Individual Research Participants Research Articles

Risk-benefit assessment in medical research--critical review and open questions

One of the central ethical requirements for medical research is that the risks to individual research participants should not be excessive. Despite widespread endorsement of this requirement, how it should be implemented remains controversial. This paper critically reviews the four existing approaches to evaluating the risks and benefits of medical research. It argues that the ‘net risks test’ is superior to ‘component analysis’, the ‘agreement principle’, and the ‘integrative approach’ and ends by highlighting several important questions that remain to be addressed.

The Management of Incidental Findings in Neuro-Imaging Research: Framework and Recommendations

This paper addresses the question of how incidental findings (IFs) in clinical research should be managed by researchers, focusing in detail on IFs discovered in neuroimaging research. It begins by engaging the larger research ethics issue of whether researchers have any obligations of clinical care to participants, and assesses the content and merits of one particular framework for answering this question, Richardson and Belsky's ancillary care model. From here the paper develops an organizational structure for integrating the ancillary care model with existing research ethics standards, with the aim of better understanding their respective domains. It makes a distinction between incidental findings that are anticipated by informed consent documents, and those that are unanticipated, arguing that this distinction is critical for evaluating researcher obligations. Finally, it takes on the issue of incidental findings in neuroimaging research, translating the standards discussed into recommendations for both unanticipated and anticipated findings.

Completing the circle: a model for effective community review of environmental health research.

While it is well understood that multiple and cumulative environmental stressors negatively impact health at the community level, existing ethical research review procedures are designed to protect individual research participants but not communities. Increasing concerns regarding the ethical conduct of research in general and environmental and genetic research in particular underscore the need to expand the scope of current human participant research regulations and ethical guidelines to include protections for communities. In an effort to address this issue, West Harlem Environmental Action (WE ACT), a nonprofit, community-based environmental justice organization in New York City that has been involved in community-academic partnerships for the past decade, used qualitative interview data to develop a pilot model for community review of environmental health science research.

Constraints on Data Sharing

Constraints on Data Sharing

Biobank Research: Reporting Results to Individual Participants

Over the last years we conducted an extensive study on the question whether and, if so, how, any results to be derived from research with large scale biobanks shoud be communicated to individual research participants. More specifically, our research intended (1) to assess the attitudes and information preferences of major stakeholders (participants/researchers), and (2) to examine whether there are any legal obligations of researchers to provide feedback to individuals. Our aim was to elaborate a general normative framework that could provide (further) guidance in this matter and be taken into account in the establishment and operation of biobanks. In this article, we first summarize the results of the empirical study on attitudes and preferences; subsequently, address the legal aspects. The article ends with a section that discusses our main findings and provides the basis for the guiding principles we propose; the principles themselves are located in an Annex.

The Declaration of Helsinki and public health

The Declaration of Helsinki and public health

Ethics and the ethnography of medical research in Africa

The ethics of medical research have grown as an area of expertise and debate in recent years, with two broad approaches emerging in relation to transnational research: (1) the refinement of guidelines and strengthening of review, processes primarily to protect the right of individual research participants and strengthen interpersonal relations at the micro-level; and (2) considering more centrally, as crucial ethical concerns, the wider interests of whole populations, the functioning of research institutions, the processes of collaboration, and the ethics of inequitable international relations. We see the two areas of debate and action as complementary, and believe that social science conducted in and around transnational medical research environments can bring these two perspectives together in a more ‘situated ethics’ of research. To explore this idea for medical research in Africa, we organized a conference in December 2005 in Kilifi, Kenya. In this introduction we outline the two emerging approaches to medical ethics, summarise each of seven papers selected from the conference for inclusion in this special issue on ethics and ethnography, and finally highlight two areas of lively debate at the conference itself: the appropriateness and value of ethics guidelines and review boards for medical research; and the ethical review of social science research. Together, the papers and debates point to the importance of focusing on the ethics of relationships and on justice in both biomedicine and social science research, and on giving greater voice and visibility to the field staff who often play a crucial and under-supported role in ‘doing ethics’ in the field. They also point to the potential value of social science research on the range of relationships operating at different levels and time scales in medical research, including those surrounding community engagement activities, and the role and functioning of ethics review boards. We conclude by highlighting the ethical priority of capacity strengthening in medical research, social science and research ethics in Africa to ensure that local and national priorities and concerns are considered at both the micro and macro levels.

