Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance
Corrected by
- Corrigendum to Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, 32014R0536R(04), November 17, 2016
(1) "Clinical study" means any investigation in relation to humans intended: (a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products; (b) to identify any adverse reactions to one or more medicinal products; or (c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products;
with the objective of ascertaining the safety and/or efficacy of those medicinal products; (2) "Clinical trial" means a clinical study which fulfils any of the following conditions: (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned; (b) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
(3) "Low-intervention clinical trial" means a clinical trial which fulfils all of the following conditions: (a) the investigational medicinal products, excluding placebos, are authorised; (b) according to the protocol of the clinical trial, (i) the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or (ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and
(c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned;
(4) "Non-interventional study" means a clinical study other than a clinical trial; (5) "Investigational medicinal product" means a medicinal product which is being tested or used as a reference, including as a placebo, in a clinical trial; (6) "Normal clinical practice" means the treatment regime typically followed to treat, prevent, or diagnose a disease or a disorder; (7) "Advanced therapy investigational medicinal product" means an investigational medicinal product which is an advanced therapy medicinal product as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007 of the European Parliament and of the Council Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121 ).(8) "Auxiliary medicinal product" means a medicinal product used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product; (9) "Authorised investigational medicinal product" means a medicinal product authorised in accordance with Regulation (EC) No 726/2004 or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an investigational medicinal product; (10) "Authorised auxiliary medicinal product" means a medicinal product authorised in accordance with Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product; (11) "Ethics committee" means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations; (12) "Member State concerned" means the Member State where an application for authorisation of a clinical trial or of a substantial modification has been submitted under Chapters II or III of this Regulation respectively; (13) "Substantial modification" means any change to any aspect of the clinical trial which is made after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial; (14) "Sponsor" means an individual, company, institution or organisation which takes responsibility for the initiation, for the management and for setting up the financing of the clinical trial; (15) "Investigator" means an individual responsible for the conduct of a clinical trial at a clinical trial site; (16) "Principal investigator" means an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site; (17) "Subject" means an individual who participates in a clinical trial, either as recipient of an investigational medicinal product or as a control; (18) "Minor" means a subject who is, according to the law of the Member State concerned, under the age of legal competence to give informed consent; (19) "Incapacitated subject" means a subject who is, for reasons other than the age of legal competence to give informed consent, incapable of giving informed consent according to the law of the Member State concerned; (20) "Legally designated representative" means a natural or legal person, authority or body which, according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject who is an incapacitated subject or a minor; (21) "Informed consent" means a subject's free and voluntary expression of his or her willingness to participate in a particular clinical trial, after having been informed of all aspects of the clinical trial that are relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an authorisation or agreement from their legally designated representative to include them in the clinical trial; (22) "Protocol" means a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial. The term "protocol" encompasses successive versions of the protocol and protocol modifications; (23) "Investigator's brochure" means 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 humans; (24) "Manufacturing" means total and partial manufacture, as well as the various processes of dividing up, packaging and labelling (including blinding); (25) "Start of a clinical trial" means the first act of recruitment of a potential subject for a specific clinical trial, unless defined differently in the protocol; (26) "End of a clinical trial" means the last visit of the last subject, or at a later point in time as defined in the protocol; (27) "Early termination of a clinical trial" means the premature end of a clinical trial due to any reason before the conditions specified in the protocol are complied with; (28) "Temporary halt of a clinical trial" means an interruption not provided in the protocol of the conduct of a clinical trial by the sponsor with the intention of the sponsor to resume it; (29) "Suspension of a clinical trial" means interruption of the conduct of a clinical trial by a Member State; (30) "Good clinical practice" means a set of detailed ethical and scientific quality requirements for designing, conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial are reliable and robust; (31) "Inspection" means 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 clinical trial site, at the sponsor's and/or contract research organisation's facilities, or at other establishments which the competent authority sees fit to inspect; (32) "Adverse event" means any untoward medical occurrence in a subject to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment; (33) "Serious adverse event" means any untoward medical occurrence that at any dose requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death; (34) "Unexpected serious adverse reaction" means a serious adverse reaction, the nature, severity or outcome of which is not consistent with the reference safety information; (35) "Clinical study report" means a report on the clinical trial presented in an easily searchable format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and accompanying an application for marketing authorisation.
(a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and (b) it is designed to generate reliable and robust data.
