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Glossary Of Terms Clinical Research


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Glossary Of Terms Clinical Research

  1. 1. Glossary Clinical Trials Terminology absorption The process by which medica- AIDS Acquired immune deficiency syn- activities and documents to determine tions reach the blood stream when admin- drome. See also SIDA and HIV in acronym whether the evaluated trial-related activities istered other than intravenously, for exam- glossary. were conducted, and the data were ple, through nasal membranes. See also algorithm Step-by-step procedure for solving recorded, analyzed, and accurately reported ADME in acronym glossary. (pharmacokinet- a mathematical problem; also used to according to the protocol, sponsor’s stan- ics) describe step-by-step procedures for mak- dard operating procedures (SOPs), good action letter An official communication from ing a series of choices among alternative clinical practice (GCP), and the applicable FDA to an NDA sponsor announcing an decisions to reach an outcome. regulatory requirement(s). (ICH) agency decision. See also approval letter, aliquot A part that is a definite fraction of a audit certificate Document that certifies approvable letter, not-approvable letter. whole, as in aliquot samples for laboratory that an audit has taken place (at an inves- admission criteria Basis for selecting target testing or analysis. tigative site, CRO, or clinical research population for a clinical trial. Subjects must department of a pharmaceutical company). alpha error See Type 1 error. (statistics) be screened to ensure that their character- audit report A written evaluation by the analyte A substance being analyzed; in istics match a list of admission criteria and sponsor’s auditor of the results of the chromatography, a single component (com- that none of their characteristics match any audit. (ICH) pound) of a mixture. single one of the exclusion criteria set up audit trail Documentation that allows recon- for the study. See also inclusion criteria. applet A small application, typically down- struction of the course of events. (ICH) loaded from a server. (IT) adverse drug reaction (ADR) In the pre- balanced study Trial in which a particular approval clinical experience with a new approvable letter An official communication type of subject is equally represented in medicinal product or its new usages, partic- from FDA to an NDA sponsor that lists each study group. ularly as the therapeutic dose(s) may not minor issues to be resolved before an approval can be issued. bandwidth An indicator of the throughput be established: all noxious and unintended (speed) of data flow on a transmission responses to a medicinal product related approval (in relation to institutional review path; the width of the range of frequencies to any dose should be considered adverse boards) The affirmation decision of the IRB on which a transmission medium carries drug reactions. The phrase “responses to a that the clinical trial has been reviewed and electronic signals. All digital and analog sig- medicinal product” means that a causal may be conducted at the institution site nals have a bandwidth. (IT) relationship between a medicinal product within the constraints set forth by the IRB, and an adverse event is at least a reason- the institution, good clinical practice (GCP), baseline assessment Assessment of sub- able possibility, i.e., the relationship can- and the applicable regulatory requirements. jects as they enter a trial and before they not be ruled out. Regarding marketed (ICH) receive any treatment. medicinal products: a response to a drug approval letter An official communication Bayesian statistics Statistical approach which is noxious and unintended and which from FDA to inform an NDA sponsor of an named for Thomas Bayes (1701–1761) occurs at doses normally used in man for agency decision that allows commercial that has among its features, giving a sub- prophylaxis, diagnosis, or therapy of dis- marketing of the product. jective interpretation to probability, accept- eases or for modification of physiological ing the idea that it is possible to talk about function (see the ICH Guideline for Clinical audit (of a clinical trial) A systematic and the probability of hypotheses being true Safety Data Management: Definitions and independent examination of trial-related and of parameters having particular values. Standards for Expedited Reporting). (ICH) beta error See Type 2 error. (statistics) adverse event (AE) Any untoward medical Glossary Notes between-subject variation In a parallel trial occurrence in a patient or clinical investiga- design, differences between subjects are tion subject administered a pharmaceutical Some glossary entries are followed by used to assess treatment differences. product and which does not necessarily source annotations in parentheses to have a causal relationship with this treat- indicate that the definition is an bioanalytical assays Methods for quantita- ment. An adverse event (AE) can therefore official one. “ICH,” for example, tive measurement of a drug, drug metabo- be any unfavourable and unintended sign indicates that the definition is quoted lites, or chemicals in biological fluids. (including an abnormal laboratory finding), verbatim from the ICH Guideline for bioavailability Rate and extent to which a symptom, or disease temporally associated Good Clinical Practice, and a 21 CFR drug is absorbed or is otherwise available with the use of a medicinal (investigational) citation indicates a quotation from to the treatment site in the body. product, whether or not related to the the Code of Federal Regulations. bioequivalence Scientific basis on which medicinal (investigational) product. (ICH) Other annotations indicate the generic and brand-name drugs are com- See also serious adverse event, serious definition applies to a certain pared. To be considered bioequivalent, the adverse experience. discipline—for example, statistics or bioavailability of two products must not dif- information technology (IT). fer significantly when the two products are adverse reaction See adverse drug reaction. 22 APPLIED CLINICAL TRIALS December 2002
  2. 2. given in studies at the same dosage under client A program that makes a service allows sponsors to apply for approval for similar conditions. request of another program (the server) each clinical study in turn, submitting sup- biostatistics Branch of statistics applied to that fulfills the request. Web browsers porting data to the Medicines Control the analysis of biological phenomena. (such as Netscape Navigator and Microsoft Agency (MCA), which approves or rejects Explorer) are clients that request HTML the application (generally within 35 working blind study One in which the subject or the files from Web servers. (IT) days). Approval means that the company is investigator (or both) are unaware of what clinical investigation See clinical trial. exempt from the requirement to hold a clini- trial product a subject is taking. See also cal trial certificate (CTC). (UK) double-blind study, single-blind study, triple- clinical investigation brochure See investiga- blind study. tor’s brochure. clinical trial materials Complete set of sup- plies provided to an investigator by the trial blinded medications Products that appear clinical research associate (CRA) Person sponsor. identical in size, shape, color, flavor, and employed