David Wendler

What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research

In recent years there has been substantial debate about the ethics of research in developing countries. In general the controversies have centered on 3 issues: first the standard of care that should be used in research in developing countries; second the “reasonable availability” of interventions that are proven to be useful during the course of research trials; and third the quality of informed consent. The persistence of controversies on such issues reflects in part the fact that existing ethical guidelines can be interpreted in multiple ways are sometimes contradictory or rely on unstated yet controversial ethical principles. To provide unified and consistent ethical guidance we apply a previously proposed ethical framework for clinical research within developed countries to developing countries explicating a previously implicit requirement for collaboration. More importantly we propose specific and practical benchmarks to guide researchers and research-ethics committees in assessing how well the enumerated ethical principles have been fulfilled in particular cases. (excerpt)

Systematic Review: The Effect on Surrogates of Making Treatment Decisions for Others

BACKGROUND Clinical practice relies on surrogates to make or help to make treatment decisions for incapacitated adults; however, the effect of this practice on surrogates has not been evaluated. PURPOSE To assess the effect on surrogates of making treatment decisions for adults who cannot make their own decisions. DATA SOURCES Empirical studies published in English and listed in MEDLINE, EMBASE, CINAHL, BIOETHICSLINE, PsycINFO, or Scopus before 1 July 2010. STUDY SELECTION Eligible studies provided quantitative or qualitative empirical data, by evaluating surrogates, regarding the effect on surrogates of making treatment decisions for an incapacitated adult. DATA EXTRACTION Information on study location, number and type of surrogates, timing of data collection, type of decisions, patient setting, methods, main findings, and limitations. DATA SYNTHESIS 40 studies, 29 using qualitative and 11 using quantitative methods, provided data on 2854 surrogates, more than one half of whom were family members of the patient. Most surrogates were surveyed several months to years after making treatment decisions, the majority of which were end-of-life decisions. The quantitative studies found that at least one third of surrogates experienced a negative emotional burden as the result of making treatment decisions. The qualitative studies reported that many or most surrogates experienced negative emotional burden. The negative effects on surrogates were often substantial and typically lasted months or, in some cases, years. The most common negative effects cited by surrogates were stress, guilt over the decisions they made, and doubt regarding whether they had made the right decisions. Nine of the 40 studies also reported beneficial effects on a few surrogates, the most common of which were supporting the patient and feeling a sense of satisfaction. Knowing which treatment is consistent with the patients preferences was frequently cited as reducing the negative effect on surrogates. LIMITATIONS Thirty-two of the 40 articles reported data collected in the United States. Because the study populations were relatively homogenous, it is unclear whether the findings apply to other groups. In some cases, the effect of making treatment decisions could not be isolated from that of other stressors, such as grief or prognostic uncertainty. Nine of the studies had a response rate less than 50%, and 9 did not report a response rate. Many of the studies had a substantial interval between the treatment decisions and data collection. CONCLUSION Making treatment decisions has a negative emotional effect on at least one third of surrogates, which is often substantial and typically lasts months (or sometimes years). Future research should evaluate ways to reduce this burden, including methods to identify which treatment options are consistent with the patients preferences. PRIMARY FUNDING SOURCE National Institutes of Health.

Deception in Research on the Placebo Effect

A common feature of research investigating the placebo effect is deception of research participants about the nature of the research. Miller and colleagues examine the ethical issues surrounding such deception.

Should Children Decide Whether They Are Enrolled in Nonbeneficial Research

The U.S. federal regulations require investigators conducting nonbeneficial research to obtain the assent of children who are capable of providing it. Unfortunately, there has been no analysis of which children are capable of assent or even what abilities ground the capacity to give assent. Why should investigators be required to obtain the positive agreement of some children, but not others, before enrolling them in research that does not offer a compensating potential for direct benefit? We argue that the scope of childrens research decision making should be based on the principles of respect for autonomy and nonmaleficence. These principles imply that the threshold for assent should be fixed at 14 years of age, and a dissent requirement should be adopted for all children in the context of nonbeneficial research.

