Pharmacological substances that have the potential for creating abusive dependency. Abuse-liable substances can include both illicit drugs (e.g., heroine) and licit drugs (e.g., methamphetamines).
Alcohol, Drug Abuse, and Mental Health Administration; reorganized in October 1992 as the Substance Abuse and Mental Health Services Administration (SAMHSA). ADAMHA included the National Institute of Mental Health (NIMH), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), the Office for Substance Abuse Prevention (OSAP), and the Office for Treatment Intervention (OTI). NIMH, NIAAA, and NIDA are now part of the National Institutes of Health (NIH). (See also: SAMHSA.)
Therapy provided to enhance the effect of an primary therapy; auxiliary therapy.
An undesirable and unintended, although not necessarily unexpected, result of therapy or other intervention (e.g., headache following spinal tap or intestinal bleeding associated with aspirin therapy).
Agreement by an individual not competent to give legally valid informed consent (e.g., a child or cognitively impaired person) to participate in research.
A formal written, binding commitment that is submitted to a federal agency in which an institution promises to comply with applicable regulations governing research with human subjects and stipulates the procedures through which compliance will be achieved [Federal Policy §___.103].
AUTHORIZED INSTITUTIONAL OFFICIAL
An officer of an institution with the authority to speak for and legally commit the institution to adherence to the requirements of the federal regulations regarding the involvement of human subjects in biomedical and behavioral research.
Personal capacity to consider alternatives, make choices, and act without undue influence or interference of others.
Examination by dissection of the body of an individual to determine cause of death and other medically relevant facts.
A statement of basic ethical principles governing research involving human subjects issued by the National Commission for the Protection of Human Subjects in 1978.
An ethical principle discussed in the Belmont Report that entails an obligation to protect persons from harm. The principle of beneficence can be expressed in two general rules: (1) do not harm; and (2) protect from harm by maximizing possible benefits and minimizing possible risks of harm.
A valued or desired outcome; an advantage.
means that the burden to the individual resulting from participation in research are determined by the individual’s legally authorized representative to be reasonable in relation to the individual resulting from individual’s participation in research, taking into account:
- The potential short and long term effects of the participation in research on the physical, emotional, and cognitive functions of the individual;
- The degree of physical pain or discomfort, psychological distress, or loss of dignity caused to the individual by participation in research;
- The prognosis of the individual; and
- The risks, side effects, and benefits of participation in research, compared to the risks, side effects, and benefits of standard treatment, if any, or of not participating in the research
Any therapeutic serum, toxin, anti-toxin, or analogous microbial product applicable to the prevention, treatment, or cure of diseases or injuries.
BLIND STUDY DESIGNS
See: Masked Study Designs; Double-Masked Design; and Single-Masked Design.
The body of a deceased person.
(Capacity to consent to a research participation) The ability to understand the purpose, procedures, risks, benefits of and alternatives (including non participation) to a research study, including the ability to express a choice about participation and to understand that a refusal to participate involves no penalty or loss of benefits to which the person is otherwise entitled
A study comparing persons with a given condition or disease (the cases) and persons without the condition or disease (the controls) with respect to antecedent factors. (See also: Retrospective Studies.)
Abbreviation for Computerized Axial Tomography, an X-ray technique for producing images of internal bodily structures through the assistance of a computer.
Persons who have not attained the legal age for consent to treatment or procedures involved in the research, as determined under the applicable law of the jurisdiction in which the research will be conducted [45 CFR 46.401(a)].
Centers for Disease Control and Prevention; an agency within the Public Health Service, Department of Health and Human Services.
CLASS I, II, III DEVICES
Classification by the Food and Drug Administration of medical devices according to potential risks or hazards.
A controlled study involving human subjects, designed to evaluate prospectively the safety and effectiveness of new drugs or devices or of behavioral interventions.
any person, eighteen years of age or older who is related to the prospective subject and has maintained such regular contact with the prospective subject to be familiar with his or her activities, health, and religious or moral beliefs
Having either a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders, or dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. Others, including persons under the influence of or dependent on drugs or alcohol, those suffering from degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps, may also be compromised in their ability to make decisions in their best interests.
A group of subjects initially identified as having one or more characteristics in common who are followed over time. In social science research, this term may refer to any group of persons who are born at about the same time and share common historical or cultural experiences.
the federal regulations governing the protection of human subjects in research. Refer to 45 CFR 46.
Payment or medical care provided to subjects injured in research; does not refer to payment (remuneration) for participation in research. (Compare: Remuneration.)
Technically, a legal term, used to denote capacity to act on one’s own behalf; the ability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. (See also: Incompetence, Incapacity.)
Pertains to the treatment of information that an individual has disclosed in a relationship of trust and with the expectation that it will not be divulged to others without permission in ways that are inconsistent with the understanding of the original disclosure.
