PRINCIPLISM AND THE ETHICAL APPRAISAL OF CLINICAL TRIALS

For nearly two decades, the process of reviewing the ethical merit of research involving human subjects has been based on the application of principles initially described in the U.S. National Commission's Belmont Report, and later articulated more fully by Beauchamp and Childress in their Principles of Biomedical Ethics. Recently, the use of ethical principles for deliberating about moral problems in medicine and research, referred to in the pejorative sense as “principlism”, has come under scrutiny. In this paper we argue that these principles can provide a foundation for the source of ethical appraisal of human research, but are not themselves wholly adequate for this purpose. Therefore, we further propose that (1) principles should be understood as heuristics that can be “specified” as described by DeGrazia (1992), and (2) that the principle-based approach should be supplemented by formally incorporating “sensitivity to context” into the evaluation of clinical trials     

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.     

General principles regarding the use of adult stem cells

Abstract.  With only a few, almost inevitable exceptions, biomedical research has developed within the last 50 years under the tutelage of ethical standards of notable precision. In the vast world of scientific investigation, few disciplines can boast of having realized documents of such ethical rigour, and respect for the integrity and intrinsic value of the human person has been one of the cardinal principles of the researcher. Research is intrinsic to the medical profession; the reward of research is knowledge and its techniques are ordered towards maintenance of human health. Since this end concerns human beings, it demands an extremely rigorous ethical approach. Ethical aspects are present from the first moments of the experimental project and occur on three levels: choice of the objectives, selection and use of the appropriate means for the study, and application of resultant new discoveries. Today, our moral attention cannot be reduced to a cost–benefit analysis. Biomedical sciences and medicine have overlapping areas of interest that can be sources of tension: the good of the subject versus scientific utility; profit versus complexity of research; liberty versus ethical and juridical bonds; the public versus the private; and the individual versus the community. Here, I attempt to formulate some essential principles that should guarantee humane measures for research on humans.     

The ethics of HIV research in developing nations

This paper discusses a dispute concerning the ethics of research on preventing the perinatal transmission of HIV in developing nations. Critics of this research argue that it is unethical because it denies a proven treatment to placebo-control groups. Since studies conducted in developed nations would not deny this treatment to subjects, the critics maintain that these experiments manifest a double standard for ethical research and that a single standard of ethics should apply to all research on human subjects. Proponents of the research, however, argue that these charges fail to understand the ethical complexities of research in developing nations, and that study designs can vary according to the social, economic, and scientific conditions of research. This essay explores some of the ethical issues raised by this controversial case in order to shed some light on the deeper, meta-ethical questions. The paper argues that standards of ethical research on human subjects are universal but not absolute: there are some general ethical principles that apply to all cases of human subjects research but the application of these principles must take into account factors inherent in particular situations.     

The ethics and obligations of long-term ethnographic relationships: revelatory moments and the concept of solidarity

This article reflects on an ethical and revelatory moment in the development of my long-term fieldwork relationships with people of the Lihir Islands in Papua New Guinea. Ethnographic research globally is now shaped through formal processes of ethical review, with the requirements for informed consent, privacy, and consideration of harm and beneficence. Researchers then have to put these procedures into practice, often encountering the need to weigh competing ethical principles, particularly when unforeseen events occur. Reflexivity has been argued to be crucial on these occasions. Yet both ethical codes and reflexivity fall short of managing ethical and relational implications of long-term field relationships. This article suggests that the concept of solidarity as theorized recently in bioethics may be helpful, particularly the discernment of three layers of relationship. What responsibilities might we as anthropologists have to the people we work with that go beyond procedural ethics? And how do moments such as the one described in this article shape ongoing field research?     

Mapping out structural features in clinical care calling for ethical sensitivity: a theoretical approach to promote ethical competence in healthcare personnel and clinical ethical support services (CESS)

Clinical ethical support services (CESS) represent a multifaceted field of aims, consultancy models, and methodologies. Nevertheless, the overall aim of CESS can be summed up as contributing to healthcare of high ethical standards by improving ethically competent decision-making in clinical healthcare. In order to support clinical care adequately, CESS must pay systematic attention to all real-life ethical issues, including those which do not fall within the 'favourite' ethical issues of the day. In this paper we attempt to capture a comprehensive overview of categories of ethical tensions in clinical care. We present an analytical exposition of ethical structural features in judgement-based clinical care predicated on the assumption of the moral equality of human beings and the assessment of where healthcare contexts pose a challenge to achieving moral equality. The account and the emerging overview is worked out so that it can be easily contextualized with regards to national healthcare systems and specific branches of healthcare, as well as local healthcare institutions. By considering how the account and the overview can be applied to i) improve the ethical competence of healthcare personnel and consultants by broadening their sensitivity to ethical tensions, ii) identify neglected areas for ethical research, and iii) clarify the ethical responsibility of healthcare institutions' leadership, as well as specifying required institutionalized administration, we conclude that the proposed account should be considered useful for CESS.     

