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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

Type Regulation

Publication 2014-04-16

Last updated 2022-12-05

State In force

Department Council of the European Union, European Parliament

Source EUR-Lex

articles 100

Reform history JSON API

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)

CHAPTER I

GENERAL PROVISIONS

Article 1

Scope

This Regulation applies to all clinical trials conducted in the Union.

It does not apply to non-interventional studies.

Article 2

Definitions

For the purposes of this Regulation, the following definitions also apply:

(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 (¹);

(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.

Article 3

General principle

A clinical trial may be conducted only if:

(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.

CHAPTER II

AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL

Article 4

Prior authorisation

A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this Regulation.

The ethical review shall be performed by an ethics committee in accordance with the law of the Member State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate for each Member State concerned.

Member States shall ensure that the timelines and procedures for the review by the ethics committees are compatible with the timelines and procedures set out in this Regulation for the assessment of the application for authorisation of a clinical trial.

Article 5

Submission of an application

The sponsor shall propose one of the Member States concerned as reporting Member State.

If a Member State concerned other than the proposed reporting Member State is willing to be the reporting Member State or where the proposed reporting Member State does not wish to be the reporting Member State, this shall be notified through the EU portal to all Member States concerned not later than three days after the application dossier is submitted.

If only one Member State concerned is willing to be the reporting Member State or if the clinical trial involves only one Member State, that Member State shall be the reporting Member State.

If there is no Member State concerned willing to be the reporting Member State or if there is more than one Member State concerned willing to be the reporting Member State, the reporting Member State shall be selected by agreement among the Member States concerned taking into account the recommendations referred to in point (c) of Article 85(2).

If there is no agreement among the Member States concerned, the proposed reporting Member State shall be the reporting Member State.

The reporting Member State shall notify the sponsor and the other Member States concerned that it is the reporting Member State, through the EU portal, within six days from the submission of the application dossier.

Within 10 days from the submission of the application dossier, the reporting Member State shall validate the application taking into account considerations expressed by the other Member States concerned and notify the sponsor, through the EU portal, of the following:

(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;

Member States concerned may communicate to the reporting Member State any considerations relevant to the validation of the application within seven days from the submission of the application dossier.

Within five days from receipt of the comments or the completed application dossier, the reporting Member State shall notify the sponsor as to whether or not the application complies with the requirements set out in points (a) and (b) of the first subparagraph of paragraph 3.

Where the reporting Member State has not notified the sponsor within the period referred to in the second subparagraph, the clinical trial applied for shall be deemed to fall within the scope of this Regulation and the application dossier shall be considered complete.

Where the sponsor has not provided comments or completed the application dossier within the period referred to in the first subparagraph, the application shall be deemed to have lapsed in all Member States concerned.

Article 6

Assessment report — Aspects covered by Part I

The reporting Member State shall assess the application with regard to the following aspects:

(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 (²); — 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.

The assessment report shall contain one of the following conclusions concerning the aspects addressed in Part I of the assessment report:

(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

For clinical trials involving more than one Member State, the assessment process shall include three phases:

(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.

During the initial assessment phase, the reporting Member State shall develop a draft Part I of the assessment report and circulate it to all other Member States concerned.

During the coordinated review phase, all Member States concerned shall jointly review the application based on the draft Part I of the assessment report and shall share any considerations relevant to the application.

During the consolidation phase, the reporting Member State shall take due account of the considerations of the other Member States concerned when finalising Part I of the assessment report and shall record how all such considerations have been dealt with. The reporting Member State shall submit the final Part I of the assessment report to the sponsor and all other Member States concerned within the period referred to in paragraph 4.

For the purpose of obtaining and reviewing this additional information from the sponsor in accordance with the third and fourth subparagraph, the reporting Member State may extend the period referred to in paragraph 4 by a maximum of 31 days.

The sponsor shall submit the requested additional information within the period set by the reporting Member State which shall not exceed 12 days from the receipt of the request.

Upon receipt of the additional information, the Member States concerned shall jointly review any additional information provided by the sponsor together with the original application and shall share any considerations relevant to the application. The coordinated review shall be performed within a maximum of 12 days of the receipt of the additional information and the further consolidation shall be performed within a maximum of seven days of the end of coordinated review. When finalising Part I of the assessment report, the reporting Member State shall take due account of the considerations of the Member States concerned and shall record how all such considerations have been dealt with.

Where the sponsor does not provide additional information within the period set by the reporting Member State in accordance with the third subparagraph, the application shall be deemed to have lapsed in all Member States concerned.

