Benjamin Freedman

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-controlled trials and the logic of clinical purpose.

The exercise of human intelligence ramifies in numerous and diverse ways. Nevertheless, as applied in theory or practice, in work or play, directed toward life or toward death, each manifestation shares a common underlying method: organized comparison. Whether deriving equations in mathematics, or developing progressions of chords in jazz, or, in business, studying the impact of advertisements upon defined populations, reason is at bottom engaged in the single process of comparison, the delineation of sameness and difference. Medicine partakes of this commonality of method, and has come to grant greatest credence to those propositions established by the cleanest possible comparison: the controlled clinical trial that methodically examines sameness and difference in outcome across cohorts. All of the diverse strategies introduced to reduce bias (e.g., stratification and randomization) in fact simply aim to ensure the precision of comparison. In pursuing the strategy of organized comparison, however, a prior question must be posed: For what purpose is comparison sought? Many of the controversies concerning the design of clinical trials can be best understood as

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

Ethics Review for Sale? Conflict of Interest and Commercial Research Review Boards

Research review boards, established to protect the rights and welfare of human research subjects, have to ensure that conflicts of interest do not interfere with the ethical conduct of medical research. Private, commercial review boards, which increasingly review research protocols, are themselves affected by a structural conflict of interest. Within the regulatory setting, procedural conflict-of-interest rules are essential because of the absence of clear substantive rules in research review and the reliance on the fairness and good judgment of institutional review board members. Current guidelines and regulations lack adequate conflict-of-interest rules and provide insufficient details on the substantive rules. Because commercial review boards are similar to administrative courts and tribunals, rules of administrative law on bias are applied to determine when a conflict of interest jeopardizes the purposes of research review; administrative law has always judged financial conflicts of interest severely. The structure of private review tends to breach a core principle of administrative law and procedural justice. Reform of the research review system will reinforce public trust in the process.

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.

Reporting the study populations of clinical trials: Clear transmission or static on the line?

In contrast to attempts that have been made to measure the clarity of reporting of the methods of clinical trials in journal articles, we report here an attempt to measure the accuracy of methods reporting. We focus in this article on eligibility criteria as a test case for the reporting of clinical trial methods. We examined the reporting of eligibility criteria in the protocol, methods paper (if applicable), journal article, and Clinical Alert for articles appearing in print between January 1988 and September 1994 for which a Clinical Alert had been issued. Eligibility criteria were further classified into five categories in order to examine the content of information loss, if any. On average, 82% of protocol eligibility criteria were reported in methods papers. Journal articles and Clinical Alerts fared somewhat worse: 63% of criteria were reported in journal articles, 19% in Clinical Alerts. In all three categories of medical communication, the reporting of criteria that defined the study disease tended to be complete; reporting of criteria relating to trial precision, patient safety, legal and ethical concerns, and administrative considerations, was not complete. We found that criteria for clinical trial eligibility are frequently under-reported in medical communications. Moreover, some of the criteria omitted are of considerable clinical importance. We suggest that in the design phase of clinical trials, proposed eligibility criteria be scrutinized closely. Those criteria that survive this scrutiny and that have clinical import must be reported upon fully and accurately when communicating trial results.

Ethics and statistics in clinical research: towards a more comprehensive examination

Abstract The ethical analysis of research with human subjects has been greatly developed over the last 20 years, with input from researchers and statisticians as well as philosophers. That all such research must satisfy ethical norms, what those ethical norms are, and how these norms should be applied to clinical research, are all now matters of common agreement. Certain critical questions, such as informed consent to research and the risk–benefit ratio associated with trial participation, have been carefully parsed in the literature. However, it remains the case that major aspects of clinical trials are rarely subjected to ethical scrutiny, particularly those of most concern to statisticians. By specific reference to two such questions — the size of the clinical study, and the patient population eligible for the trial — and their numerous ethical as well as scientific implications, we argue for an approach to clinical trial ethics that comprehensively subjects each aspect of a trial to ethical analysis.

Respectful service and reverent obedience. A Jewish view on making decisions for incompetent parents.

Too often, caregivers and ethicists misunderstand the motivations of adult children who are involved in the care of their parents. They sometimes fail to appreciate the ways in which adult children may be trying to carry out their filial obligations toward a parent, obligations dictated by their religious commitments. Exploring these obligations within the Jewish tradition can help illuminate these issues and provide an alternative to a rights-based framework in which to reason about them.

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.

Case notes and charting of bioethical case consultations

In summary, the usual elements of a typical health care ethics consultation note might reasonably accommodate the needs and expectations of relevant parties, and would therefore include: 1. identification of the relevant ethical issues, questions, or dilemmas; 2. reference to any relevant facts--medical, nursing, social, psychological, spiritual, legal, political, etc.; 3. a prioritized list of recommendations to improve coordinated care; 4. a clear and concise articulation of relevant arguments, wtih specific reference to the list of recommendations as well as to the institutions overall ethos; 5. a contextual statement, identifying the perceived degree of consensus or support for the recommendations and conclusions, as well as any inherent agendas.