|Compiled by: |
Douglas S. Kalman MS, RD, FACN
Miami Research Associates
A sign, symptom, or laboratory result not characteristic of normal individuals.
The ICH defines an adverse event as: “Any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment” (see ICH Guideline: Clinical safety data management: definitions and standards for expedited reporting). For non-marketed drugs/product, or new indications of marketed drugs/product, an adverse event is referred to as an adverse reaction when there is a reasonable possibility that it was caused by the medicinal product, i.e. a causal relationship cannot be ruled out.
Adverse experience See adverse event.
Unwanted effect(s) (i.e., physical and psychological symptoms and signs) resulting from treatment. A less rigid definition of adverse reaction includes the previous definition plus any undesirable effect or problem that is present during the period of treatment and may or may not be a well-known or obvious complication of the disease itself. Thus, many common personality, physical, psychological, and behavioral characteristics that are observed in medicine studies are sometimes characterized as adverse reactions even if they were present during baseline.
Synonyms of adverse reactions generally include adverse medical effects, untoward effects, side effects, adverse drug/product experiences, and adverse drug/product reactions. Specific distinctions among some of these terms may be defined operationally. For example, the term adverse reaction is used to denote those signs and symptoms at least possibly related to a medicine, whereas the term adverse experiences is used to include nonmedicine-related medical problems in a trial such as those emanating from trauma or concurrent illness. Distinctions among side effects, adverse events, and adverse reactions are illustrated in the definitions of the two former terms.
(1) A point of view that prevents impartial judgment on issues relating to that point of view. Clinical trials attempt to control this through double blinding. (2) Any tendency for a value to deviate in one direction from the true value. Statisticians attempt to prevent this type of bias by various techniques, including randomization.
A measure that is an indicator of a normal physiologic process, or a pathologic state or the response of an organism to an intervention that can be used in clinical research. When a biomarker can replace a clinical endpoint it is called a surrogate endpoint.
The term “blind” refers to a lack of knowledge of the identity of the trial treatment. Subjects, investigators, date review committees, ancillary personnel, statisticians, and monitors are the major groups of individuals who may be kept blind during a clinical trial. Blinding is used to decrease the biases that occur in a clinical trial when subjects are evaluated during treatment and to avoid a placebo effect that often occurs in open-label trials.
Clinical Drug/Product Development Phase
This classification assumes a sequential approach to drug/product development. However, the clinical pharmacology programmed will overlap the later phases with a number of studies that are required for registration (e.g. interaction studies, or studies in special populations – elderly, renally or hepatically-impaired), and are performed at the same time as the Phase II/III studies.
A measure of how a subject feels functions or survives.
Clinical Investigator’s Brochure
An extensive summary of all that is known about a research compound with regard to pre-clinical and clinical data.
The quality of a study’s outcome that convinces physicians to modify or maintain their current practice of medicine. The greater the clinical significance, the greater is the influence on the practice of medicine. The assessment of clinical significance is usually based on the magnitude of the effect observed, the quality of the study that yielded the data, and the probability that the effect is a true one. Although this operational definition is presented from the physician’s perspective, the term could operationally be defined from the subject’s perspective. Subjects are primarily concerned with results that will lead to an improved quality of life or a lengthening of their life. In addition, clinical significance may be applied to either positive data of efficacy or negative safety data such as for adverse reactions. Synonyms include clinical importance, clinical relevance, and clinical meaningfulness.
The class of all scientific approaches to evaluate medical disease preventions, diagnostic techniques, and treatments. Investigational and marketed prescription medicine evaluations plus over-the-counter medicines or other agents (dietary supplements) are included.
A subset of those clinical studies that evaluates investigational medicines in Phases I, II, and III. Phase IV evaluations of marketed medicines in formal clinical trials using the same or similar types of protocols to those used in Phases I and III are also referred to as clinical trials.
Combination of blinds
(a) In part 1 of a clinical trial, one type of blind may be used (e.g., single blind), and in part 2 of the same trial, another blind (e.g., double blind) may be used. A third part of the same trial may utilize the same blind as part 1 or use an entirely different type of blind. (b) Some subjects may follow a protocol under one type of blind and others follow the same protocol under a different type of blind. (c) The blind used may be changed during the course of the clinical trial according to certain criteria (e.g., when study is done with medical patients, the double blind may be broken, and they may continue their treatment on open-label medication).
Adherence of subjects to following medical advice and prescriptions. Primarily applied to taking medicine as directed, but also applies to following advice on diet, exercise, or other aspects of a subject’s life.
Adherence of investigators to following a protocol and related administrative and regulatory responsibilities.
Adherence of sponsors to following regulatory, legal, and other responsibilities and requirements relating to a clinical trial.
A chemical synthesized or prepared from natural sources that is evaluated for its biological activities in preclinical tests.
