The definitions given below apply specifically to the terms used in this guide. They may have different meanings in other contexts.
Any untoward medical occurrence in a clinical trial subject administered a pharmaceutical product; it does not necessarily have a causal relationship with the treatment.
A response to a pharmaceutical product that is noxious and unintended and which occurs at doses normally used or tested in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. In clinical trials, injuries caused by overdosing, abuse or dependence and interactions with any other product should be considered adverse reactions.
audit of a trial
A systematic examination, carried out independently of those directly involved in the trial, to determine whether the conduct of a trial complies with the agreed protocol and whether the data reported are consistent with the records on site, e.g. whether data reported or recorded in the case-report forms (CRFs) are consonant with those found in hospital files and other original records.
case - report form (CRF)
A document that is used to record data on each trial subject during the course of the trial, as defined by the protocol. The data should be collected by procedures which guarantee preservation, retention and retrieval of information and allow easy access for verification, audit and inspection.
A systematic study on pharmaceutical products in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the object of ascertaining their efficacy and safety.
Clinical trials are generally classified into Phases I to IV. It is not possible to draw distinct lines between the phases, and diverging opinions about details and methodology do exist. A brief description of the individual phases, based on their purposes as related to clinical development of pharmaceutical products, are given below:
These are the first trials of a new active ingredient or new formulations in man, often carried out in healthy volunteers. Their purpose is to establish a preliminary evaluation of safety, and a first outline of the pharmacokinetic and, where possible, a pharmacodynamic profile of the active ingredient in humans.
These trials are performed in a limited number of subjects and are often, at a later stage, of a comparative (e.g. placebo-controlled) design. Their purpose is to demonstrate therapeutic activity and to assess short-term safety of the active ingredient in patients suffering from a disease or condition for which the active ingredient is intended. This phase also aims at the determination of appropriate dose ranges or regimens and (if possible) clarification of dose-response relationships in order to provide an optimal background for the design of extensive therapeutic trials.
Trials in larger (and possibly varied) patient groups with the purpose of determining the short- and long-term safety/efficacy balance of formulation(s) of the active ingredient, and of assessing its overall and relative therapeutic value. The pattern and profile of any frequent adverse reactions must be investigated and special features of the product must be explored (e.g. clinically-relevant drug interactions, factors leading to differences in effect such as age). These trials should preferably be of a randomized double-blind design, but other designs may be acceptable, e.g. long-term safety studies. Generally, the conditions under which these trials are carried out should be as close as possible to normal conditions of use.
Studies performed after marketing of the pharmaceutical product. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, or assessment of therapeutic value or treatment strategies. Although methods may differ, these studies should use the same scientific and ethical standards as applied in premarketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new pharmaceutical products.
A pharmaceutical or other product (which may be a placebo) used as a reference in a clinical trial.
Maintenance of the privacy of trial subjects including their personal identity and all personal medical information.
A document, dated and signed by the investigator, institution and sponsor, that sets out any agreements on financial matters and delegation/distribution of responsibilities. The protocol may also serve as a contract when it contains such information and is signed.
contract research organization (CRO)
A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing.
Any supplementary treatment provided to relieve the trial subject of symptoms caused by the investigated disease in the clinical trial. Escape treatment is often used in order to alleviate pain in placebo-controlled trials.
An independent body (a review board or a committee, institutional, regional or national), constituted of medical professionals and non-medical members, whose responsibility it is to verify that the safety, integrity and human rights of the subjects participating in a particular trial are protected and to consider the general ethics of the trial, thereby providing public reassurance. Ethics committees should be constituted and operated so that their tasks can be executed free from bias and from any influence of those who are conducting the trial.
A comprehensive description of the trial after its completion including a description of experimental methods (including statistical methods) and materials, a presentation and evaluation of the results, statistical analyses and a critical, ethical, statistical and clinical appraisal.
Good Clinical Practice (GCP)
A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.
Good Manufacturing Practice (GMP)
That part of pharmaceutical quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. In these guidelines, GMP refers to the current GMP Guidelines published by WHO (1).
A subject’s voluntary confirmation of willingness to participate in a particular trial, and the documentation thereof. This consent should only be sought after all appropriate information has been given about the trial including an explanation of its status as research, its objectives, potential benefits, risks and inconveniences, alternative treatment that may be available, and of the subject’s rights and responsibilities in accordance with the current revision of the Declaration of Helsinki (see Appendix 1).
