Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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1 Introduction
1 Introduction
Pages 25-57
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From page 25... ...
v) T he scientific community today recognizes how crucial it is to under stand and to honor ethical research conduct as well as scientific progress if it is to sustain the trust placed in it by policymakers and the public, including parents who are considering whether to enroll their child in clinical research.
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. Three controlled clinical trials demonstrated oxygen's toxic effects on the developing retina (James and Lanman, 1976)
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Notwithstanding the expected benefits of policies to increase the amount of research involving infants, children, and adolescents, some cau 1Sometimes the concern is not the lack of pediatric studies per se but the choice of research sponsors not to disclose unfavorable research findings to clinicians and the public. Recent warnings by British and American regulatory agencies that a popular antidepressant might increase suicide-related behaviors among children prompted controversy following reports that several manufacturers of antidepressants had refused to publish results from a number of clinical studies involving children (Vedantam, 2004; see also, Boseley, 2003; Neergaard, 2003; FDA, 2003c)
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From page 28... ...
Their vulnerability demands special consideration from researchers and policymakers and additional protections beyond those provided to mentally competent adult participants in research. As discussed later in this chapter, instances of unethical research practices involving children have prompted public criticism and concern that has contributed to the development of current federal regulations to protect both child and adult participants in research.
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From page 29... ...
All investigators conducting studies that include infants, children, and adolescents should work under the umbrella of a formal program for the protection of human research participants. · Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research.
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; Preserving Public Trust: Accreditation and Human Research Participant Protection Programs (IOM, 2001) ; Integrity in Scientific Research: Creating an Environment That Promotes Responsible Conduct (IOM/NRC, 2002)
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It is written for a broad audience that may not be familiar with the technical aspects of clinical research nor the intricacies of federal regulations. The remainder of this chapter offers arguments for a systems perspective on human research protection, summarizes core principles for ethical research involving humans, and reviews the evolution of policies based on these principles.
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Drawing the line between research and certain health care management strategies continues to be a challenge and suggests the need for better communication between human research protection programs and institutional quality improvement activities (see, e.g., Bellin and Dubler, 2001)
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Some statements of ethical principles for research have made an implicit or explicit distinction between therapeutic and nontherapeutic research.4 The former category of research would, for example, include the 3In other FDA regulations related specifically to drugs, clinical investigation is defined as "any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice" (21 CFR 312.3(b)
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Even when parents are not research participants in this direct way, they may be "surrogate" participants in certain respects; for example, when outcome measurements rely in whole or in part on parental assessments of aspects of the child's quality of life.
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. The challenges of accommodating the physical, intellectual, social, and emotional characteristics and needs of infants, children, and adolescents may make pediatric research even more costly than studies that involve only adults.
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The central objective of this system of interrelated elements is to protect research participants by encouraging and sustaining responsible behavior from all those involved in sponsoring, reviewing, monitoring, or regulating research and disseminating research findings. This systems perspective can be applied to clinical research involving children by considering whether each component of the system is adequate to the specialized responsibilities of protecting child participants in re
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Figure 1.1 depicts, in highly simplified form, a program of human research protections operating within a larger social, economic, and political environment and a surrounding ethical culture and climate. As shown in Figure 1.1, a significant system component is a human research participants protection program.
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38 ETHICAL CONDUCT OF CLINICAL RESEARCH INVOLVING CHILDREN Ethical Culture and Climate Research Population/Community Child Parents/Family Investigator Data Safety Research Monitoring Institution Bodies Institutional Review Sponsor Board Human Research Participants Protection Program Specific Laws and Regulatory Bodies Social, Economic, and Political Environment FIGURE 1.1 Simplified representation of a system for protecting human research participants (IOM/NRC, 2002; IOM, 2003)
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ETHICAL PRINCIPLES FOR A SYSTEM TO PROTECT HUMAN RESEARCH PARTICIPANTS If a study is unethical to start with, it does not become ethical because it produces useful results. Henry Beecher, 1970, p.
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.5 The U.S. Congress created the National Commission in 1974 and charged it with, among other tasks, identifying basic principles for ethical research involving human subjects and developing ethical guidelines for applying those principles to the conduct of research.
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Although the report does not mention financial incentives for research participation, much attention has been devoted to payments to research participants as a potential source of undue influence (see Chapter 6 of this report)
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These include imbalances in information and power between clinicians and patients and between investigators and research participants or their parents. For parents, the physical and emotional stresses associated with a child's illness or injury and, frequently, the time constraints on decision making also may compromise their ability to obtain, absorb, and evaluate information, weigh options, and then provide truly informed permission for their child to be treated or enrolled in research.
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-- and, generally, for not limiting clinical studies to nonelderly white adult males. The Belmont Report emphasized the societal benefits "that serve to justify research involving children -- even when individual research subjects are not direct beneficiaries" (National Commission, 1978a, p.
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Policymakers then took longer to adopt special proposals to increase protections for children than to accept proposals affecting pregnant women, fetuses, and prisoners. Nonetheless, controversies about the ethics of research involving children have frequently served as a stimulus for proposals -- if not action -- to adopt or strengthen human research protection policies.
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The nineteenth and early twentieth centuries saw scattered or passing comments on ethical research conduct.7 In Prussia at the turn of the last century, public controversy over research practices (including the inoculation of healthy children with syphilis serum) led to appointment of a committee that issued recommendations for ethical research practices (Grodin, 1992; Vollmann and Winau, 1996)
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. Despite considerable controversy, neither public action nor voluntary standards for human research won acceptance in the United States before World War II.
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Strictly construed, they would have precluded research involving children or mentally or legally incapacitated adults.10 Although ethicists, investigators, and policymakers have considerably refined and extended the principles of ethical research (e.g., to cover children) , many of the basic tenets in current national and international statements on the conduct of research are similar to those set forth by the Nuremberg judges in 1947.
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With respect to research involving children, the 1995 report of the Advisory Committee on Human Radiation Experiments stated that "in the 1940s and 1950s there were apparently no written rules of professional ethics for pediatric research in general" (ACHRE, 1995, p.
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. This institution-level review was to consider the methods for obtaining informed consent, the balance of risks and benefits in proposed research, and the welfare of the research participants.
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During the 1960s, criticisms of unethical research practices in research involving children gained new attention (see, e.g., ACHRE, 1995 and Lowen, 1995)
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further formalized its policies on protecting human research participants in the Institutional Guide to DHEW Policy for the Protection of Human Subjects. Faden and Beauchamp (1986, p.
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As noted earlier, it also established the National Commission and directed it to identify ethical principles for research involving humans with additional attention to research involving vulnerable individuals, including children, prisoners, and those with mental disabilities. 1975 to 1995 By the time that its mandate expired in 1978, the National Commission had produced 17 reports and supplementary documents.
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Finally, in 1983, 10 years after its first proposals and 6 years after the National Commission report on children, DHHS issued special regulations for research involving children (Subpart D)
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. Recent Years Except for some limited revisions, the regulations issued in the 1980s still govern research conducted, supported, or regulated by DHHS, including research involving children.
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. To underscore program goals, the Office for Protection from Research Risks became the Office for Human Research Protections (OHRP)
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of the International Conference on Harmonisation (ICH) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects of the Council for International Organizations of Medical Sciences (CIOMS, 2002, updating guidelines first issued in 1982)
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. It also reflects the higher prevalence of many serious medical problems in less developed countries and, thus, the larger pool of potential research participants.
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