Assent in paediatric research: theoretical and practical considerations

Guidelines around the world require children to provide assent for their participation in most research studies. Yet, little further guidance is provided on how review committees should implement this requirement, including which children are capable of providing assent and when the requirement for assent may be waived on the grounds that the research offers participating children the potential for important clinical benefit. The present paper argues that the assent requirement is supported by the importance of allowing children who are capable to make their own decisions. This suggests children are capable of assent when they become able to understand the research in question. While development varies across individual children, existing data suggest most children develop this ability by approximately age 14. Until instruments are developed to assess the assent capacity of individual children, this age should be used as the threshold for assent. In addition, the importance of protecting children from harm suggests that the sustained dissent of all children, including those who are unable to provide assent, should be respected. While the assent requirement may be waived when research participation offers the potential for important medical benefit that is unavailable outside the research context, analysis suggests that children’s sustained dissent should be respected in all cases.

Broad Consent for Research With Biological Samples: Workshop Conclusions.

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Centers Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

Evaluating the Risks of Clinical Research

The ethical appropriateness of clinical research depends on protecting participants from excessive risks. Yet no systematic framework has been developed to assess research risks, and as a result, investigators, funders, and review boards rely only on their intuitive judgments. Because intuitive judgments of risk are subject to well-documented cognitive biases, this approach raises concern that research participants are not being adequately protected. To address this situation, we delineate a method called the systematic evaluation of research risks (SERR), which evaluates the risks of research interventions by comparing these interventions with the risks of comparator activities that have been deemed acceptable. This method involves a 4-step process: (1) identify the potential harms posed by the proposed research intervention; (2) categorize the magnitude of the potential harms into 1 of 7 harm levels on a harm scale; (3) quantify or estimate the likelihood of each potential harm; and (4) compare the likelihood of each potential harm from the research intervention with the likelihood of harms of the same magnitude occurring as a result of an appropriate comparator activity. By explicitly delineating, quantifying, and comparing the risks of research interventions with the risks posed by appropriate comparator activities, SERR offers a way to minimize the influence of cognitive biases on the evaluation of research risks and thereby better protect research participants from excessive risks.

Disclosure of Incidental Findings From Next-Generation Sequencing in Pediatric Genomic Research

Next-generation sequencing technologies will likely be used with increasing frequency in pediatric research. One consequence will be the increased identification of individual genomic research findings that are incidental to the aims of the research. Although researchers and ethicists have raised theoretical concerns about incidental findings in the context of genetic research, next-generation sequencing will make this once largely hypothetical concern an increasing reality. Most commentators have begun to accept the notion that there is some duty to disclose individual genetic research results to research subjects; however, the scope of that duty remains unclear. These issues are especially complicated in the pediatric setting, where subjects cannot currently but typically will eventually be able to make their own medical decisions at the age of adulthood. This article discusses the management of incidental findings in the context of pediatric genomic research. We provide an overview of the current literature and propose a framework to manage incidental findings in this unique context, based on what we believe is a limited responsibility to disclose. We hope this will be a useful source of guidance for investigators, institutional review boards, and bioethicists that anticipates the complicated ethical issues raised by advances in genomic technology.

A Framework for Risk-Benefit Evaluations in Biomedical Research

Essentially all guidelines and regulations require that biomedical research studies have an acceptable risk-benefit profile. However, these documents offer little concrete guidance for implementing this requirement and determining when it is satisfied. As a result, those charged with risk-benefit evaluations currently assess the risk-benefit profile of biomedical research studies in unsystematic ways, raising concern that some research participants are not being protected from excessive risks and that some valuable studies involving acceptable risk are being rejected. The present paper aims to address this situation by delineating the first comprehensive framework, which is based on existing guidelines and regulations as well as the relevant literature, for risk-benefit evaluations in biomedical research.

The 50th anniversary of the Declaration of Helsinki: progress but many remaining challenges.

Since 1964, through 7 revisions, the World Medical Association’s Declaration of Helsinki has stood as an important statement regarding the ethical principles guiding medical research with human participants. It is consulted by ethics review committees, funders, researchers, and research participants. It has been incorporated into national legislation and is routinely invoked to ascertain the ethical appropriateness of clinical trials.