Marilyn E. Coors

Research ethics consultation: ethical and professional practice challenges and recommendations.

The complexity of biomedical research has increased considerably in the last decade, as has the pace of translational research. This complexity has generated a number of novel ethical issues for clinical investigators, institutional review boards (IRBs), and other oversight committees. In response, many academic medical centers have created formal research ethics consultation (REC) services to help clinical investigators and IRBs navigate ethical issues in biomedical research. Key functions of a REC service include assisting with research design and implementation, providing a forum for deliberative exploration of ethical issues, and supplementing regulatory oversight. As increasing numbers of academic research institutions establish REC services, there is a pressing need for consensus about the primary aims and policies that should guide these activities. Establishing clear expectations about the aims and policies of REC services is important if REC programs are to achieve their full potential. Drawing on the experiences of a Clinical and Translational Science Award Research Ethics Consultation Working Group, this article describes three major ethical and professional practice challenges associated with the provision of REC: (1) managing multiple institutional roles and responsibilities, (2) managing sensitive information, and (3) communicating with consultation requestors about how these issues are managed. The paper also presents several practical strategies for addressing these challenges and enhancing the quality of REC services.

Exploring ethical conflicts in emergency trauma research: The COMBAT (Control of Major Bleeding after Trauma) study experience

BACKGROUND Up to 25% of severely injured patients develop trauma-induced coagulopathy. To study interventions for this vulnerable population for whom consent cannot be obtained easily, the Food and Drug Administration issued regulations for emergency research with an exception from informed consent (ER-EIC). We describe the community consultation and public disclosure (CC/PD) process in preparation for an ER-EIC study, namely the Control Of Major Bleeding After Trauma (COMBAT) study. METHODS The CC/PD was guided by the four bioethical principles. We used a multimedia approach, including one-way communications (newspaper ads, brochures, television, radio, and web) and two-way communications (interactive in-person presentations at community meetings, printed and online feedback forms) to reach the trials catchment area (Denver Countys population: 643,000 and the Denver larger metro area where commuters reside: 2.9 million). Particular attention was given to special-interests groups (eg, Jehovah Witnesses, homeless) and to Spanish-speaking communities (brochures and presentations in Spanish). Opt-out materials were available during on-site presentations or via the COMBAT study website. RESULTS A total of 227 community organizations were contacted. Brochures were distributed to 11 medical clinics and 3 homeless shelters. The multimedia campaign had the potential to reach an estimated audience of 1.5 million individuals in large metro Denver area, the majority via one-way communication and 1900 in two-way communications. This resource intensive process cost more than

Reporting Actionable Research Results: Shared Secrets Can Save Lives

84,000. CONCLUSION The CC/PD process is resource-intensive, costly, and complex. Although the multimedia CC/PD reached a large audience, the effectiveness of this process remains elusive. The templates can be helpful to similar ER-EIC studies.

A Foucauldian Foray into the New Genetics

Controlled use of a cryptographic method for returning research results to human subjects can improve medical care with a modest cost to privacy. In this Commentary, we describe a cryptographic method for returning research results to individuals who participate in clinical studies. Controlled use of this method, which relaxes the typical anonymization guarantee, can ensure that clinically actionable results reach participants while also addressing most privacy concerns.

Substance use disorder genetic research: investigators and participants grapple with the ethical issues

A Foucauldian assessment of the common presumption that genetic information is potent and thus oppressive demonstrates that the concern may be misplaced. Foucaults concept of “technologies of self” reveals that genetic power originates not only from the potency of genetic information but from the penchant of individuals to victimize themselves in the name of optimal health, enhanced intelligence, perfect babies, or would-be immortality. Rather than seeking liberation from the power of the new genetics, Foucaults reinterpretation of the ancient understanding of concern for the self offers the possibility to avoid control by the scientific discourse. His ethical response calls for resistance rather than opposition and places responsibility for resistance in the hands of the subject. Characteristically, he avoids a generalizable form of morality but clarifies that resistance includes acknowledging the human appetite for perfection and subordinating science to ethical and aesthetic matters.

Evaluation of genetic enhancement: Will human wisdom properly acknowledge the value of evolution?