The request for additional information and the additional information shall be submitted through the EU portal.

Article 7

Assessment report — Aspects covered by Part II

Each Member State concerned shall assess, for its own territory, the application with respect to the following aspects:

(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;

(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.

The assessment of the aspects referred to in the first subparagraph shall constitute Part II of the assessment report.

Each Member State concerned may request, with justified reasons, additional information from the sponsor regarding the aspects referred to in paragraph 1 only within the period referred to in the first subparagraph.

The sponsor shall submit the requested additional information within the period set by the Member State concerned which shall not exceed 12 days from the receipt of the request.

Upon receipt of the additional information, the Member State concerned shall complete its assessment within a maximum of 19 days.

Where the sponsor does not provide additional information within the period set by the Member State concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in that Member State concerned.

The request for additional information and the additional information shall be submitted through the EU portal.

Article 8

Decision on the clinical trial

Notification shall be done by way of one single decision within five days from the reporting date or from the last day of the assessment referred to in Article 7, whichever is later.

An authorisation of a clinical trial subject to conditions is restricted to conditions which by their nature cannot be fulfilled at the time of that authorisation.

Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the reporting Member State as regards Part I of the assessment report only on the following grounds:

(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.

Where a Member State concerned disagrees with the conclusion on the basis of the second subparagraph, it shall communicate its disagreement, together with a detailed justification, through the EU portal, to the Commission, to all Member States, and to the sponsor.

Article 9

Persons assessing the application

In order to guarantee independence and transparency, the Member States shall ensure that persons admitting and assessing the application as regards the aspects addressed in Parts I and II of the assessment report have no financial or personal interests which could affect their impartiality. These persons shall make an annual declaration of their financial interests.

Article 10

Specific considerations for vulnerable populations

Article 11

Submission and assessment of applications limited to aspects covered by Part I or Part II of the assessment report

Where the sponsor so requests, the application for authorisation of a clinical trial, its assessment and the conclusion shall be limited to the aspects covered by Part I of the assessment report.

After the notification of the conclusion on the aspects covered by Part I of the assessment report, the sponsor may within two years apply for an authorisation limited to aspects covered by Part II of the assessment report. In that application the sponsor shall declare that he is not aware of any new substantial scientific information that would change the validity of any item submitted in the application on the aspects covered by Part I of the assessment report. In this case, that application shall be assessed in accordance with Article 7 and the Member State concerned shall notify its decision on the clinical trial in accordance with Article 8. In those Member States where the sponsor does not apply for an authorisation limited to aspects covered by Part II of the assessment report within two years, the application on the aspects covered by Part I of the assessment report shall be deemed to have lapsed.

Article 12

Withdrawal

The sponsor may withdraw the application at any time until the reporting date. In such a case, the application may only be withdrawn with respect to all Member States concerned. The reasons for the withdrawal shall be communicated through the EU portal.

Article 13

Resubmission

This Chapter is without prejudice to the possibility for the sponsor to resubmit, following the refusal to grant an authorisation or the withdrawal of an application, an application for authorisation to any intended Member State concerned. That application shall be deemed to be a new application for authorisation of another clinical trial.

Article 14

Subsequent addition of a Member State concerned

The application dossier may be submitted only after the notification date of the initial authorisation decision.

An authorisation of a clinical trial subject to conditions is restricted to conditions which by their nature cannot be fulfilled at the time of that authorisation.

Notwithstanding the first subparagraph, an additional Member State concerned may disagree with the conclusion of the reporting Member State as regards Part I of the assessment report only on the following grounds:

(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;

Where an additional Member State concerned disagrees with the conclusion on the basis of the second subparagraph, it shall communicate its disagreement, together with a detailed justification, through the EU portal, to the Commission, to all Member States, and to the sponsor.

For the purpose of obtaining and reviewing this additional information from the sponsor in accordance with the third and fourth subparagraphs, the reporting Member State may extend the period referred to in the first subparagraph of paragraph 3 by a maximum of 31 days.

The sponsor shall submit the requested additional information within the period set by the reporting Member State which shall not exceed 12 days from receipt of the request.

Upon receipt of the additional information, the additional Member State concerned together with all other Member States concerned shall jointly review any additional information provided by the sponsor together with the original application and shall share any considerations relevant to the application. The coordinated review shall be performed within a maximum of 12 days from the receipt of the additional information and the further consolidation shall be performed within a maximum of seven days from the end of the coordinated review. The reporting Member State shall take due account of the considerations of the Member States concerned and shall record how all such considerations have been dealt with.

