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

• CELEX: Regulation (EU) No 536/2014
• Articles: 106

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

1.   For the purposes of this Regulation, the definitions of ‘medicinal product’, ‘radiopharmaceutical’, ‘adverse reaction’, ‘serious adverse reaction’, ‘immediate packaging’ and ‘outer packaging’ set out in points (2), (6), (11), (12), (23) and (24), respectively, of Article 1 of Directive 2001/83/EC apply.

2.   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  ( 11 ) ;

(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.

3.   For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’ and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.

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.

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

1.   In order to obtain an authorisation, the sponsor shall submit an application dossier to the intended Member States concerned through the portal referred to in Article 80 (the ‘EU portal’).

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.

2.   The sponsor shall, when applying for a low-intervention clinical trial, where the investigational medicinal product is not used in accordance with the terms of the marketing authorisation but the use of that product is evidence-based and supported by published scientific evidence on the safety and efficacy of that product, propose one of the Member States concerned where the use is evidence-based, as reporting Member State.

3.   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.

4.   Where the reporting Member State has not notified the sponsor within the period referred to in the first subparagraph of paragraph 3, the clinical trial applied for shall be deemed to fall within the scope of this Regulation and the application dossier shall be considered complete.

5.   Where the reporting Member State, taking into account considerations expressed by the other Member States concerned, finds that the application dossier is not complete, or that the clinical trial applied for does not fall within the scope of this Regulation, it shall inform the sponsor thereof through the EU portal and shall set a maximum of 10 days for the sponsor to comment on the application or to complete the application dossier through the EU portal.

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.

6.   For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 3 or 5 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the respective periods referred to in paragraphs 3 and 5.

Article 6 Assessment report — Aspects covered by Part I

1.   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  ( 12 ) ;

—

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.

2.   The reporting Member State shall draw up an assessment report. The assessment of the aspects referred to in paragraph 1 shall constitute Part I of the assessment report.

3.   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

(c)

the conduct of the clinical trial is not acceptable in view of the requirements set out in this Regulation.

4.   The reporting Member State shall submit, through the EU portal, the final Part I of the assessment report, including its conclusion, to the sponsor and to the other Member States concerned within 45 days from the validation date.

5.   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.

6.   For the purposes of this Chapter, the date on which the final Part I of the assessment report is submitted by the reporting Member State to the sponsor and to the other Member States concerned shall be the reporting date.

7.   The reporting Member State may also extend the period referred to in paragraph 4 by a further 50 days for clinical trials involving an advanced therapy investigational medicinal products or a medicinal product as defined in point 1 of the Annex to Regulation (EC) No 726/2004, for the purpose of consulting with experts. In such case, the periods referred to in paragraphs 5 and 8 of this Article shall apply mutatis mutandis .

8.   Between the validation date and the reporting date, only the reporting Member State may request additional information from the sponsor, taking into account the considerations referred to in paragraph 5.

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

1.   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;

(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.

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

2.   Each Member State concerned shall complete its assessment within 45 days from the validation date and submit, through the EU portal, Part II of the assessment report, including its conclusion, to the sponsor.

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.

3.   For the purpose of obtaining and reviewing the additional information referred to in the second subparagraph of paragraph 2 from the sponsor in accordance with the second and third subparagraph, the Member State concerned may extend the period referred to in the first subparagraph of paragraph 2 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 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

1.   Each Member State concerned shall notify the sponsor through the EU portal as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.

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.

2.   Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.

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.

3.   Where, regarding the aspects covered by Part I of the assessment report, the clinical trial is acceptable or acceptable subject to compliance with specific conditions, the Member State concerned shall include in its decision its conclusion on Part II of the assessment report.

4.   A Member State concerned shall refuse to authorise a clinical trial 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 of paragraph 2, or if it finds, on duly justified grounds, that the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has issued a negative opinion which in accordance with the law of the Member State concerned is valid for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.

5.   Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the clinical trial is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned.

6.   Where the Member State concerned has not notified the sponsor of its decision within the relevant periods referred to in paragraph 1, the conclusion on Part I of the assessment report shall be deemed to be the decision of the Member State concerned on the application for authorisation of the clinical trial.

7.   The Member States concerned shall not request additional information regarding the aspects addressed in Part I of the assessment report from the sponsor after the reporting date.

8.   For the purposes of this Chapter, the notification date shall be the date on which the decision referred to in paragraph 1 is notified to the sponsor. Where the sponsor has not been notified in accordance with paragraph 1, the notification date shall be deemed to be the last day of the period provided for in paragraph 1.