See: Informed Consent.
An agreement; as used here, an agreement that a specific research activity will be performed at the request, and under the direction, of the agency providing the funds. Research performed under contract is more closely controlled by the agency than research performed under a grant. (Compare: Grant.)
CONTROL (SUBJECTS) or CONTROLS
Subject(s) used for comparison who are not given a treatment under study or who do not have a given condition, background, or risk factor that is the object of study. Control conditions may be concurrent (occurring more or less simultaneously with the condition under study) or historical (preceding the condition under study). When the present condition of subjects is compared with their own condition on a prior regimen or treatment, the study is considered historically controlled.
Disadvantageous, perhaps dangerous; a treatment that should not be used in certain individuals or conditions due to risks (e.g., a drug may be contraindicated for pregnant women and persons with high blood pressure).
A statistical index of the degree of relationship between two variables. Values of correlation coefficients range from -1.00 through zero to +1.00. A correlation coefficient of 0.00 indicates no relationship between the variables. Correlations approaching -1.00 or +1.00 indicate strong relationships between the variables. However, causal inferences about the relationship between two variables can never be made on the basis of correlation coefficients, no matter how strong a relationship is indicated.
A type of clinical trial in which each subject experiences, at different times, both the experimental and control therapy. For example, half of the subjects might be randomly assigned first to the control group and then to the experimental intervention, while the other half would have the sequence reversed.
DATA AND SAFETY MONITORING BOARD
A committee of scientists, physicians, statisticians, and others that collects and analyzes data during the course of a clinical trial to monitor for adverse effects and other trends (such as an indication that one treatment is significantly better than another, particularly when one arm of the trial involves a placebo control) that would warrant modification or termination of the trial or notification of subjects about new information that might affect their willingness to continue in the trial.
An expelled or delivered fetus that exhibits no heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, or pulsation of the umbilical cord (if still attached) [45 CFR 46.203(f)]. Generally, some organs, tissues, and cells (referred to collectively as fetal tissue) remain alive for varying periods of time after the total organism is dead.
Giving subjects previously undisclosed information about the research project following completion of their participation in research. (Note that this usage, which occurs within the behavioral sciences, departs from standard English, in which debriefing is obtaining rather than imparting information.)
DECISIONALLY INCAPACITATED INDIVIDUAL
an individual who is at least 18 years of age, and who cannot give a valid informed consent to participate as the subject of research because the individual cannot sufficiently understand the nature, extent, or probably consequence of the proposed research participation, cannot make a sufficient evaluation of burdens, risks, and benefits of the proposed research participation, or cannot communicate a research participation decision by a court. An adult individual who is able to communicate by means other than speech shall not be deemed incapacitated solely by reason of inability to speak
DECLARATION OF HELSINKI
A code of ethics for clinical research approved by the World Medical Association in 1964 and widely adopted by medical associations in various countries. It was revised in 1975 and 1989.
The outcomes that are measured in an experiment. Dependent variables are expected to change as a result of an experimental manipulation of the independent variable(s).
Any study that is not truly experimental (e.g., quasi-experimental studies, correlational studies, record reviews, case histories, and observational studies).
See: Medical Device.
A federal agency: U.S. Department of Health, Education and Welfare; reorganized in 1980 as the Department of Health and Human Services (DHHS) and the Department of Education.
A federal agency: U.S. Department of Health and Human Services; formerly the Department of Health, Education and Welfare (DHEW).
Tests used to identify a disorder or disease in a living person.
means: 1. Not being in a position to gain personal benefit from: 2. Not participating in any way, including authorship of publications, in the research concerning which an individual performs duties under these regulations; and 3. Not having any investment or other financial interest in any business entity sponsoring the research
A study design in which neither the investigators nor the subjects know the treatment group assignments of individual subjects. Sometimes referred to as “double-blind.”
Any chemical compound that may be used on or administered to humans as an aid in the diagnosis, treatment, cure, mitigation, or prevention of disease or other abnormal conditions.
A legal status conferred upon persons who have not yet attained the age of legal competency as defined by state law (for such purposes as consenting to medical care), but who are entitled to treatment as if they had by virtue of assuming adult responsibilities such as being self-supporting and not living at home, marriage, or procreation. (See also: Mature Minor.)
Early stages of a developing organism, broadly used to refer to stages immediately following fertilization of an egg through implantation and very early pregnancy (i.e., from conception to the eighth week of pregnancy). (See also: Fetus.)
A scientific discipline that studies the factors determining the causes, frequency, and distribution of diseases in a community or given population.
Fair or just; used in the context of selection of subjects to indicate that the benefits and burdens of research are fairly distributed [Federal Policy §___.111(a)(3)].