by a sponsor, or by a contract other attributes to make it very difficult for research organization acting on a sponsor’s clinical trial report See final report. subjects and investigators to determine behalf, who monitors the progress of inves- coding In clinical trials, the process of which medication is being administered. tigator sites participating in a clinical study. assigning data to categories for analysis. blinding/masking A procedure in which one At some sites (primarily in academic set- Adverse events, for example, may be coded or more parties to the trial are kept tings), clinical research coordinators are using MedDRA. See acronym glossary. unaware of the treatment assignment(s). called CRAs. See monitor. cohort Group of subjects in a clinical trial Single-blinding usually refers to the sub- clinical research coordinator (CRC) Person followed up at regular, predetermined inter- ject(s) being unaware, and double-blinding who handles most of the administrative vals. usually refers to the subject(s), investiga- responsibilities of a clinical trial, acts as cohort study See prospective study. tor(s), monitor, and, in some cases, data liaison between investigative site and spon- comparative study One in which the inves- analyst(s) being unaware of the treatment sor, and reviews all data and records before tigative drug is compared against another assignment(s). (ICH) a monitor’s visit. Synonyms: trial coordina- product, either active drug or placebo. browser Computer program that runs on the tor, study coordinator, research coordinator, clinical coordinator, research nurse, protocol comparator (product) An investigational or user’s desktop computer and is used to nurse. marketed product (i.e., active control), or navigate the World Wide Web. See also Web placebo, used as a reference in a clinical browser. (IT) clinical significance Change in a subject’s trial. (ICH) cache Storage area on a computer’s hard clinical condition regarded as important whether or not due to the test article. Competent Authority (CA) The regulatory drive where the browser stores (for a lim- Some statistically significant changes (in body charged with monitoring compliance ited time) Web pages and/or graphic ele- blood tests, for example) have no clinical with the national statutes and regulations ments. (IT) significance. The criterion or criteria for clin- of European Member States. carry-over effect Effects of treatment that ical significance should be stated in the compliance (in relation to trials) Adherence persist after treatment has been stopped, protocol. to all the trial-related requirements, good sometimes beyond the time of a medica- clinical study See clinical trial/study. clinical practice (GCP) requirements, and tion’s known biological activity. the applicable regulatory requirements. case record form See case report form. clinical trial Systematic study of a test arti- (ICH) cle (treatment, drug, device) in one or more case report form (CRF) A printed, optical, or confidentiality Prevention of disclosure, to human subjects. Synonyms: clinical study, electronic document designed to record all other than authorized individuals, of a spon- clinical investigation. (21 CFR 50.3) of the protocol required information to be sor’s proprietary information or of a sub- reported to the sponsor on each trial sub- clinical trial/study Any investigation in ject’s identity. (ICH) ject. (ICH) human subjects intended to discover or ver- ify the clinical, pharmacological and/or Conformity Assessment The process by which categorical data Data evaluated by sorting compliance with the Essential Requirements other pharmacodynamic effects of an inves- values (for example, severe, moderate, and (ERs) is assessed. See also Notified Body. tigational product(s), and/or to identify any mild) into various categories. adverse reactions to an investigational consent form (CF) Document used during the causality assessment Determining whether product(s), and/or to study absorption, dis- consent process that is the basis for there is a reasonable possibility that the tribution, metabolism, and excretion of an explaining to potential subjects the risks drug caused or contributed to an adverse investigational product(s), with the object of and potential benefits of a study and the event. It includes assessing temporal rela- ascertaining its safety and/or efficacy. The rights and responsibilities of the parties tionships, dechallenge/rechallenge infor- terms “clinical trial” and “clinical study” involved. mation, association (or lack of association) are synonymous. (ICH) consumer safety officer FDA official who coor- with underlying disease, and the presence clinical trial/study report A written descrip- dinates the review process of various appli- (or absence) of a more likely cause. tion of a trial/study of any therapeutic, pro- cations. circadian rhythm Biological timing and phylactic, or diagnostic agent conducted in contract A written, dated, and signed agree- rhythmicity that, in human beings, is char- human subjects, in which the clinical and ment between two or more involved parties acterized by cycles of approximately 24 statistical description, presentations, and that sets out any arrangements on delega- hours. Synonym: biological clock. analyses are fully integrated into a single tion and distribution of tasks and obliga- clean database (or file) One from which report (see the ICH Guideline for Structure tions and, if appropriate, on financial mat- errors have been eliminated and in which and Content of Clinical Study Reports). (ICH) ters. The protocol may serve as the basis of measurements and other values are pro- clinical trial exemption (CTX) A scheme that a contract. (ICH) vided in the same units. December 2002 APPLIED CLINICAL TRIALS 23
  3. 3. contract research organization (CRO) A per- report forms are examined for complete- nation of new tags and options, style son or an organization (commercial, aca- ness, consistency, and accuracy. sheets, and programming that lets you cre- demic, or other) contracted by the sponsor data monitoring committee See independent ate Web pages in Hypertext Mark-up Lan- to perform one or more of a sponsor’s trial- data-monitoring committee. guage (HTML) that are more responsive to related duties and functions. (ICH) user interaction than previous versions of Declaration of Helsinki A set of recommen- control group The group of subjects in a HTML. (IT) dations or basic principles that guide medi- controlled study that receives no treatment, cal doctors in the conduct of biomedical effectiveness The desired measure of a a standard treatment, or a placebo. research involving human subjects. It was drug’s influence on a disease condition as controlled study A study in which a test arti- originally adopted by the 18th World Medi- proved by substantial evidence from ade- cle is compared with a treatment that has cal Assembly (Helsinki, Finland, 1964); the quate and well-controlled investigations. known effects. The control group may recently revised document (52nd WMA Gen- efficacy A product’s ability to produce bene- receive no treatment, standard treatment, eral Assembly, Edinburgh, Scotland, Octo- ficial effects on the course or duration of a or placebo. ber 2000). disease. coordinating center Headquarters for a mul- demographic data Characteristics of sub- endpoint An indicator measured in a sub- tisite trial that collects all data. jects or study populations, which