Kathleen Cranley Glass

Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

Abstract Objective To establish whether an association exists between use of selective serotonin reuptake inhibitors (SSRIs) and suicide attempts. Design Systematic review of randomised controlled trials. Data sources Medline and the Cochrane Collaborations register of controlled trials (November 2004) for trials produced by the Cochrane depression, anxiety, and neurosis group. Selection of studies Studies had to be randomised controlled trials comparing an SSRI with either placebo or an active non-SSRI control. We included clinical trials that evaluated SSRIs for any clinical condition. We excluded abstracts, crossover trials, and all trials whose follow up was less than one week. Results Seven hundred and two trials met our inclusion criteria. A significant increase in the odds of suicide attempts (odds ratio 2.28, 95% confidence 1.14 to 4.55, number needed to treat to harm 684) was observed for patients receiving SSRIs compared with placebo. An increase in the odds ratio of suicide attempts was also observed in comparing SSRIs with therapeutic interventions other than tricyclic antidepressants (1.94, 1.06 to 3.57, 239). In the pooled analysis of SSRIs versus tricyclic antidepressants, we did not detect a difference in the odds ratio of suicide attempts (0.88, 0.54 to 1.42). Discussion Our systematic review, which included a total of 87 650 patients, documented an association between suicide attempts and the use of SSRIs. We also observed several major methodological limitations in the published trials. A more accurate estimation of risks of suicide could be garnered from investigators fully disclosing all events.

Reporting Genetic Results in Research Studies: Summary and Recommendations of an NHLBI Working Group

Prospective epidemiologic studies aid in identifying genetic variants associated with diseases, health risks, and physiologic traits. These genetic variants may eventually be measured clinically for purposes of diagnosis, prognosis, and treatment. As evidence of the potential clinical value of such information accrues, research studies face growing pressure to report these results to study participants or their physicians, even before sufficient evidence is available to support widespread screening of asymptomatic persons. There is thus a need to begin to develop consensus on whether and when genetic findings should be reported to participants in research studies. The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on Reporting Genetic Results in Research Studies to discuss if, when, and how genetic information should be reported to study participants. The Working Group concluded that genetic test results should be reported to study participants when the associated risk for the disease is significant; the disease has important health implications such as premature death or substantial morbidity or has significant reproductive implications; and proven therapeutic or preventive interventions are available. Finally, the Working Group recommended procedures for reporting genetic research results and encouraged increased efforts to create uniform guidelines for this activity. Published 2006 Wiley‐Liss, Inc.

Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?

Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery. Randomized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987, and systematic reviews were conducted in 1992 and 1997. Methods A systematic search was conducted for all RCTs of aprotinin that used placebo controls or were open-label with no active control treatment. Data collected included the primary outcome, objective of each study, whether a systematic review was cited or conducted as part of the background and/or rationale for the study and the number of previously published RCTs cited. Cumulative meta-analyses were performed. Results Sixty-four randomized, controlled trials of aprotinin were found, conducted between 1987 and 2002, reporting an endpoint of perioperative transfusion. Median trial size was 64 subjects, with a range of 20 to 1784. A cumulative meta-analysis indicated that aprotinin greatly decreased the need for perioperative transfusion, stabilizing at an odds ratio of 0.25 (p, 10 2 6) by the 12th study, published in June of 1992. The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups. Citation of previous RCTs was extremely low, with a median of 20% of prior trials cited. Only 7 of 44 (15%) of subsequent reports referenced the largest trial (N 1/4 1784), which was 28 times larger than the median trial size. Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research, resulting in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered. Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate searches for prior evidence and conducting systematic reviews.

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.

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

Human genetic research, DNA banking and consent: a question of ‘form’?