Incidental Findings in Human Subjects Research: What Do Investigators Owe Research Participants?

The use of brain imaging technology as a common tool of research has spawned concern and debate over how investigators should respond to incidental findings discovered in the course of research. In this article, we argue that investigators have an obligation to respond to incidental findings in view of their entering into a professional relationship with research participants in which they are granted privileged access to private information with potential relevance to participants' health. We discuss the scope and limits of this professional obligation to respond to incidental findings, bearing in mind that the relationship between investigators and research participants differs fundamentally from the doctor-patient relationship.

Understanding Incidental Findings in the Context of Genetics and Genomics

Human genetic and genomic research can yield information that may be of clinical relevance to the individuals who participate as subjects of the research. It has been common practice among researchers to notify participants during the informed consent process that no individual results will be disclosed, "incidental" or otherwise. However, as genetic information obtained in research becomes orders of magnitude more voluminous, increasingly accessible online, and more informative, this precedent may no longer be appropriate. There is not yet consensus on the responsibilities of researchers to disclose individual research results to research participants. Empirical research suggests that participants want to know individual research results. On the other hand, the increased resolution and power afforded by new genomic analyses may lead to findings of statistical, but not necessarily clinical, significance. This paper addresses the issues to be considered in deciding whether and how to disclose "incidental" findings or other findings of clinical significance that arise in the course of human genomic and genetic research. What research results should be offered, and what should not be offered? For which research should individual results be offered to research participants, when should they be offered, how, and to whom?

Managing incidental findings in human subjects research: analysis and recommendations.

No consensus yet exists on how to handle incidental findings (IFs) in human subjects research. Yet empirical studies document IFs in a wide range of research studies, where IFs are findings beyond the aims of the study that are of potential health or reproductive importance to the individual research participant. This paper reports recommendations of a two-year project group funded by NIH to study how to manage IFs in genetic and genomic research, as well as imaging research. We conclude that researchers have an obligation to address the possibility of discovering IFs in their protocol and communications with the IRB, and in their consent forms and communications with research participants. Researchers should establish a pathway for handling IFs and communicate that to the IRB and research participants. We recommend a pathway and categorize IFs into those that must be disclosed to research participants, those that may be disclosed, and those that should not be disclosed.

The association of specific neuropsychological deficits with capacity to consent to research or treatment

Informed consent is key to ethical clinical research and treatment, but partially rests on the ability of individual patients or research participants to use disclosed information to make a meaningful choice. Although the construct of decisional capacity emerged from legal and philosophical traditions, several investigators have begun examining the relationship of specific neuropsychological abilities to decisional capacity. This line of research may foster development of better consent procedures, as well as aid in refining the construct of decisional capacity toward a form that better reflects the underlying neurocognitive processes. We conducted a systematic search of the published literature and thereby identified and reviewed 16 published reports of empirical studies that examined the relationship between specific neuropsychological abilities and capacity to consent to research or treatment. Significant relationships between neuropsychological scores and decisional capacity were present across all the reviewed studies. The degree to which specific neuropsychological abilities have particular relevance to decisional capacity remains uncertain, but the existing studies provide a solid basis for a priori hypotheses for future investigations. These ongoing efforts represent an important conceptual and empirical bridge between bioethical, legal, and neuropsychological approaches to understanding meaningful decision-making processes.