include ject or biological sample to assess the coordinating committee A committee that a such information as age, sex, family history safety, efficacy, or other objective of a trial. sponsor may organize to coordinate the of the disease or condition for which they See also surrogate marker. conduct of a multicenter trial. (ICH) are being treated, and other characteristics equipoise A state in which an investigator is relevant to the study in which they are par- uncertain about which arm of a clinical trial coordinating investigator An investigator ticipating. would be therapeutically superior for a assigned the responsibility for the coordina- tion of investigators at different centers direct access Permission to examine, ana- patient. An investigator who has a treat- participating in a multicenter trial. (ICH) lyze, verify, and reproduce any records and ment preference or finds out that one arm reports that are important to evaluation of of a comparative trial offers a clinically ther- correlation The relationship of one variable a clinical trial. Any party (e.g., domestic and apeutic advantage should disclose this to another, not to be confused with causa- foreign regulatory authorities, sponsor’s information to subjects participating in the tion. (statistics) monitors and auditors) with direct access trial. crossover trial In crossover trials, each sub- should take all reasonable precautions essential documents Documents which indi- ject receives both treatments being com- within the constraints of the applicable reg- vidually and collectively permit evaluation of pared or the treatment and control. Such ulatory requirement(s) to maintain the confi- the conduct of a study and the quality of trials are used for patients who have a sta- dentiality of subject’s identities and spon- the data produced. (ICH) ble, usually chronic, condition during both sor’s proprietary information. (ICH) treatment periods. ethics committee See institutional review distribution In pharmacokinetics, the pro- board. curriculum vitae (cv) Document that outlines cesses that control transfer of a drug from a person’s educational and professional exclusion criteria A list of criteria, any one the site of measurement to its target and history. of which excludes a potential subject from other tissues. See also ADME in acronym participation in a study. See also inclusion daltons Units of atomic mass. glossary. (pharmacokinetics) criteria. data and safety monitoring board (DSMB) documentation All records, in any form excretion The act or process of eliminating Researchers—ideally independent of the tri- (including, but not limited to, written, elec- waste products from the body. See also als they monitor—who periodically review tronic, magnetic, and optical records, and ADME in acronym glossary. (pharmacokinet- data from blinded, placebo-controlled trials. scans, x-rays, and electrocardiograms) that ics) A DSMB can stop a trial if toxicities are describe or record the methods, conduct found or if treatment is proved beneficial. and/or results of a trial, the factors affect- explanatory trial Term used to describe a See also independent data-monitoring com- ing a trial and the actions taken. (ICH) clinical study designed to demonstrate the mittee. efficacy of a product. See also pragmatic domain name The way a particular Web trial. data base A collection of data, typically server is identified on the Internet. For organized for easy search and retrieval. example, names the World external consistency The consistency of a Wide Web (www) server for Tripod (tripod), procedure between sets of data. database Data stored in computer form for retrieval, processing, and/or analysis. which is a commercial (com) entity. (IT) File Transfer Protocol (FTP) A standard proto- dosage regimen (a) The number of doses col for exchanging files between computers Data Encryption Standard (DES) A widely per given time period; (b) the time that on the Internet. Used to transfer Web page used method of data encryption using a pri- elapses between doses (for example, every files to the computer that acts as a server vate (secret) key. Each message uses one six hours) or the time that the doses are to for everyone on the Internet. Also com- of 72 quadrillion or more possible encryp- be given (for example, at 8 a.m. and 4 p.m. monly used to download programs and tion keys that are chosen at random. The daily); or (c) the amount of a medicine (the other files to your computer from other sender and receiver must both know and number of capsules, for example) to be servers. FTP is usually one of the programs use the same private key. DES applies a given at each specific dosing time. that come with TCP/IP See TCP/IP in Glos- . 56-bit key to each 64-bit block of data. The sary of Acronyms, Abbreviations & Initials. U.S. government judged the key so difficult double-blind study A study in which neither to break that it restricted the key’s export the subject(s) nor the investigator(s) know final report Complete, comprehensive to other countries. what treatment a subject is receiving. description of a completed trial that describes the experimental materials and data monitoring Process by which case dynamic HTML Collective term for a combi- statistical design. It also presents and 24 APPLIED CLINICAL TRIALS December 2002
  4. 4. evaluates the trial results and statistical analyses. Consent In any research on human beings, each potential subject must be adequately firewall A set of related programs, located at a network gateway server, that protects a informed of the aims, methods, sources of funding, any possible conflicts of private computer network from users from interest, institutional affiliations of the researcher, the anticipated benefits and other networks. Also the security policy that potential risks of the study and the discomfort it may entail. The subject should is used with the programs. (IT) be informed of the right to abstain from participation in the study or to withdraw first-in-humans study The first Phase 1 consent to participate at any time without reprisal. After ensuring that the sub- study in which the test product is adminis- ject has understood the information, the physician should then obtain the sub- tered to human beings. ject’s freely-given informed consent, preferably in writing. If the consent cannot first-in-man study See first-in-humans study. be obtained in writing, the non-written consent must be formally documented and witnessed. —Article 22, Declaration of Helsinki Food and Drug Administration (FDA) The United States regulatory authority charged with, among other responsibilities, granting Huriet Law France’s regulations covering the ethics committees may differ among coun- IND and NDA approvals. initiation and conduct of clinical trials. tries, but should allow the independent hypertext Links in a document that permit ethics committee to act in agreement with gas chromatography (GC) A process by which GCP as described in the [ICH] guideline. the components of a mix are separated you to jump immediately to another docu- ment. In most Web browsers links are dis- (ICH) See also institutional review board. from one another by volatilizing the sample into a carrier gas stream and passing the played as colored, underlined text. (IT) informed consent A process by which a sub- gas through a column containing a sub- HyperText Markup Language (HTML) A set of ject voluntarily confirms his or her willing- stance