Objective This qualitative research examined the ethical concerns regarding the psychosocial issues, research design and implementation, and application of psychiatric genetic research on substance use disorders (SUD) from multiple perspectives. Methods A literature review of the bioethics literature related to psychiatric genetics and focus groups explored the ethical implications of SUD genetic research. Twenty-six National Institute on Drug Abuse funded principal investigators in the field of psychiatric genetic research, nine adolescent patients in residential SUD treatment, and 10 relatives of patients participated in focus groups (held separately). The focus groups were recorded, transcribed, and the content was analyzed. The themes that emerged from the literature and the focus group transcripts were organized by using NVIVO7, a software package designed to manage, analyze, and compare narrative data. Results Investigators and the literature expressed similar concerns regarding the ethical concerns associated with psychiatric genetic research including violation of privacy, misunderstanding about psychiatric genetics, stigmatization, commercialization, discrimination, eugenics, consequences of research on illegal behavior, unforeseen consequences, altered notion of individual responsibility, and others. Patients and their relatives showed little familiarity with the ethical issues as identified by professionals and little concern regarding most of the potential risks. The exception was apprehension associated with potential criminal justice uses of stored genetic information, in particular enforced therapy and stigmatization, which elicited some concern from all perspectives. Conclusion The challenge for further research is to identify risks and benefits of SUD research that are germane in a behaviorally disinhibited population and devise effective tools to communicate information to participants through an improved informed consent process.

Informed Consent Process in Alpha-1 Testing of At-Risk Children: Views of Parents and Adults Tested as Children