An officially-conducted examination (i.e. review of the conduct of the trial, including quality assurance, personnel involved, any delegation of authority and audit) by relevant authorities at the site of investigation and/or at the site of the sponsor in order to verify adherence to Good Clinical Practice as set out in this document.
A person responsible for the trial and for the rights, health and welfare of the subjects in the trial. The investigator should have qualifications and competence in accordance with local laws and regulations as evidenced by an up-to-date curriculum vitae and other credentials. Decisions relating to, and the provision of, medical or dental care must always be the responsibility of a clinically competent person legally allowed to practise medicine or dentistry.
Labelling developed specifically for products involved in a clinical trial.
investigational product (synonym: study product)
Any pharmaceutical product (see definition) or placebo being tested or used as a reference in a clinical trial.
A collection of data for the investigator consisting of all the relevant information on the investigational product(s), including chemical and pharmaceutical data and toxicological, pharmacokinetic and pharmacodynamic data obtained from studies in animals as well as in humans, and the results of earlier clinical trials. There should be adequate data to justify the nature, scale and duration of the proposed trial and to evaluate the potential safety and need for special precautions. If new data are generated, the investigator’s brochure must be updated.
A person appointed by, and responsible to, the sponsor or Contract Research Organization (CRO) for the monitoring and reporting of progress of the trial and for verification of data.
A collection of data consisting of all relevant information on the patient or subject (such as hospital file, consultation records or special subject file) that permits the authenticity of the information presented in case-record forms to be verified and, where necessary, completed or corrected. The conditions regulating the use and consultation of such documents must be respected.
Any substance or combination of substances which has a therapeutic, prophylactic or diagnostic use, or is intended to modify physiological functions, and is presented in a dosage form suitable for administration to humans.
The investigator serving as coordinator for certain kinds of clinical trials, e.g. multicentre trials.
A document which states the background, rationale and objectives of the trial and describes its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed. The protocol should be dated and signed by the investigator, the institution involved and the sponsor. It can also function as a contract.
quality assurance relating to clinical trials
Systems and quality control procedures that are established to ensure that the trial is performed and the data are generated in compliance with Good Clinical Practice. These include procedures to be followed which apply to ethical and professional conduct, standard operating procedures (SOP), reporting, and professional or personnel qualifications.
All records or certified copies of original observations, clinical findings or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Such material includes laboratory notes, memoranda, calculations and documents, as well as all records of data from automated instruments or exact, verified copies in the form of photocopies, microfiches etc. Raw data can also include photographic negatives, microfilm or magnetic media (e.g. computer diskettes).
serious adverse event
An event that is associated with death, admission to hospital, prolongation of a hospital stay, persistent or significant disability or incapacity, or is otherwise life-threatening in connection with a clinical trial.
An individual, a company, an institution or an organization which takes responsibility for the initiation, management and/or financing of a clinical trial. When an investigator initiates and takes full responsibility for a trial, the investigator then also assumes the role of the sponsor.
standard operating procedures (SOP)
Standard, detailed, written instructions for the management of clinical trials. They provide a general framework enabling the efficient implementation and performance of all the functions and activities for a particular trial as described in this document.
study product (synonym: investigational product)
Any pharmaceutical product or placebo being tested or used as reference in a clinical trial.
An individual who participates in a clinical trial, either as a recipient of the pharmaceutical product under investigation or as a control The individual may be:
- a healthy person who volunteers to participate in a trial;
- a person with a condition unrelated to the use of the investigational product;
- a person (usually a patient) whose condition is relevant to the use of the investigational product.
Action of proving, in accordance with the principles of Good Clinical Practice, that any procedure, process, equipment (including the software or hardware used), material, activity or system actually leads to the expected results.
verification (validation) of data
The procedures carried out to ensure that the data contained in the final report match original observations. These procedures may apply to raw data, data in case-report forms (in hard copy or electronic form), computer print-outs and statistical analyses and tables.
A person who will not be influenced in any way by those who are involved in the clinical trial, who is present and may provide assistance if required when the subject’s informed consent is obtained, and documents that this consent is given freely by signing and dating the informed-consent form.