that selectively retains (adsorbs) codes that describe the way type, graphics, ness to participate in a particular trial, and releases the volatile constituents. and other elements are displayed on a Web after having been informed of all aspects of page. (IT) the trial that are relevant to the subject’s good clinical practice (GCP) A standard for decision to participate. Informed consent is the design, conduct, performance, monitor- impartial witness A person, who is indepen- documented by means of a written, signed, ing, auditing, recording, analyses, and dent of the trial, who cannot be unfairly and dated informed consent form. (ICH) reporting of clinical trials that provides influenced by people involved with the trial, Under 21 CFR 50.20, no informed consent assurance that the data and reported who attends the informed consent process may include any “language through which results are credible and accurate, and that if the subject or the subject’s legally accept- the subject or the representative is made the rights, integrity, and confidentiality of able representative cannot read, and who to waive or appear to waive any of the sub- trial subjects are protected. (ICH) reads the informed consent form and any ject’s legal rights, or releases or appears to good clinical research practice (GCRP) Term other written information supplied to the release the investigator, the sponsor, the sometimes used to describe GCP See also . subject. (ICH) institution, or its agents from liability for good clinical practice. inclusion criteria The criteria that prospec- negligence.” Harmonized Standard A European Norm (EN) tive subjects must meet to be eligible for inspection The act by a regulatory author- that has been accepted by all Member participation in a study. See also exclusion ity(ies) of conducting an official review of States and published in the Official Journal criteria. documents, facilities, records, and any of the European Communities. independent data-monitoring committee (IDMC) other resources that are deemed by the Health Level 7 (HL7) A clinical data inter- A committee that may be established by the authority(ies) to be related to the clinical change messaging system in which mes- sponsor to assess at intervals the progress trial and that may be located at the site of sages are structured according to a prede- of a clinical trial, the safety data, and the the trial, at the sponsor’s and/or contract fined format and sent from one system to critical efficacy endpoints, and to recom- research organization’s (CRO’s) facilities, or another. The sending system needs to know mend to the sponsor whether to continue, at other establishments deemed appropri- only how to convert its data into an HL7 modify, or stop a trial. (ICH) ate by the regulatory authority(ies). (ICH) message; the receiving system needs to independent ethics committee (IEC) An inde- institution (medical) Any public or private know only how to extract the data. pendent body (a review board or a commit- entity or agency or medical or dental facility healthy volunteer A healthy person who tee, institutional, regional, national, or where clinical trials are conducted. (ICH) agrees to participate in a clinical trial for supranational) constituted of medical/ institutional review board (IRB) An indepen- reasons other than medical and receives no scientific professionals and non-scientific dent body constituted of medical, scientific, direct health benefit from participating. See members, whose responsibility it is to and non-scientific members, whose respon- also human subject. ensure the protection of the rights, safety, sibility it is to ensure the protection of the and well-being of human subjects involved heterologous Consisting of different rights, safety, and well-being of human sub- in a trial and to provide public assurance of elements, or of elements in differing jects involved in a trial by, among other that protection by, among other things, proportions. things, reviewing, approving, and providing reviewing and approving/providing favorable continuing review of trial protocol and of the human subject A human subject, defined in opinion on the trial protocol, the suitability methods and material to be used in obtain- 21 CFR 50.3, is an “individual who is or of the investigator(s), facilities, and the ing and documenting informed consent of becomes a participant in research, either methods and material to be used in obtain- the trial subjects. (ICH) Other names for as a recipient of the test article or as a ing and documenting informed consent of such bodies include independent review control. A subject may be either a healthy the trial subjects. The legal status, compo- board, independent ethics committee, com- human or a patient.” Synonym: subject/trial sition, function, operations, and regulatory mittee for the protection of human subjects. subject. requirements pertaining to independent December 2002 APPLIED CLINICAL TRIALS 25
  5. 5. to relevant factors, then randomize them so Ethics Committees that one receives Treatment A and the other Bodies convened to protect human clinical research subjects work under a variety Treatment B. See also pairing. of other names. For convenience and consistency, Applied Clinical Trials generally matching See pairing. uses the terms institutional review board and ethics committee. Other names and mean The sum of the values of all abbreviations for such bodies are shown below. observations or data points divided by the CCI committee on clinical investigations number of observations, an arithmetical CCPPRB Comité Consultative pour la Protection des Personnes dans les average. Recherches Biomédicales (France) median The middle value in a data set CHR committee on human research when they are arranged in order of CPPHS committee for the protection of human subjects magnitude. That is, just as many values are greater than the median and lower than the CRB central review board median value (with an even number of EAB ethical advisory board values, the conventional median is halfway EC ethics committee between the two middle values). HEX human experimentation committee medical practice computer system A PC- or IEC independent ethics committee network-based computer system used to manage electronic patient files. Defined by IRB independent review board; institutional review board the European Forum for GCP such a system , LREC local research ethics committees (UK) is neither sponsor-supplied nor trial- MREC multicentre research ethics committees (UK) specific. NRB noninstitutional review board, also known as an independent review board Medicines Control Agency (MCA) The United Kingdom regulatory authority that approves REB research ethics board (Canada) or rejects CTX/CTC and PL applications. interactivity Interactions in cyberspace with at a trial site, the investigator is the megatrials Massive randomized clinical other people, information, and computers. responsible leader of the team and may be trials that test the advantages of marginally Examples of interactivity include sending an called the principal investigator. (ICH). 