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Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance

Type Regulation

Publication 2014-05-27

Last updated 2022-12-05

State In force

Department Council of the European Union, European Parliament

Source EUR-Lex

articles 100

Reform history JSON API

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.

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.

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.

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.

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

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.

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.

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

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.

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

(a) the information required under points (a), (b), (d) and (e) of Article 29(2) is given, in accordance with what is laid down in the protocol, prior to the inclusion of the subject in the clinical trial, and this information makes clear, in particular, that the subject can refuse to participate in, or withdraw at any time from, the clinical trial without any resulting detriment; and

(b) the potential subject, after being informed, does not object to participating in the clinical trial.

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

(a) the simplified means for obtaining informed consent do not contradict national law in the Member State concerned;

(b) the methodology of the clinical trial requires that groups of subjects rather than individual subjects are allocated to receive different investigational medicinal products in a clinical trial;

(c) the clinical trial is a low-intervention clinical trial and the investigational medicinal products are used in accordance with the terms of the marketing authorisation;

(d) there are no interventions other than the standard treatment of the subjects concerned;

(e) the protocol justifies the reasons for obtaining informed consent with simplified means and describes the scope of information provided to the subjects, as well as the ways of providing information.

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

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.

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.

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

Article 32

Clinical trials on minors

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

(a) the informed consent of their legally designated representative has been obtained;

(b) the minors have received the information referred to in Article 29(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children;

(c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is respected by the investigator;

(d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial;

(e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in minors or the clinical trial is essential with respect to minors to validate data obtained in clinical trials on persons able to give informed consent or by other research methods;

(f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors;

(g) there are scientific grounds for expecting that participation in the clinical trial will produce:
(i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
(ii) some benefit for the population represented by the minor concerned and such a clinical trial will pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with the standard treatment of the minor's condition.

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

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

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

(a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical trial;

(b) there are scientific grounds to expect that participation of the subject in the clinical trial will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition;

(c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative;

(d) the investigator certifies that he or she is not aware of any objections to participate in the clinical trial previously expressed by the subject;

(e) the clinical trial relates directly to the subject's medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical trial is of such a nature that it may be conducted exclusively in emergency situations;

(f) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition.

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

(a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 29(2) shall be given as soon as possible to the subject and to his or her legally designated representative;

(b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever is sooner and the information referred to in Article 29(2) shall be given as soon as possible to the the subject or his or her legally designated representative, whichever is sooner.

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

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.

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

Article 36

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

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

CHAPTER VII SAFETY REPORTING IN THE CONTEXT OF A CLINICAL TRIAL

Article 40

Electronic database for safety reporting

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’).

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

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.

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.

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

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

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

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:
(i) by that sponsor, or
(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorisation holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

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

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.

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

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

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.

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.

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

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

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

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).

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

Article 49

Suitability of individuals involved in conducting the clinical trial

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

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

Article 50

Suitability of clinical trial sites

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

Article 51

Traceability, storage, return and destruction of investigational medicinal products

Investigational medicinal products shall be traceable. They shall be stored, returned and/or destroyed as appropriate and proportionate to ensure the safety of the subject and the reliability and robustness of the data generated in the clinical trial, in particular, taking into account whether the investigational medicinal product is an authorised investigational medicinal product, and whether the clinical trial is a low-intervention clinical trial.

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

The relevant information regarding the traceability, storage, return and destruction of medicinal products referred to in paragraph 1 shall be contained in the application dossier.

Article 52

Reporting of serious breaches

The sponsor shall notify the Member States concerned about a serious breach of this Regulation or of the version of the protocol applicable at the time of the breach through the EU portal without undue delay but not later than seven days of becoming aware of that breach.

For the purposes of this Article, a ‘serious breach’ means a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial.

Article 53

Other reporting obligations relevant for subject safety

The sponsor shall notify the Member States concerned through the EU portal of all unexpected events which affect the benefit-risk balance of the clinical trial, but are not suspected unexpected serious adverse reactions as referred to in Article 42. That notification shall be made without undue delay but no later than 15 days from the date the sponsor became aware of this event.

