Charles Weijer

Protecting Communities in Research: Current Guidelines and Limits of Extrapolation

As genetic research increasingly focuses on communities, there have been calls for extending research protections to them. We critically examine guidelines developed to protect aboriginal communities and consider their applicability to other communities. These guidelines are based on a model of researcher-community partnership and span the phases of a research project, from protocol development to publication. The complete list of 23 protections may apply to those few non-aboriginal communities, such as the Amish, that are highly cohesive. Although some protections may be applicable to less-cohesive communities, such as Ashkenazi Jews, analysis suggests substantial problems in extending these guidelines in toto beyond the aboriginal communities for which they were developed.

When are research risks reasonable in relation to anticipated benefits

The question “When are research risks reasonable in relation to anticipated benefits?” is at the heart of disputes in the ethics of clinical research. Institutional review boards are often criticized for inconsistent decision-making, a problem that is compounded by a number of contemporary controversies, including the ethics of research involving placebo controls, developing countries, incapable adults and emergency rooms. If this pressing ethical question is to be addressed in a principled way, then a systematic approach to the ethics of risk in research is required. Component analysis provides such a systematic approach.

Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths

lacebo-controlled trials are held by many, including regulators at agencies like the United States Food P and Drug Administration (FDA), to be the gold standard in the assessment of new medical interventions. Yet the use of placebo controls in clinical trials has been the focus of considerable controversy.’ In this two-part article, we challenge a number of common beliefs concerning the value of placebo controls. Part I critiques statistical and other scientific justifications for the use of placebo controls in clinical research. The continued use of placebo controls in clinical trials on diseases for which accepted treatment exists raises equally important ethical, legal, and regulatory issues for which various justifications have been given. Defense of this practice relies on normative as well as empirical myths.

The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials

The Ottawa Ethics of Cluster Trials Consensus Group sets out 15 recommendations for the ethical design and conduct of cluster randomized trials.

Protecting Communities in Research: Philosophical and Pragmatic Challenges

The issue of the protection of communities in clinical research first arose 10 years ago in studies conducted in technologically developing countries by scientists from technologically developed nations. The question was, which ethical standards ought to apply, those of the Western investigators or local standards?

Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths

he use of statistics in medical research has been compared to a religion: it has its high priests (statistiT cians), supplicants (journal editors and researchers), and orthodoxy (for example, p < .05 is “significant”).’ Although the comparison may be more unfair to religion than to research, a useful lesson can nonetheless be drawn: the practice of clinical research may benef i tas does the spirit-from critical self-examination. Arguably, no aspect of the conduct of clinical trials is currently more controversial-and thus in as dire need of critical examinationthan the use of placebo controls. The ethical and scientific controversies associated with placebo-controlled trials, never far below the surface, have once again seized public attention.2 Clearly, concern about these issues within the professional community runs deep and wide, as evidenced by the volume of response generated by Kenneth Rothman and Karin Michels’s recent ~r i t ique.~ Criticisms of the use of placebo controls in clinical research are scattered through the l i terat~re;~ our objective is to present the case against placebos in a compendious form that takes account of scientific and statistical as well as normative issues. Many previous criticisms of the use of placebo had focused on the violence it does to truth-telling.5 As Robert Levine has argued, this concern is misplaced: placebos in clinical research, unlike clinical practice, typically are not given before an explanation has been provided to the subject.6 The central focus of the current debate concerns the role of the placebo in biomedical investigation and in the regulation of new treatments, especially drugs. At present, a large segment of the scientific community considers placebo-controlled studies to render a unique and irreplaceable service, in their ability to test whether a treatment has

Impact of CONSORT extension for cluster randomised trials on quality of reporting and study methodology: review of random sample of 300 trials, 2000-8