Sandel’s condemnation of any technology for human genetic enhancement as ungrateful for the “gift” that is our genetic heritage fails to properly engage with the process that shaped that heritage (Sandel 2004, 55). By attending carefully to what evolution tells us about the nature of human biology, it becomes possible to acknowledge the profound challenges of properly managing the risks inherent in genetic enhancement, while granting that there may be potential benefits to a technology that is nearly inevitable. Rather than simply reject enhancement because it interferes with our relationship to nature as Sandel does (humans interfere with nature every day in both beneficial and harmful ways; Sandel 2004, 62), we propose that there is a non-obvious value in our genetic heritage (as a product of evolution) that should be balanced against the sometimes-competing values embodied in human desires. Furthermore, this balancing provides a reasoned approach to the evaluation of proposed genetic enhancements that is applicable to the practical cases that are likely to confront us shortly. The rapid adoption of related biomedical interventions such as cosmetic surgery and performance-enhancing drugs suggest that human genetic enhancement will likely happen as soon as it appears safe and “effective.” However, enhancing genetic interventions will be particularly difficult to evaluate, for reasons beyond the uncertainty surrounding what should count as an “effective” enhancement. An appreciation of how our genetic heritage arose, and of how it unfolds in the life of an organism, should give pause to those who would advocate treating genetic enhancements as just another instance of the kinds of enhancements alluded to above. In addition to concerns raised elsewhere about, for example, deleterious social consequences of individually beneficial genetic modifications, we wish to emphasize the difficulty of making safe and effective enhancements to evolved systems in the first place. In order to design safe and effective departures from naturally occurring genomes (i.e., enhancements), biomedical researchers must correctly predict the phenotypic consequences of previously unobserved genetic combinations. There are two related aspects of our genetic heritage that make this task particularly difficult. First, the process of evolution does not prefer modular designs; instead, biomolecular systems are densely interdependent. Second, most genes appear to be pleiotropic, meaning that they have multiple functions, which further complicates the understanding of the system as a whole. These characteristics of evolved systems suggest that the challenge of discovering genuinely enhancing genetic alterations will be much more difficult than designing therapeutic ones. While the insertion of foreign genes into laboratory animals (and some agricultural organisms) has sometimes succeeded in creating the desired function, there is no way to assess how often such attempted interventions have failed. Furthermore, the potential dependence of the response to a foreign gene to the entire genetic background (i.e., every specific detail of the genome) of the host means that interventions that appear to function as predicted in one organism may have a completely different effect in another, even if the two organisms are closely related. It is for this reason that a genetic change can have radically different consequences among people; what is safe for one may not be safe for another. An illustrative example can be drawn from the recent molecular biology literature. p53 is a well-studied gene that has been highly conserved throughout the evolution of animals. p53 is so well studied primarily because damage to it is observed in a very large number of human cancers (DePinho 2000). Our current understanding of its function is that it detects damage to DNA, triggering either repairs or, in the case of damage that cannot be repaired, causing cells with damaged DNA to stop replicating or even die (Itahana et al. 2001; Ryan et al. 2001). One might therefore imagine (as some have) that an increase in p53 activity would be protective against cancer. Such a vision would be typical of the idea behind many potential genetic enhancements: If gene X plays an important role in valuable process Y, making more of X will lead to more Y, which would be a good thing. Yet our genomes are not so easy to understand, and the balancing act achieved by evolution may be more delicate than we imagine. In 2002, an accidental error in an attempt to modify to the p53 gene created a line of mice that overexpressed the gene, (i.e., those mice created much more p53 in their cells than normal mice do; Tyner et al. 2002). These mice developed normally and did, in fact, have a reduced incidence of tumors. However, despite their resistance to cancer, the altered mice died younger than their normal counterparts. Furthermore, the altered mice appeared to age at an accelerated rate, showing such symptoms as osterporosis, atrophy of muscle and skin, weight loss, and depletion of hematopoietic stem cells (Campisi 2002). Increasing p53 production beyond its normal level did prevent cancer, but it also caused premature aging. Several possible explanations for this counterintuitive observation have been suggested (Campisis 2002), but what is relevant to the idea of genetic enhancement is that even modest alterations in the best studied genes can, by virtue of their position in densely interdependent biomolecular systems, have completely unexpected consequences for aspects of the organism that were not at all suspected to be related to the function of the gene. Another concern raised by the dense interconnectedness of living systems and illustrated by this example is the possibility of harms to the host from putatively enhancing genetic interventions which take a long time to become apparent, and occur in systems that were not a priori thought to be related to the intervention. While evolution does not produce optimal or perfect organisms, it has explored a very large number of genetic variants that were not as successful as the organisms that exist in the present day. While not impossible, it is awfully hard to do better than evolution; any modest genetic alteration that would increase our reproductive fitness even by a tiny amount would have been rapidly distributed throughout the human population. The idea that human minds, with our newfound (and still quite basic) understanding of molecular biology could design genuine improvements over our evolved genetic heritage is an idea bristling with hubris. Kamm (2005) worries “whether we have the ability to alter ourselves without making things worse”; we clearly share this concern. The desire for enhancements by a public ill-equipped to understand the molecular biological detail of any proposed intervention, coupled with the financial incentives on the part of promoters of the technology, have the potential to lead to grievous and potentially irremediable harms to many individuals. It is this potential that drives us to recommend that any proposed somatic cell genetic intervention for purposes of enhancement be tightly regulated by a body of experts without financial conflicts of interest, much as therapeutic interventions are. Germ line genetic enhancements raise distinct intergenerational ethical issues that are outside the scope of this response (Coors 2003). A thorough analysis of each intervention should weigh the anticipated beneficial consequences against the anticipated harmful consequences including an evaluation of the state of existing knowledge and possible unanticipated consequences both for the individual and society, now and in the future. The consequentialist weighing of harms and benefits is necessary but not sufficient to assess proposed genetic enhancements. It is the exercise of human wisdom that empowers us to choose a mean between imprudent experimentation and outright rejection of potentially desirable technology when assessing enhancement. Wisdom is linked to truth, knowledge, and reason; it is the disposition to deliberate correctly on what is good or bad, and to consider how to act well in order to live well. The goal of enhancement is living well, and we contend wise choices in its pursuit will be difficult. Wisdom requires the use and extension of our knowledge of the evolutionary processes that created our genetic heritage, and the humility to recognize and appreciate the importance of aspects of that heritage that are not yet fully understood. Public opinion or sentiment based on shallow values, ephemeral fads, and market demand cannot substitute for this wisdom if we are to assuage Kamm’s concerns. Hans Jonas, a twentieth-century philosopher who proposed an ethic that emphasizes the role of wisdom in the genetic age, stressed predictive wisdom, which is the ability to recognize the limitations of scientific knowledge and the confines of human ability to predict the ramifications of that knowledge. Predictive wisdom acknowledges that it is not possible to know with certainty the future results of present actions (Jonas 1984). As such, it encompasses the virtue of humility, revived by Jonas to correlate with the magnitude of human control over our genome. Humility in this new role emphasizes the “excess of our power to act over our power to foresee and our power to evaluate and to judge” (Jonas 1984). Our impending power to alter our genetic heritage, which arose as a result of billions of years of hard-won experience, coupled with a limited ability to predict the consequences of alterations to an evolved system, cries out for a cautious and humble approach. Wisdom requires nothing less.