The request for additional information and the additional information shall be submitted through the EU portal.

The sponsor shall submit the requested additional information within the period set by the additional Member State concerned which shall not exceed 12 days from receipt of the request.

Upon receipt of the additional information, the Member State concerned shall complete its assessment within a maximum of 19 days.

Where the sponsor does not provide additional information within the period set by the additional Member State concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in the additional Member State concerned.

The request for additional information and the additional information shall be submitted through the EU portal.

CHAPTER III

AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL

Article 15

General principles

A substantial modification, including the addition of a clinical trial site or the change of a principal investigator in the clinical trial site, may only be implemented if it has been approved in accordance with the procedure set out in this Chapter.

Article 16

Submission of application

In order to obtain an authorisation, the sponsor shall submit an application dossier to the Member States concerned through the EU portal.

Article 17

Validation of an application for the authorisation of a substantial modification of an aspect covered by Part I of the assessment report

Member States concerned may communicate to the reporting Member State any considerations relevant to the validation of the application of a substantial modification within five days from the submission of the application dossier.

Within six days from the submission of the application dossier, the reporting Member State shall validate the application taking into account considerations expressed by the other Member States concerned and notify the sponsor through the EU portal as to whether:

(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.

Where the reporting Member State has not notified the sponsor within the period referred to in the second subparagraph, the substantial modification applied for shall be deemed to concern an aspect covered by Part I of the assessment report and the application dossier shall be deemed to be complete.

Article 18

Assessment of a substantial modification of an aspect covered by Part I of the assessment report

The assessment report shall contain one of the following conclusions concerning the aspects addressed in Part I of the assessment report:

(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

For the purposes of this Article and Articles 19 and 23, the reporting date shall be the date on which the final assessment report is submitted to the sponsor and to the other Member States concerned.

For clinical trials involving more than one Member State the assessment process of substantial modification shall include three phases:

(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.

During the initial assessment phase, the reporting Member State shall develop a draft assessment report and circulate it to all Member States concerned.

During the coordinated review phase, all Member States concerned shall jointly review the application based on the draft assessment report and shall share any considerations relevant to the application.

During the consolidation phase, the reporting Member State shall take due account of the considerations of the other Member States concerned when finalising the assessment report and shall record how all such considerations have been dealt with. The reporting Member State shall submit the final assessment report to the sponsor and all other Member States concerned by the reporting date.

The sponsor shall submit the requested additional information within the period set by the reporting Member State which shall not exceed 12 days from receipt of the request.

Upon receipt of the additional information, the Member States concerned shall jointly review any additional information provided by the sponsor together with the original application and shall share any considerations relevant to the application. The coordinated review shall be performed within a maximum of 12 days from receipt of the additional information and the further consolidation shall be performed within a maximum of seven days from the end of the coordinated review. When finalising the assessment report, the reporting Member State shall take due account of the considerations of the other Member States concerned and shall record how all such considerations have been dealt with.

Where the sponsor does not provide additional information within the period determined by the reporting Member State in accordance with the third subparagraph, the application shall be deemed to have lapsed in all Member States concerned.

The request for additional information and the additional information shall be submitted through the EU portal.

Article 19

Decision on the substantial modification of an aspect covered by Part I of the assessment report

Notification shall be done by way of a single decision within five days from the reporting date.

An authorisation of a substantial modification subject to conditions is restricted to conditions which by their nature cannot be fulfilled at the time of that authorisation.

Notwithstanding the first subparagraph, a Member State concerned may disagree with that conclusion of the reporting Member State only on the following grounds:

(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.

Where the Member State concerned disagrees with the conclusion on the basis of the second subparagraph, it shall communicate its disagreement, together with a detailed justification, through the EU portal, to the Commission, to all Member States and to the sponsor.

A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the conclusion of the reporting Member State as regards Part I of the assessment report on any of the grounds referred to in the second subparagraph, or where an ethics committee has issued a negative opinion which, in accordance with the law of that Member State concerned, is valid for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.

Article 20

Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the assessment report

Within six days from the submission of the application dossier, the Member State concerned shall notify the sponsor through the EU portal of the following:

(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.

Where the Member State concerned has not notified the sponsor within the period referred to in the second subparagraph, the substantial modification shall be deemed to concern an aspect covered by Part II of the assessment report and the application dossier shall be deemed to be complete.

Where the sponsor has not provided comments nor completed the application dossier within the period referred to in the first subparagraph, the application shall be deemed to have lapsed in the Member State concerned.

