Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.

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A tutorial on pilot studies: the what, why and how

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

4. UNHCR notes with concern that although the country acceded to the 1951 Convention and the 1967 Protocol in 1999, incorporation of the 1951 Convention obligations into national legislation and normative acts has been slow and to date Kazakhstan has failed to comply with its obligation to give full effect to the Covenant in the domestic legal order, inter alia providing for effective judicial and other remedies for violations of these rights

United Nations High Commission for Refugees

Trauma and Recovery: The Aftermath of Violence — from Domestic Abuse to Political Terror, Judith Lewis Herman. New York: Basic Books, 1992. 276 pp. $27.00. ISBN 0-465-08765–5.Shattered Assumptions: Toward A New Psychology of Trauma, Ronnie Janoff-Bulman. New York: The Free Press, 1992, 256 pp. $24.95. ISBN 0-02-916015–4.

Trauma and Recovery: The Aftermath of Violence — from Domestic Abuse to Political Terror

There is little consensus about the meaning of the terms "health disparities," "health inequalities," or "health equity." The definitions can have important practical consequences, determining the measurements that are monitored by governments and international agencies and the activities that will be supported by resources earmarked to address health disparities/inequalities or health equity. This paper aims to clarify the concepts of health disparities/inequalities (used interchangeably here) and health equity, focusing on the implications of different definitions for measurement and hence for accountability. Health disparities/inequalities do not refer to all differences in health. A health disparity/inequality is a particular type of difference in health (or in the most important influences on health that could potentially be shaped by policies); it is a difference in which disadvantaged social groups-such as the poor, racial/ethnic minorities, women, or other groups who have persistently experienced social disadvantage or discrimination-systematically experience worse health or greater health risks than more advantaged social groups. ("Social advantage" refers to one's relative position in a social hierarchy determined by wealth, power, and/or prestige.) Health disparities/inequalities include differences between the most advantaged group in a given category-e.g., the wealthiest, the most powerful racial/ethnic group-and all others, not only between the best- and worst-off groups. Pursuing health equity means pursuing the elimination of such health disparities/inequalities.

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Health disparities and health equity: concepts and measurement.

The atrocities committed by Nazi physicians and researchers during World War II prompted the development of the Nuremberg Code to define the ethics of modern medical experimentation utilizing human subjects Since its enunciation, the Code has been viewed as one of the cornerstones of modern bioethical thought The sources and ramifications of this important document are thoroughly discussed in this book by a distinguished roster of contemporary professionals from the fields of history, philosophy, medicine, and law Contributors also include the chief prosecutor of the Nuremberg Military Tribunal and a moving account by a survivor of the Mengele Twin Experiments The book sheds light on keenly debated issues of both science and jurisprudence, including the ethics of human experimentation; the doctrine of informed consent; and the Code's impact on today's international human rights agenda The historical setting of the Code's creation, some modern parallels, and the current attitude of German physicians toward the crimes of the Nazi era, are discussed in early chapters The book progresses to a powerful account of the Doctors' Trial at Nuremberg, its resulting verdict, and the Code's development The Code's contemporary influence on both American and international law is examined in its historical context and discussed in terms of its universality: are the foundational ethics of the Code as valid today as when it was originally penned? The editors conclude with a chapter on foreseeable future developments and a proposal for an international covenant on human experimentation enforced by an international court A major work in medical law and ethics, this volume provides stimulating, provocative reading for physicians, legal professionals, bioethicists, historians, biomedical researchers, and concerned laypersons

The Nazi Doctors and the Nuremberg Code Human Rights in Human Experimentation

Most children who become ifi, even those with lifothreatening disorders, recover to lead satisfying lives. Nonetheless, the course of disease may at times cause health care professionals and families to consider whether continued treatment truly represents the best option. Sometimes limiting or stopping life support seems most appropriate, especially if treatment only preserves biological existence or if the overall goal of therapy has shifted to the maintenance of comfort. Based on the existing consensus in ethics and law, the following guidelines for professionals caring for children suggest elements in decisions to forgo lifosustaining medical treatment (LSMT). Decisions to withhold or withdraw LSMT may soriously tax the intellectual and emotional reserves of all parties. Patients, families, physicians, and other members of the medical care team should have access to and feel free to use ethics consultants or ethics cornmittees in addition to the other resources on which they usually rely.5’6

