Appendix D
Glossary and Acronyms

This Glossary is intended to define terms and acronyms that are commonly used throughout this report as well as those terms and acronyms that are commonly used during the Food and Drug Administration (FDA) regulatory review process. This glossary is not all-inclusive. New terms and new uses of existing terms will emerge with time and advances in technology. Definitions for the terms and acronyms herein were compiled from a multitude of sources, which are listed at the end of the Glossary.


Adverse drug reaction:

Any noxious, unintended, or undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. This World Health Organization definition excludes therapeutic failures, intentional and accidental poisoning (i.e., overdose), and drug abuse. Additionally, this also does not include adverse events due to errors in administration or noncompliance (taking a drug at more or less than the prescribed dosage).

Analysis:

Comparison of the outcomes for the study and control groups.

Audits, Food and Drug Administration:

Process by which the Food and Drug Administration reviews the clinical data as part of clinical drug trials.


Benchmark standard:

A criterion of evaluation or measurement used as a reference point in observation.

Bioresearch Monitoring Program:

A comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of Food and Drug Administration-regulated research. This program monitors sponsors, Institutional Review Boards, clinical investigators, and nonclinical laboratories involved in the testing of investigational devices.



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Appendix D Glossary and Acronyms This Glossary is intended to define terms and acronyms that are commonly used throughout this report as well as those terms and acronyms that are commonly used during the Food and Drug Administration (FDA) regulatory review process. This glossary is not all-inclusive. New terms and new uses of existing terms will emerge with time and advances in technology. Definitions for the terms and acronyms herein were compiled from a multitude of sources, which are listed at the end of the Glossary. Adverse drug reaction: Any noxious, unintended, or undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. This World Health Organization definition excludes therapeutic failures, intentional and accidental poisoning (i.e., overdose), and drug abuse. Additionally, this also does not include adverse events due to errors in administration or noncompliance (taking a drug at more or less than the prescribed dosage). Analysis: Comparison of the outcomes for the study and control groups. Audits, Food and Drug Administration: Process by which the Food and Drug Administration reviews the clinical data as part of clinical drug trials. Benchmark standard: A criterion of evaluation or measurement used as a reference point in observation. Bioresearch Monitoring Program: A comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of Food and Drug Administration-regulated research. This program monitors sponsors, Institutional Review Boards, clinical investigators, and nonclinical laboratories involved in the testing of investigational devices.

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Blinding: A study design feature that helps ensure that bias does not distort the conduct of a study or the integration of its results. In a single-blind study, only the clinical investigators are aware of which intervention (e.g., investigational drug or control) each patient is receiving. In a double-blind study, neither the patients nor the clinical investigators know the identity of the intervention. In a triple-blind study, neither the patients, the clinical investigators, nor the committee monitoring the response variables is told the identity of the groups. Carcinogenicity: Producing or tending to produce cancer. Case report form: A standardized data entry form used in a clinical trial. Generally, all information collected in trials appears on Case Report Forms (CRFs), or is referred to and explained by CRFs. Center for Biologics Evaluation and Research (CBER): A center of the Food and Drug Administration whose mission is to protect and enhance the public health through regulation of biological and related products including blood, vaccines, and biological therapeutics according to statutory authorities (www.fda.gov/cber). Center for Devices and Radiological Health (CDRH): The center of the Food and Drug Administration whose responsibility is to ensure that medical devices are safe and effective, including ensuring the minimization of exposure from radiation-emitting electronic products (www.fda.gov/cdrh). Center for Drug Evaluation and Research (CDER): A center of the Food and Drug Administration whose mission is to ensure that safe and effective drugs are available to the American people (www.fda.gov/cder). Clinical reviewer: A person with responsibility for critically evaluating a medical perspective information contained in a marketing application. Clinical studies: The class of all scientific approaches used to evaluate medical means of disease prevention, medical diagnostic techniques, and medical treatments. Investigational and marketed prescription drug evaluations plus over-the-counter drugs are included. Clinical trials: Medical research studies conducted with volunteers. Each study is designed to answer scientific questions and to find better ways to prevent, detect, or treat human medical conditions. Clinical trial protocol: Document describing a clinical study and how it is to be conducted. A protocol includes the objectives of the study, the study design, a description of the drug and the dosage, the experimental procedure, handling of adverse reactions, how the results will be analyzed, and patient consent and clearance provisions. Comparative studies: Studies conducted to determine statistically whether one procedure is better than another. Compliance: A quantitative indicator of whether a set of procedures or practices were carried out in accordance with established guidelines or standards stated in the protocol of a study.