21 effective experimental drugs by enrolling email message and filling out an Applied CFR 50.3 expands on the ICH definition by 10,000 or more subjects. Synonym: large- Clinical Trials subscription form at stating that an investigator is the individual sample trials. (IT) “under whose immediate direction the test Memorandum of understanding (MOU) An interim clinical trial/study report A report of article is administered or dispensed to, or MOU between FDA and a regulatory agency intermediate results and their evaluation used involving, a subject, or, in the event of in another country allows mutual based on analyses performed during the an investigation conducted by a team of recognition of inspections. course of a trial. (ICH) individuals, is the responsible leader of meta-analysis A statistical process for internal consistency A property of data that that team.” See also sponsor-investigator. pooling data from many clinical trials and does not contradict itself. investigator/institution A term used in the summarizing it through formal statistical ICH guideline to indicate “the investigator means. Also called overview. (statistics) Internet A global system of computer net- works that provides the infrastructure for and/or institution, where required by the metabolism The sum of the processes by email, the World Wide Web, and other applicable regulatory requirements.” (ICH) which a substance is handled in the living online activities. investigator’s brochure A compilation of the body. See also ADME in acronym glossary. clinical and nonclinical data on the (pharmacokinetics) Internet service provider (ISP) A company that provides access to the Internet for individu- investigational product(s) which is relevant mode The most frequently occurring value als and organizations. ISPs range in size to the study of the investigational in a data set. (statistics) from small local services to huge national product(s) in human subjects. (ICH) modem From modulator/demodulator. A providers, like Netcom and AT&T, and inter- IRB See institutional review board. device that converts the digital data that national full-service providers like America legally acceptable representative An your computer uses into analog data that Online (AOL). individual or juridical or other body can travel on telephone lines. (IT) investigational product A pharmaceutical authorized under applicable law to consent, monitor Person employed by the sponsor or form of an active ingredient or placebo on behalf of a prospective subject, to the CRO who is responsible for determining being tested or used as a reference in a subject’s participation in the clinical trial. that a trial is being conducted in clinical trial, including a product with a mar- (ICH) accordance with the protocol. A monitor’s keting authorization when used or assem- duties may include, but are not limited to, longitudinal study Investigation in which bled (formulated or packaged) in a way dif- helping to plan and initiate a trial, data are collected from a number of ferent from the approved form, or when assessing the conduct of trials, and subjects over a long period of time (a well- used for an unapproved indication, or when assisting in data analysis, interpretation, known example is the Framingham Study). used to gain further information about an and extrapolation. Monitors work with the approved use. (ICH) masking See blinding/masking. clinical research coordinator to check all investigator A person responsible for the matched-pair design A type of parallel trial data and documentation from the trial. See conduct of the clinical trial at a trial site. If design in which investigators identify pairs also clinical research associate. a trial is conducted by a team of individuals of subjects who are “identical” with respect monitoring The act of overseeing the 26 APPLIED CLINICAL TRIALS December 2002
  6. 6. Nuremberg Code—Directives for Human Experimentation 1. The voluntary consent of the human subject is absolutely 5. No experiment should be conducted where there is an essential. This means that the person involved should have legal a priori reason to believe that death or disabling injury will occur; capacity to give consent; should be so situated as to be able to except, perhaps, in those experiments where the experimental exercise free power of choice, without the intervention of any ele- physicians also serve as subjects. ment of force, fraud, deceit, duress, over-reaching, or other ulte- 6. The degree of risk to be taken should never exceed that rior form of constraint or coercion; and should have sufficient determined by the humanitarian importance of the problem to be knowledge and comprehension of the elements of the subject solved by the experiment. matter involved as to enable him to make an understanding and 7. Proper preparations should be made and adequate facilities enlightened decision. This latter element requires that before the provided to protect the experimental subject against even remote acceptance of an affirmative decision by the experimental subject possibilities of injury, disability, or death. there should be made known to him the nature, duration, and 8. The experiment should be conducted only by scientifically purpose of the experiment; the method and means by which it is qualified persons. The highest degree of skill and care should be to be conducted; all inconveniences and hazards reasonable to required through all stages of the experiment of those who con- be expected; and the effects upon his health or person which duct or engage in the experiment. may possibly come from his participation in the experiment. The 9. During the course of the experiment the human subject duty and responsibility for ascertaining the quality of the consent should be at liberty to bring the experiment to an end if he has rests upon each individual who initiates, directs or engages in the reached the physical or mental state where continuation of the experiment. It is a personal duty and responsibility which may not experiment seems to him to be impossible. be delegated to another with impunity. 10. During the course of the experiment the scientist in charge 2. The experiment should be such as to yield fruitful results for must be prepared to terminate the experiment at any stage, if he the good of society, unprocurable by other methods or means of has probable cause to believe, in the exercise of the good faith, study, and not random and unnecessary in nature. superior skill and careful judgment required of him that a continu- 3. The experiment should be so designed and based on the ation of the experiment is likely to result in injury, disability, or results of animal experimentation and a knowledge of the natural death to the experimental subject. history of the disease or other problem under study that the Reprinted from Trials of War Criminals before the Nuremberg Mili- anticipated results will justify the performance of the experiment. tary Tribunals under Control Council Law No. 10, Vol. 2, pp. 4. The experiment should be so conducted as to avoid all 181–182. Washington, D.C.: U.S. Government Printing Office, 1949. unnecessary physical and mental suffering and injury. progress of a clinical trial, and of ensuring sponsor that the important deficiencies subject is receiving; opposite of double- that it is conducted, recorded, and reported described therein preclude approval unless blind study. in accordance with the protocol, standard corrected. open-label study See open study. operating procedures (SOPs), good clinical Notified Body (NB) A private institution opinion (in relation to independent ethics practice (GCP), and the applicable charged by the Competent Authority with committee) The judgment and/or the regulatory requirement(s). (ICH) verifying compliance with the applicable