetic information by insurance companies and employers has also been an issue that legislators have taken seriously.     

UNCERTAIN TRANSLATION,UNCERTAIN BENEFIT AND UNCERTAIN RISK: ETHICAL CHALLENGES FACING FIRST‐IN‐HUMAN TRIALS OF INDUCED PLURIPOTENT STEM (IPS) CELLS

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First‐in‐human trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross‐fertilisation of knowledge and better clinical outcomes.     

TRAINING NEEDS ASSESSMENT IN RESEARCH ETHICS EVALUATION AMONG RESEARCH ETHICS COMMITTEE MEMBERS IN THREE AFRICAN COUNTRIES: CAMEROON,MALI AND TANZANIA

Background: As actors with the key responsibility for the protection of human research participants, Research Ethics Committees (RECs) need to be competent and well‐resourced in order to fulfil their roles. Despite recent programs designed to strengthen RECs in Africa, much more needs to be accomplished before these committees can function optimally. Objective: To assess training needs for biomedical research ethics evaluation among targeted countries. Methods: Members of RECs operating in three targeted African countries were surveyed between August and November 2007. Before implementing the survey, ethical approvals were obtained from RECs in Switzerland, Cameroon, Mali and Tanzania. Data were collected using a semi‐structured questionnaire in English and in French. Results: A total of 74 respondents participated in the study. The participation rate was 68%. Seventy one percent of respondents reported having received some training in research ethics evaluation. This training was given by national institutions (31%) and international institutions (69%). Researchers and REC members were ranked as the top target audiences to be trained. Of 32 topics, the top five training priorities were: basic ethical principles, coverage of applicable laws and regulations, how to conduct ethics review, evaluating informed consent processes and the role of the REC. Conclusion: Although the majority of REC members in the targeted African countries had received training in ethics, they expressed a need for additional training. The results of this survey have been used to design a training program in research ethics evaluation that meets this need.     

Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3

Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-alpha-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions.     

Ethics and cultural diversity--a framework for decision-making

Believing that healthcare outcomes will be more satisfying if the patients' cultural knowledge and values are understood and integrated appropriately in care planning, the author proposes a culturally competent ethical decision making model based on human rights--the fundamental right of individuals, families, groups, and populations to healthcare that is meaningful, supportive, and beneficial--and a reconceptualization of ethical principles to include the values and assumptions of clients. The ideal result is culturally congruent healthcare in which practitioners learn about their clients' lifeways and work with them to find satisfying ways to resolve clinical and ethical issues.     

Ethical Implications of Case‐Based Payment in China: A Systematic Analysis

How health care providers are paid affects how medicine is practiced. It is thus important to assess provider payment models not only from the economic perspective but also from the ethical perspective. China recently started to reform the provider payment model in the health care system from fee‐for‐service to case‐based payment. This paper aims to examine this transition from an ethical perspective. We collected empirical studies on the impact of case‐based payment in the Chinese health care system and applied a systematic ethical matrix that integrates clinical ethics and public health ethics to analyze the empirical findings. We identified eleven prominent ethical issues related to case‐based payment. Some ethical problems of case‐based payment in China are comparable to ethical problems of managed care and diagnosis related groups in high‐income countries. However, in this paper we discuss in greater detail four specific ethical issues in the Chinese context: professionalism, the patient‐physician relationship, access to care and patient autonomy. Based on the analysis, we cautiously infer that case‐based payment is currently more ethically acceptable than fee‐for‐service in the context of China, mainly because it seems to lower financial barriers to access care. Nonetheless, it will be difficult to justify the implementation of case‐based payment if no additional measures are taken to monitor and minimize its existing negative ethical implications.