A group of clinical trial participants that receives the placebo or standard therapy for a condition while another group is given the experimental treatment. The control group serves as a measuring stick to gauge the effectiveness of the experimental treatment.
Development of Medicines
The term development as applied to medicines is used in several different contexts, even within the pharmaceutical industry. This often leads to confusion and misunderstanding. No single definition is preferred, but the particular meaning intended should be made clear by all people using the term. Three operational definitions are presented, from the broadest to the narrowest.
All stages and processes involved in discovering, evaluating, and formulating a new medicine, until it reaches the market (i.e., commercial sale).
All stages involving the evaluation and formulation of a new medicine (after the medicine has been discovered and has gone through preclinical testing), until it reaches the market.
Those stages after the preclinical discovery and evaluation that involve technical development. These processes include formulation work, stability testing, scaling-up the compound for larger-scale synthesis, and providing analytical support. Clinical trials are not included in this definition.
Disorders (e.g., anxiety disorders, seizure disorders), conditions (e.g., obesity, menopause), syndromes, specific illnesses, and other medical problems that are an acquired morbid change in a tissue, organ, or organism. Synonyms are illness and sickness.
(1) The number of doses per given time period (usually days), (2) the time that elapses between doses (e.g., dose to be given every six hours) or the time that the doses are to be given (e.g., dose to be given at 8 a.m., noon, and 4 p.m. each day) or (3) the quantity of a medicine (e.g., number of tablets, capsules, etc.) that are given at each specific time of dosing.
Neither the subject nor the investigator is aware of which treatment the subject is receiving. A double-blind design is generally considered to provide the most reliable data from a clinical trial. This type of clinical trial, however, is usually more complicated to initiate and conduct than single-blind or open-label trails.
A drug is defined as:
- A substance recognized by an official pharmacopoeia or formulary.
- A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
- A substance (other than food) intended to affect the structure or any function of the body.
- A substance intended for use as a component of of a medicine but not a device or a component, part or accessory of a device.
- Biologic 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 vs. biological process.)
The finished dosage form that contains a drug substance, generally, but not necessarily in association with other active or inactive ingredients.
A licit or illicit substance that is abused. Medicines should be described as drugs/product when they are being purposely abused.
A relative concept referring to the ability of a medicine to elicit a beneficial clinical effect. This may be measured or evaluated using objective or subjective parameters, and in terms ranging from global impressions, to highly precise measurements. Efficacy is assessed at one or more levels of organization (e.g.-subcellular, cellular, tissue, organ, whole body) and may be extrapolated to other levels.
An indicator measured in a subject or biological sample to assess safety, efficacy, or another trial objective. Some endpoints are derived from primary endpoints (e.g., cardiac output is derived from stroke volume and heart rate). Synonyms include outcome, variable, parameter, marker, and measure. See surrogate endpoint in the text. Also defined as the final trial objective by some authors.
An independent group of professionals often complimented by a non-scientific member of the public responsible for approval of study protocols before a study is actually carried out. Subject safety and scientific integrity of the protocol are the main concerns.
Good Clinical Practice
A standard to ensure protection of research subjects and data integrity in clinical studies of new drugs/product.
The rate of occurrence of new cases of a disease, adverse reaction, or other event in a given population at risk (e.g., the incidence of disease X is Y subjects per year per 100,000 population).
International Conference on Harmonization
The International Conference on Harmonization (ICH) has produced guidelines on Good Clinical Practice (GCP) encompassing the requirements of the European Union (EU), Japan and the United States (US) as well as those of the World Health Organization (WHO), Australia, New Zealand and the Nordic countries (ICH Topic E6, Guidelines on Good Clinical Practice).
The processes whereby one determines the clinical meaning or significance of data after the relevant statistical analyses have been performed. These processes often involve developing an explanation of the data that are being evaluated.
A suitably trained scientist (often medically qualified) involved in the execution of a clinical drug/product study. The person with ultimate responsibility for this is called principle or responsible investigator.
When a compound or substance is tested for biological and clinical activity in humans, it is considered to be a medicine. Some individuals prefer to define a medicine as a compound that has demonstrated clinically useful properties in subjects. This definition, however, would restrict the term to use sometime during or after phase II. Others use the term loosely and apply it to compounds with biological properties during the preclinical period that suggest medical usefulness in humans. The author has adopted the first definition for use in this book.
Med Watch (FDA-AER’s)
The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The ultimate goal of AERS is to improve the public health by providing the best available tools for storing and analyzing safety reports.