advice provided by an independent ethics monitoring committee See independent data- Essential Requirements stated in the committee. (ICH) monitoring committee. Medical Device Directive. This process, original medical record See source monitoring report A written report from the called Conformity Assessment, has EU-wide documents. monitor to the sponsor after each site visit validity once completed by the NB. outcomes research See pharmacoeconomics. and/or other trial-related communication null hypothesis A null hypothesis (for according to the sponsor’s SOPs. (ICH) example, “subjects will experience no overview See meta-analysis. (statistics) multicenter trial A clinical trial conducted change in blood pressure as a result of p value The lowest level of significance at according to a single protocol but at more administration of the test product”) is used which a given null hypothesis can be than one site, and therefore, carried out by to rule out every possibility except the one rejected; that is, the probability of more than one investigator. (ICH) Synonym: the researcher is trying to prove, an observing a result as extreme or more multicenter study. assumption about a research population extreme than that observed if the null that may or may not be rejected as a result hypothesis is true. See statistical n-of-1 study A trial in an individual subject of testing. Used because most statistical significance. (statistics) is administered a treatment repeatedly over methods are less able to prove something pairing A method by which subjects are a number of episodes to establish the true than to provide strong evidence that it selected so that two subjects with similar treatment’s effect in that person, often with is false. See also research hypothesis. characteristics (for example, weight, experimental and control treatments randomized. Nuremberg Code Code of ethics for smoking habits) are assigned to a set, but conducting human medical research set one receives Treatment A and the other New Drug Application (NDA) An application to forth in 1947. receives Treatment B. FDA for a license to market a new drug in the United States. objective measurement A measurement that parallel trial Volunteers are randomized to cannot be influenced by investigator bias; one of two differing treatment groups nonclinical study Biomedical studies not for example, blood glucose levels or ECG (usually medicine and placebo) and usually performed on human subjects. (ICH) tracings. receive the assigned treatment during the not-approvable letter An official entire trial. Also called parallel group trial, open study A trial in which subjects and communication from FDA to inform an NDA parallel design trial. investigators know which product each 28 APPLIED CLINICAL TRIALS December 2002
  7. 7. parameter A constant in a model, or a Although usually conducted with healthy formulations, dosages, durations of constant that wholly or partially volunteers, Phase 1 trials are sometimes treatment, medicine interactions, and other characterizes a function of probability conducted with severely ill subjects, for factors. Subjects from various demographic distribution. (mathematics and statistics) example, those with cancer or AIDS. When groups may be studied. An important part patient Person under a physician’s care for pharmacokinetic issues are being of many Phase 4 studies is detecting and a particular disease or condition. See also addressed (for example, metabolism of a defining previously unknown or inadequately subject/trial subject, healthy volunteer. new antiepileptic medicine in stable quantified adverse reactions and related epileptic subjects whose microsomal liver risk factors. Phase 4 studies that are patient file Contains demographic, medical, enzymes have been induced by other primarily observational or nonexperimental and treatment information about a patient antiepileptic medicines), trials may be are frequently called postmarketing or subject. It may be paper-based or a conducted in less-ill subjects. surveillance. mixture of computer and paper records. Pharmacokinetic trials are usually Phase 5 studies. Postmarketing surveillance period effect Designated period during the considered Phase 1 trials regardless of is sometimes referred to as Phase 5. course of a trial in which subjects are when they are conducted during a observed and no treatment is administered. placebo A pharmaceutical preparation that medicine’s development. contains no active agent. In blinded pharmacodynamics (PD) The branch of Phase 2a studies. Pilot clinical trials to studies, it is generally made to look just pharmacology that studies reactions evaluate efficacy and safety in selected like the active product. between drugs and living structures, populations of about 100 to 300 subjects including the processes of bodily responses postmarketing surveillance Ongoing safety who have the disease or condition to be to pharmacological, biochemical, monitoring of marketed drugs. See Phase 4 treated, diagnosed, or prevented. Often physiological, and therapeutic effects. studies, Phase 5 studies. involve hospitalized subjects who can be pharmacoeconomics Branch of economics closely monitored. Objectives may focus on pragmatic trial Term used to describe a that applies cost-benefit, cost-utility, cost- dose-response, type of patient, frequency clinical study designed to examine the minimization, and cost-effectiveness of dosing, or any of a number of other benefits of a product under real world analyses to compare the economics of issues involved in safety and efficacy. conditions. different pharmaceutical products or to Phase 2b studies. Well-controlled trials to preclinical studies Animal studies that compare drug therapy to other treatments. evaluate safety and efficacy in subjects support Phase 1 safety and tolerance Sometimes referred to as outcomes who have the disease or condition to be studies and must comply with good research. treated, diagnosed, or prevented. These laboratory practice (GLP). Data about a pharmacogenetics The study of the way trials usually represent the most rigorous drug’s activities and effects in animals help drugs interact with genetic makeup or the demonstration of a medicine’s efficacy. establish boundaries for safe use of the genetic response to a drug. Synonym: pivotal trials. drug in subsequent human testing (clinical studies or trials). Because many animals pharmacokinetics (PK) The study of the Phase 3 studies. Multicenter studies in have much shorter life spans than humans, processes of bodily absorption, populations of perhaps 1000 to 3000 preclinical studies can provide valuable distribution, metabolism, and excretion subjects (or more) for whom the medicine information about a drug’s possible toxic (ADME) of compounds and medicines. is eventually intended. Phase 3 trials effects over an animal’s life cycle and on its pharmacology The science that deals with generate additional safety and efficacy data offspring. the characteristics, effects, and uses of from relatively large numbers of subjects in both controlled and uncontrolled designs prospective study Investigation in which a drugs and their interactions with living and are used to support a PLA. Trials are group of subjects is recruited and organisms. also conducted in special groups of monitored in accordance with criteria pharmacovigilance Term used for adverse subjects or under special conditions described in a protocol. event monitoring