Notification shall be done by way of a single decision within 38 days from the validation date.

An authorisation of a substantial modification subject to conditions is restricted to conditions which by their nature cannot be fulfilled at the time of that authorisation.

For the purpose of obtaining and reviewing this additional information from the sponsor, the Member State concerned may extend the period referred to in the second subparagraph of paragraph 5 by a maximum of 31 days.

The sponsor shall submit the requested additional information within the period set by the Member State concerned which shall not exceed 12 days from receipt of the request.

Upon receipt of the additional information, the Member State concerned shall complete its assessment within a maximum of 19 days.

Where the sponsor does not provide additional information within the period set by the Member State concerned in accordance with the third subparagraph, the application shall be deemed to have lapsed in that Member State.

The request for additional information and the additional information shall be submitted through the EU portal.

Article 21

Substantial modification of aspects covered by Parts I and II of the assessment report

Article 22

Assessment of a substantial modification of aspects covered by Parts I and II of the assessment report — Assessment of the aspects covered by Part II of the assessment report

The sponsor shall submit the requested additional information within the period set by the Member State concerned which shall not exceed 12 days from the receipt of the request.

Upon receipt of the additional information, the Member State concerned shall complete its assessment within a maximum of 19 days.

Where the sponsor does not provide the requested additional information within the period set by the Member State concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in that Member State.

The request for additional information and the additional information shall be submitted through the EU portal.

Article 23

Decision on the substantial modification of aspects covered by Parts I and II of the assessment report

Notification shall be done by way of a single decision within five days from the reporting date or from the last day of the assessment period referred to in Article 22, whichever is later.

An authorisation of a substantial modification subject to conditions is restricted to conditions which by their nature cannot be fulfilled at the time of that authorisation.

Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the reporting Member State only on the following grounds:

(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.

Where the Member State concerned disagrees with the conclusion regarding the substantial modification of aspects covered by Part I of the assessment report on the basis of the second subparagraph, it shall communicate its disagreement, together with a detailed justification through the EU portal to the Commission, to all Member States, and to the sponsor.

Article 24

Persons assessing the application for a substantial modification

Article 9 applies to assessments made under this Chapter.

CHAPTER IV

APPLICATION DOSSIER

Article 25

Data submitted in the application dossier

The application dossier for the authorisation of a clinical trial shall contain all required documentation and information necessary for the validation and assessment referred to in Chapter II and relating to:

(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.

The list of required documentation and information is set out in Annex I.

The application dossier for the authorisation of a substantial modification shall contain all required documentation and information necessary for the validation and assessment referred to in Chapter III:

(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;

(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.

The list of required documentation and information is set out in Annex II.

Data from a clinical trial started before the date referred to in the second paragraph of Article 99 shall only be submitted in an application dossier if that clinical trial is registered in a public register which is a primary or partner registry of, or a data provider to, the WHO ICTRP or if the results of that clinical trial have been published in an independent peer-reviewed scientific publication.

Article 26

Language requirements

The language of the application dossier, or parts thereof, shall be determined by the Member State concerned.

Member States, in applying the first paragraph, shall consider accepting, for the documentation not addressed to the subject, a commonly understood language in the medical field.

Article 27

Update by way of delegated acts

The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in respect of amending Annexes I and II in order to adapt them to technical progress or to take account of international regulatory developments in which the Union or the Member States are involved, in the field of clinical trials.

CHAPTER V

Article 28

General rules

A clinical trial may be conducted only where all of the following conditions are met:

(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.

The scientific research making use of the data outside the protocol of the clinical trial shall be conducted in accordance with the applicable law on data protection.

Article 29

Information given to the subject or, where the subject is not able to give informed consent, his or her legally designated representative for the purposes of obtaining his or her informed consent shall:

(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.

Article 30

For clinical trials that fulfil the conditions set out in paragraph 3, informed consent shall be deemed to have been obtained if:

(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.

Informed consent may be obtained by the simplified means set out in paragraph 2, if all the following conditions are fulfilled:

(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.

Article 31

Clinical trials on incapacitated subjects

In the case of incapacitated subjects who have not given, or have not refused to give, informed consent before the onset of their incapacity, a clinical trial may be conducted only where, in addition to the conditions set out in Article 28, all of the following conditions are met:

(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.

Article 32

Clinical trials on minors

A clinical trial on minors may be conducted only where, in addition to the conditions set out in Article 28, all of the following conditions are met:

(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.

