D
Glossary, Acronyms, and Laws and Regulations

GLOSSARY


Accreditation.

A voluntary certification that institutions, programs, or facilities have adhered to a set of standards for the protection of human research participants as determined by a nongovernmental organization.

Active treatment.

Therapy intended to affect a patient’s condition in a clinical trial; not a placebo or monitoring only.

Adverse event.

An occurrence that causes harm to a patient or research participant or that has the potential to do so. Regulations related to the protection of human subjects focus on serious and unexpected adverse events.

Age of majority.

The age designated by state law at which individuals can enter into contracts, consent to medical care, and make other crucial decisions in their own right.

Assent.

A child’s affirmative agreement to participate in research.

Assurance of compliance.

A formal declaration of an institution’s commitment to the protection of human subjects. Pursuant to Section 491 of the Public Health Service Act, 42 U.S.C. 289, and to human subjects protection regulations at 45 CFR 46.103, institutions engaged in human subjects research covered by U.S. Department of Health and Human Services (DHHS) regulations and conducted or supported by DHHS must submit a written assurance of compliance satisfactory to the secretary.



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Ethical Conduct of Clinical Research Involving Children D Glossary, Acronyms, and Laws and Regulations GLOSSARY Accreditation. A voluntary certification that institutions, programs, or facilities have adhered to a set of standards for the protection of human research participants as determined by a nongovernmental organization. Active treatment. Therapy intended to affect a patient’s condition in a clinical trial; not a placebo or monitoring only. Adverse event. An occurrence that causes harm to a patient or research participant or that has the potential to do so. Regulations related to the protection of human subjects focus on serious and unexpected adverse events. Age of majority. The age designated by state law at which individuals can enter into contracts, consent to medical care, and make other crucial decisions in their own right. Assent. A child’s affirmative agreement to participate in research. Assurance of compliance. A formal declaration of an institution’s commitment to the protection of human subjects. Pursuant to Section 491 of the Public Health Service Act, 42 U.S.C. 289, and to human subjects protection regulations at 45 CFR 46.103, institutions engaged in human subjects research covered by U.S. Department of Health and Human Services (DHHS) regulations and conducted or supported by DHHS must submit a written assurance of compliance satisfactory to the secretary.

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Ethical Conduct of Clinical Research Involving Children Benefit. A positive or valued outcome of an action or event. Benefits resulting from research participation may be physical, psychological, or social. Blinded. A design feature of clinical trials in which information about whether research participants are in the experimental or control arm is withheld from participants only (single-blinded trials) or both participants and researchers (double-blinded trials). Certificate of Confidentiality. Certificates issued by the National Institutes of Health to research institutions to protect the privacy of research participants involved in sensitive research by protecting investigators and institutions from being compelled to release identifying information in any federal, state, or local civil, criminal, administrative, legislative, or other proceeding. Clinical research. Commonly viewed as research that uses human participants to test the safety or effectiveness of medical interventions, especially drugs, or to study the diagnosis or pathophysiology of diseases, disorders, or injuries. More broadly conceived, it “includes all studies intended to produce knowledge valuable to the prevention, diagnosis, prognosis, treatment, or cure of human disease” which involve direct interactions with child participants in research (IOM, 1994a, p. 35). Disease, in this context, can be interpreted to include disorders and injuries. Commensurate. Reasonably similar to (procedures that prospective research participants ordinarily experience). Common Rule. The general term for Subpart A of federal regulations protecting human subjects in research as it applies to the U.S. Department of Health and Human Services (45 CFR 46) and 16 other federal agencies. Compensation. A payment for the time and inconvenience involved in research participation. Condition. A specific (or set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children’s health and well-being or their risk of developing a health problem in the future. Conflict of interest. Any financial or other personal interest in the outcome of a research study that may, in actuality or appearance, compromise the objectivity of a researcher and the integrity of the research being conducted. Consent. An autonomous decision made by an individual with the legal and cognitive capacity to choose voluntarily participate in research.