ETHICS ADVISORY BOARD
An interdisciplinary group that advises the Secretary, HHS, on general policy matters and on research proposals (or classes of proposals) that pose ethical problems.
Ethnography is the study of people and their culture. Ethnographic research, also called fieldwork, involves observation of and interaction with the persons or group being studied in the group’s own environment, often for long periods of time. (See also: Fieldwork.)
Policy and procedure that permits individuals who have serious or life-threatening diseases for which there are no alternative therapies to have access to investigational drugs and devices that may be beneficial to them. Examples of expanded availability mechanisms include Treatment INDs, Parallel Track, and open study protocols.
Review of proposed research by the IRB chair or a designated voting member or group of voting members rather than by the entire IRB. Federal rules permit expedited review for certain kinds of research involving no more than minimal risk and for minor changes in approved research [Federal Policy §___.110].
Term often used to denote a therapy (drug, device, procedure) that is unproven or not yet scientifically validated with respect to safety and efficacy. A procedure may be considered “experimental” without necessarily being part of a formal study (research) to evaluate its usefulness. (See also: Research.)
A true experimental study is one in which subjects are randomly assigned to groups that experience carefully controlled interventions manipulated by the experimenter according to a strict logic allowing causal inference about the effects of the interventions under investigation. (See also: Quasi-Experimental Study).
When a test wrongly shows an effect or condition to be absent (e.g., that a woman is not pregnant when, in fact, she is).
When a test wrongly shows an effect or condition to be present (e.g. that is woman is pregnant when, in fact, she is not).
Food and Drug Administration; an agency of the federal government established by Congress in 1912 and presently part of the Department of Health and Human Services.
FEDERAL POLICY (THE)
The federal policy that provides regulations for the involvement of human subjects in research. The Policy applies to all research involving human subjects conducted, supported, or otherwise subject to regulation by any federal department or agency that takes appropriate administrative action to make the Policy applicable to such research. Currently, sixteen federal agencies have adopted the Federal Policy. (Also known as the “Common Rule.”)
The placenta, amniotic fluid, fetal membranes, and umbilical cord.
The product of conception from the time of implantation until delivery. If the delivered or expelled fetus is viable, it is designated an infant [45 CFR 46.203(c)]. The term “fetus” generally refers to later phases of development; the term “embryo” is usually used for earlier phases of development. (See also: Embryo.)
Behavioral, social, or anthropological research involving the study of persons or groups in their own environment and without manipulation for research purposes (distinguished from laboratory or controlled settings). (See also: Ethnographic Research.)
A medical device that is considered substantially equivalent to a device that was or is being legally marketed. A sponsor planning to market such a device must submit notification to the FDA 90 days in advance of placing the device on the market. If the FDA concurs with the sponsor, the device may then be marketed. 510(k) is the section of the Food, Drug and Cosmetic Act that describes premarket notification; hence the designation “510(k) device.”
FULL BOARD REVIEW
Review of proposed research at a convened meeting at which a majority of the membership of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. For the research to be approved, it must receive the approval of a majority of those members present at the meeting [Federal Policy §___.108].
The treatment of genetic disease accomplished by altering the genetic structure of either somatic (nonreproductive) or germline (reproductive) cells.
Obsolete term, previously used to denote an institutional assurance covering multiple research projects. (See also: Assurance.)
Certain FDA statutory provisions designed to control the safety of marketed drugs and devices. The general controls include provisions on adulteration, misbranding, banned devices, good manufacturing practices, notification and record keeping, and other sections of the Medical Device Amendments to the Food, Drug and Cosmetic Act [21 U.S. Code §360(c) (Food, Drug and Cosmetic Act §513)].
Tests to identify persons who have an inherited predisposition to a certain phenotype or who are at risk of producing offspring with inherited diseases or disorders.
The genetic constitution of an individual.
Financial support provided for research study designed and proposed by the principal investigator(s). The granting agency exercises no direct control over the conduct of approved research supported by a grant. (Compare: Contract.)
An individual who is authorized under applicable state or local law to give permission on behalf of a child to general medical care [45 CFR 46.402(3)].
HEALTH CARE AGENT
a legally authorized representative to whom authority to make health decisions delegate under a health care proxy as authorized by Public Health Law Article 29-C
HEALTH CARE PROXY
a document delegating authority to make health care decisions executed in accordance with the requirements of Public Health Law Article 29-C
See: Declaration of Helsinki.
Control subjects (followed at some time in the past or for whom data are available through records) who are used for comparison with subjects being treated concurrently. The study is considered historically controlled when the present condition of subjects is compared with their own condition on a prior regimen or treatment.
HUMAN IN VITRO FERTILIZATION
Any fertilization involving human sperm and ova that occurs outside the human body.