(a) whether the clinical trial applied for falls within the scope of this Regulation; (b) whether the application dossier is complete in accordance with Annex I;
(a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor; (b) Compliance with Chapter V with respect to the following: (i) The anticipated therapeutic and public health benefits taking account of all of the following: the characteristics of and knowledge about the investigational medicinal products; the relevance of the clinical trial, including whether the groups of subjects participating in the clinical trial represent the population to be treated, or if not, the explanation and justification provided in accordance with point (y) of paragraph 17 of Annex I to this Regulation; the current state of scientific knowledge; whether the clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment and authorisation of the placing on the market of medicinal products; and, where applicable, any opinion formulated by the Paediatric Committee on a paediatric investigation plan in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 378, 27.11.2006, p. 1 ).the reliability and robustness of the data generated in the clinical trial, taking account of statistical approaches, design of the clinical trial and methodology, including sample size and randomisation, comparator and endpoints;
(ii) The risks and inconveniences for the subject, taking account of all of the following: the characteristics of and knowledge about the investigational medicinal products and the auxiliary medicinal products; the characteristics of the intervention compared to normal clinical practice; the safety measures, including provisions for risk minimisation measures, monitoring, safety reporting, and the safety plan; the risk to subject health posed by the medical condition for which the investigational medicinal product is being investigated;
(c) Compliance with the requirements concerning the manufacturing and import of investigational medicinal products and auxiliary medicinal products set out in Chapter IX; (d) Compliance with the labelling requirements set out in Chapter X; (e) The completeness and adequateness of the investigator's brochure.
(a) the conduct of the clinical trial is acceptable in view of the requirements set out in this Regulation; (b) the conduct of the clinical trial is acceptable in view of the requirements set out in this Regulation, but subject to compliance with specific conditions which shall be specifically listed in that conclusion; or (c) the conduct of the clinical trial is not acceptable in view of the requirements set out in this Regulation.
(a) an initial assessment phase performed by the reporting Member State within 26 days from the validation date; (b) a coordinated review phase performed within 12 days from the end of the initial assessment phase involving all Member States concerned; (c) a consolidation phase performed by the reporting Member State within seven days from the end of coordinated review phase.
(a) compliance with the requirements for informed consent as set out in Chapter V; (b) compliance of the arrangements for rewarding or compensating subjects with the requirements set out in Chapter V and investigators; (c) compliance of the arrangements for recruitment of subjects with the requirements set out in Chapter V; (d) compliance with Directive 95/46/EC; (e) compliance with Article 49; (f) compliance with Article 50; (g) compliance with Article 76; (h) compliance with the applicable rules for the collection, storage and future use of biological samples of the subject.
(a) when it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment than in normal clinical practice in the Member State concerned; (b) infringement of its national law as referred to in Article 90; (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 8 of Article 6.
(a) when it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment than in normal clinical practice in the Member State concerned; (b) infringement of its national law as referred to in Article 90; (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 6.
(a) the substantial modification concerns an aspect covered by Part I of the assessment report; and (b) the application dossier is complete in accordance with Annex II.
(a) the substantial modification is acceptable in view of the requirements set out in this Regulation; (b) the substantial modification is acceptable in view of the requirements set out in this Regulation, but subject to compliance with specific conditions which shall be specifically listed in that conclusion; or (c) the substantial modification is not acceptable in view of the requirements set out in this Regulation.
(a) an initial assessment phase performed by the reporting Member State within 19 days from the validation date; (b) a coordinated review phase performed within 12 days from the end of the initial assessment phase involving all Member States concerned; and (c) a consolidation phase performed by the reporting Member State within seven days from the end of coordinated review phase.
(a) when it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment than in normal clinical practice in the Member State concerned; (b) infringement of its national law as referred to in Article 90; (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 4 or 6 of Article 18.
(a) whether the substantial modification concerns an aspect covered by Part II of the assessment report; and (b) whether the application dossier is complete in accordance with Annex II.
(a) when it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment than in normal clinical practice in the Member State concerned; (b) infringement of its national law as referred to in Article 90; (c) considerations as regards suject safety and data reliability and robustness submitted under paragraph 4 or 6 of Article 18.
(a) the conduct of the clinical trial, including the scientific context and arrangements taken, (b) the sponsor, investigators, potential subjects, subjects, and clinical trial sites; (c) the investigational medicinal products and, where necessary, the auxiliary medicinal products, in particular their properties, labelling, manufacturing and control; (d) measures to protect subjects; (e) justification as to why the clinical trial is a low-intervention clinical trial, in cases where this is claimed by the sponsor.