The importance of consent in research involving humans has long been recognized. The first article of the Nuremberg Code (1) states that free and informed consent is fundamental. Today, the consent process is accompanied by a form given to the participant describing the pertinent aspects of the research. It is a tool that stimulates dialogue between researchers and potential participants. Although agreement exists on the necessity for consent to ensure respect for the integrity and inviolability of the person, in practice it can be difficult to determine which elements of information are required for consent to be truly informed. This presents a challenge for both researchers and Research Ethics Board (REB). They must identify relevant topics, treat them accurately and ensure that they are communicated in a way that is effective and personalized. The challenge is all the more daunting for those involved in the rapidly evolving domain of human genetic research and DNA banking. This is a complex domain, not only scientifically but ethically and legally as well (2). Genetic research takes place along a continuum which is difficult to subdivide. The researcher must project into the future and anticipate the progress of research, the possible results it may yield and the ensuing consequences for participants. It is therefore important that the consent process include forms that adequately address these issues. In this new field of endeavor, researchers may require assistance in drafting consent forms – assistance to simplify the language, to encourage a certain uniformity of approach, to identify the relevant issues to be addressed (3) and finally to incorporate the many standards which regulate research involving DNA banking. Therefore, we undertook a detailed study of consent forms with the intention of developing one which is modular and which offers the choice of various standard * Mylène Deschênes and Geneviève Cardinal are Research Associates at the Centre de recherche en droit public of the Université de Montréal. Bartha Maria Knoppers is Full Professor at Université de Montréal and Senior Researcher at the Centre de recherche en droit public and Canada Research Chair in Law and Medicine. Kathleen Cranley Glass is Assistant Professor at McGill University, Director of the McGill Biomedical Ethics Unit and Clinical Ethicist at The Montreal Children’s Hospital. This paper was completed with the financial support from the Institut interuniversitaire de recherches sur les populations (IREP), the Réseau de Médecine Génétique Appliquée du FRSQ (RMGA), the Medical Research Council of Canada, the Genetics and Society Project (GSP) of the CRDP, as well as the Fonds FCAR number 06ER1076. This is a revised English text based on an earlier French version and adapted to the international context (see G. Cardinal, M Deschênes, BM Knoppers and KC Glass, ‘Recherche en génétique humaine et consentement’, in La recherche en génétique humaine: cadre éthique (Quebec Network of Applied Genetic Medicine, 2000) at 18).

Research Ethics Review and Aboriginal Community Values: Can the Two be Reconciled?

Contemporary research ethics review committees (RECs) are heavily influenced by the established academic or health care institutional frameworks in which they operate, sharing a cultural, methodological and ethical perspective on the conduct of research involving humans. The principle of autonomous choice carries great weight in what is a highly individualistic decision-making process in medical practice and research. This assumes that the best protection lies in the ability of patients or research participants to make competent, voluntary, informed choices, evaluating the risks and benefits from a personal perspective. Over the past two decades, North American and international indigenous researchers, policy makers and communities have identified key issues of relevance to them, but ignored by most institutional or university-based RECs. They critique the current research review structure, and propose changes on a variety of levels in an attempt to develop more community sensitive research ethics review processes. In doing so, they have emphasized recognition of collective rights including community consent. Critics see alternative policy guidelines and community-based review bodies as challenging the current system of ethics review. Some view them as reflecting a fundamental difference in values. In this paper, we explore these developments in the context of the political, legal and ethical frameworks that have informed REC review. We examine the process and content of these frameworks and ask how this contrasts with emerging Aboriginal proposals for community-based research ethics review. We follow this with recommendations on how current REC review models might accommodate the requirements of both communities and RECs.

Rethinking risk in pediatric research.

This article reviews four areas of pediatric research in which we have identified questionable levels of allowable risk, exceeding those foreseen by the Commission. They are the following: (1) the categorization of increasingly risky interventions as minimal risk in a variety of protocols; (2) the increasing number of applications for federal panel review of research not otherwise approvable because of higher projected risk levels; (3) research on asymptomatic at risk children; and (4) the inclusion of children and adolescents in placebo-controlled trials for participants of all ages without performing subgroup analysis. While embracing the imperative to include children in research is an encouraging step towards providing the pediatric population with effective medical care and finally eradicating the therapeutic orphan, we must ensure that this research does not become overly permissive.

Structuring the Review of Human Genetics Protocols Part-III: Gene Therapy Studies

In this article, the authors propose a framework to assist the review of gene therapy protocols. The authors provide a general description of three gene therapy techniques: gene marking, gene supplementation and gene therapy. They then set out a checklist identifying issues for IRB review. Finally, they discuss in greater detail four points of controversy raised by this kind of research: the appropriate forum for review; the risks associated with gene therapy studies, including risks to both subjects and society; interventions that may affect the germ line intentionally or unintentionally; and advantages and disadvantages of germ-line therapy. Because a number of the issues discussed in their previous papers are relevant to gene therapy, the authors suggest that all three papers be read together.

Structuring the Review of Human Genetics Protocols: Gene Localization and Identification Studies

The review of genetic research protocols raises specific medical, ethical and legal questions. This article is intended to assist investigators and IRB members in their review of gene localization and identification protocols, sometimes referred to as gene hunting research. The authors provide a general description of gene hunting studies, set out a checklist identifying issues for IRB review, and discuss in greater detail several points of controversy raised by this kind of research. These issues include evaluating the validity of a research protocol, and the effect a subjects participation in a study may have on his or her family members, with a particular emphasis on the issues surrounding disclosure of test results to research subjects.