and reporting in some dictated by the nature of a particular protocol A document that describes the countries. medicine and/or disease. Phase 3 trials objective(s), design, methodology, Phase 1 unit A facility designed specifically often provide much of the information statistical considerations, and organization for conducting studies involving normal, needed for the package insert and labeling of a trial. The protocol usually also gives healthy volunteers. It may be operated by a of the medicine. the background and rationale for the trial, sponsor company, a contract research Phase 3b studies. Trials conducted after but these could be provided in other organization (CRO), or a special unit of a submission of a new drug application protocol referenced documents. Throughout hospital. (NDA), but before the product’s approval the ICH GCP Guideline the term “protocol” phases of clinical trials Clinical trials are and market launch. Phase 3b trials, refers to protocol and protocol generally categorized into four (sometimes sometimes called peri-approval studies, amendments. (ICH) five) phases. An investigational medicine or may supplement or complete earlier trials, protocol amendment A written description of product may be evaluated in two or more or they may seek different kinds of a change(s) to or formal clarification of a phases simultaneously in different trials, information (for example, quality of life or protocol. (ICH) and some trials may overlap two different marketing). Phase 3b is the period between qualitative variable One that cannot be phases. submission for approval and receipt of measured numerically (race and sex, for Phase 1 studies. Initial safety trials on a marketing authorization. example). new medicine in which investigators Phase 4 studies. After a medicine is quality assurance (QA) All those planned and attempt to establish the dose range marketed, Phase 4 trials provide additional systematic actions that are established to tolerated by about 20 to 80 healthy details about the product’s safety and ensure that the trial is performed and the volunteers for single and multiple doses. efficacy. They may be used to evaluate 30 APPLIED CLINICAL TRIALS December 2002
  8. 8. data are generated, documented research hypothesis The research source documents Original documents, data, (recorded), and reported in compliance with hypothesis is the conclusion a study sets and records (e.g., hospital records, clinical good clinical practice (GCP) and the out to support (or disprove); for example, and office charts, laboratory notes, applicable regulatory requirement(s). (ICH) “blood pressure will be lowered by [specific memoranda, subjects’ diaries or evaluation quality control (QC) The operational endpoint] in subjects who receive the test checklists, pharmacy dispensing records, techniques and activities undertaken within product.” See also null hypothesis. recorded data from automated instruments, the quality assurance system to verify that risk In clinical trials, the probability of harm copies or transcriptions certified after the requirements for quality of the trial- or discomfort for subjects. Acceptable risk verification as being accurate copies, related activities have been fulfilled. (ICH) differs depending on the condition for which microfiches, photographic negatives, a product is being tested. A product for microfilm or magnetic media, x-rays, subject quantitative variable One that can be sore throat, for example, will be expected files, and records kept at the pharmacy, at measured (blood pressure, for example). to have a low incidence of side effects. the laboratories and at medico-technical random allocation Assignment of subjects to departments involved in the clinical trial). However, unpleasant side effects may be treatment (or control) groups in an (ICH) an acceptable risk when testing a unpredictable way. Assignment sequences promising treatment for a life-threatening sponsor An individual, company, institution, are concealed, but available for disclosure illness. or organization which takes responsibility in the event a subject has an adverse safety Relative freedom from harm; in for the initiation, management, and/or experience. clinical trials, this refers to an absence of financing of a clinical trial. (ICH) According random number table Table of numbers with to 21 CFR 50.3, a corporation or agency harmful side effects resulting from use of no apparent pattern used in the selection whose employees conduct the investigation the product and may be assessed by of random samples for clinical trials. is considered a sponsor and the employees laboratory testing of biological samples, random sample Members of a population special tests and procedures, psychiatric are considered investigators. selected by a method designed to ensure evaluation, and/or physical examination of sponsor-investigator An individual who both that each person in the target group has an subjects. initiates and conducts, alone or with equal chance of selection. others, a clinical trial, and under whose script A program or a sequence of randomization The process of assigning trial instructions that are interpreted or carried immediate direction the investigational subjects to treatment or control groups out by another program. (IT) product is administered to, dispensed to, using an element of chance to determine or used by a subject. The term does not search engine An online service that the assignments in order to reduce bias. include any person other than an individual compares your search criteria with its (ICH) (e.g., it does not include a corporation or database of information about the Internet raw data Records of original observations, an agency). The obligations of a sponsor- and displays the results. (IT) measurements, and activities (such as investigator include both those of a serious adverse event (SAE) or serious sponsor and those of an investigator. (ICH) laboratory notes, evaluations, data adverse drug reaction (serious ADR) Any Under 21 CFR 50.3, the term is used only recorded by automated instruments) untoward medical occurrence that at any for an individual person; it does not apply without conclusions or interpretations. dose: results in death, is life threatening, to corporations or agencies. recruitment (investigators) Process used by requires inpatient hospitalization or sponsors to select investigators for a standard deviation Indicator of the relative prolongation of existing hospitalization, clinical study. variability of a variable around its mean; results in persistent or significant the square root of the variance. (statistics) recruitment (subjects) Process used by disability/incapacity, or is a congenital investigators to enroll appropriate subjects anomaly/birth defect. (ICH) standard operating procedures (SOPs) into a clinical study, i.e., those selected on Detailed, written instructions to achieve serious adverse experience The Nordic the basis of the protocol’s inclusion and uniformity of the performance of a specific Guidelines for Good Clinical Trial Practice exclusion criteria. function. (ICH) define a serious AE as “Any experience that recruitment period Time period during which suggests a significant hazard, contra- statistical significance State that applies investigators must complete enrollment of indication, side effect or precaution.” when a hypothesis is rejected. Whether or their quota of subjects for a trial. not a given result is