(a) a reference to the clinical trial or clinical trials which are substantially modified using the EU trial number referred to in the third subparagraph of Article 81(1) (the "EU trial number"); (b) a clear description of the substantial modification, in particular, the nature of and the reasons for substantial modification; (c) a presentation of data and additional information in support of the substantial modification, where necessary; (d) a clear description of the consequences of the substantial modification as regards the rights and safety of the subject and the reliability and robustness of the data generated in the clinical trial.
(a) the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored; (b) the subjects, or where a subject is not able to give informed consent, his or her legally designated representative, have been informed in accordance with Article 29(2) to (6); (c) the subjects, or where a subject is not able to give informed consent, his or her legally designated representative, have given informed consent in accordance with Article 29(1), (7) and (8); (d) the rights of the subjects to physical and mental integrity, to privacy and to the protection of the data concerning them in accordance with Directive 95/46/EC are safeguarded; (e) the clinical trial has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible for the subjects and both the risk threshold and the degree of distress are specifically defined in the protocol and constantly monitored; (f) the medical care provided to the subjects is the responsibility of an appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner; (g) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has been provided with the contact details of an entity where further information can be received in case of need; (h) no undue influence, including that of a financial nature, is exerted on subjects to participate in the clinical trial.
(a) enable the subject or his or her legally designated representative to understand: (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical trial; (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her right to refuse to participate and the right to withdraw from the clinical trial at any time without any resulting detriment and without having to provide any justification; (iii) the conditions under which the clinical trial is to be conducted, including the expected duration of the subject's participation in the clinical trial; and (iv) the possible treatment alternatives, including the follow-up measures if the participation of the subject in the clinical trial is discontinued;
(b) be kept comprehensive, concise, clear, relevant, and understandable to a layperson; (c) be provided in a prior interview with a member of the investigating team who is appropriately qualified according to the law of the Member State concerned; (d) include information about the applicable damage compensation system referred to in Article 76(1); and (e) include the EU trial number and information about the availability of the clinical trial results in accordance with paragraph 6.
(a) the information required under points (a), (b), (d) and (e) of Article 29(2) is given, in accordance with what is laid down in the protocol, prior to the inclusion of the subject in the clinical trial, and this information makes clear, in particular, that the subject can refuse to participate in, or withdraw at any time from, the clinical trial without any resulting detriment; and (b) the potential subject, after being informed, does not object to participating in the clinical trial.
(a) the simplified means for obtaining informed consent do not contradict national law in the Member State concerned; (b) the methodology of the clinical trial requires that groups of subjects rather than individual subjects are allocated to receive different investigational medicinal products in a clinical trial; (c) the clinical trial is a low-intervention clinical trial and the investigational medicinal products are used in accordance with the terms of the marketing authorisation; (d) there are no interventions other than the standard treatment of the subjects concerned; (e) the protocol justifies the reasons for obtaining informed consent with simplified means and describes the scope of information provided to the subjects, as well as the ways of providing information.
(a) the informed consent of their legally designated representative has been obtained; (b) the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in view of their capacity to understand it; (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subjects or their legally designated representatives, except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial; (e) the clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical trials on persons able to give informed consent, or by other research methods; (f) the clinical trial relates directly to a medical condition from which the subject suffers; (g) there are scientific grounds for expecting that participation in the clinical trial will produce: (i) a direct benefit to the incapacitated subject outweighing the risks and burdens involved; or (ii) some benefit for the population represented by the incapacitated subject concerned when the clinical trial relates directly to the life-threatening or debilitating medical condition from which the subject suffers and such trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject concerned in comparison with the standard treatment of the incapacitated subject's condition.
(a) the informed consent of their legally designated representative has been obtained; (b) the minors have received the information referred to in Article 29(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children; (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial; (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in minors or the clinical trial is essential with respect to minors to validate data obtained in clinical trials on persons able to give informed consent or by other research methods; (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors; (g) there are scientific grounds for expecting that participation in the clinical trial will produce: (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or (ii) some benefit for the population represented by the minor concerned and such a clinical trial will pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with the standard treatment of the minor's condition.
(a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, it can be conducted only if: (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant or breastfeeding; (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding women or other women in relation to reproduction or other embryos, foetuses or children; and (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or breastfeeding woman concerned, her embryo, foetus or child after birth;
(c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse impact on the health of the child; and (d) no incentives or financial inducements are given to the subject except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial.