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Concomitant medication: An additional therapy or regimen that is either self-administered or prescribed concurrently with a study therapy. Contract Research Organizations (CROs): Organizations that are hired by companies to perform specific studies on a given topic. Cooperative Clinical Trials Group (CCTG): A community-based organization that conducts research involving human volunteers under agreement with the National Institutes of Health. Data: All collected and recorded information on patients considered for enrollment or actually enrolled in a trial. Database: A collection of data files that are organized in a specified manner and that are accessed by designated personnel for designated purposes. Defibrillator: An electronic apparatus used to counteract atrial or ventricular fibrillation by the application of brief electroshock to the heart, either directly or through electrodes placed on the chest wall. Discovery: The early phases of the overall drug development process dealing with the synthesis of or search for compounds and the screening process developed to identify lead compounds. Disease: The condition in which the functioning of the body or a part of the body is interfered with or damaged. In a person with an infectious disease, the infectious agent that has entered the body causes it to function abnormally in some way(s). The type of abnormal functioning that occurs is the disease. Usually, the body will show signs and symptoms of the problems that it is having with functioning. Disease should not be confused with infection. Double blinding: In a clinical trial, a procedure for issuing and administering treatment assignments by code number to keep study patients and all members of the clinical staff, especially those responsible for patient treatment and data collection, from knowing the assigned treatments so that the information does not influence some measurement, observation, or process. Drug (from the Food and Drug Administration Food, Drug, & Cosmetic Act): (1) a substance recognized by an official pharmacopoeia or formulary; (2) a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; (3) a substance other than food intended to affect the structure or function of the body; (4) a substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device. Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process). Drug development process: The entirety of the activities and decision making that must be completed from the identification of a lead compound to regulatory agency approval for marketing of a compound as a new drug product.

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Effectiveness: The desired measure of a drug's influence on a disease condition. Effectiveness must be proven by substantial evidence consisting of adequate and well-controlled investigations, including human studies by qualified experts, which prove that the drug will have the effect claimed in its labeling. Efficacy: A relative concept referring to the ability of a drug to elicit a beneficial clinical effect. This may be measured or evaluated by using objective or subjective parameters and in terms ranging from global impressions to highly precise measurements. Equivalence trials: A trial typically conducted to demonstrate that there is no clinically significant difference between a standard and an experimental treatment. The study is designed with the desired outcome being equivalence in efficacy, while immediate toxicity, long-term adverse effects, or costs may be demonstrated to be advantageous for the experimental treatment. Federal Food, Drug, and Cosmetic Acts of 1938 and 1962: Law that requires a manufacturer to prove the safety and effectiveness of a drug before it can be marketed. Food and Drug Administration (FDA): A public health agency charged with protecting American consumers by enforcing the Federal Food, Drug, and Cosmetic Act and several related health laws (www.fda.gov). Food and Drug Administration Modernization Act of 1997 (FDAMA): Major legislation focused on reforming the regulation of food, medical products, and cosmetics. Some of the provisions of the act include prescription drug user fees, Food and Drug Administration initiatives and programs, information on off-label use and drug economics, risk-based regulation of medical devices, and standards for medical products. Form FDA 483: An official Food and Drug Administration form on which any objectionable conditions and/or practices noted during an inspection are listed. A Food and Drug Administration investigator issues Form FDA 483 to an establishment (e.g. investigator, sponsor, monitor, contract research organization, or Institutional Review Board) at the conclusion of an inspection. Gene therapy: The process of introducing new genes into the DNA of a person's cells to correct a genetic disease or flaw. Generic Drug Enforcement Act of 1992: A law authorizing the Secretary of Health and Human Services to impose debarments and to take other action to ensure the integrity of abbreviated drug applications under the Federal Food, Drug, and Cosmetic Act. Genomics: The study of genomes, which includes genome mapping, gene sequencing, and gene function. Good Clinical Practices (GCP): Food and Drug Administration-promulgated guidelines governing the conduct of clinical studies from which data will be