Article 33

Clinical trials on pregnant or breastfeeding women

A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 28, the following conditions are met:

(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.

Article 34

Additional national measures

Member States may maintain additional measures regarding persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical trials, or persons in residential care institutions.

Article 35

Clinical trials in emergency situations

By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a clinical trial may be obtained, and information on the clinical trial may be given, after the decision to include the subject in the clinical trial, provided that this decision is taken at the time of the first intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the following conditions are fulfilled:

(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.

Following an intervention pursuant to paragraph 1, informed consent in accordance with Article 29 shall be sought to continue the participation of the subject in the clinical trial, and information on the clinical trial shall be given, in accordance with the following requirements:

(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.

For the purposes of point (b), where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical trial shall be obtained from the subject as soon as he or she is capable of giving informed consent.

CHAPTER VI

START, END, TEMPORARY HALT, AND EARLY TERMINATION OF A CLINICAL TRIAL

Article 36

Notification of the start of a clinical trial and of the end of the recruitment of subjects

That notification shall be made within 15 days from the start of the clinical trial in relation to that Member State.

That notification shall be made within 15 days from the first visit of the first subject in relation to that Member State.

That notification shall be made within 15 days from the end of the recruitment of subjects. In case of re-start of recruitment, paragraph 1 shall apply.

Article 37

End of a clinical trial, temporary halt and early termination of a clinical trial and submission of the results

That notification shall be made within 15 days from the end of the clinical trial in relation to that Member State.

That notification shall be made within 15 days from the end of the clinical trial in the last Member State concerned.

That notification shall be made within 15 days from the end of the clinical trial in the last of the Member States concerned and third countries in which the clinical trial has been conducted.

It shall be accompanied by a summary written in a manner that is understandable to laypersons. The content of that summary is set out in Annex V.

However, where, for scientific reasons detailed in the protocol, it is not possible to submit a summary of the results within one year, the summary of results shall be submitted as soon as it is available. In this case, the protocol shall specify when the results are going to be submitted, together with a justification.

In addition to the summary of the results, where the clinical trial was intended to be used for obtaining a marketing authorisation for the investigational medicinal product, the applicant for marketing authorisation shall submit to the EU database the clinical study report within 30 days after the day the marketing authorisation has been granted, the procedure for granting the marketing authorisation has been completed, or the applicant for marketing authorisation has withdrawn the application.

For cases where the sponsor decides to share raw data on a voluntary basis, the Commission shall produce guidelines for the formatting and sharing of those data.

That notification shall be made within 15 days from the temporary halt of the clinical trial in all Member States concerned and shall include the reasons for such action.

That notification shall be made within 15 days from the restart of the temporarily halted clinical trial in all Member States concerned.

In the case of early termination of the clinical trial for reasons not affecting the benefit-risk balance, the sponsor shall notify each Member State concerned through the EU portal of the reasons for such action and, when appropriate, follow-up measures for the subjects.

Article 38

That notification shall be made without undue delay but not later than in 15 days of the date of the temporary halt or early termination. It shall include the reasons for such action and specify follow-up measures.

Article 39

Update of the contents of the summary of results and summary for laypersons

The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in order to amend Annexes IV and V, in order to adapt them to technical progress or to take account of international regulatory developments, in which the Union or the Member States are involved, in the field of clinical trials.

CHAPTER VII

SAFETY REPORTING IN THE CONTEXT OF A CLINICAL TRIAL

Article 40

Electronic database for safety reporting

Article 41

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial.

Article 42

The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions.:

(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.

The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(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.

Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex III, submit an initial incomplete report followed up by a complete report.

Article 43

Article 44

Assessment by Member States

Article 45

Technical aspects

Technical aspects for safety reporting in accordance with Articles 41 to 44 are contained in Annex III. Where necessary in order to improve the level of protection of subjects, the Commission shall be empowered to adopt delegated acts in accordance with Article 89 in order to amend Annex III for any of the following purposes:

(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.

Article 46

Reporting with regard to auxiliary medicinal products

Safety reporting with regard to auxiliary medicinal products shall be made in accordance with Chapter 3 of Title IX of Directive 2001/83/EC.

CHAPTER VIII

Article 47

Compliance with the protocol and good clinical practice

The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice.

Without prejudice to any other provision of Union law or Commission guidelines, the sponsor and the investigator, when drawing up the protocol and when applying this Regulation and the protocol, shall also take appropriate account of the quality standards and the ICH guidelines on good clinical practice.

The Commission shall make publicly available the detailed ICH guidelines on good clinical practice referred to in the second paragraph.