(a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical trial; (b) there are scientific grounds to expect that participation of the subject in the clinical trial will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition; (c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative; (d) the investigator certifies that he or she is not aware of any objections to participate in the clinical trial previously expressed by the subject; (e) the clinical trial relates directly to the subject's medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical trial is of such a nature that it may be conducted exclusively in emergency situations; (f) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition.
(a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 29(2) shall be given as soon as possible to the subject and to his or her legally designated representative; (b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever is sooner and the information referred to in Article 29(2) shall be given as soon as possible to the the subject or his or her legally designated representative, whichever is sooner.
(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country; (b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored: (i) by that sponsor, or (ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorisation holder on safety matters shall not be considered a joint development; and
(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.
(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction; (b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction; (c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.
(a) improving the information on the safety of medicinal products; (b) adapting technical requirements to technical progress; (c) taking account of international regulatory developments in the field of safety requirements in clinical trials, endorsed by bodies in which the Union or the Member States participate.
(a) whether the clinical trial is a low-intervention clinical trial; (b) the objective and methodology of the clinical trial; and (c) the degree of deviation of the intervention from normal clinical practice.
(a) it shall have at its disposal, for manufacture or import, suitable and sufficient premises, technical equipment and control facilities complying with the requirements set out in this Regulation; (b) it shall have permanently and continuously at its disposal the services of at least one qualified person who fulfils the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC ("qualified person").
(a) re-labelling or re-packaging, where those processes are carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member State concerned to carry out such processes, and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State; (b) preparation of radiopharmaceuticals used as diagnostic investigational medicinal products where this process is carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member State concerned to carry out such process, and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State; (c) the preparation of medicinal products referred to in points (1) and (2) of Article 3 of Directive 2001/83/EC for use as investigational medicinal products, where this process is carried out in hospitals, health centres or clinics legally authorised in the Member State concerned to carry out such process and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State.
(a) information to identify contact persons or persons involved in the clinical trial; (b) information to identify the clinical trial; (c) information to identify the medicinal product; (d) information related to the use of the medicinal product.
(a) in accordance with Article 66(1); or (b) in accordance with Title V of Directive 2001/83/EC.
(a) a sponsor responsible for compliance with the obligations of a sponsor in the authorisation procedures set out in Chapters II and III; (b) a sponsor responsible for being a contact point for receiving all questions from subjects, investigators or any Member State concerned regarding the clinical trial and providing answers to them; (c) a sponsor responsible for implementing the measures taken in accordance with Article 77.
(a) revoke the authorisation of a clinical trial; (b) suspend a clinical trial; (c) require the sponsor to modify any aspect of the clinical trial.
(a) whether Member States correctly supervise compliance with this Regulation; (b) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that point 8 of the Introduction and general principles contained in Annex I to Directive 2001/83/EC is complied with; (c) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that Article 25(5) of this Regulation is complied with.
(a) protecting personal data in accordance with Regulation (EC) No 45/2001; (b) protecting commercially confidential information, in particular through taking into account the status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in disclosure; (c) protecting confidential communication between Member States in relation to the preparation of the assessment report; (d) ensuring effective supervision of the conduct of a clinical trial by Member States.
(a) to support the exchange of information between the Member States and the Commission on the experience acquired with regard to the implementation of this Regulation; (b) to assist the Commission in providing the support referred to in the second paragraph of Article 84; (c) to prepare recommendations on criteria regarding the selection of a reporting Member State.
(a) non-compliance with the provisions laid down in this Regulation on submission of information intended to be made publicly available to the EU database; (b) non-compliance with the provisions laid down in this Regulation on subject safety.
(a) the information provided is complete; (b) the attached documents contain an accurate account of the information available; (c) the clinical trial is to be conducted in accordance with the protocol; and (d) the clinical trial is to be conducted in accordance with this Regulation.
(a) specific features of the clinical trial population, such as subjects not able to give informed consent, minors and pregnant or breastfeeding women; (b) whether the clinical trial involves the first administration of a new active substance to humans; (c) whether scientific advice relating to the clinical trial or the investigational medicinal product has been given by the Agency, a Member State or a third country; (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a decision on the PIP, the cover letter contains the link to the decision of the Agency on its website); (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic, psychotropic or radiopharmaceutical; (f) whether the investigational medicinal products consist of or contain a genetically-modified organism or organisms; (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for an orphan condition; (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and a list of all auxiliary medicinal products; and (i) a list of medical devices which are to be investigated in the clinical trial but which are not part of the investigational medicinal product or products, together with a statement as to whether the medical devices are CE-marked for the intended use.