Genetic Nondiscrimination Legislation: A Critical Prerequisite for Pharmacogenomics Data Sharing

Russ B Altman1†, Neal Benowitz2, David Gurwitz3, Jeantine Lunshof4, Mary Relling5, Jatinder Lamba5, Eric Wieben6, Sean Mooney7, Kathleen Giacomini2, Scott Weiss8, Julie A Johnson9, Howard McLeod10, David Flockhart7, Richard Weinshilboum6, Alan R Shuldiner11, Dan Roden12, Ronald M Krauss13 & Mark Ratain14 †Author for correspondence 1Stanford University, Department of Genetics and Bioengineering, Clark S172, Stanford, CA 94305-5444, USA E-mail: Russ.Altman@ stanford.edu 2University of California, San Francisco 3Tel-Aviv University 4VU University Medical Center 5St Jude Children’s Research Hospital 6Mayo Clinic 7Indiana University School of Medicine 8Harvard Medical School 9University of Florida 10University of North Carolina 11University of Maryland 12Vanderbilt School of Medicine 13Children’s Hospital Oakland Research Institute 14University of Chicago On 31st January 2007, the US Senate Health, Education, Labor and Pensions Committee approved the Genetic Information Nondiscrimination Act (GINA) by a vote of 19:2. It was unanimously approved by the US Congress Committee on Education and Labor 2 weeks later. This legislation, aimed at preventing genetic discrimination in employment and insurance [1], will be imperative for protecting altruistic individuals who volunteer for genetic research [2]. There is an emerging consensus among researchers that genetic data must be accessible to individual research participants upon their request [3], while not putting them at risk with respect to their employment, insurance and additional personal aspects [4]. The GINA balances individual freedoms and privacy rights with societal needs for affordable and more effective healthcare and helps to pave the way for more personalized medicine [5]. Indeed, genetic information can be used to improve healthcare, in particular with regard to reducing the alarming rates of adverse drug reactions, which led to 6.7% of all US hospital admissions during 2004–2005 [6], consistent with earlier studies in the UK [7]. Increased use of individual genetic information about drug-metabolizing and drug-target gene alleles as part of healthcare treatment decisions may substantially reduce such morbidity [8]. However, building up the required knowledge depends on the analysis of large individual genotype/phenotype data sets from patient cohorts and requires open data sharing so that large, meaningful and less biased data sets are available to researchers [9]. Lack of open data sharing, in particular between the private and public sectors, hinders our ability to assemble large aggregated data sets [9]. A key obstacle for data sharing is concern about depositing data sets from individual study participants into public databases; some researchers fear they will be held responsible in cases where the data are re-identified (using computational data-mining techniques) and subsequently used (by employers or insurers) to discriminate against study participants. We therefore believe that legislation that offers protection to individuals or groups who share genetic information – against both re-identification and discrimination – is essential for efforts to move genomic medicine into practice. Legislation barring discrimination or stigmatization based on genetic information has been proposed for years, but enactment has become particularly urgent in view of rapidly falling genotyping costs [10], the scope of ongoing genome-wide association studies [11] and the increasing availability of comprehensive personal data in the public domain [4]. We therefore strongly support the current efforts to establish a solid legal framework as a primary means to protect individuals against misuse of their genetic information and as an essential tool for allowing open data sharing in pharmacogenomics.

Introduction: Data Sharing and Disclosure Limitation Techniques

THIS SPECIAL SECTION OF JERHRE is in response to the needs of institutions to develop advanced data sharing capabilities. On October 1, 2003, the National Institutes of Health (NIH) initiated a requirement that investigator-initiated proposals for grants with direct costs over $500,000 in any year incorporate plans to accommodate sharing research data. The requirement stipulates that such plans describe the procedures through which shared data would be rendered "free of identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of the identity of individual subjects." (http://grants2.nih.gov/grants/policy/data_sharing). We expect that many researchers who deal with human research data are unfamiliar with the procedures presented in the ensuing articles. These sophisticated procedures have been developed to help protect confidentiality of subjects' data in files that are shared, while simultaneously preserving the analytic value of data for secondary users. Among these are procedures developed by government statisticians that include innovative methods to prevent deductive disclosure of identities. More recently, academic researchers and data experts have adapted or extended these methods. Together, these methods aim to achieve both disclosure limitation and retention of key analytic usefulness of the shared data.