Individuals whose physiologic or behavioral characteristics and responses are the object of study in a research project. Under the federal regulations, human subjects are defined as: living individual(s) about whom an investigator conducting research obtains: (1) data through intervention or interaction with the individual; or (2) identifiable private information [Federal Policy §___.102(f)]. IDE See: Investigational Device Exemptions.
Refers to a person’s mental status and means inability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. Often used as a synonym for incompetence. (See also: Incompetence.)
Technically, a legal term meaning inability to manage one’s own affairs. Often used as a synonym for incapacity. (See also: Incapacity.) IND See: Investigational New Drug.
INDEPENDENT CONSENT MONITOR
a disinterested adult who is designated by an IRB, to monitor the informed consent process when a legally authorized representative is considering whether to give informed consent to the participation by decisional incapacitated individuals in research. The role of the independent consent monitor is:
1. To confirm to the IRB that:
A. The risk/benefit category of the proposed research is unambiguously included in an advance research directive authorizing research participation, if one exists;
B. The legally authorized representative understand the goals and risks of the research; and
2. To witness the process by which an investigator provides the legally authorized representative with the information required by an IRB for informed consent
INDEPENDENT DATA AND SAFETY MONITORING BOARD
two or more disinterested individuals, independent of the research, authorized by an IRB to monitor data from a specific research study to ensure safety of subjects and to periodically report findings to the IRB
The conditions of an experiment that are systematically manipulated by the investigator.
A person’s voluntary agreement, based upon adequate knowledge and understanding of relevant information, to participate in research or to undergo a diagnostic, therapeutic, or preventive procedure. In giving informed consent, subjects may not waive or appear to waive any of their legal rights, or release or appear to release the investigator, the sponsor, the institution or agents thereof from liability for negligence [Federal Policy §116; 21 CFR 50.20 and 50.25].
(1) Any public or private entity or agency (including federal, state, and local agencies) [Federal Policy §___.102(b)].
(2) A residential facility that provides food, shelter, and professional services (including treatment, skilled nursing, intermediate or long-term care, and custodial or residential care). Examples include general, mental, or chronic disease hospitals; inpatient community mental health centers; halfway houses and nursing homes; alcohol and drug addiction treatment centers; homes for the aged or dependent, residential schools for the mentally or physically handicapped; and homes for dependent and neglected children.
INSTITUTIONAL REVIEW BOARD
A specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in biomedical or behavioral research [Federal Policy §§___.102(g), ___.108, ___.109].
Confined, either voluntarily or involuntarily (e.g., a hospital, prison, or nursing home).
INSTITUTIONALIZED COGNITIVELY IMPAIRED
Persons who are confined, either voluntarily or involuntarily, in a facility for the care of the mentally or otherwise disabled (e.g., a psychiatric hospital, home, or school for the retarded).
INVESTIGATIONAL DEVICE EXEMPTIONS (IDE)
Exemptions from certain regulations found in the Medical Device Amendments that allow shipment of unapproved devices for use in clinical investigations [21 CFR 812.20].
INVESTIGATIONAL NEW DRUG OR DEVICE
A drug or device permitted by FDA to be tested in humans but not yet determined to be safe and effective for a particular use in the general population and not yet licensed for marketing.
In clinical trials, an individual who actually conducts an investigation [21 CFR 312.3]. Any interventions (e.g., drugs) involved in the study are administered to subjects under the immediate direction of the investigator. (See also: Principal Investigator.)
Literally, “in glass” or “test tube;” used to refer to processes that are carried out outside the living body, usually in the laboratory, as distinguished from in vivo.
Literally, “in the living body;” processes, such as the absorption of a drug by the human body, carried out in the living body rather than in a laboratory (in vitro). IRB See: Institutional Review Board.
An ethical principle discussed in the Belmont Report requiring fairness in distribution of burdens and benefits; often expressed in terms of treating persons of similar circumstances or characteristics similarly.
The period of time during which a woman is providing her breast milk to an infant or child.
LEGALLY AUTHORIZED REPRESENTATIVE
A person authorized either by statute or by court appointment to make decisions on behalf of another person. In human subjects research, an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research [Federal Policy §___.102(c)].
An expression of the probability that a gene and a marker are linked.
A study designed to follow subjects forward through time.
MASKED STUDY DESIGNS
Study designs comparing two or more interventions in which either the investigators, the subjects, or some combination thereof do not know the treatment group assignments of individual subjects. Sometimes called “blind” study designs. (See also: Double-Masked Design; Single-Masked Design.)
Someone who has not reached adulthood (as defined by state law) but who may be treated as an adult for certain purposes (e.g., consenting to medical care). Note that a mature minor is not necessarily an emancipated minor. (See also: Emancipated Minor.)