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used to support applications for marketing permits (New Drug Applications). Good Clinical Practices (GCP) document: An international ethical and scientific quality standard for the design, conduct, recording, and reporting of trials that involve the participation of human subjects. Good Review Practices: A Food and Drug Administration initiative designed to promote standardization of the quality and consistency of reviews of New Drug Applications and Investigational New Drugs. Institutional Review Board (IRB): Any board, committee, or other group of experts and laypeople formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects. The primary purpose of such review is to ensure the protection of the rights and welfare of the human subjects. International Conference on Harmonization (ICH): An organization with representation from the regulatory parties of the European Union, Japan, and the United States, established to create common standards for safety, efficacy, and quality of medical products (www.ich.org). Investigational agents: A medical product (e.g., drug, biologic, or medical device) used for research purposes to diagnose, prevent, or treat disease. Investigational New Drug (IND): Status given an experimental drug after the Food and Drug Administration approves an application for it to be tested with humans. Investigational New Drug (IND) application: Application that a drug sponsor must submit to the Food and Drug Administration before beginning tests of a new drug on humans. The Investigational New Drug application contains the plan for the study and is supposed to give a complete picture of the drug, including structural formula, animal test results, and manufacturing information. Managed care: Arrangements for integrated health care delivery and financing that are designed to provide appropriate, effective, and efficient health care through organized relationships with providers. Includes formal programs for ongoing quality assurance and utilization review, financial incentives for covered members to use the plan's providers, and financial incentives for providers to contain costs. Managed care plans vary greatly in the degree to which benefit coverage is offered, monitored, and conditioned upon certain criteria being met by the subscriber and the subscriber's primary care physician. Medical device: A diagnostic or therapeutic contrivance that does not interact chemically with a person's body. Monitor: A person who oversees the ongoing evaluation of a continuing process to determine when and if changes in that process are necessary for reasons of efficiency, data quality, safety, and so forth.

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National Cancer Institute (NCI): The federal government's principal agency for cancer research and training. The National Cancer Institute is a component of the National Institutes of Health (www.nci.nih.gov). National Institutes of Health (NIH): A group of institutes and related support structures responsible for funding basic and applied research in the health field. The National Institutes of Health also initiates and carries out medical research on an intramural and extramural basis (www.nih.gov). New Drug Application (NDA): An application requesting Food and Drug Administration approval to market a new drug for human use in interstate commerce. The application must contain, among other things, data from specific technical viewpoints for Food and Drug Administration review, including chemistry, pharmacology, medicine, biopharmaceutics, and statistics, as well as for anti-infectives and microbiology. Oncology: The study of diseases that cause cancer. Orphan drugs: Drugs (and other products) for the treatment of a rare disease that affects fewer than 200,000 people or a drug that may offer little or no profit to the manufacturer but that may benefit people with rare diseases. Outliers: In statistics, an observation so distant from the central mass of data that it is considered an obvious mistake or anomaly that should be removed from the data whether or not a cause of the deviation can be found. Outsourcing: Hiring of contract employees to perform support services rather than use of a company's own employees. Patient: In the clinical trial setting, patient refers to any subject involved in the trial. Pharmaceutical: A medicinal drug. Pharmacokinetics: The action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, metabolism, and excretion. Pharmacology: The science that deals with the origin, nature, chemistry, and effects of drugs and the uses of drugs for living organisms. Phase 1 trials: The first trials in humans that test a compound for safety, tolerance, and pharmacokinetics. The Phase 1 trials usually use healthy volunteers. For known toxic compounds, such as anticancer agents, only patients with the targeted illness are used. Phase 2 trials: The pilot studies that define efficacy and further test safety with selected populations of patients with the disease or condition to be treated, diagnosed, or prevented. Dose and dosing regimens are assessed for magnitude and duration of effect during this phase. Phase 3 trials: Expanded clinical trials intended to gather additional evidence of effectiveness for specific indications and to better understand safety and drug-related adverse effects. Phase 3 trials are usually large multicenter trials that achieve substantial safety experience and may also include specialized studies needed for labeling.