9.   If no subject has been included in the clinical trial in a Member State concerned within two years from the notification date of the authorisation, the authorisation shall expire in that Member State concerned unless an extension, on request of the sponsor, has been approved following the procedure set out in Chapter III.

Article 9 Persons assessing the application

1.   Member States shall ensure that the persons validating and assessing the application do not have conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators involved and of persons financing the clinical trial, as well as free of any other undue influence.

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.

2.   Member States shall ensure that the assessment is done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience.

3.   At least one layperson shall participate in the assessment.

Article 10 Specific considerations for vulnerable populations

1.   Where the subjects are minors, specific consideration shall be given to the assessment of the application for authorisation of a clinical trial on the basis of paediatric expertise or after taking advice on clinical, ethical and psychosocial problems in the field of paediatrics.

2.   Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant disease and the patient population concerned or after taking advice on clinical, ethical and psychosocial questions in the field of the relevant disease and the patient population concerned.

3.   Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant condition and the population represented by the subject concerned.

4.   If according to the protocol a clinical trial provides for the participation of specific groups or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of the application for authorisation of that clinical trial on the basis of expertise in the population represented by the subjects concerned.

5.   In any application for authorisation of a clinical trial referred to in Article 35, specific consideration shall be given to the circumstances of the conduct of the clinical trial.

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

1.   Where the sponsor wishes to extend an authorised clinical trial to another Member State (‘additional Member State concerned’), the sponsor shall submit an application dossier to that Member State through the EU portal.

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

2.   The reporting Member State for the application dossier referred to in paragraph 1 shall be the reporting Member State for the initial authorisation procedure.

3.   The additional Member State concerned shall notify the sponsor through the EU portal, within 52 days from the date of submission of the application dossier referred to in paragraph 1, by way of one single decision as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether the authorisation is refused.

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.

4.   Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of the additional Member State concerned.

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;

(c)

considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 6.

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.

5.   Between the date of submission of the application dossier referred to in paragraph 1 and five days before the expiry of the period referred to in paragraph 3, the additional Member State concerned may communicate to the reporting Member State and the other Member States concerned any considerations relevant to the application through the EU portal.

6.   Between the date of submission of the application dossier referred to in paragraph 1 and the expiry of the period referred to in paragraph 3, only the reporting Member State may request additional information from the sponsor concerning the aspects addressed in Part I of the assessment report, taking into account the considerations referred to in paragraph 5.

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.

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 the additional Member State concerned.

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

7.   The additional Member State concerned shall assess, for its territory, the aspects addressed in Part II of the assessment report within the period referred to in paragraph 3 and submit, through the EU portal, Part II of the assessment report, including its conclusion, to the sponsor. Within that period it may request, with justified reasons, additional information from the sponsor regarding aspects addressed in Part II of the assessment report as far as its territory is concerned.

8.   For the purpose of obtaining and reviewing the additional information referred to in paragraph 7 from the sponsor in accordance with the second and third subparagraphs, the additional Member State concerned may extend the period referred to in paragraph 7 by a maximum of 31 days.

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.

9.   Where, regarding the aspects covered by Part I of the assessment report, the conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions, the additional Member State concerned shall include in its decision its conclusion on Part II of the assessment report.

10.   The additional Member State concerned shall refuse to authorise the clinical trial 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 second subparagraph of paragraph 4, or if it finds, on duly justified grounds, that the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has issued a negative opinion which, in accordance with the law of the additional Member State concerned, is valid for that entire additional Member State. That additional Member State concerned shall provide for an appeal procedure in respect of such refusal.

11.   Where the additional Member State concerned has not notified the sponsor of its decision within the period referred to in paragraph 3, or in case that period has been extended in accordance with paragraph 6 or 8 where that additional Member State concerned has not notified the sponsor of its decision within the extended period, the conclusion on Part I of the assessment report shall be deemed to be the decision of that additional Member State concerned on the application for authorisation of the clinical trial.

12.   A sponsor shall not submit an application dossier in accordance with this Article where a procedure set out in Chapter III is pending as regards that 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

1.   The reporting Member State for the authorisation of a substantial modification shall be the reporting Member State for the initial authorisation procedure.

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.

2.   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.

3.   Where the reporting Member State has not notified the sponsor within the period referred to in paragraph 2, 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.

4.   Where the reporting Member State, taking into account considerations expressed by the other Member States concerned, finds that the application does not concern an aspect covered by Part I of the assessment report or that the application dossier is not complete, it shall inform the sponsor thereof through the EU portal and shall set a maximum of 10 days for the sponsor to comment on the application or to complete the application dossier through the EU portal.

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 paragraph 2.

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.

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.