A diagnostic or therapeutic article that does not achieve any of its principal intended purpose through chemical action within or on the body. Such devices include diagnostic test kits, crutches, electrodes, pacemakers, arterial grafts, intraocular lenses, and orthopedic pins or other orthopedic equipment.
MEDICAL DEVICE AMENDMENTS (MDA)
Amendments to the Federal Food, Drug and Cosmetic Act passed in 1976 to regulate the distribution of medical devices and diagnostic products.
MEDICALLY RESPONSIBLE CLINICIAN
a licensed medical doctor or other practitioner skilled and knowledgeable about caring for persons with the kinds of conditions/disease represented by the specific study population, who is designated by an investigator and approved by and IRB to evaluate whether decisionally incapable subjects’ continued participation is appropriate in research that presents a minor increase over minimal risk is more than a minor increase over minimal risk
See: Cognitively Impaired.
METABOLISM (OF A DRUG)
The manner in which a drug is acted upon (taken up, converted to other substances, and excreted) by various organs of the body.
A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests [Federal Policy §___.102(i)]. For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of routine physical examination. The definition of minimal risk for research involving prisoners differs somewhat from that given for noninstitutionalized
adults. [See 45 CFR 46.303(d) and Guidebook Chapter 6, Section E, “Prisoners.”]
MINOR INCREASE OVER MINIMAL RISK
the probability and magnitude of harm or discomfort anticipated in the research, including psychological harm and loss of privacy or other aspects of personal dignity, are only slightly greater in and of themselves that those ordinarily encountered during the performance if routine physical or psychological examination or tests
The collection and analysis of data as the project progresses to assure the appropriateness of the research, its design and subject protections.
MORE THAN MINOR INCREASE OVER MINIMAL RISK
subjects, as a result of research participation, would be exposed to more than remote possibility of: 1. Substantial or prolonged pain, discomfort, or distress; or 2. Clinically significant deterioration of medical or mental condition
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. An interdisciplinary advisory body, established by Congressional legislation in 1974, which was in existence until 1978, and which issued a series of reports and recommendations on ethical issues in research and medicine, many of which are now embodied in federal regulations. NDA See: New Drug Application.
NEW DRUG APPLICATION
Request for FDA approval to market a new drug.
National Institute on Alcohol Abuse and Alcoholism; an institute in NIH.
National Institute on Drug Abuse; an institute in NIH.
National Institutes of Health: a federal agency within the Public Health Service, DHHS, comprising 21 institutes and centers. It is responsible for carrying out and supporting biomedical and behavioral research.
National Institute of Mental Health; an institute in NIH.
Member of an Institutional Review Board who has no ties to the parent institution, its staff, or faculty. This individual is usually from the local community (e.g., minister, business person, attorney, teacher, homemaker).
NONSIGNIFICANT RISK DEVICE
An investigational medical device that does not present significant risk to the patient. (See also: Significant Risk Device.)
Research that has no likelihood or intent of producing a diagnostic, preventive, or therapeutic benefit to the current subjects, although it may benefit subjects with a similar condition in the future.
An expelled or delivered fetus which, although it is living, cannot possibly survive to the point of sustaining life independently, even with the support of available medical therapy [45 CFR 46.203 (d) and (e)]. Although it may be presumed that an expelled or delivered fetus is nonviable at a gestational age less than 20 weeks and weight less than 500 grams [Federal Register 40 (August 8, 1975): 33552], a specific determination as to viability must be made by a physician in each instance. (See also: Viable Infant.)
Volunteer subjects used to study normal physiology and behavior or who do not have the condition under study in a particular protocol, used as comparisons with subjects who do have the condition. “Normal” may not mean normal in all respects. For example, patients with broken legs (if not on medication that will affect the results) may serve as normal volunteers in studies of metabolism, cognitive development, and the like. Similarly, patients with heart disease but without diabetes may be the “normals” in a study of diabetes complicated by heart disease.
The proposition, to be tested statistically, that the experimental intervention has “no effect,” meaning that the treatment and control groups will not differ as a result of the intervention. Investigators usually hope that the data will demonstrate some effect from the intervention, thereby allowing the investigator to reject the null hypothesis.
A code of research ethics developed during the trials of Nazi war criminals following World War II and widely adopted as a standard during the 1950s and 1960s for protecting human subjects.
OFFICE FOR PROTECTION FROM RESEARCH RISKS (OPRR)
The office within the National Institutes of Health, an agency of the Public Health Service, Department of Health and Human Services, responsible for implementing DHHS regulations (45 CFR Part 46) governing research involving human subjects.
An experimental design in which both the investigator(s) and the subjects know the treatment group(s) to which subjects are assigned.
See: Office for Protection from Research Risks.
Making decisions for others against or apart from their wishes with the intent of doing them good.