Article 48

Monitoring

In order to verify that the rights, safety and well-being of subjects are protected, that the reported data are reliable and robust, and that the conduct of the clinical trial is in compliance with the requirements of this Regulation, the sponsor shall adequately monitor the conduct of a clinical trial. The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics of the clinical trial, including the following characteristics:

(a) whether the clinical trial is a low-intervention clinical trial;

(b) the objective and methodology of the clinical trial; and

Article 49

Suitability of individuals involved in conducting the clinical trial

The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognised in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care.

Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks.

Article 50

Suitability of clinical trial sites

The facilities where the clinical trial is to be conducted shall be suitable for the conduct of the clinical trial in compliance with the requirements of this Regulation.

Article 51

Traceability, storage, return and destruction of investigational medicinal products

The first subparagraph shall also apply to unauthorised auxiliary medicinal products.

Article 52

Reporting of serious breaches

Article 53

Other reporting obligations relevant for subject safety

Article 54

Urgent safety measures

That notification shall be made without undue delay but no later than seven days from the date the measures have been taken.

Article 55

Investigator's brochure

Article 56

Recording, processing, handling and storage of information

Article 57

Clinical trial master file

The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated, taking into account all characteristics of the clinical trial, including in particular whether the clinical trial is a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to the Member States.

The clinical trial master file kept by the investigator and that kept by the sponsor may have a different content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.

Article 58

Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.

Article 59

Auxiliary medicinal products

CHAPTER IX

MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS

Article 60

Scope of this Chapter

This Chapter shall apply to the manufacture and import of investigational medicinal products and auxiliary medicinal products.

Article 61

Authorisation of manufacturing and import

However, the import of investigational medicinal products from other parts of the United Kingdom into Northern Ireland and, until 31 December 2024, into Cyprus, Ireland and Malta shall not be subject to the holding of such an authorisation provided that all of the following conditions are fulfilled:

(a) the investigational medicinal products have undergone certification of batch release either in the Union or in parts of the United Kingdom other than Northern Ireland to verify compliance with the requirements set out in Article 63(1);

(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.

In order to obtain the authorisation referred to in paragraph 1, the applicant shall meet the following requirements:

(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’).

Paragraph 1 shall not apply to any of the following processes:

(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.

Article 62

Responsibilities of the qualified person

Article 63

Manufacturing and import

In addition, the Commission shall also adopt and publish detailed guidelines in line with those principles of good manufacturing practice and revise them when necessary in order to take account of technical and scientific progress.

Article 64

Modification of authorised investigational medicinal products

Articles 61, 62 and 63 shall apply to authorised investigational medicinal products only as regards any modification of such products not covered by a marketing authorisation.

Article 65

Manufacturing of auxiliary medicinal products

Where the auxiliary medicinal product is not authorised, or where an authorised auxiliary medicinal product is modified while such modification is not covered by a marketing authorisation, it shall be manufactured according to the good manufacturing practice referred to in Article 63(1) orto at least an equivalent standard, in order to ensure appropriate quality.

CHAPTER X

LABELLING

Article 66

Unauthorised investigational and unauthorised auxiliary medicinal products

The following information shall appear on the outer packaging and on the immediate packaging of unauthorised investigational medicinal products and unauthorised auxiliary medicinal products:

(a) information to identify contact persons or persons involved in the clinical trial;

(b) information to identify the clinical trial;

(d) information related to the use of the medicinal product.

The information which is to appear on the outer packaging and immediate packaging shall be clearly legible.

A list of information which is to appear on the outer packaging and immediate packaging is set out in Annex VI.

Article 67

Authorised investigational and authorised auxiliary medicinal products

Authorised investigational medicinal products and authorised auxiliary medicinal products shall be labelled:

(a) in accordance with Article 66(1); or

(b) in accordance with Title V of Directive 2001/83/EC.

Article 68

Radiopharmaceuticals used as investigational medicinal products or as auxiliary medicinal products for a medical diagnosis

Articles 66 and 67 shall not apply to radiopharmaceuticals used as diagnostic investigational medicinal products or as diagnostic auxiliary medicinal products.

The products referred to in the first paragraph shall be labelled appropriately in order to ensure the safety of the subject and the reliability and robustness of data generated in the clinical trial.

Article 69

Language

The language of the information on the label shall be determined by the Member State concerned. The medicinal product may be labelled in several languages.

Article 70

Delegated act

The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in respect of amending Annex VI in order to ensure subject safety and the reliability and robustness of data generated in a clinical trial or to take account of technical progress.