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Ethical Conduct of Clinical Research Involving Children Control group. The group in a clinical trial that does not receive the experimental intervention. Data and safety monitoring board. An independent committee charged with periodically reviewing and comparing safety and outcome data collected during a study to determine whether a trial should continue as originally designed, should be altered, or should be terminated. Data monitoring committee. The term that the Food and Drug Administration and the International Conference on Harmonisation use instead of data and safety monitoring board. See Data and safety monitoring board. Determination letter. Correspondence issued by the Office for Human Research Protection that describes findings of an investigation, which may include findings of noncompliance and listing of corrective steps to be taken. Direct benefit. A tangible positive outcome of an event or action. Emancipated minor. A person under the age of majority who is granted adult rights by a court on the basis of the maturity of the minor and the minor’s need for adult status, usually determined through certain actions, marriage, military enlistment, or being self-supporting and living independently. Experimental. Unproven or investigational intervention. Guardian. An individual who is authorized under applicable state or local law to give permission on behalf of a child to participation in research. Harm. A hurtful or adverse outcome of an action or event, whether temporary or permanent. Harms resulting from research participation may be physical, psychological, or social. Human research participant protection program. A program consisting of a set of organizational structures, policies, and procedures that apply to a particular research protocol or group of protocols. Specific components may differ depending on the characteristics of a particular study. Human subject. “A living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject’s environment that are performed for research purposes)” (45 CFR 46.102(f)). The preferred term in this report is human research participant. Incentive payment. A payment that is intended to attract research participants, that is not linked to expense reimbursement or compensation for time spent in research, and that exceeds a token amount. Institutional review board (IRB). A group of qualified individuals charged under federal regulation with protecting the rights and welfare of people

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Ethical Conduct of Clinical Research Involving Children involved in research in accord with federal regulations. IRBs review and approve plans for research involving humans. International Conference on Harmonisation. An organization created to develop universal guidelines and requirements for scientific and technical aspects of product registration. Members include regulatory authorities and experts from the pharmaceutical industries of Europe, Japan, and the United States. Mature minor. A minor who has not reached the age of majority (as defined by state law), but is—as directed by state law—subjectively assessed as being capable of giving the same degree of informed consent for health care purposes. Minimal risk. A risk associated with research in which the probability and magnitude of harm or discomfort anticipated are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical psychological examinations or tests of normal, average, healthy children. Minor increase over minimal risk. A slight or small increase in the potential for harm or discomfort beyond the minimal risk level that is allowed for healthy, normal average children. Multicenter trial. A clinical trial that is undertaken at multiple sites using a common protocol. Off-label use. Use of a drug or medical device for a purpose, dose form, patient group, or other use not approved by the Food and Drug Administration for use as indicated on the product label. Parent. A child’s biological or adoptive parent. Parental permission. Decision made by a parent(s) or guardian with legal authority to allow a child to participate in research. Participant. Preferred description of human subjects in research. Pharmacodynamics. The study of the effects of a drug on the body. Pharmacokinetics. Study of how medicines are absorbed, distributed in, and eliminated from the body. Phase 1 clinical trial. Initial test of a drug or other intervention with humans. For drugs, Phase 1 trials typically assess tolerability, bioavailability, and pharmacokinetics with a small group of healthy, adult volunteers. Phase 2 clinical trial. Clinical testing that usually involves a larger group of participants and an assessment of efficacy as well as further evaluation of safety and adverse effects. These trials typically involve participants with a particular disease or condition. Phase 3 clinical trial. Rigorous controlled clinical studies that extend efficacy and safety testing to a larger number of research participants who usually are randomly assigned to receive the intervention or a standard treatment or placebo.