The agreement of parent(s) or guardian to the participation of their child or ward in research [45 CFR 46.402(c)].
The scientific discipline that studies the action of drugs on living systems (animals or human beings).
PHASE 1, 2, 3, 4 DRUG TRIALS
Different stages of testing drugs in humans, from first application in humans (Phase 1) through limited and broad clinical tests (Phase 3), to postmarketing studies (Phase 4).
PHASE 1 DRUG TRIAL
Phase 1 trials include the initial introduction of an investigational new drug into humans. These studies are typically conducted with healthy volunteers; sometimes, where the drug is intended for use in patients with a particular disease, however, such patients may participate as subjects. Phase 1 trials are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness; they are typically closely monitored. The ultimate goal of Phase 1 trials is to obtain sufficient information about the drug’s pharmacokinetics and pharmacological effects to permit the design of well-controlled, sufficiently valid Phase 2 studies. Other examples of Phase 1 studies include studies of drug metabolism, structure-activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase 1 investigations is generally in the range of 20-80. ·
PHASE 2 DRUG TRIAL
Phase 2 trials include controlled clinical studies conducted to evaluate the drug’s effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well-controlled, closely monitored, and conducted with a relatively small number of patients, usually involving no more than several hundred subjects. ·
PHASE 3 DRUG TRIAL
Phase 3 trials involve the administration of a new drug to a larger number of patients in different clinical settings to determine its safety, efficacy, and appropriate dosage. They are performed after preliminary evidence of effectiveness has been obtained, and are intended to gather necessary additional information about effectiveness and safety for evaluating the overall benefit-risk relationship of the drug, and to provide and adequate basis for physician labeling. In Phase 3 studies, the drug is used the way it would be administered when marketed. When these studies are completed and the sponsor believes that the drug is safe and effective under specific conditions, the sponsor applies to the FDA for approval to market the drug. Phase 3 trials usually involve several hundred to several thousand patient-subjects.
PHASE 4 DRUG TRIAL
Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (Phase 4) studies to delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time [21 CFR §312.85].
The physical manifestation of a gene function.
Public Health Service. Part of the U.S. Department of Health and Human Services, it includes FDA, NIH, CDC, SAMHSA, and HRSA.
A chemically inert substance given in the guise of medicine for its psychologically suggestive effect; used in controlled clinical trials to determine whether improvement and side effects may reflect imagination or anticipation rather than actual power of a drug.
Medical devices marketed after enactment of the 1976 Medical Device Amendments.
Medical devices marketed before enactment of the 1976 Medical Device Amendments.
Laboratory and animal studies designed to test the mechanisms, safety, and efficacy of an intervention prior to its applications to humans.
Currently legally marketed devices to which new devices may be found substantially equivalent under the 510(k) process.
The period of time from confirmation of implantation of a fertilized egg within the uterus until the fetus has entirely left the uterus (i.e., has been delivered). Implantation is confirmed through a presumptive sign of pregnancy such as missed menses or a positive pregnancy test [45 CFR 46.203(b)]. This “confirmation” may be in error, but, for research purposes, investigators would presume that a living fetus was present until evidence to the contrary was clear. Although fertilization occurs a week or more before implantation, the current inability to detect the fertilization event or the presence of a newly fertilized egg makes a definition of pregnancy based on implantation necessary.
Process of scientific and regulatory review by the FDA to ensure the safety and effectiveness of Class III devices.
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. An interdisciplinary advisory group, established by congressional legislation in 1978, which was in existence until 1983, and which issued reports on ethical problems in health care and in research involving human subjects.
The scientist or scholar with primary responsibility for the design and conduct of a research project. (See also: Investigator.)
An individual involuntarily confined in a penal institution, including persons: (1) sentenced under a criminal or civil statue; (2) detained pending arraignment, trial, or sentencing; and (3) detained in other facilities (e.g., for drug detoxification or treatment of alcoholism) under statutes or commitment procedures providing such alternatives to criminal prosecution or incarceration in a penal institution [45 CFR 46.303(c)].
Control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others.
The person whose case serves as the stimulus for the study of other members of the family to identify the possible genetic factors involved in a given disease, condition, or characteristic.
Preventive or protective; a drug, vaccine, regimen, or device designed to prevent, or provide protection against, a given disease or disorder.
PROSPECT OF DIRECT BENEFIT
on the basis of scientific evidence, a realistic possibility exists that some subjects physical, medical or mental conditions and related functioning might be improved as a direct result of participation in research, including ameliorating symptoms or avoiding side effects of standard therapy
Studies designed to observe outcomes or events that occur subsequent to the identification of the group of subjects to be studied. Prospective studies need not involve manipulation or intervention but may be purely observational or involve only the collection of data.