5.   For the purposes of Articles 18, 19 and 22, the date on which the sponsor is notified in accordance with paragraph 2 or 4 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the respective periods referred to in paragraphs 2 and 4.

Article 18 Assessment of a substantial modification of an aspect covered by Part I of the assessment report

1.   The reporting Member State shall assess the application with regard to an aspect covered by Part I of the assessment report, including whether the clinical trial will remain a low-intervention clinical trial after its substantial modification, and draw up an assessment report.

2.   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

(c)

the substantial modification is not acceptable in view of the requirements set out in this Regulation.

3.   The reporting Member State shall submit, through the EU portal, the final assessment report including its conclusion, to the sponsor and to the other Member States concerned within 38 days from the validation date.

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.

4.   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.

5.   The reporting Member State may extend the period referred to in paragraph 3 by a further 50 days for clinical trials involving an advanced therapy investigational medicinal product or a medicinal product as set out in point 1 of the Annex to Regulation (EC) No 726/2004, for the purpose of consulting with experts. In such case, the periods referred to in paragraphs 4 and 6 of this Article shall apply mutatis mutandis .

6.   Between the validation date and the reporting date, only the reporting Member State may request additional information from the sponsor, taking into account the considerations 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 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 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

1.   Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.

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.

2.   Where the conclusion of the reporting Member State is that the substantial modification is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.

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.

3.   Where the conclusion of the reporting Member State, as regards the substantial modification of aspects covered by Part I of the assessment report, is that the substantial modification is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned.

4.   Where the Member State concerned has not notified the sponsor of its decision within the period referred to in paragraph 1, the conclusion of the assessment report shall be deemed to be the decision of the Member State concerned on the application for authorisation of the substantial modification.

Article 20 Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the assessment report

1.   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.

2.   Where the Member State concerned has not notified the sponsor within the period referred to in paragraph 1, the substantial modification applied for 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.

3.   Where the Member State concerned finds that the substantial modification does not concern an aspect covered by Part II of the assessment report or that the application dossier is not complete, it shall inform the sponsor thereof through the EU portal and shall set a maximum of 10 days for the sponsor to comment on the application or to complete the application dossier through the EU portal.

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 paragraph 1.

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.

4.   For the purpose of this Article, the date on which the sponsor is notified in accordance with paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the respective periods referred to in paragraphs 1 and 3.

5.   The Member State concerned shall assess the application and shall submit to the sponsor, through the EU portal, Part II of the assessment report, including its conclusion, and the decision as to whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.

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.

6.   During the period referred to in the second subparagraph of paragraph 5, the Member State concerned may request, with justified reasons, additional information from the sponsor regarding the substantial modification as far as its territory is concerned.

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.

7.   A Member State concerned shall refuse to authorise a substantial modification if it finds, on duly justified grounds, that the aspects covered by Part II of the assessment report are not complied with 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.

8.   Where the Member State concerned has not notified the sponsor of its decision within the periods set out in paragraphs 5 and 6, the substantial modification shall be deemed to be authorised in that Member State.

Article 21 Substantial modification of aspects covered by Parts I and II of the assessment report

1.   Where a substantial modification relates to aspects covered by Parts I and II of the assessment report, the application for authorisation of that substantial modification shall be validated in accordance with Article 17.

2.   The aspects covered by Part I of the assessment report shall be assessed in accordance with Article 18 and the aspects covered by Part II of the assessment report shall be assessed in accordance with Article 22.

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

1.   Each Member State concerned shall assess, for its own territory, the aspects of the substantial modification which are covered by Part II of the assessment report and submit, through the EU portal, that report, including its conclusion, to the sponsor within 38 days from the validation date.

2.   During the period referred to in paragraph 1, the Member State concerned may request, with justified reasons, additional information from the sponsor regarding this substantial modification as far as its territory is concerned.

3.   For the purpose of obtaining and reviewing the additional information referred to in paragraph 2 from the sponsor in accordance with the third and fourth subparagraph, the Member State concerned may extend the period referred to paragraph 1 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 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

1.   Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.

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.

2.   Where the conclusion of the reporting Member State is that the substantial modification of aspects covered by Part I of the assessment report is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.

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.

3.   Where, regarding the substantial modification of aspects covered by Part I of the assessment report, the substantial modification is acceptable or acceptable subject to compliance with specific conditions, the Member State concerned shall include in its decision its conclusion on the substantial modification of aspects covered by Part II of the assessment report.

4.   A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the conclusion of the reporting Member State as regards the substantial modification of aspects covered by Part I of the assessment report on any of the grounds referred to in second subparagraph of paragraph 2, or if it finds, on duly justified grounds, that the aspects covered by Part II of the assessment report are not complied with, or where an ethics committee has issued a negative opinion which in accordance with the law of the Member State concerned, is valid for that entire Member State. That Member State concerned shall provide for an appeal procedure in respect of such refusal.