The FDA receives adverse drug reaction reports from manufacturers as required by regulation. Health care professionals and consumers send reports voluntarily through the MedWatch program. These reports become part of a database. The structure of this database is in compliance with the international safety reporting guidance (www.fda.gov/medwatch/report/iche2b.pdf) issued by the International Conference on Harmonisation. The guidance describes the content and format for the electronic submission of reports from manufacturers. FDA codes all reported adverse events using a standardized international terminology, MedDRA (the Medical Dictionary for Regulatory Activities). Among AERS system features are: the on-screen review of reports; searching tools; and various output reports. FDA staff use reports from AERS in conducting postmarketing drug surveillance and compliance activities and in responding to outside requests for information.
The reports in AERS are evaluated by clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to detect safety signals and to monitor drug safety. They form the basis for further epidemiological studies when appropriate. As a result, the FDA may take regulatory actions to improve product safety and protect the public health, such as updating a product’s labeling information, sending out a "Dear Health Care Professional" letter, or re-evaluating an approval decision.
No blind is used. Both investigator and subject know the identity of the medicine.
The scientific discipline involved in the study of drug/product action on molecular or cellular targets or on the whole organism.
The study of the time course of the concentration of a substance and its metabolites in body fluids like blood and urine.
Phases of clinical trials and medicine development
Four phases of clinical trials and medicine development exist and are defined below. Each of these definitions is a functional one and the terms are not defined on a strict chronological basis. An investigational medicine is often evaluated in two or more phases simultaneously in different clinical trials. Also, some clinical trials may overlap two different phases.
Clinical Pharmacology Studies in healthy volunteers (sometimes subjects) to determine the safety and tolerability of the drug/product, other dynamic effects and the pharmacokinetic profile (absorption. distribution, metabolism and excretion – ADME). Evidence of efficacy may be gained if subjects, disease models or biomarkers are used.
Clinical Investigation studies in subjects with the target disease, to determine efficacy, safety and tolerability in carefully controlled dose-ranging studies.
Pilot clinical trials to evaluate efficacy (and safety) in selected populations of subjects with the disease or condition to be treated, diagnosed, or prevented. Objectives may focus on dose-response, type of subject, frequency of dosing, or numerous other characteristics of safety and efficacy.
Well-controlled trials to evaluate efficacy (and safety) in subjects with the disease or condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy.
Formal clinical trials. Large-scale placebo controlled and active comparator studies in subjects to confirm efficacy, and provide further information on the safety and tolerability of the drug/product.
Trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug/product Application (NDA) or other dossier. These clinical trials are conducted in subjects’ populations for which the medicine is eventually intended. Phase IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of subjects in both controlled and uncontrolled trials. Clinical trials are also conducted in special groups of subjects (e.g. renal failure subjects), or under special conditions dictated by the nature of the medicine and disease. These trials often provide much of the information needed for the package insert and labeling of the medicine.
Clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine’s approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed towards new types of trials (e.g., quality of life, marketing) or phase IV evaluations. This is the period between submission and approval of a regulatory dossier for marketing authorization.
Post-marketing surveillance to expand safety and efficacy data in a large population, including further formal therapeutic trials and comparisons with other active comparators.
A pilot trial is used to obtain information, and work out the logistics and management, deemed necessary for further clinical trials. Although pilot trials are often unblind and use open-label medicines, they may also be single or double blind and may include tight control on all appropriate variables. The term “pilot” refers to the purpose of the trial (2).
Means “I shall please” in Latin; it is a term applied to a remedy that does not affect the “specific mechanisms” of the disease in question, or to the favorable response that the treatment often elicits.
Pre-clinical Drug/product Development
The studies done in cells, tissues and whole animals as well as the chemical and pharmaceutical investigations to obtain adequate Assurance that a new drug/product may safely be given to man in clinical studies.
The total number of people in a population that are affected with a particular disease at a given time. This term is expressed as the rate of all cases (e.g., the prevalence of disease X is Y subjects per 100,000 population) at a given point or period of time.
The procedures ad control systems in place during a clinical trial to ensure integrity of the data and protection of the subjects.
The checks performed to ensure that the quality control system is adhered to.
Each subject has a known chance, usually equal chance, of being given each treatment, but the treatment to be given cannot be predicted. The idea of randomness accords with our intuitive ideas of chance and probability, but it is distinct from those of haphazard or arbitrary allocation.
Numerous definitions of research are used both in the literature and among scientists. In the broadest sense, research in the pharmaceutical industry includes all processes of medicine discovery, preclinical and clinical evaluation, and technical development. In a more restricted sense, research concentrates on the preclinical discovery phase, where the basic characteristics of a new medicine are determined. Once a decision is reached to study the medicine in humans to evaluate its therapeutic potential, the compound passes from the research to the development phase.
Research and development
When research and development are used together, it refers to the broadest definition for research (see above). Some people use the term research colloquially to include most or all of the scientific and medical areas (discovery, evaluation, and development) covered by the single term research and development. Medicine development has several definitions and, in its broadest definition, is exactly the same as the broad definition of research.