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Ethical Conduct of Clinical Research Involving Children Placebo. An inactive substance (e.g., a sugar pill) or a sham action (e.g., an injection of sterile water) used with a control group as part of a Phase 3 clinical trial. Protocol. A document that describes the purpose, design, methods, organization, and other key features of a research study. Reimbursement. A payment for out-of-pocket expenses directly related to research participation. Risk. A potential harm or the potential of an action or event to cause harm. Serious adverse event. An unwanted outcome, which may or may not be related to an experimental intervention, that involves death, hospitalization (new or extended), disability, birth defect, or another major medical event that may jeopardize a research participant and require intervention to prevent one of the above outcomes. Standard treatment. A treatment currently in use that is believed to be effective. Subpart A. Federal regulations providing for general protections of human subjects in research (the basic policy of the U.S. Department of Health and Human Services for the protection of human research subjects). See also Common Rule. Subpart D. Federal regulations providing for special protections of child participants in research. The regulations have been adopted only by the U.S. Department of Health and Human Services, the U.S. Department of Education, the Central Intelligence Agency, and the Social Security Administration. Therapeutic misconception. The belief that the purpose of research is to treat a disease or condition rather than to generate scientific knowledge. Ward. A child who is placed in the legal custody of the state or other agency, institution, or entity, consistent with applicable federal, state, or local law (21 CFR 50.3q).

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Ethical Conduct of Clinical Research Involving Children ACRONYMS AND ABBREVIATIONS AAHRPP Association for the Accreditation of Human Research Protection Programs AAP American Academy of Pediatrics ACHRE Advisory Committee on Human Radiation Experiments AMA American Medical Association CDC Centers for Disease Control and Prevention CFF Cystic Fibrosis Foundation CIOMS Council for International Organizations of Medical Sciences COG Children’s Oncology Group DHEW U.S. Department of Health Education and Welfare DHHS U.S. Department of Health and Human Services (formerly U.S. Department of Health Education and Welfare) DSMB data and safety monitoring board FDA Food and Drug Administration GAO General Accounting Office HIV human immunodeficiency virus ICH International Conference on Harmonisation IND Investigational New Drug IOM Institute of Medicine IRB institutional review board NAS National Academy of Sciences NBAC National Bioethics Advisory Committee NCHS National Center for Health Statistics NCI National Cancer Institute NHRPAC National Human Research Protections Advisory Committee NICHD National Institute for Child Health and Human Development NIH National Institutes of Health NRC National Research Council OHRP Office for Human Research Protections (formerly Office for Protection from Research Risk) OIG Office of Inspector General OMH Office of Mental Health OPRR Office for Protection from Research Risk PPRA Protection of Pupil Rights Amendment SACHRP Secretary’s Advisory Committee on Human Research Protections STD sexually transmitted disease TDN Therapeutic Development Network USDA U.S. Department of Agriculture WMA World Medical Association

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Ethical Conduct of Clinical Research Involving Children LAWS AND REGULATIONS P.L. 87-781. The Drug Amendments of 1962. This act expanded the scope of the Food and Drug Administration’s authority by including provisions that required investigators to obtain a subject’s consent to participation in research unless it was not feasible or was not in the subject’s best interest. P.L. 93-348. National Research Act of 1974. This Act explicitly provided for the creation of institutional review boards (IRBs) to review biomedical and behavioral research that involved humans. It established and directed the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to identify ethical principles for research involving humans, specifically, to consider research involving vulnerable individuals, including children, prisoners, and those with mental disabilities. P.L. 105-115. Food and Drug Administration Modernization and Accountability Act of 1997 P.L. 106-310. Children’s Health Act of 2000. This legislation requires the Food and Drug Administration to bring its regulations into conformity with Subpart D to provide special protections for children participating in research. P.L. 107-109. Best Pharmaceuticals for Children Act of 2002. The broad purpose of the legislation was to improve the safety and efficacies of drugs for children. One key provision renewed incentives for pharmaceutical manufacturers to test drugs in studies with children to establish safe doses of medications that had been approved as safe and effective for adults. The legislation also requested a study by the Institute of Medicine of research involving children. P.L. 108-146. Pediatric Research Equity Act of 2003. This legislation grants authority to the Food and Drug Administration to require pediatric studies of certain drugs to ensure their safety and efficacy for children. 21 CFR 50. The Food and Drug Administration policy on the Protection of Human Subjects. 21 CFR 56. The Food and Drug Administration policy on institutional review boards. 45 CFR 46. The U.S. Department of Health and Human Services policy on Public Welfare, the Protection of Human Subjects. Section 404. Research not involving greater than minimal risk. Section 405. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. Section 406. Research involving greater than minimal risk and no

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Ethical Conduct of Clinical Research Involving Children prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. Section 407. Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.