Human and animal research guidelines: aligning ethical constructs with new scientific developments

Both human research and animal research operate within established standards and procedures. Although the human research environment has been criticized for its sometimes inefficient and imperfect process, reported abuses of human subjects in research served as the impetus for the establishment of the Nuremberg Code, Declaration of Helsinki, and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and the resulting Belmont Report. No similar, comprehensive and principled effort has addressed the use of animals in research. Although published policies regarding animal research provide relevant regulatory guidance, these policies have not emerged from the process of specifying consistent and reasoned ethical principles. The lack of a fundamental effort to explore the ethical issues and principles regarding the use of animals in research has led to unclear and disparate policies. Recent studies have increased our understanding of animal cognition and emotion, suggesting that animals' potential for experiencing a wide variety of harms, such as pain and fear, is greater than has been previously appreciated. Furthermore, relationships between methods of captivity and certain laboratory procedures and the resulting adverse physical, social and psychological effects have been established. In light of this information, current protections may need to be reconsidered and modified. This paper explores the historical convergence and divergence in the creation of human and animal research guidelines, as well as opportunities to align ethical frameworks with new scientific discoveries.     

Cluster randomization and political philosophy

In this paper, I will argue that, while the ethical issues raised by cluster randomization can be challenging, they are not new. My thesis divides neatly into two parts. In the first, easier part I argue that many of the ethical challenges posed by cluster randomized human subjects research are clearly present in other types of human subjects research, and so are not novel. In the second, more difficult part I discuss the thorniest ethical challenge for cluster randomized research--cases where consent is genuinely impractical to obtain. I argue that once again these cases require no new analytic insight; instead, we should look to political philosophy for guidance. In other words, the most serious ethical problem that arises in cluster randomized research also arises in political philosophy.     

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.     

"Who owns your poop?": insights regarding the intersection of human microbiome research and the ELSI aspects of biobanking and related studies

Background

While the social, ethical, and legal implications of biobanking and large scale data sharing are already complicated enough, they may be further compounded by research on the human microbiome.

Discussion

The human microbiome is the entire complement of microorganisms that exists in and on every human body. Currently most biobanks focus primarily on human tissues and/or associated data (e.g. health records). Accordingly, most discussions in the social sciences and humanities on these issues are focused (appropriately so) on the implications of biobanks and sharing data derived from human tissues. However, rapid advances in human microbiome research involve collecting large amounts of data on microorganisms that exist in symbiotic relationships with the human body. Currently it is not clear whether these microorganisms should be considered part of or separate from the human body. Arguments can be made for both, but ultimately it seems that the dichotomy of human versus non-human and self versus non-self inevitably breaks down in this context. This situation has the potential to add further complications to debates on biobanking.

Summary

In this paper, we revisit some of the core problem areas of privacy, consent, ownership, return of results, governance, and benefit sharing, and consider how they might be impacted upon by human microbiome research. Some of the issues discussed also have relevance to other forms of microbial research. Discussion of these themes is guided by conceptual analysis of microbiome research and interviews with leading Canadian scientists in the field.

     

CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool

With the emergence of CRISPR technology, targeted editing of a wide variety of genomes is no longer an abstract hypothetical, but occurs regularly. As application areas of CRISPR are exceeding beyond research and biomedical therapies, new and existing ethical concerns abound throughout the global community about the appropriate scope of the systems' use. Here we review fundamental ethical issues including the following: 1) the extent to which CRISPR use should be permitted; 2) access to CRISPR applications; 3) whether a regulatory framework(s) for clinical research involving human subjects might accommodate all types of human genome editing, including editing of the germline; and 4) whether international regulations governing inappropriate CRISPR utilization should be crafted and publicized. We conclude that moral decision making should evolve as the science of genomic engineering advances and hold that it would be reasonable for national and supranational legislatures to consider evidence-based regulation of certain CRISPR applications for the betterment of human health and progress.     