5.   Where the conclusion of the reporting Member State as regards the substantial modification of aspects covered by Part I of the assessment report is that the substantial modification is not acceptable, that conclusion shall be deemed to be the conclusion of the Member State concerned.

6.   Where the Member State concerned has not notified the sponsor of its decision within the periods referred to in paragraph 1, the conclusion on the substantial modification of aspects covered by Part I of the assessment report shall be deemed to be the decision of the Member State concerned on the application for authorisation of the substantial modification.

Article 24 Persons assessing the application for a substantial modification

Article 9 applies to assessments made under this Chapter.

Article 25 Data submitted in the application dossier

1.   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.

2.   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;

(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.

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

3.   Non-clinical information submitted in an application dossier shall be based on data derived from studies complying with Union law on the principles of good laboratory practice, as applicable at the time of performance of those studies.

4.   Where reference is made in the application dossier to data generated in a clinical trial, that clinical trial shall have been conducted in accordance with this Regulation or, if conducted prior to the date referred to in the second paragraph of Article 99, in accordance with Directive 2001/20/EC.

5.   Where the clinical trial referred to in paragraph 4 has been conducted outside the Union, it shall have been conducted in accordance with principles equivalent to those of this Regulation as regards the rights and safety of the subject and the reliability and robustness of the data generated in the clinical trial.

6.   Data from a clinical trial started as from the date referred to in the second paragraph of Article 99 shall only be submitted in an application dossier if that clinical trial has been registered prior to its start in a public register which is a primary or partner registry of, or a data provider to, the WHO ICTRP.

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.

7.   Data submitted in an application dossier which do not comply with paragraphs 3 to 6 shall not be considered in the assessment of an application for authorisation of a clinical trial or of a substantial modification.

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.

Article 28 General rules

1.   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.

2.   Without prejudice to Directive 95/46/EC, the sponsor may ask the subject or, where the subject is not able to give informed consent, his or her legally designated representative at the time when the subject or the legally designated representative gives his or her informed consent to participate in the clinical trial to consent to the use of his or her data outside the protocol of the clinical trial exclusively for scientific purposes. That consent may be withdrawn at any time by the subject or his or her legally designated representative.

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.

3.   Any subject, or, where the subject is not able to give informed consent, his or her legally designated representative, may, without any resulting detriment and without having to provide any justification, withdraw from the clinical trial at any time by revoking his or her informed consent. Without prejudice to Directive 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and the use of data obtained based on informed consent before its withdrawal.

Article 29 Informed consent

1.   Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document (or the record) by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical trial.

2.   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.

3.   The information referred to in paragraph 2 shall be prepared in writing and be available to the subject or, where the subject is not able to give informed consent, his or her legally designated representative.

4.   In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information.

5.   In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood the information.

6.   The subject shall be informed that the summary of the results of the clinical trial and a summary presented in terms understandable to a layperson will be made available in the EU database, referred to in Article 81 (the ‘EU database’), pursuant to Article 37(4), irrespective of the outcome of the clinical trial, and, to the extent possible, when the summaries become available.

7.   This Regulation is without prejudice to national law requiring that both the signature of the incapacitated person and the signature of his or her legally designated representative may be required on the informed consent form.

8.   This Regulation is without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical trial.

Article 30 Informed consent in cluster trials

1.   Where a clinical trial is to be conducted exclusively in one Member State, that Member State may, without prejudice to Article 35, and by way of derogation from points (b), (c), and (g) of Article 28(1), Article 29(1), point (c) of Article 29(2), Article 29(3), (4) and (5), points (a), (b) and (c) of Article 31(1) and points (a), (b) and (c) of Article 32(1), allow the investigator to obtain informed consent by the simplified means set out in paragraph 2 of this Article, provided that all of the conditions set out in paragraph 3 of this Article are fulfilled.

2.   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.

3.   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.

4.   The investigator shall document all refusals and withdrawals and shall ensure that no data for the clinical trial are collected from subjects that refuse to participate in or have withdrawn from the clinical trial.

Article 31 Clinical trials on incapacitated subjects

1.   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.

2.   Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific grounds to expect that participation in the clinical trial will produce a direct benefit to the subject outweighing the risks and burdens involved.

3.   The subject shall as far as possible take part in the informed consent procedure.

Article 32 Clinical trials on minors

1.   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.

2.   The minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity.

3.   If during a clinical trial the minor reaches the age of legal competence to give informed consent as defined in the law of the Member State concerned, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical trial.