(a) the title of the clinical trial; (b) the EU trial number; (c) the sponsor's protocol code number specific for all versions of it (if relevant); (d) the date and number of the version, to be updated when it is amended; (e) a short title or name assigned to the protocol; and (f) the name and address of the sponsor, as well as the name and function of the representative or representatives of the sponsor authorised to sign the protocol or any substantial modification to the protocol.
(a) a statement that the clinical trial is to be conducted in compliance with the protocol, with this Regulation and with the principles of good clinical practice; (b) a comprehensive list of all investigational medicinal products and of all auxiliary medicinal products; (c) a summary of findings from non-clinical studies that potentially have clinical significance and from other clinical trials that are relevant to the clinical trial; (d) a summary of the known and potential risks and benefits including an evaluation of the anticipated benefits and risks to allow assessment in accordance with Article 6; for subjects in a clinical trial in an emergency situation, the scientific grounds for expecting that the participation of the subjects has the potential to produce a direct clinically relevant benefit shall be documented; (e) where patients were involved in the design of the clinical trial, a description of their involvement; (f) a description of, and justification for, the dosage, the dosage regime, the route and mode of administration, and the treatment period for all investigational medicinal products and auxiliary medicinal products; (g) a statement of whether the investigational medicinal products and auxiliary medicinal products used in the clinical trial are authorised; if authorised, whether they are to be used in the clinical trial in accordance with the terms of their marketing authorisations, and, if not authorised, a justification for the use of non-authorised auxiliary medicinal products in the clinical trial; (h) a description of the groups and subgroups of the subjects participating in the clinical trial, including, where relevant, groups of subjects with specific needs, for example. age, gender, participation of healthy volunteers, subjects with rare and ultra rare diseases; (i) references to literature and data that are relevant to the clinical trial, and that provide background for the clinical trial; (j) a discussion of the relevance of the clinical trial in order to allow assessment in accordance with Article 6; (k) a description of the type of clinical trial to be conducted and a discussion of the trial design (including a schematic diagram of trial design, procedures and stages, if relevant); (l) a specification of the primary end-points and the secondary end-points, if any, to be measured during the clinical trial; (m) a description of the measures taken to minimise bias, including, if applicable, randomisation and blinding; (n) a description of the expected duration of subject participation and a description of the sequence and duration of all clinical trial periods, including follow-up, if relevant; (o) a clear and unambiguous definition of the end of the clinical trial in question and, if it is not the date of the last visit of the last subject, a specification of the estimated end date and a justification thereof; (p) a description of the criteria for discontinuing parts of the clinical trial or the entire clinical trial; (q) arrangements for the maintenance of clinical trial treatment randomisation codes and procedures for breaking codes, if relevant; (r) a description of procedures for the identification of data to be recorded directly on the Case Report Forms considered as source data; (s) a description of the arrangements to comply with the applicable rules for the collection, storage and future use of biological samples from clinical trial subjects, where applicable, unless contained in a separate document; (t) a description of the arrangements for tracing, storing, destroying and returning the investigational medicinal product and unauthorised auxiliary medicinal product in accordance with Article 51; (u) a description of the statistical methods to be employed, including, if relevant: timing of any planned interim analysis and the number of subjects planned to be enrolled; reasons for choice of sample size; calculations of the power of the clinical trial and clinical relevance; the level of significance to be used; criteria for the termination of the clinical trial; procedures for accounting for missing, unused, and spurious data and for reporting any deviation from the original statistical plan; and the selection of subjects to be included in the analyses;
(v) a description of the subject inclusion and exclusion criteria, including criteria for withdrawing individual subjects from treatment or from the clinical trial; (w) a description of procedures relating to the withdrawal of subjects from treatment or from the clinical trial including procedures for the collection of data regarding withdrawn subjects, procedures for replacement of subjects and the follow-up of subjects that have withdrawn from treatment or from the clinical trial; (x) a justification for including subjects who are incapable of giving informed consent or other special populations, such as minors; (y) a justification for the gender and age allocation of subjects and, if a specific gender or age group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and justification for these exclusion criteria; (z) a detailed description of the recruitment and informed consent procedure, especially