Objective To assess the impact of the 2004 extension of the CONSORT guidelines on the reporting and methodological quality of cluster randomised trials. Design Methodological review of 300 randomly sampled cluster randomised trials. Two reviewers independently abstracted 14 criteria related to quality of reporting and four methodological criteria specific to cluster randomised trials. We compared manuscripts published before CONSORT (2000-4) with those published after CONSORT (2005-8). We also investigated differences by journal impact factor, type of journal, and trial setting. Data sources A validated Medline search strategy. Eligibility criteria for selecting studies Cluster randomised trials published in English language journals, 2000-8. Results There were significant improvements in five of 14 reporting criteria: identification as cluster randomised; justification for cluster randomisation; reporting whether outcome assessments were blind; reporting the number of clusters randomised; and reporting the number of clusters lost to follow-up. No significant improvements were found in adherence to methodological criteria. Trials conducted in clinical rather than non-clinical settings and studies published in medical journals with higher impact factor or general medical journals were more likely to adhere to recommended reporting and methodological criteria overall, but there was no evidence that improvements after publication of the CONSORT extension for cluster trials were more likely in trials conducted in clinical settings nor in trials published in either general medical journals or in higher impact factor journals. Conclusion The quality of reporting of cluster randomised trials improved in only a few aspects since the publication of the extension of CONSORT for cluster randomised trials, and no improvements at all were observed in essential methodological features. Overall, the adherence to reporting and methodological guidelines for cluster randomised trials remains suboptimal, and further efforts are needed to improve both reporting and methodology.

A Study in Contrasts: Eligibility Criteria in a Twenty-Year Sample of NSABP and POG Clinical Trials

We studied changes in eligibility criteria--the largest impediment to patient accrual--in two samples of clinical trials. Trials from the NSABP (National Surgical Adjuvant Breast and Bowel Program) and POG (Pediatric Oncology Group) were analyzed. After eliminating duplications, the criteria in each protocol were enumerated and classified according to a novel schema. NSABP trials contained significantly more criteria than POG trials, and added precision criteria (making study populations homogeneous) at a faster rate than POG studies. The difference between NSABP studies (explanatory trials) and POG studies (pragmatic trials) suggest that large numbers of eligibility criteria are not necessary for quality studies. We recommend that: (1) the inclusion/exclusion criteria distinction be abandoned; (2) eligibility criteria be explicitly justified; (3) the need for each criterion be assessed when new trials are planned; (4) criteria in phase III trials restricting patient accrual be minimized; and (5) further research be done to assess the impact of criteria on generalizability.

When is informed consent required in cluster randomized trials in health research

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the second of the questions posed, namely, from whom, when, and how must informed consent be obtained in CRTs in health research? The ethical principle of respect for persons implies that researchers are generally obligated to obtain the informed consent of research subjects. Aspects of CRT design, including cluster randomization, cluster level interventions, and cluster size, present challenges to obtaining informed consent. Here we address five questions related to consent and CRTs: How can a study proceed if informed consent is not possible? Is consent to randomization always required? What information must be disclosed to potential subjects if their cluster has already been randomized? Is passive consent a valid substitute for informed consent? Do health professionals have a moral obligation to participate as subjects in CRTs designed to improve professional practice?We set out a framework based on the moral foundations of informed consent and international regulatory provisions to address each of these questions. First, when informed consent is not possible, a study may proceed if a research ethics committee is satisfied that conditions for a waiver of consent are satisfied. Second, informed consent to randomization may not be required if it is not possible to approach subjects at the time of randomization. Third, when potential subjects are approached after cluster randomization, they must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomized; detailed information on interventions in other trial arms need not be provided. Fourth, while passive consent may serve a variety of practical ends, it is not a substitute for valid informed consent. Fifth, while health professionals may have a moral obligation to participate as subjects in research, this does not diminish the necessity of informed consent to study participation.

Providing Research Results to Participants: Attitudes and Needs of Adolescents and Parents of Children With Cancer

PURPOSE There is an increasing demand for researchers to provide research results to participants. Our aim was to define an appropriate process for this, based on needs and attitudes of participants. METHODS A multicenter survey in five sites in the United States and Canada was offered to parents of children with cancer and adolescents with cancer. Respondents indicated their preferred mode of communication of research results with respect to implications; timing, provider, and content of the results; reasons for and against providing results; and barriers to providing results. RESULTS Four hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n = 385; 94.2%) felt that they had a strong right to research results. For positive results, most wanted a letter or e-mail summary (n = 238; 58.2%) or a phone call followed by a letter (n = 100; 24.4%). If the results were negative, phone call (n = 136; 33.3%) or personal visits (n = 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n = 341; 83.4%), effect on future treatments (n = 341; 83.4%), and subsequent research steps (n = 284; 69.5%). Understanding the researcher was a main concern about receiving results (n = 145; 35.5%). Parents felt that results provide information to support quality of life (n = 315; 77%) and raise public awareness of research (n = 282; 68.9%). Adolescents identified similar preferences. CONCLUSION Parents of children with cancer and adolescents with cancer feel strongly that they have a right to be offered research results and have specific preferences of how and what information should be communicated.