The formal design or plan of an experiment or research activity; specifically, the plan submitted to an IRB for review and to an agency for research support. The protocol includes a description of the research design or methodology to be employed, the eligibility requirements for prospective subjects and controls, the treatment regimen(s), and the proposed methods of analysis that will be performed on the collected data.
The relative absence of extraneous matter in a drug or vaccine that may or may not be harmful to the recipient or deleterious to the product.
A study that is similar to a true experimental study except that it lacks random assignments of subjects to treatment groups. (See also: Experimental Study.)
Any substance defined as a drug in §201(b)(1) of the Federal Food, Drug and Cosmetic Act that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons [21 CFR 310.3(n)]. Included are any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of a radioactive drug and “radioactive biological products,” as defined in 21 CFR 600.3(ee). Drugs such as carbon-containing compounds or potassium-containing salts containing trace quantities of naturally occurring radionuclides are not considered radioactive drugs.
RADIOACTIVE DRUG RESEARCH COMMITTEE (RDRC)
An institutional committee responsible for the use of radioactive drugs in human subjects for research purposes. Research involving human subjects that proposes to use radioactive drugs must meet various FDA requirements, including limitations on the pharmacological dose and the radiation dose. Furthermore, the exposure to radiation must be justified by the quality of the study and the importance of the information it seeks to obtain. The committee is also responsible for continuing review of the drug use to ensure that the research continues to comply with FDA requirements, including reporting obligations. The committee must include experts in nuclear medicine and the use of radioactive drugs, as well as other medical and scientific members [21 CFR 36.1].
RADIOPAQUE CONTRAST AGENTS
Materials that stop or attenuate radiation that is passed through the body, creating an outline on film of the organ(s) being examined. Contrast agents, sometimes called “dyes,” do not contain radioisotopes. When such agents are used, exposure to radiation results only from the X-ray equipment used in the examination. The chemical structure of radiopaque contrast agents can produce a variety of adverse reactions, some of which may be severe – and possibly life-threatening – in certain individuals.
Drugs (compounds or materials) that may be labeled or tagged with a radioisotope. These materials are largely physiological or subpharmacological in action, and, in many cases, function much like materials found in the body. The principal risk associated with these materials is the consequent radiation exposure to the body or to specific organ systems when they are injected into the body.
RANDOM, RANDOM ASSIGNMENT, RANDOMIZATION, RANDOMIZED
Assignment of subjects to different treatments, interventions, or conditions according to chance rather than systematically (e.g., as dictated by the standard or usual response to their condition, history, or prognosis, or according to demographic characteristics). Random assignment of subjects to conditions is an essential element of experimental research because it makes more likely the probability that differences observed between subject groups are the result of the experimental intervention.
RECOMBINANT DNA TECHNOLOGY
“The ability to chop up DNA, the stuff of which genes are made, and move the pieces, [which] permits the direct examination of the human genome,” and the identification of the genetic components of a wide variety of disorders [Holtzman (1989), p. 1]. Recombinant DNA technology is also used to develop diagnostic screens and tests, as well as drugs and biologics for treating diseases with genetic components. See Guidebook Chapter 5, Section H, “Human Genetic Research.” REM Acronym for Roentgen Equivalent in Man; the unit of measurement for a dose of an ionizing radiation that produces the same biological effect as a unit of absorbed does (1 rad) of ordinary X-rays. One millirem is equal to 1/1000 of a rem.
A period in which the signs and symptoms of a disease are diminished or in abeyance. The term “remission” is used when one cannot say with confidence that the disease has been cured.
Payment for participation in research. (NOTE: It is wise to confine use of the term “compensation” to payment or provision of care for research-related injuries.) (Compare: Compensation.)
A systematic investigation (i.e., the gathering and analysis of information) designed to develop or contribute to generalizable knowledge [Federal Policy §___.102(d)].
RESPECT FOR PERSONS
An ethical principle discussed in the Belmont Report requiring that individual autonomy be respected and that persons with diminished autonomy be protected.
Research conducted by reviewing records from the past (e.g., birth and death certificates, medical records, school records, or employment records) or by obtaining information about past events elicited through interviews or surveys. Case control studies are an example of this type of research.
REVIEW (OF RESEARCH)
The concurrent oversight of research on a periodic basis by an IRB. In addition to the at least annual reviews mandated by the federal regulations, reviews may, if deemed appropriate, also be conducted on a continuous or periodic basis [Federal Policy §___.108(e)]. RISK The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant. Federal regulations define only “minimal risk.” (See also: Minimal Risk.)
Substance Abuse and Mental Health Services Administration; includes the Center for Substance Abuse Prevention, the Center for Substance Abuse Treatment and the Center on Mental Health Services. Previously the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA). (See also: ADAMHA.)