CHAPTER XI

Article 71

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.

The investigator and the sponsor may be the same person.

Article 72

Co-sponsorship

By way of derogation from paragraph 1, the sponsors shall be jointly responsible for establishing:

(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;

Article 73

Principal investigator

A principal investigator shall ensure compliance of a clinical trial at a clinical trial site with the requirements of this Regulation.

The principal investigator shall assign tasks among the members of the team of investigators in a way which is not compromising the safety of subjects and the reliability and robustness of the data generated in the clinical trial at that clinical trial site.

Article 74

Article 75

Liability

This Chapter shall not affect the civil and criminal liability of the sponsor, investigator, or persons to whom the sponsor has delegated tasks.

CHAPTER XII

DAMAGE COMPENSATION

Article 76

Damage compensation

CHAPTER XIII

SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS

Article 77

Corrective measures to be taken by Member States

Where a Member State concerned has justified grounds for considering that the requirements set out in this Regulation are no longer met, it may take the following measures on its territory:

(a) revoke the authorisation of a clinical trial;

(b) suspend a clinical trial;

Article 78

Member State inspections

Article 79

Union controls

The Commission may conduct controls in order to verify:

(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.

The Commission shall prepare in cooperation with the Member States a programme for the Union controls referred to in points (b) and (c) of paragraph 1.

The Commission shall report on the findings of each Union control carried out. Those reports shall, if appropriate, contain recommendations. The Commission shall submit those reports through the EU portal.

CHAPTER XIV

IT INFRASTRUCTURE

Article 80

EU portal

The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a portal at Union level as a single entry point for the submission of data and information relating to clinical trials in accordance with this Regulation. The EU portal shall be technically advanced and user-friendly so as to avoid unnecessary work.

Data and information submitted through the EU portal shall be stored in the EU database.

Article 81

EU database

The EU database shall contain the data and information submitted in accordance with this Regulation.

The EU database shall identify each clinical trial by a unique EU trial number. The sponsor shall refer to this EU trial number in any subsequent submission relating or referring to that clinical trial.

The data submitted, in accordance with the first subparagraph, describing medicinal products and substances shall comply with Union and international standards for the identification of medicinal products and active substances. When an investigational medicinal product which already has a marketing authorisation in the Union and/or an active substance which is part of a medicinal product with a marketing authorisation in the Union, is to be used in a clinical trial, the relevant product and active substance numbers shall be referred to in the application for that clinical trial.

The EU database shall be publicly accessible unless, for all or part of the data and information contained therein, confidentiality is justified on any of the following grounds:

(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;

(d) ensuring effective supervision of the conduct of a clinical trial by Member States.

Article 82

Functionality of the EU portal and the EU database

CHAPTER XV

COOPERATION BETWEEN MEMBER STATES

Article 83

National contact points

Article 84

Support by the Agency and the Commission

The Agency shall support the functioning of the cooperation of the Member States in the framework of the authorisation procedures set out in Chapters II and III of this Regulation by maintaining and updating the EU portal and the EU database in accordance with the experience acquired during the implementation of this Regulation.

The Commission shall support the functioning of the cooperation of the Member States referred to in Article 44(2).

Article 85

Clinical Trials Coordination and Advisory Group

The CTAG shall have the following tasks:

(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;

CHAPTER XVI

FEES

Article 86

General principle

This Regulation shall be without prejudice to the possibility for Member States to levy a fee for the activities set out in this Regulation, provided that the level of the fee is set in a transparent manner and on the basis of cost recovery principles. Member States may establish reduced fees for non-commercial clinical trials.

Article 87

One payment per activity per Member State

A Member State shall not require, for an assessment as referred to in Chapters II and III, multiple payments to different bodies involved in this assessment.

CHAPTER XVII

IMPLEMENTING ACTS AND DELEGATED ACTS

Article 88

Committee procedure

Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third subparagraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply.

Article 89

Exercise of the delegation

CHAPTER XVIII

MISCELLANEOUS PROVISIONS

Article 90

Specific requirements for special groups of medicinal products

This Regulation shall not affect the application of national law prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products containing, consisting of or derived from those cells, or of medicinal products used as abortifacients or of medicinal products containing narcotic substances within the meaning of the relevant international conventions in force such as the Single Convention on Narcotic Drugs of 1961 of the United Nations. The Member States shall communicate that national law to the Commission.

No gene therapy clinical trials may be carried out which result in modifications to the subject's germ line genetic identity.