when subjects are incapable of giving informed consent; (aa) a description of the treatments, including medicinal products, which are permitted or not permitted, before or during the clinical trial; (ab) a description of the accountability procedures for the supply and administration of medicinal products to subjects including the maintenance of blinding, if applicable; (ac) a description of procedures for monitoring subject compliance, if applicable; (ad) a description of arrangements for monitoring the conduct of the clinical trial; (ae) a description of the arrangements for taking care of the subjects after their participation in the clinical trial has ended, where such additional care is necessary because of the subjects' participation in the clinical trial and where it differs from that normally expected for the medical condition in question; (af) a specification of the efficacy and safety parameters as well as the methods and timing for assessing, recording, and analysing these parameters; (ag) a description of ethical considerations relating to the clinical trial if those have not been described elsewhere; (ah) a statement from the sponsor (either in the protocol or in a separate document) confirming that the investigators and institutions involved in the clinical trial are to permit clinical trial-related monitoring, audits and regulatory inspections, including provision of direct access to source data and documents; (ai) a description of the publication policy; (aj) duly substantiated reasons for the submission of the summary of the results of the clinical trials after more than one year; (ak) a description of the arrangements to comply with the applicable rules on the protection of personal data; in particular organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed; (al) a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects; (am) a description of measures that will be implemented in case of data security breach in order to mitigate the possible adverse effects.
(a) adverse events or laboratory anomalies that are critical to safety evaluations and must be reported by the investigator to the sponsor, and (b) serious adverse events which do not require immediate reporting by the investigator to the sponsor.
(a) eliciting and recording adverse events by the investigator, and the reporting of relevant adverse events by the investigator to the sponsor; (b) reporting by the investigator to the sponsor of those serious adverse events which have been identified in the protocol as not requiring immediate reporting; (c) reporting of suspected unexpected serious adverse reactions by the sponsor to the Eudravigilance database; and (d) follow-up of subjects after adverse reactions including the type and duration of follow-up.
(a) a copy of the authorisation referred to in Article 61; and (b) certification by the qualified person in the Union that the manufacturing complies with GMP at least equivalent to the GMP in the Union, unless there are specific arrangements provided for in mutual recognition agreements between the Union and third countries.
| Types of previous assessment | Quality data | Non-clinical data | Clinical data |
|---|---|---|---|
| The investigational medicinal product is authorised or has a marketing authorisation in an ICH country and is used in the clinical trial: | |||
| SmPC | |||
| SmPC | If appropriate | If appropriate | |
| P+A | SmPC | SmPC | |
| Another pharmaceutical form or strength of the investigational medicinal product is authorised or has a marketing authorisation in an ICH country and the investigational medicinal product is supplied by the marketing authorisation holder | SmPC+P+A | Yes | Yes |
| The investigational medicinal product is not authorised and has no marketing authorisation in an ICH country but the active substance is contained in an authorised medicinal product, and | |||
| SmPC+P+A | Yes | Yes | |
| SmPC+S+P+A | Yes | Yes | |
| The investigational medicinal product was subject to a previous clinical trial application and authorised in the Member State concerned and has not been modified, and | |||
| Reference to previous submission | |||
| New data | New data | New data | |
| If appropriate | If appropriate | If appropriate | |
(a) in clinical trials with minors or incapacitated subjects, the procedures to obtain informed consent from the legally designated representatives, and the involvement of the minor or incapacitated subject shall be described; (b) if a procedure with consent witnessed by an impartial witness is to be used, relevant information on the reason for using an impartial witness, on the selection of the impartial witness and on the procedure for obtaining informed consent shall be provided; (c) in the case of clinical trials in emergency situations as referred to in Article 35, the procedure for obtaining the informed consent of the subject or the legally designated representative to continue the clinical trial shall be described; (d) in the case of clinical trials in emergency situations as referred to in Article 35, the description of the procedures followed to identify the urgency of the situation and to document it; (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual subjects are allocated to receive different investigational medicinal products, as referred to in Article 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified means shall be described.
(a) the information provided is complete; (b) the attached documents contain an accurate account of the information available; and (c) the clinical trial will be conducted in accordance with the amended documentation.