Guidelines on forgoing life-sustaining medical treatment

Health and human rights : a reader

An April 1998 New York Times Magazine article described Ronald Munger's efforts to obtain blood samples from a group of extremely impoverished people in the Philippine island of Cebu.[1] Munger sought the blood to study whether there was a genetic cause for this group's unusually high incidence of cleft lip and palate. One of many obstacles to the research project was the need to obtain the cooperation of the local health officer. It was not clear to Munger, or the reader, whether the health officer had a bona fide interest in protecting the populace or was looking for a bribe. The health officer asked Munger a few perfunctory questions about informed consent and the study's ethical review in the United States, which Munger answered. Munger also explained the benefits that mothers and children would derive from participating in the research. The mothers would learn their blood types (which they apparently desired) and whether they were anemic. If they were anemic, they would be given iron pills. Lunch would be served, and raffles arranged so that families could win simple toys and other small items. Munger told the health officer that if his hypotheses were correct, the research would benefit the population of Cebu: if the research shows that increased folate and vitamin B6 reduces the risk of cleft lip and palate, families could reduce the risk of facial deformities in their future offspring. The reporter noted that the health officer "laughs aloud at the suggestion that much of what is being discovered in American laboratories will make it back to Cebu any time soon." Reflecting on his experience with another simple intervention, iodized salt, the health officer said that when salt was iodized, the price rose threefold "so those who need it couldn't afford it and those who didn't need it are the only ones who could afford it." The simple blood collecting mission to Cebu illustrates almost all the issues presented by research in developing countries. First is the threshold question of the goal of the research and its importance to the population represented by the research subjects. Next is the quality of informed consent, including whether the potential subjects thought that participation in the research was related to free surgical care that was offered in the same facility (although it clearly was not) and whether one could adequately explain genetic hypotheses to an uneducated populace. Finally, there is the question whether the population from which subjects were drawn could benefit from the research. This research intervention is very low risk--the collection of 10 drops of blood from affected people and their family members. The risk of job or insurance discrimination that genetic research poses in this country did not exist for the Cebu population; ironically, they were protected from the risk of economic discrimination by the profound poverty in which they lived. Even this simple study raises the most fundamental question: "Why is it acceptable for researchers in developed countries to use citizens of developing countries as research subjects?" A cautionary approach to permitting research with human subjects in underdeveloped countries has been recommended because of the risk of their inadvertent or deliberate exploitation by researchers from developed countries. This cautionary approach generally is invoked when researchers propose to use what are considered "vulnerable populations," such as prisoners and children, as research subjects.[2] Vulnerable populations are those that are less able to protect themselves, either because they are not capable of making their own decisions or because they are particularly susceptible to mistreatment.[3] For example, children may be incapable of giving informed consent or of standing up to adult authority, while prisoners are especially vulnerable to being coerced into becoming subjects. Citizens of developing countries are often in vulnerable situations because of their lack of political power, lack of education, unfamiliarity with medical interventions, extreme poverty, or dire need for health care and nutrition. …

Research in Developing Countries: Taking `Benefit' Seriously

The human rights issues raised by the conduct of maternal-fetal human immunodeficiency virus transmission trials in Africa are not unique to either acquired immunodeficiency syndrome or Africa, but public discussion of these trials presents an opportunity for the United States and other wealthy nations to take the rights and welfare of impoverished populations seriously. The central issue at stake when developed countries perform research on subjects in developing countries is exploitation. The only way to prevent exploitation of a research population is to insist not only that informed consent be obtained but also that, should an intervention be proven beneficial, the intervention will be delivered to the impoverished population. Human rights are universal and cannot be compromised solely on the basis of beliefs or practices of any one country or group. The challenge to the developed countries is to implement programs to improve the health of the people in developing countries both by improving public health infrastructure and by delivering effective drugs and vaccines to the people.

https://ajph.aphapublications.org/doi/pdfplus/10.2105/AJPH.88.4.560

Michael A. Grodin

Papers

The Nazi Doctors and the Nuremberg Code Human Rights in Human Experimentation

Guidelines on forgoing life-sustaining medical treatment

Health and human rights : a reader

Research in Developing Countries: Taking `Benefit' Seriously

Human rights and maternal-fetal HIV transmission prevention trials in Africa.