A measure of (1) the probability of occurrence of harm to human health or (2) the severity of harm that may occur. Such a measure includes the judgment of the acceptability of risk. Assessment of safety involves judgment, and there are numerous perspectives (e.g., subjects, physicians, company, regulatory authorities) used for judging it.
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 medicine or nonmedicine use. Safety is usually measured with one or more of the following: physical examination (e.g., vital signs, neurological, opthalmological, general physical), laboratory evaluations of biological samples (e.g., hematology, clinical chemistry, urinalysis), special tests and procedures (e.g., electrocardiogram, pulmonary function tests), psychiatric tests and evaluations, and determination of clinical signs and symptoms.
A secondary site at which subjects in a clinical trial are seen, usually by the same investigator who sees subjects at the primary site. A satellite site may be the same type of site (e.g., private office, hospital) or a different type from the primary site.
Serious Adverse Event (SAE)
An adverse event that leads to death, permanent disability or (prolongation of) hospital admission. These events are of obvious importance to authorities and fellow researchers working on the same drug/product and have to be reported to the local and international authorities with the greatest possible urgency. The details of the reporting are given in the study protocol.
Serious adverse reaction
Multiple definitions are possible and no single one is correct in all situations. In general usage referring to subjects in clinical trials, a serious adverse reaction may be (1) any bad adverse reaction that is observed, (2) any bad adverse reaction that one does not expect to observe, (3) any bad adverse reaction that one does not expect to observe and is not in the label, or (4) any bad adverse reaction that has not been reported with standard therapy. Definitions may also be based on the degree to which an adverse reaction compromises a subject’s function or requires treatment.
A common used definition is “an adverse event that leads to death, permanent disability or (prolongation of) hospital admission”. The details of reporting these events are often given in the study protocol.
Any effect other than the primary intended effect(s) resulting from medicine or non-medicine treatment or intervention. Side effects may be negative (i.e., an adverse reaction), neutral, or positive (i.e., a beneficial effect) for the subject. This term, therefore, includes all adverse reactions plus other effects of treatment. See definition of adverse reaction.
The subject is unaware of which treatment is being received, but the investigator has this information. In unusual cases, the investigator and not the subject may be kept blind to the identity of the treatment.
This refers to the place where a clinical trial is conducted. A physician who has offices and sees subjects in three separate locations is viewed as having one site. A physician who is on the staff of four hospitals could be viewed as having one or four sites, depending on how similar or different the subject populations are and whether the data from these four locations will be pooled and considered a single site. For example, a single physician who enrolls groups of subjects at a university hospital, private clinic, community hospital, and Veterans Administration Hospital should generally be viewed as having four sites, since the subject populations would be expected to differ at each site. See satellite site.
An organization (often a pharmaceutical company) funding a trial of a new drug/product or other intervention for registration purposes.
Standard Operating Procedure (SOP)
A detailed description of a certain activity or organizing principle in a clinical trial. Such procedures must be adhered to when performing a trial under the Good Clinical Practice standards.
This term relates to the probability that an event or difference significanceoccurred by chance alone. Thus, it is a measure of whether a difference is likely to be real, but it does not indicate whether the difference is small or large, important or trivial. The level of statistical significance depends on the number of subjects studied or observations made, as well as that magnitude of difference observed.
The document describing the rationale, the subject population, the drugs/product to be used and the full time schedule of a clinical study as well as the endpoints to be evaluated. The study protocol for independent evaluation.
A biomarker that has been extensively studied to be sufficiently confident that it can replace a clinical endpoint for registration purposes.
This term is applied to the difference between the minimum and maximum doses that may be given subjects to obtain an adequate clinical response and avoid intolerable toxic effects. The greater the value calculated for the therapeutic window, the greater a medicine’s margin of safety. Synonyms are therapeutic ratio and therapeutic index.
A normal individual who participates in a clinical trial for reasons other than medical need and who does not receive any direct medical benefit from participating in the trial.
1.) Cohen A, Posner J. A Guide to Clinical Drug Research 2nd Edition. 2002. Kluwer Academic Publishers. Dordrecht, The Netherlands.
2.) Spilker B. Guide to Clinical Trials. 2000. Lippincott, Williams & Wilkins. Philadelphia , PA.
3.) Association of Clinical Research Professionals. www.acrpnet.org Accessed December 22, 2004
4.) Food and Drug Administration website (Center for Drug Evaluation and Research): http://www.fda.gov/cder/drugsatfda/glossary.htm
5.) Gallin, J.I. 2002, Principals and Practice of Clinical Research, Academic Press, California.
6.) http://www.mayoclinic.com/invoke.cfm?id=SA00073 Accessed January 24th, 2005.