(a) in its subject line, the EU trial number with the title of the clinical trial and the substantial modification code number which allows unique identification of the substantial modification, and which shall be used consistently throughout the application dossier; (b) identification of the applicant; (c) identification of the substantial modification (the sponsor's substantial modification code number and date), whereby the modification may refer to several changes in the protocol or scientific supporting documents; (d) a highlighted indication of any special issues relating to the modification and an indication as to where the relevant information or text is located in the original application dossier; (e) identification of any information not contained in the modification application form that might impact on the risk to subjects; and (f) where applicable, a list of all clinical trials which are substantially modified, with EU trial numbers and respective modification code numbers.
(a) an extract from the documents to be amended showing previous and new wording in track changes, as well as an extract showing only the new wording, and a explanation of the changes; and (b) notwithstanding point (a), if the changes are so widespread or far-reaching that they justify an entirely new version of the document, a new version of the entire document (in such cases, an additional table lists the amendments to the documents, whereby identical changes can be grouped).
(a) summaries of data; (b) an updated overall risk/benefit assessment; (c) possible consequences for subjects already included in the clinical trial; (d) possible consequences for the evaluation of the results; (e) documents which relate to any changes to the information provided to subjects or their legally designated representatives, the informed consent procedure, informed consent forms, information sheets, or to letters of invitation; and (f) a justification for the changes sought in the application for a substantial modification.
(a) a valid EU trial number; (b) a sponsor study number; (c) an identifiable coded subject; (d) an identifiable reporter; (e) a SUSAR; (f) a suspect investigational medicinal product (including active substance name-code); (g) a causality assessment.
(a) the sender's (case) safety report unique identifier; (b) the receive date of the initial information from the primary source; (c) the receipt date of the most recent information; (d) the worldwide unique case identification number; (e) the sender identifier.
1. Clinical trial identification (including title of the trial and protocol number); 2. Identifiers (including EU trial number, other identifiers); 3. Sponsor details (including scientific and public contact points);. 4. Paediatric regulatory details (including information whether the clinical trial is a part of a Paediatric Investigation Plan); 5. Result analysis stage (including information about intermediate data analysis date, interim or final analysis stage, date of global end of the clinical trial). For clinical trials replicating studies on already authorised investigational medicinal products and used in accordance with the terms of the marketing authorisation, the summary of the results should also indicate identified concerns in the overall results of the clinical trial relating to relevant aspects of the efficacy of the related medicinal product; 6. General information about the clinical trial (including information about main objectives of the trial, trial design, scientific background and explanation of rationale for the trial; date of the start of the trial, measures of protection of subjects taken, background therapy; and statistical methods used); 7. Population of subjects (including information with actual number of subjects included in the clinical trial in the Member State concerned, in the Union and in third countries; age group breakdown, gender breakdown).
1. Recruitment (including information on the number of subjects screened, recruited and withdrawn; inclusion and exclusion criteria; randomisation and blinding details; investigational medicinal products used); 2. Pre-assignment Period; 3. Post Assignment Periods.
1. Baseline Characteristics (Required) Age; 2. Baseline Characteristics (Required) Gender; 3. Baseline Characteristics (Optional) Study Specific Characteristic.
1. End point definitions Information shall be provided for as many end points as defined in the protocol. 2. End Point #1 Statistical Analyses 3. End Point #2 Statistical Analyses
1. Adverse events information; 2. Adverse event reporting group; 3. Serious adverse event; 4. Non-serious adverse event.
1. Global Substantial Modifications; 2. Global Interruptions and re-starts; 3. Limitations, addressing sources of potential bias and imprecisions and Caveats; 4. A declaration by the submitting party on the accuracy of the submitted information.
1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other identifiers); 2. Name and contact details of the sponsor; 3. General information about the clinical trial (including where and when the trial was conducted, the main objectives of the trial and an explanation of the reasons for conducting it); 4. Population of subjects (including information on the number of subjects included in the trial in the Member State concerned, in the Union and in third countries; age group breakdown and gender breakdown; inclusion and exclusion criteria); 5. Investigational medicinal products used; 6. Description of adverse reactions and their frequency; 7. Overall results of the clinical trial; 8. Comments on the outcome of the clinical trial; 9. Indication if follow up clinical trials are foreseen; 10. Indication where additional information could be found.
