‘clinical trial’: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy;

This includes clinical trials carried out in either one site or multiple sites, whether in one or more than one Member State;

‘multi-centre clinical trial’: a clinical trial conducted according to a single protocol but at more than one site, and therefore by more than one investigator, in which the trial sites may be located in a single Member State, in a number of Member States and/or in Member States and third countries;

‘non-interventional trial’: a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data;

‘investigational medicinal product’: a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form;

‘sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial;

‘investigator’: a doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires. The investigator is responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator;

‘investigator's brochure’: a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects;

‘protocol’: a document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial. The term protocol refers to the protocol, successive versions of the protocol and protocol amendments;

‘subject’: an individual who participates in a clinical trial as either a recipient of the investigational medicinal product or a control;

‘informed consent’: decision, which must be written, dated and signed, to take part in a clinical trial, taken freely after being duly informed of its nature, significance, implications and risks and appropriately documented, by any person capable of giving consent or, where the person is not capable of giving consent, by his or her legal representative; if the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation.

‘ethics committee’: an independent body in a Member State, consisting of healthcare professionals and non-medical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent;

‘inspection’: the act by a competent authority of conducting an official review of documents, facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organisation's facilities, or at other establishments which the competent authority sees fit to inspect;

‘adverse event’: any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment;

‘adverse reaction’: all untoward and unintended responses to an investigational medicinal product related to any dose administered;

‘serious adverse event or serious adverse reaction’: any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect;

‘unexpected adverse reaction’: an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator's brochure for an unauthorised investigational product or summary of product characteristics for an authorised product).

the informed consent of the parents or legal representative has been obtained; consent must represent the minor's presumed will and may be revoked at any time, without detriment to the minor;

the minor has received information according to its capacity of understanding, from staff with experience with minors, regarding the trial, the risks and the benefits;

the explicit wish of a minor who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is considered by the investigator or where appropriate the principal investigator;

no incentives or financial inducements are given except compensation;

some direct benefit for the group of patients is obtained from the clinical trial and only where such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods; additionally, such research should either relate directly to a clinical condition from which the minor concerned suffers or be of such a nature that it can only be carried out on minors;

the corresponding scientific guidelines of the Agency have been followed;

clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored;

the Ethics Committee, with paediatric expertise or after taking advice in clinical, ethical and psychosocial problems in the field of paediatrics, has endorsed the protocol; and

the interests of the patient always prevail over those of science and society.

the informed consent of the legal representative has been obtained; consent must represent the subject's presumed will and may be revoked at any time, without detriment to the subject;

the person not able to give informed legal consent has received information according to his/her capacity of understanding regarding the trial, the risks and the benefits;

the explicit wish of a subject who is capable of forming an opinion and assessing this information to refuse participation in, or to be withdrawn from, the clinical trial at any time is considered by the investigator or where appropriate the principal investigator;

no incentives or financial inducements are given except compensation;

such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods and relates directly to a life-threatening or debilitating clinical condition from which the incapacitated adult concerned suffers;

clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress shall be specially defined and constantly monitored;

the Ethics Committee, with expertise in the relevant disease and the patient population concerned or after taking advice in clinical, ethical and psychosocial questions in the field of the relevant disease and patient population concerned, has endorsed the protocol;

the interests of the patient always prevail over those of science and society; and

there are grounds for expecting that administering the medicinal product to be tested will produce a benefit to the patient outweighing the risks or produce no risk at all.

after the commencement of the clinical trial, the sponsor may make amendments to the protocol. If those amendments are substantial and are likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant, the sponsor shall notify the competent authorities of the Member State or Member States concerned of the reasons for, and content of, these amendments and shall inform the ethics committee or committees concerned in accordance with Articles 6 and 9.

On the basis of the details referred to in Article 6(3) and in accordance with Article 7, the Ethics Committee shall give an opinion within a maximum of 35 days of the date of receipt of the proposed amendment in good and due form. If this opinion is unfavourable, the sponsor may not implement the amendment to the protocol.

If the opinion of the Ethics Committee is favourable and the competent authorities of the Member States have raised no grounds for non-acceptance of the abovementioned substantial amendments, the sponsor shall proceed to conduct the clinical trial following the amended protocol. Should this not be the case, the sponsor shall either take account of the grounds for non-acceptance and adapt the proposed amendment to the protocol accordingly or withdraw the proposed amendment;

without prejudice to point (a), in the light of the circumstances, notably the occurrence of any new event relating to the conduct of the trial or the development of the investigational medicinal product where that new event is likely to affect the safety of the subjects, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects against any immediate hazard. The sponsor shall forthwith inform the competent authorities of those new events and the measures taken and shall ensure that the Ethics Committee is notified at the same time;

within 90 days of the end of a clinical trial the sponsor shall notify the competent authorities of the Member State or Member States concerned and the Ethics Committee that the clinical trial has ended. If the trial has to be terminated early, this period shall be reduced to 15 days and the reasons clearly explained.

the investigational medicinal products imported into Cyprus, Ireland, Malta or Northern Ireland have undergone certification of batch release either in the Union, as provided for in paragraph 3, point (a), or in parts of the United Kingdom other than Northern Ireland in compliance with the requirements set out in paragraph 3, point (b);

the investigational medicinal products are only made available to subjects in the Member State into which those investigational medicinal products are imported, or, if imported into Northern Ireland, are only made available to subjects in Northern Ireland.