Bioethics for clinicians: 10. Research ethics

Medical research involving human subjects raises complex ethical, legal and social issues. Investigators sometimes find that their obligations with respect to a research project come into conflict with their obligations to individual patients. The ethical conduct of research rests on 3 guiding principles: respect for persons, beneficience, and justice. Respect for persons underlies the duty to obtain informed consent from study participants. Beneficence demands a favourable balance between the potential benefits and harms of participation. Justice requires that vulnerable people not be exploited and that eligible candidates who may benefit from participation not be excluded without good cause. Studies must be designed in a way that ensures the validity of findings and must address questions of sufficient importance to justify the risks of participation. In any clinical trial there must be genuine uncertainty as to which treatment arm offers the most benefit, and placebo controls should not be used if effective standard therapies exist. Researchers have a responsibility to inform themselves about the ethical, legal and policy standards that govern their activities. When difficulties arise, they should consult the existing literature and seek the advice of experts in research ethics.     

The genetics of muscle atrophy and growth: the impact and implications of polymorphisms in animals and humans

Much of the vast diversity we see in animals and people is governed by genetic loci that have quantitative effects of phenotype (quantitative trait loci; QTLs). Here we review the current knowledge of the genetics of atrophy and hypertrophy in both animal husbandry (meat quantity and quality), and humans (muscle size and performance). The selective breeding of animals for meat has apparently led to a few genetic loci with strong effects, with different loci in different animals. In humans, muscle quantitative trait loci (QTLs) appear to be more complex, with few "major" loci identified to date, although this is likely to change in the near future. We describe how the same phenotypic traits we see as positive, greater lean muscle mass in cattle or a better exercise results in humans, can also have negative "side effects" given specific environmental challenges. We also discuss the strength and limitations of single nucleotide polymorphisms (SNP) association studies; what the reader should look for and expect in a published study. Lastly we discuss the ethical and societal implications of this genetic information. As more and more research into the genetic loci that dictate phenotypic traits become available, the ethical implications of testing for these loci become increasingly important. As a society, most accept testing for genetic diseases or susceptibility, but do we as easily accept testing to determine one's athletic potential to be an Olympic endurance runner, or quarterback on the high school football team.     

Informing about mammographic screening: Ethical challenges and suggested solutions

Providing high quality and user oriented information about mammographic screening is no easy task, as screening has been subject to heated professional and public debates. Although the information has to be developed and provided in context for each screening program, the basic challenges are very much the same for all programs. Accordingly, the objective of this article is to analyze key ethical challenges in informing about mammographic screening, and based on these, to suggest some guiding principles for practical solutions. A literature review identifies five crucial issues with respect to informing women about mammographic screening. By analyzing and addressing these issues, five guiding principles are suggested: the content and the form of information should be developed through open and transparent processes with strong stakeholder involvement. Facts should be presented in a balanced way and uncertainties should be acknowledged, e.g., by presenting outcomes in ranges. Information should be layered without attempts to frame information. Attending mammographic screening should be as easy as not attending. Although apparently trivial, the suggested principles can be useful for elaborating specific information material about mammographic screening in a field of great ethical controversy.     

Developing the ethics of implementation research in health

Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review.     

The ethics of animal research: a UK perspective

The Nuffield Council on Bioethics, an independent body in the United Kingdom, has published a 2005 report titled The Ethics of Research Involving Animals. The Report, produced by a Working Party that represented a wide range of views, seeks to clarify the debate that surrounds this topic and aims to help people identify and analyze the relevant scientific and ethical issues. The Working Party considered the arguments surrounding whether animal research yields useful results, and recommends that its predictability and transferability should be evaluated more fully, particularly in controversial areas. Commonly encountered ethical questions and arguments were considered in order to understand what lies behind disagreement on the moral justification of animal research. Four possible ethical positions on animal research, which represent points on a continuum, are described. Despite the range of views that exist among members of the Working Party, the Report presents a "Consensus Statement" that identifies agreement on several important issues. Building on this statement, recommendations are made for improving the quality of the debate and promoting the 3Rs (refinement, reduction, and replacement).     

Reexamining the categorical exclusion of pediatric participants from controlled human infection trials

Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public’s trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable.