The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.

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Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration.

Many believe that informed consent makes clinical research ethical. However, informed consent is neither necessary nor sufficient for ethical clinical research. Drawing on the basic philosophies underlying major codes, declarations, and other documents relevant to research with human subjects, we propose 7 requirements that systematically elucidate a coherent framework for evaluating the ethics of clinical research studies: (1) value-enhancements of health or knowledge must be derived from the research; (2) scientific validity-the research must be methodologically rigorous; (3) fair subject selection-scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects; (4) favorable risk-benefit ratio-within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (5) independent review-unaffiliated individuals must review the research and approve, amend, or terminate it; (6) informed consent-individuals should be informed about the research and provide their voluntary consent; and (7) respect for enrolled subjects-subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored. Fulfilling all 7 requirements is necessary and sufficient to make clinical research ethical. These requirements are universal, although they must be adapted to the health, economic, cultural, and technological conditions in which clinical research is conducted. JAMA. 2000;283:2701-2711.

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What Makes Clinical Research Ethical

Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans

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)

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

It has been almost three years since the Journal 1 published the results of AIDS Clinical Trials Group (ACTG) Study 076, the first randomized, controlled trial in which an intervention was proved to reduce the incidence of human immunodeficiency virus (HIV) infection. The antiretroviral drug zidovudine, administered orally to HIV-positive pregnant women in the United States and France, administered intravenously during labor, and subsequently administered to the newborn infants, reduced the incidence of HIV infection by two thirds.2 The regimen can save the life of one of every seven infants born to HIV-infected women. Because of these findings, the study was . . .

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Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries

served and the difficulty for this reviewer is to understand how this contract is to be developed. By and large, it must be through the individual to do otherwise must be, as Hamilton points out, to change the medical ethic. Several of the participants share these doubts. Dr McWhinney, for example, points out that we must not make too much of a distinction between clinical and population competency for the latter will be applied through the former. Put another way by Sir Douglas Black: 'The ideal curriculum should recognise that population problems are aggregations of individual problems'. Moreover, while doctors must know about and understand the effect of the environment, both natural and manmade, on the distribution of ill-health, the resolution of such problems is not within the power of the medical school whose essential function, as Inui puts it, is to educate physicians. How we are educating them is another matter. It may well be that the 'humanitarian dimensions' of doctoring are being sacrificed to the rote of science and it is certain that the undergraduate medical curriculum is too crowded. Perhaps we should avoid the concept of the five or sixyear undergraduate training programme and think more in terms of a ten-year graduate curriculum. In any event, the sweeping re-orientation suggested throughout the book is probably unattainable. The major difficulty is that the majority of, at least UK, hospitals are not community-based and the graduates go out to serve disparate populations not excluding those of developing countries whose needs may be completely different. The paper by Marmot and Zwi, 'A model exercise in public health', demonstrates this only too well. Several contributors come from medical schools which claim that population-based education of the type envisaged can be achieved but one suspects that Newcastle, NSW, for example, is, by reason of geography, the classic community-based medical school. In fact, the contributions from discussants are, in many ways, more readable than the primary papers insofar as they bring us back from Utopia to Camberwell. This is a very seriously written book which is, incidentally, beautifully edited and well produced. In so far as medical ethics are founded in the medical school, it has an interest for readers of this journal but it takes a long time to make a relatively narrow point. It is essentially for educationists and community physicians who will follow the discussions with interest and benefit.

https://jme.bmj.com/content/medethics/20/2/123.full.pdf

International ethical guidelines for biomedical research involving human subjects

Those involved in medical research on humans and its regulation take, from time to time, a hurried look back at the dark and fearful days of the Third Reich, wondering whether the activities of today bear any resemblance at all to those of the physicians working in Hitler's Germany. Most of us have insufficient knowledge of the details of what went on, and have thought too little about the justifications that were given at the famous doctors' trial at Nuremberg, to be able to make a sound comparison (or contrast). The arguments remain hazy yet the spectre of Nazi-style activities is frequently raised. This laudable collection of essays does much to dispel the confusion and put the whole episode in a proper perspective for those of us who need to know. It is divided into three sections: the first looks at the involvement of physicians as a professional group in the sinister intentions of the Nazi social and racial policy. The evidence (some of which is relatively new) indicates there was a great involvement. Far from being forced to comply with Nazi laws on sterilization, euthanasia and the notorious Nuremberg laws, physicians were instrumental in their conception, planning and administration. Robert N Proctor, the author of the first of the essays on this subject, muses: 'Given the effort to destroy entire peoples, and given the medical complicity in Nazi racial crime, it is hardly surprising that physicians attempted to exploit concentration camp inmates as subjects in human experimentation'. There follows a first-hand account of some of the Nazi experimentation by a surviving 'Mengele twin'. Having described the horror, Eva Mozes-Kor then questions whether the Nazi doctors were wrong because of the physical harm they did or wrong because of the violation ofhuman dignity by treating the twins merely as a means. She concludes that the real crime was in the latter the total lack of respect for their autonomy. The second section consists of source documents of the Nuremberg Trial, providing a fascinating account of the accusations, justifications' and judgments. Michael A Grodin in 'Historical Origins of the Nuremberg Code', sets the code in the context of the Nuremberg trials. He shows that although its form and content, in particular the primacy of informed consent, were in response to the particular circumstances, it is still of relevance today. Its sources are many: the writings of Percival, Beaumont and Bemard; early German guidelines on human experimentation were considered. Andrew Ivy and Leo Alexander were the primary compilers; their memo to the judges was mostly but not entirely used, and the judges added notes of their own. The final section analyses the role the code has today in international and US law and in medical ethics. The consent principle, of such primary importance in the code, is relegated to ninth place in the Helsinki Declaration, which has taken the place of the Nuremberg Code as the universally accepted code governing medical research. One essay discusses ethical relativism and imperialism, and makes a case for moral progress. Another questions the use of analogies to the Holocaust in contemporary ethical debates. A third looks at editorial responsibility, and the additional check on ethical standards which can be provided by the editors of academic journals. A fourth looks at the effect that AIDS activists have had on assumptions about what is good medical research. In conclusion the two editors ask what the next appropriate step should be, and propose that the United Nations should establish a mechanism for the more adequate control of research. In all, this volume of essays is well worth reading.

https://jme.bmj.com/content/medethics/21/4/247.1.full.pdf

Claire Gilbert Foster

Papers

International ethical guidelines for biomedical research involving human subjects

The Nazi doctors and the Nuremberg Code: human rights in human experimentation