(a) name, address and telephone number of the main contact for information on the product, clinical trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the purpose of this Annex this is referred to as the "main contact"); (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the name of the substance is to appear with the name of the comparator or placebo on the packaging of both the unauthorised investigational medicinal product and the comparator or placebo; (c) pharmaceutical form, route of administration, quantity of dosage units; (d) the batch or code number identifying the contents and packaging operation; (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere; (f) the subject identification number and/or the treatment number and, where relevant, the visit number; (g) the name of the investigator (if not included in (a) or (e)); (h) directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product); (i) "For clinical trial use only" or similar wording; (j) the storage conditions; (k) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity; and (l) "Keep out of reach of children", except when the product is for use in trials where the product is not taken home by subjects.
(a) name of the main contact; (b) pharmaceutical form, route of administration (may be excluded for oral solid dose forms), quantity of dosage units and, in the case of clinical trials which do not involve the blinding of the label, the name/identifier and strength/potency; (c) batch and/or code number identifying the contents and packaging operation; (d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere; (e) the subject identification number and/or the treatment number and, where relevant, the visit number; and (f) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity.
(a) name of the main contact; (b) route of administration (may be excluded for oral solid dose forms) and, in the case of clinical trials which do not involve the blinding of the label, the name/identifier and strength/potency; (c) batch or code number identifying the contents and packaging operation; (d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere; (e) the subject identification number/treatment number and, where relevant, the visit number; and (f) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity.
(a) name of the main contact; (b) name of the medicinal product, followed by its strength and pharmaceutical form; (c) statement of the active substances expressed qualitatively and quantitatively per dosage unit; (d) batch or code number identifying the contents and packaging operation; (e) clinical trial reference code allowing identification of the clinical trial site, investigator and subject; (f) directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product); (g) "For clinical trial use only" or similar wording; (h) the storage conditions; and (i) period of use (expiry date or retest date as applicable).
(a) name of the main contact; (b) clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor and subject; (c) "For clinical trial use only" or similar wording.
(a) paragraph 1, points (b), (c), (d), (f), (j) and (k); (b) paragraph 4, points (b), (c), (e), and (f); (c) paragraph 5, points (b), (c), (e), and (f); (d) paragraph 6, points (b), (d), (e), (h), and (i).
| Directive 2001/20/EC | This Regulation |
|---|---|
| Article 1(1) | Article 1 and Article 2(1) and (2) points (1), (2) and (4) |
| Article 1(2) | Article 2(2) point (30) |
| Article 1(3), first subparagraph | — |
| Article 1(3), second subparagraph | Article 47, third subparagraph |
| Article 1(4) | Article 47, second subparagraph |
| Article 2 | Article 2 |
| Article 3(1) | — |
| Article 3(2) | Articles 4, 28, 29 and 76 |
| Article 3(3) | Article 28(1)(f) |
| Article 3(4) | Article 28(1)(g) |
| Article 4 | Articles 10(1), 28, 29 and 32 |
| Article 5 | Articles 10(2), 28, 29 and 31 |
| Article 6 | Articles 4 to 14 |
| Article 7 | Articles 4 to 14 |
| Article 8 | — |
| Article 9 | Articles 4 to 14 |
| Article 10(a) | Articles 15 to 24 |
| Article 10(b) | Article 54 |
| Article 10(c) | Articles 37 and 38 |
| Article 11 | Article 81 |
| Article 12 | Article 77 |
| Article 13(1) | Article 61(1) to (4) |
| Article 13(2) | Article 61(2) |
| Article 13(3), first subparagraph | Articles 62(1) and 63(1) and (3) |
| Article 13(3), second subparagraph | Article 63(1) |
| Article 13(3), third subparagraph | — |
| Article 13(4) | Article 62 |
| Article 13(5) | — |
| Article 14 | Articles 66 to 70 |
| Article 15(1) | Article 78(1), (2) and (5) |
| Article 15(2) | Article 78(6) |
| Article 15(3) | — |
| Article 15(4) | — |
| Article 15(5) | Articles 57, 58 and 78(7) |
| Article 16 | Article 41 |
| Article 17(1)(a) to (c) | Article 42 |
| Article 17(1)(d) | — |
| Article 17(2) | Article 43 |
| Article 17(3)(a) | — |
| Article 17(3)(b) | Article 44(1) |
| Article 18 | — |
| Article 19, first paragraph, first sentence | Article 75 |
| Article 19, first paragraph, second sentence | Article 74 |
| Article 19, second paragraph | Article 92 |
| Article 19, third paragraph | — |
| Article 20 | — |
| Article 21 | Article 88 |
| Article 22 | — |
| Article 23 | — |
| Article 24 | — |