Equipoise and the Criteria for Reasonable Action

In her recent article, “Evidence, Belief, and Action: The Failure of Equipoise to Resolve the Ethical Tension in the Randomized Clinical Trial,” Deborah Hellman gives a new twist to an old objection against clinical equipoise. Roughly, clinical equipoise is the requirement that there exist credible uncertainty in the expert medical community regarding the preferred treatment for a particular condition. This uncertainty is widely regarded as a necessary condition for enrolling participants in a clinical trial. The old objection is that clinical equipoise represents an overly permissive, and therefore morally unacceptable, mechanism for resolving the fundamental tension in clinical research between fidelity to the interests of the individual research participant, and fidelity to the statistical and scientific methods that are necessary to produce generalizable data in a reliable manner. Hellman's new twist on this objection utilizes some of the rudimentary architecture of Bayesian statistical theory to argue that clinical equipoise focuses our moral attention on the wrong issue.

Participant-centered analysis in complementary and alternative medicine comparative trials.

Participant-centered analysis involves applying the customary methods of statistical decision making at the level of the individual research participant. Consequently, each individual is declared a responder who benefited, a nonresponder, or possibly a responder who was harmed, using intensively collected data that were specific to that individual. There are several implications of the participant-centered approach. More data actually relevant to the important outcome need to be collected on individuals. The study results can be summarized in a simple table of responders/nonresponders by treatment group, and probabilities of true response can be estimated. The actual nature of the data collected and the statistical models used to analyze them drop into the background. Finally, production of individual-level decisions permits standard statistical approaches to be applied to the issue of which modality should be recommended for which person, instead of focusing on average effects and which modality should be recommended for everyone.

Threats to the Common Good: Biochemical Weapons and Human Subjects Research

Chemical and biological weapons are rightly regarded with a special sense of horror. Their effects can be both devastating and indiscriminate, taking the harshest toll on the most vulnerable classes of noncombatants. A biological attack may not even be discovered until long after a disease has spread through a population. Moreover, chemical and biological weapons are especially attractive alternatives for groups that lack the ability to construct nuclear weapons. The 1995 release of sarin gas into the Tokyo subway by the Aum Shinri Kyo group suggested that effective delivery devices may be harder to procure than the chemical agents themselves, but the 2001 anthrax attack in the United States, which used the postal service as a delivery device, showed there could also be surprisingly low-tech solutions to delivery and dispersal. All this makes chemical and biological weapons uniquely potent tools for insurgency and destabilization. (1) Responding to the threat of chemical and biological weapons raises complex but important ethical questions. In a very real sense, the bulwark of last against such agents must be mounted, not atop a wall or in a distant trench, but within the very bodies of military and civilian personnel. Questions about the limits of what can be justified in the name of were raised during the first Gulf War. (2) The controversy surrounded a waiver that the Department of Defense sought from the Food and Drug Administration that would allow it to administer pyridostigmine and botulinum toxoid vaccine to U.S. military personnel without their consent. The consent waiver was granted, but the vaccine was made available only on a voluntary basis. As the possibility materializes that chemical and biological weapons could be used as instruments of terror in a domestic context, similar questions are being raised for civilian populations as well. (3) Smallpox, for example, was eradicated from the world in 1980, and there has not been a case within the United States since 1949. The United States ended routine vaccinations against it in 1972. Since there is no accepted treatment for the disease once it has been acquired, the possibility that it might return to the world in a more virulent, weaponized form has prompted a new though limited vaccination program, with its own risks. (4) Yet as public health countermeasures are implemented, the logic of escalation naturally leads those seeking weaponized forms of the smallpox virus, or other agents, to enhance them to known countermeasures. (5) This raises the prospect that a protracted war on terror will require ongoing research to develop new countermeasures, or to assess the effectiveness of existing measures, against new variants. (6) All this raises basic questions about how aggressive such programs may be, given that there are no disease populations in which treatments and vaccines that target chemical and biological weapons can be readily tested. These questions take on special urgency in light of the insistence of the current U. S. administration that we are engaged in what will be a long and far-reaching war against terrorism. To paraphrase Cicero, law is often muted by the exigencies of war. Indeed, some have openly speculated about the fate of such traditional bioethical principles as informed consent in a social climate that is increasingly preoccupied with homeland defense and social solidarity. (7) Perhaps a climate that privileges public well-being and the professionals and institutions that protect it will be more tolerant of exceptions to such principles. These worries represent building tensions between the imperative to safeguard and protect the common good and the justification for accept ed safeguards for individual research participants. In times of peace, lingering tensions at this fault line do not generally pose a special challenge. However, in times of crisis, when group cohesion, patriotism, and themes of civic responsibility take on renewed meaning, appeals to the common good provide a natural way of expressing and justifying plans for collective action. …