Article 91

Relation with other Union legislation

This Regulation shall be without prejudice to Council Directive 97/43/Euratom (³), Council Directive 96/29/Euratom (⁴), Directive 2001/18/EC of the European Parliament and of the Council (⁵), Directive 2004/23/EC of the European Parliament and of the Council (⁶), Directive 2002/98/EC of the European Parliament and of the Council (⁷), Directive 2010/53/EC of the European Parliament and of the Council (⁸), and Directive 2009/41/EC of the European Parliament and of the Council. (⁹)

Article 92

Investigational medicinal products, other products and procedures, free of charge for the subject

Without prejudice to the Member States' competence for the definition of their health policy and for the organisation and delivery of health services and medical care, the costs for investigational medicinal products, auxiliary medicinal products, medical devices used for their administration and procedures specifically required by the protocol shall not be borne by the subject, unless the law of the Member State concerned provides otherwise.

Article 93

Data protection

Article 94

Penalties

The rules referred to in paragraph 1 shall address, inter alia, the following:

(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.

Article 95

Civil and criminal liability

This Regulation is without prejudice to national and Union law on the civil and criminal liability of a sponsor or an investigator.

CHAPTER XIX

FINAL PROVISIONS

Article 96

Repeal

Article 97

Review

Five years after the date referred to in the second paragraph of Article 99, and every five years thereafter, the Commission shall present a report to the European Parliament and to the Council on the application of this Regulation. That report shall include an assessment of the impact that the Regulation has had on scientific and technological progress, comprehensive information on the different types of clinical trials authorised pursuant to this Regulation, and the measures required in order to maintain the competitiveness of European clinical research. The Commission shall, if appropriate, present a legislative proposal based on that report in order to update the provisions set out in this Regulation.

Article 98

Transitional provision

Article 99

Entry into force

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

It shall apply as from six months after the publication of the notice referred to in Article 82(3), but in any event no earlier than 28 May 2016.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

ANNEX I

A. INTRODUCTION AND GENERAL PRINCIPLES

1.The sponsor shall, where appropriate, refer to any previous applications. If these applications have been submitted by another sponsor, the written agreement from that sponsor shall be submitted.

2.Where a clinical trial has more than one sponsor, detailed information of the responsibilities of each of the sponsors shall be submitted in the application dossier.

3.The application shall be signed by the sponsor or a representative of the sponsor. This signature confirms that the sponsor is satisfied that:

(a) the information provided is complete;

(b) the attached documents contain an accurate account of the information available;

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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

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)

CHAPTER I

GENERAL PROVISIONS

Article 1

Scope

Article 2

Definitions

Article 3

General principle

CHAPTER II

AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL

Article 4

Prior authorisation

Article 5

Submission of an application

Article 6

Assessment report — Aspects covered by Part I

Article 7

Assessment report — Aspects covered by Part II

Article 8

Decision on the clinical trial

Article 9

Persons assessing the application

Article 10

Specific considerations for vulnerable populations

Article 11

Submission and assessment of applications limited to aspects covered by Part I or Part II of the assessment report

Article 12

Withdrawal

Article 13

Resubmission

Article 14

Subsequent addition of a Member State concerned

CHAPTER III

AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL

Article 15

General principles

Article 16

Submission of application

Article 17

Validation of an application for the authorisation of a substantial modification of an aspect covered by Part I of the assessment report

Article 18

Assessment of a substantial modification of an aspect covered by Part I of the assessment report

Article 19

Decision on the substantial modification of an aspect covered by Part I of the assessment report

Article 20

Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the assessment report

Article 21

Substantial modification of aspects covered by Parts I and II of the assessment report

Article 22

Assessment of a substantial modification of aspects covered by Parts I and II of the assessment report — Assessment of the aspects covered by Part II of the assessment report

Article 23

Decision on the substantial modification of aspects covered by Parts I and II of the assessment report

Article 24

Persons assessing the application for a substantial modification

Article 9 applies to assessments made under this Chapter.

CHAPTER IV

APPLICATION DOSSIER

Article 25

Data submitted in the application dossier

Article 26

Language requirements

Article 27

Update by way of delegated acts

CHAPTER V

PROTECTION OF SUBJECTS AND INFORMED CONSENT

Article 28

General rules

Article 29

Informed consent

Article 30

Informed consent in cluster trials

Article 31

Clinical trials on incapacitated subjects

Article 32

Clinical trials on minors

Article 33

Clinical trials on pregnant or breastfeeding women

Article 34