Adolescent perspectives on the return of individual results in genomic addiction research.

Targeted testing programs are identifying increasing numbers of adults affected by Alpha-1 Antitrypsin Deficiency (Alpha-1) who are making decisions about genetic testing for their at-risk children. Although there are possible benefits, there are also potential risks. The purpose of this pilot study was to explore attitudes toward testing at-risk children from the first hand perspective of those involved, identify the benefits and risks experienced therein, and compare the views of parents and adults tested as children (ATC). The results of this pilot study suggest that ATC were significantly more favorable to including children in testing decisions than parents. ATC strongly indicated that they want to be involved in the testing decision and give permission prior to testing (p = 0.007). While the majority of ATC and parents were in favor of newborn screening for Alpha-1, parents had more extreme views, both positive and negative (p = 0.04). Both ATC and parents expressed significantly higher likelihoods of possible risks and benefits following Alpha-1 testing than they actually experienced. Results do not reveal serious harms from testing at-risk children. The two groups indicated that they want information regarding access to insurance, inheritance and expression, impact on anxiety, association with smoking, and usefulness in future planning prior to a decision to test or not to test at risk children. From the resulting data and ethical analysis we recommend that parents and children have relevant information prior to testing for Alpha-1 and that at risk children are directly involved in the decision-making process prior to testing.

Anxiety Related to Genetic Testing for Alpha-1 Antitrypsin Deficiency and Cystic Fibrosis in COPD and/or Bronchiectasis Patients

This study surveyed all adolescents who were enrolled in behavioral genomic research and provided DNA to a biobank, including 320 patients undergoing treatment for substance and conduct problems (SCPs) and 109 non-SCP controls. Participants selected from three options on the return of individual genomic results (RIR) and rated eight methods of re-contact. Most individuals with SCPs (77.8%) and non-SCP controls (72.5%) wanted RIR involving health or behavioral implications. The majority of individuals with SCPs (67.2%) and non-SCP controls (69.7%) indicated that phone re-contact was ‘best’, with e-mail (22.5% SCPs, 33.9% non-SCPs) and social networking websites (21.3% SCPs, 20.2% non-SCPs) being viable options. These results suggest a layered approach for RIR: phone calls, followed by e-mails and a secure message to a social networking account. Data from this special and vulnerable population, which includes youth involved in the criminal justice system and substantial minority participation, bring an essential and missing perspective to the discussion of RIR.

Responsible patient advocacy: Perspectives from the alpha-1 foundation

Objective: To describe the psychological reaction to information about diagnostic genetic testing for α-1 antitrypsin deficiency (Alpha-1) and cystic fibrosis (CF) in chronic obstructive pulmonary disease and/or bronchiectasis patients who were tested but did not know the results. Methods: One hundred and three adults took the State-Trait Anxiety Inventory before and after a standardized educational intervention and responded to a questionnaire. Results:Information about the limitations, risks and benefits of Alpha-1 and CF testing did not raise mean anxiety levels. Mean anxiety was slightly lower after the educational intervention than at baseline (mean pretest score 35.0, posttest score 33.7; p < 0.05). Participants whose physician preinformed them of genetic testing had slightly higher mean anxiety than other participants, both before and after the intervention, but scores were comparable to those in a normative sample of general medical and surgical patients. Conclusions: Disclosure of information regarding Alpha-1 and CF testing appears to be potentially acceptable to patients and unlikely to prevent clinicians from conducting useful diagnostic procedures. This study is a step in alleviating concerns about raising issues related to genetic testing for Alpha-1 and CF in chronic obstructive pulmonary disease patients during the informed consent process.