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Pivotal trial: A clinical trial for a marketing application that is considered an essential component to supporting the safe and effective use of a medical product. Placebo: A pharmacologically inactive agent given to a patient as a substitute for an active agent. When trials with placebos are conducted, the patient is not informed whether he or she is receiving the active or the inactive agent (the placebo). Postmarketing surveillance: Requirement that drug firms report to the Food and Drug Administration the adverse experiences from the use of all marketed drugs of which they are aware. If the adverse experiences result in death, prolonged hospitalization, or permanent disability, the firm must report the incident within 15 days of its notification of the adverse experience. All other adverse experiences can be reported on an annual basis. Premarket Approval Application (PMA): An application requesting Food and Drug Administration approval to market a new medical device for human use in interstate commerce. The application must contain, among other things, data from specific technical viewpoints for Food and Drug Administration review. Prescription Drug User Fee Act of 1992 (PDUFA): Requires manufacturers to pay fees for certain new drug applications and supplements, an annual establishment fee, and annual product fees. Quality assurance (QA): Any procedure, method, or philosophy for collecting, processing, or analyzing data that is aimed at maintaining or improving the reliability or validity of the data and the associated procedures used to generate them. Remote data capture: A process by which information is entered directly into a computer or a centralized database without being recorded on paper. Safety: A relative concept referring to the freedom from harm or damage resulting from adverse reactions or physical, psychological, or behavioral abnormalities that occur as a result of drug or nondrug use. No drug is completely safe or without the potential for side effects. Before a drug may be approved for marketing, the law requires the submission of results of tests adequate to show that the drug is safe under the conditions of use in the proposed labeling. ''Safety'' is thus determined on a case-by-case basis and reflects the drug's risk-versus-benefit relationship. Site monitoring: The act of overseeing the progress of a clinical trial and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, Good Clinical Practices, and the applicable regulatory requirements. Special populations: A subset of the population that may be more sensitive than the general public to the effects of a medical product (e.g., pediatric and

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geriatric populations and patients with compromised liver or kidney function). Standard operating procedure (SOP): Established or prescribed methods to be followed routinely for the performance of designated operations or in designated situations. Superiority trial: A trial typically conducted to demonstrate that there is a clinically significant difference between a standard and an experimental treatment. The study is designed with the desired outcome being superiority in efficacy in favor of the experimental treatment. Therapeutic agent: A drug, biologic, or medical device used for research purposes in the treatment of disease. Toxicology: The scientific study of poisons, their actions, their detection, and the treatment of the conditions produced by them. Trial: Any tentative or experimental action conducted to obtain data used to make some judgment or conclusion. Definitions for this Glossary were compiled from the following sources: American Medical Association. Manual of Style, 9th ed. Chicago: American Medical Association, 1998. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ (date of last update: March 9, 1999). Dorland's Illustrated Medical Dictionary, 28th ed. Philadelphia: The W.B. Saunders Co., 1994. Food and Drug Administration. From Test Tube to Patient: New Drug Development in the United States, 2nd ed. Washington, D.C.: U.S. Government Printing Office, 1997. Food and Drug Administration. Available at http://www.fda.gov/ (date of last update: March 22, 1999). Food and Drug Administration, Center for Biologics Evaluation and Research. Available at: http://www.fda.gov/cber/ (date of last update: March 22, 1999). Food and Drug Administration, Center for Devices and Radiological Health. Available at http://www.fda.gov/cdrh/ (date of last update: March 5, 1999). Food and Drug Administration, Center for Drug Evaluation and Research. Available at http://www.fda.gov/cder/ (date of last update: March 2, 1999). Institute of Medicine. Antimicrobial Resistance: Issues and Options . Workshop Report. Harrison PF, J Lederberg, eds. Washington, D.C.: National Academy Press, 1998. International Conference on Harmonization. Available at http://www.ich.org/ (date of last update: November 24, 1998). Lazarou J, B Pomeranz, and P Corey. Incidence of adverse drug reactions in hospitalized patients. JAMA 279(15):1200–1205, 1998.

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McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed. Washington, D.C.: McGraw-Hill, Inc., 1994. Medline Plus. Available at http://www.nlm.nih.gov/ (date of last update: March 22, 1999). National Cancer Institute. Available at http://www.nci.nih.gov/ (date of last update: March 25, 1999). National Institutes of Health. Available at http://www.nih.gov/ (date of last update: March 10, 1999). Webster's Third New International Dictionary. Springfield, MA: Merriam-Webster, Inc., 1986. World Health Organization. International Drug Monitoring: The Role of the Hospital. Technical Report Series No. 425. Geneva: World Health Organization, 1966.