SCIENTIFIC REVIEW GROUP
A group of highly regarded experts in a given field, convened by NIH to advise NIH on the scientific merit of applications for research grants and contracts. Scientific review groups are also required to review the ethical aspects of proposed involvement of human subjects. Various kinds of scientific review groups exist, and are known by different names in different institutes of the NIH (e.g., Study Sections, Initial Review Groups, Contract Review Committees, or Technical Evaluation Committees).
A U.S. Cabinet Officer. In the context of DHHS-conducted or -supported research, usually refers to the Secretary of Health and Human Services.
SIGNIFICANT RISK DEVICE
An investigational medical device that presents a potential for serious risk to the health, safety, or welfare of the subject.
Typically, a study design in which the investigator, but not the subject, knows the identity of the treatment assignment. Occasionally the subject, but not the investigator, knows the assignment. Sometimes called “single-blind design.”
A visit by agency officials, representatives, or consultants to the location of a research activity to assess the adequacy of IRB protection of human subjects or the capability of personnel to conduct the research.
Systematic manipulation of, or experimentation in, social or economic systems; used in planning public policy.
SPONSOR (OF A DRUG TRIAL)
A person or entity that initiates a clinical investigation of a drug – usually the drug manufacturer or research institution that developed the drug. The sponsor does not actually conduct the investigation, but rather distributes the new drug to investigators and physicians for clinical trials. The drug is administered to subjects under the immediate direction of an investigator who is not also a sponsor. A clinical investigator may, however, serve as a sponsor-investigator. The sponsor assumes responsibility for investigating the new drug, including responsibility for compliance with applicable laws and regulations. The sponsor, for example, is responsible for obtaining FDA approval to conduct a trial and for reporting the results of the trial to the FDA.
An individual who both initiates and actually conducts, alone or with others, a clinical investigation. Corporations, agencies, or other institutions do not qualify as sponsor-investigators.
A determination of the probability of obtaining the particular distribution of the data on the assumption that the null hypothesis is true. Or, more simply put, the probability of coming to a false positive conclusion. [See McLarty (1987), p. 2.] If the probability is less than or equal to a predetermined value (e.g., 0.05 or 0.01), then the null hypothesis is rejected at that significance level (0.05 or 0.01).
The absence of viable contaminating microorganisms; aseptic state.
The inability to procreate; the inability to conceive or induce conception.
See: Scientific Review Group.
See: Human Subjects.
a family member or close friend authorized by these regulations to make human subject research decisions for n adults without capacity to consent to research participation in the absence of a health care agent and a research agent. The surrogate for an adult without capacity to consent to research participation would be one person from the following list, chosen from the class highest in priority when persons in prior class are not reasonably available, willing, and competent to act:
1. The spouse, if not legally separated from the adult;
2. A son or daughter eighteen years or older;
3. A parent;
4. A brother or sister eighteen years or older;
5. A close friend or relative eighteen years or older.
Studies designed to obtain information from a large number of respondents through written questionnaires, telephone interviews, door-to-door canvassing, or similar procedures.
The research physician’s intent to provide some benefit to improving a subject’s condition (e.g., prolongation of life, shrinkage of tumor, or improved quality of life, even though cure or dramatic improvement cannot necessarily be effected.) This term is sometimes associated with Phase 1 drug studies in which potentially toxic drugs are given to an individual with the hope of inducing some improvement in the patient’s condition as well as assessing the safety and pharmacology of a drug.
Treatment intended and expected to alleviate a disease or disorder.
UNIFORM ANATOMICAL GIFT ACT
Legislation adopted by all 50 States and the District of Columbia that indicates procedures for donation of all or part of a decedent’s body for such activities as medical education, scientific research, and organ transplantation.
A biologic product generally made from an infectious agent or its components – a virus, bacterium, or other microorganism – that is killed (inactive) or live-attenuated (active, although weakened). Vaccines may also be biochemically synthesized or made through recombinant DNA techniques.
An element or factor that the research is designed to study, either as an experimental intervention or a possible outcome (or factor affecting the outcome) of that intervention.
When referring to a delivered or expelled fetus, the term “viable infant” means likely to survive to the point of sustaining life independently, given the benefit of available medical therapy [45 CFR 46.203(d)]. This judgment is made by a physician. In accordance with DHHS regulations, the Secretary, HHS, may publish guidelines to assist in the determination of viability. Such guidelines were published in 1975, and specify an estimated gestational age of 20 weeks or more and a body weight of 500 grams or more as indices of fetal viability [Federal Register 40 (August 8, 1975): 33552]. These indices depend on the state of present technology and may be revised periodically. (See also: Nonviable Fetus.)
Free of coercion, duress, or undue inducement. Used in the research context to refer to a subject’s decision to participate (or to continue to participate) in a research activity.