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

1.   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.

2.   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.

3.   If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical trial.

Article 36 Notification of the start of a clinical trial and of the end of the recruitment of subjects

1.   The sponsor shall notify each Member State concerned of the start of a clinical trial in relation to that Member State through the EU portal.

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

2.   The sponsor shall notify each Member State concerned of the first visit of the first subject in relation to that Member State through the EU portal.

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

3.   The sponsor shall notify each Member State concerned of the end of the recruitment of subjects for a clinical trial in that Member State through the EU portal.

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

1.   The sponsor shall notify each Member State concerned of the end of a clinical trial in relation to that Member State through the EU portal.

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

2.   The sponsor shall notify each Member State concerned of the end of a clinical trial in all Member States concerned through the EU portal.

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

3.   The sponsor shall notify each Member State concerned of the end of a clinical trial in all Member States concerned and in all third countries in which the clinical trial has been conducted through the EU portal.

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.

4.   Irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial in all Member States concerned, the sponsor shall submit to the EU database a summary of the results of the clinical trial. The content of that summary is set out in Annex IV.

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.

5.   The sponsor shall notify each Member State concerned of a temporary halt of a clinical trial in all Member States concerned for reasons not affecting the benefit-risk balance through the EU portal.

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.

6.   When a temporarily halted clinical trial referred to in paragraph 5 is resumed the sponsor shall notify each Member State concerned through the EU portal.

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

7.   If a temporarily halted clinical trial is not resumed within two years, the expiry date of this period or the date of the decision of the sponsor not to resume the clinical trial, whichever is earlier, shall be deemed to be the date of the end of the clinical trial. In the case of early termination of the clinical trial, the date of the early termination shall be deemed to be the date of the end of the clinical trial.

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.

8.   Without prejudice to paragraph 4, where the clinical trial protocol provides for an intermediate data analysis date prior to the end of the clinical trial, and the respective results of the clinical trial are available, a summary of those results shall be submitted to the EU database within one year of the intermediate data analysis date.

Article 38 Temporary halt or early termination by the sponsor for reasons of subject safety

1.   For the purposes of this Regulation, the temporary halt or early termination of a clinical trial for reasons of a change of the benefit-risk balance shall be notified to the Member States concerned through the EU portal.

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.

2.   The restart of the clinical trial following a temporary halt as referred to in paragraph 1 shall be deemed to be a substantial modification subject to the authorisation procedure laid down in Chapter III.

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.

Article 40 Electronic database for safety reporting

1.   The European Medicines Agency established by Regulation (EC) No 726/2004 (the ‘Agency’) shall set up and maintain an electronic database for the reporting provided for in Articles 42 and 43. That database shall be a module of the database referred to in Article 24 of Regulation (EC) No 726/2004 (the ‘Eudravigilance database’).

2.   The Agency shall, in collaboration with Member States, develop a standard web-based structured form for the reporting by sponsors to the database referred to in paragraph 1 of suspected unexpected serious adverse reactions.

Article 41 Reporting of adverse events and serious adverse events by the investigator to the sponsor

1.   The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.

2.   The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

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.

3.   The sponsor shall keep detailed records of all adverse events reported to it by the investigator.

4.   If the investigator becomes aware of a serious adverse event with a suspected causal relationship to the investigational medicinal product that occurs after the end of the clinical trial in a subject treated by him or her, the investigator shall, without undue delay, report the serious adverse event to the sponsor.

Article 42 Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1.   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.

2.   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.

3.   Where a sponsor, due to a lack of resources, does not have the possibility to report to the database referred to in Article 40(1) and the sponsor has the agreement of the Member State concerned, it may report to the Member State where the suspected unexpected serious adverse reaction occurred. That Member State shall report the suspected unexpected serious adverse reaction in accordance with paragraph 1 of this Article.

Article 43 Annual reporting by the sponsor to the Agency

1.   Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2.   In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3.   The annual report referred to in paragraph 1 shall only contain aggregate and anonymised data.

4.   The obligation referred to in paragraph 1 starts with the first authorisation of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product.

Article 44 Assessment by Member States

1.   The Agency shall, by electronic means, forward to the Member States concerned the information reported in accordance with Article 42 and 43.

2.   Member States shall cooperate in assessing the information reported in accordance with Articles 42and 43. The Commission may, by means of implementing acts, set up and modify the rules on such cooperation. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 88(2).

3.   The responsible ethics committee shall be involved in the assessment of the information referred to in paragraphs 1 and 2, if it has been provided for in the law of the Member State concerned.

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.

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

(c)

the degree of deviation of the intervention from normal clinical practice.

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.