Approaching ethical reasoning in nursing research through a communitarian perspective.

Most nurse researchers are embedded in research ethics guidelines based predominantly on the ethical principles of autonomy, beneficence, and justice. They are oriented toward protecting the rights of individual research participants. However, in cross-cultural, community-based, and international projects, further examination is required of community rights, as an entity in and of itself, to acknowledge and protect the community's rights. We suggest that communitarian philosophy is a perspective for the researcher to use in examining cross-cultural and international ethical questions. To show this assertion, dilemmas in community research are examined by using case studies and existing research ethics guidelines. Specific recommendations are offered for nursing scientists in practice, educational, and research settings seeking to balance the rights of the individual with those of the community.

Age- and Education-Corrected Independent Normative Data for the RBANS in a Community Dwelling Elderly Sample

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Randolph, 1998) is likely to become a popular screening instrument for measuring cognitive functioning, particularly in elderly patients. As such, the present study attempted to extend the original normative data by reporting on RBANS performances in a group of 718 community dwelling older adults. Participants were recruited from an outpatient primary care setting, and were assessed for demographic, medical status, functional status, and quality of life information. Utilizing four empirically supported overlapping midpoint age ranges, individual subtest raw scores were converted to age-corrected scaled scores based on their position within a cumulative frequency distribution. These age-corrected scaled scores were also converted into education-corrected scaled scores using the same methodology across four education levels. Independent Index and Total scores were also calculated based on the data from this large elderly sample. These data may considerably advance the clinical utility of the RBANS by allowing clinicians to interpret individual subtests and make direct comparisons between subtests. Practitioners and researchers who elect to use the current normative data are encouraged to consider the similarities and differences between the present sample and their individual patients or research participants.

Community involvement in the ethical review of genetic research: lessons from American Indian and Alaska Native populations.

The National Bioethics Advisory Commission has proposed that regulatory oversight for research with human subjects be extended beyond the protection of individual research participants to include the protection of social groups. To accomplish this, the commission recommends that investigators and ethics review boards a) work directly with community representatives to develop study methods that minimize potential group harms, b) discuss group implications as part of the informed consent process, and c) consider group harms in reporting research results. We examine the utility of these recommendations in the context of research with American Indian and Alaska Native communities. Because much attention has been given to the question of how best to consult with members of these communities in the design and conduct of research, we believe it behooves investigators to consider the lessons to be learned from research involving American Indians and Alaska Natives. After describing several difficulties surrounding the application of the commission's approach to these research contexts, we propose a research agenda to develop best practices for working with local communities in the ethical assessment of epidemiologic and environmental health research.

Social responsibility and research ethics in community-driven studies of industrialized hog production.

Environmental health research can document exposures and health effects that result from inequitable relationships between communities of low income or people of color and the institutions that derive benefits (profits, federal and state funding or services, avoidance of wastes) from activities and policies that burden these communities. Researchers, most of whom work in relatively privileged institutions, are placed in situations of conflicting loyalties if they conduct research in collaboration with, or on behalf of, communities burdened by environmental injustices. These conflicts can threaten the self-interest of researchers and may raise social and ethical issues that do not typically arise in research projects that respond to the agendas of institutions. This article describes how we addressed issues of research ethics and social responsibility in environmental health research on industrialized hog production in North Carolina. Researchers and institutional review boards are not well prepared to address ethical issues when interests of entire communities, as well as individual research participants, are involved. Community-driven research partnerships can help address problems in research ethics and can enhance the social responsibility of researchers and their institutions.