significant depends on server A computer program that provides the significance level adopted. For example, recruitment target Number of subjects that services to other computer programs in the one may say “significant at the 5% level.” must be recruited into a study to meet the same or other computers. See also Web This implies that a level of significance has requirements of the study protocol. In server. been applied such that when the null multicenter studies, each investigator has a single-blind study One in which subjects do hypothesis is true there is only a 1 in 20 recruitment target. not know whether they are receiving the chance of rejecting it and/or that the regulatory authorities Bodies having the active drug or a placebo. observed result has led to rejection of the power to regulate. In the ICH GCP guideline source data All information in original null hypothesis. the expression “regulatory authorities” records and certified copies of original stochastic Involving a random variable; includes the authorities that review records of clinical findings, observations, or involving chance or probability. submitted clinical data and those that other activities in a clinical trial necessary conduct inspections (see 1.29). These study coordinator See clinical research for the reconstruction and evaluation of the bodies are sometimes referred to as coordinator. trial. Source data are contained in source competent authorities. (ICH) documents (original records or certified subinvestigator Any individual member of representative See legally acceptable copies). (ICH) the clinical trial team designated and representative. supervised by the investigator at a trial site December 2002 APPLIED CLINICAL TRIALS 31
  9. 9. to perform critical trial-related procedures uniform resource locator (URL) Address of a activities to be in violation of the Federal and/or to make important trial-related Web page—, for example. FD&C Act, or other acts, and that failure of decisions (e.g., associates, residents, validation of data Procedure carried out to the responsible party to take appropriate research fellows). (ICH) See also ensure that the data contained in the final and prompt action to correct and prevent investigator. clinical trial report match original any future repeat of the violation may result subject/trial subject An individual who observations. in administrative and/or regulatory participates in a clinical trial, either as enforcement action without further notice. validity The accuracy of the relationship recipient of the investigational product(s) or (FDA) between two or more variables. as a control. (ICH) See also healthy washout period A period in a clinical study variance A measure of the variability in a volunteer, human subject. during which subjects receive no treatment sample or population. It is calculated as subject identification code A unique identifier for the indication under study and the the mean squared deviation (MSD) of the assigned by the investigator to each trial effects of a previous treatment are individual values from their common mean. subject to protect the subject’s identity and eliminated (or assumed to be eliminated). In calculating the MSD, the divisor n is used in lieu of the subject’s name when the commonly used for a population variance Web browser A computer program that investigator reports adverse events and/or and the divisor n 1 for a sample variance. interprets HTML and other Internet other trial-related data. (ICH) languages and protocols and displays Web volunteer See healthy volunteer. surrogate marker A measurement of a pages on your computer monitor. (IT) vulnerable subjects Individuals whose drug’s biological activity that substitutes for Web page A single page on a Web site, willingness to volunteer in a clinical trial a clinical endpoint such as death or pain such as a home page. (IT) may be unduly influenced by the relief. Web server A computer program that expectation, whether justified or not, of t-test A statistical test used to compare benefits associated with participation, or of delivers HTML pages or files. Sometimes the means of two groups of test data. a retaliatory response from senior the computer on which a server program trial coordinator See clinical research members of a hierarchy in case of refusal runs is also referred to as a server. (IT) coordinator. to participate. Examples are members of a Web site A collection of Web pages and trial site The location(s) where trial-related group with a hierarchical structure, such as other files. A site can consist of a single activities are actually conducted. (ICH) medical, pharmacy, dental and nursing Web page, thousands of pages, or custom- students, subordinate hospital and created pages that draw on a database triple-blind study A study in which laboratory personnel, employees of the associated with the site. (IT) knowledge of the treatment is concealed pharmaceutical industry, members of the weighting An adjustment in a value on the from the people who organize and analyze armed forces, and persons kept in basis of a judgment by the investigator. the data of a study as well as from subjects detention. Other vulnerable subjects (statistics) and investigators. include patients with incurable diseases, Type 1 (or Type I) error Error made when a well-being (of the trial subjects) The persons in nursing homes, unemployed or null hypothesis is rejected but is actually physical and mental integrity of the impoverished persons, patients in true. Also called false positive. (statistics) subjects participating in a clinical trial. emergency situations, ethnic minority (ICH) Type 2 (or Type II) error Error made when an groups, homeless persons, nomads, alternative hypothesis is rejected when it is refugees, minors, and those incapable of within-subject differences In a crossover actually true. Also called false negative. giving consent. (ICH) trial, variability in each patient is used to (statistics) assess treatment differences. (statistics) Warning Letter A written communication Type 3 (or Type III) error Some statisticians from FDA notifying an individual or firm that World Wide Web All the resources and users use this designation for an error made the agency considers one or more on the Internet that are using HTTP when calling the less effective treatment products, practices, processes, or other protocols. Also called the Web and WWW. ❏ the more effective one. (statistics) unequal randomization A technique used to allocate subjects into groups at a differential rate; for example, three Share your expertise! subjects may be assigned to a treatment group for every one assigned to the control Share your expertise and the lessons of your experience by group. submitting a manuscript to Applied Clinical Trials. unexpected adverse drug reaction An adverse When you have an idea for an article, contact the nearest editorial reaction, the nature or severity of which is office. Let us know what you have in mind, and ask for a copy of not consistent with the applicable product the magazine’s Information for Authors—also available on our information (e.g., investigator’s brochure for Web site: an unapproved investigational product or package insert/summary of product Philip Ward, European Editor Jane Ganter, Editor-in-Chief characteristics for an approved product). +44 1244 532 757 telephone: (541) 984-5251 fax: +44 1244 533 933 email: (ICH email: 32 APPLIED CLINICAL TRIALS December 2002