The sponsor shall submit to the Member States concerned, through the EU portal, all inspection reports of third country authorities concerning the clinical trial. When requested by a Member State concerned, the sponsor shall submit a translation of the report or of its summary in an official language of the Union indicated in the request.

Article 54

Urgent safety measures

Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects.

The sponsor shall notify the Member States concerned, through the EU portal, of the event and the measures taken.

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

This Article is without prejudice to Chapters III and VII.

Article 55

Investigator's brochure

The sponsor shall provide the investigator with the investigator's brochure.

The investigator's brochure shall be updated where new and relevant safety information becomes available, and shall be reviewed by the sponsor at least once per year.

Article 56

Recording, processing, handling and storage of information

All clinical trial information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable law on personal data protection.

Appropriate technical and organisational measures shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves the transmission over a network.

Article 57

Clinical trial master file

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

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

Article 58

Archiving of the clinical trial master file

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

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

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

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

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

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

Article 59

Auxiliary medicinal products

Only authorised auxiliary medicinal products may be used in a clinical trial.

Paragraph 1 shall not apply where no authorised auxiliary medicinal product is available in the Union or where the sponsor cannot reasonably be expected to use an authorised auxiliary medicinal product. A justification to this effect shall be included in the protocol.

Member States shall ensure that unauthorised auxiliary medicinal products may enter their territories for the purpose of their use in a clinical trial in accordance with paragraph 2.

CHAPTER IX MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS

Article 60

Scope of this Chapter

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

Article 61

Authorisation of manufacturing and import

The manufacturing and import of investigational medicinal products in the Union shall be subject to the holding of an authorisation.

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

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

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

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

(a) it shall have at its disposal, for manufacture or import, suitable and sufficient premises, technical equipment and control facilities complying with the requirements set out in this Regulation;

(b) it shall have permanently and continuously at its disposal the services of at least one qualified person who fulfils the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC (‘qualified person’).

The applicant shall specify, in the application for authorisation, the types and pharmaceutical forms of the investigational medicinal product manufactured or imported, the manufacturing or import operations, the manufacturing process where relevant, the site where the investigational medicinal products are to be manufactured or the site in the Union to which they are to be imported, and detailed information concerning the qualified person.

Articles 42 to 45, and point (e) of Article 46 of Directive 2001/83/EC shall apply mutatis mutandis to the authorisation referred to in paragraph 1.

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

(a) re-labelling or re-packaging, where those processes are carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member State concerned to carry out such processes, and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State;

(b) preparation of radiopharmaceuticals used as diagnostic investigational medicinal products where this process is carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member State concerned to carry out such process, and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State;

(c) the preparation of medicinal products referred to in points (1) and (2) of Article 3 of Directive 2001/83/EC for use as investigational medicinal products, where this process is carried out in hospitals, health centres or clinics legally authorised in the Member State concerned to carry out such process and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State.

Member States shall make the processes set out in paragraph 5 subject to appropriate and proportionate requirements to ensure subject safety and reliability and robustness of the data generated in the clinical trial. They shall subject the processes to regular inspections.

Article 62

Responsibilities of the qualified person

The qualified person shall ensure that each batch of investigational medicinal products manufactured in or imported into the Union complies with the requirements set out in Article 63 and shall certify that those requirements are fulfilled.

The certification referred to in paragraph 1 shall be made available by the sponsor at the request of the Member State concerned.

Article 63

Manufacturing and import

Investigational medicinal products shall be manufactured by applying manufacturing practice which ensures the quality of such medicinal products in order to safeguard the safety of the subject and the reliability and robustness of clinical data generated in the clinical trial (‘good manufacturing practice’). The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in order to specify the principles and guidelines of good manufacturing practice and the detailed arrangements for inspection for ensuring the quality of investigational medicinal products, taking account of subject safety or data reliability and robustness, technical progress and global regulatory developments in which the Union or the Member States are involved.

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

Paragraph 1 shall not apply to the processes referred to in Article 61(5).

Investigational medicinal products imported into the Union shall be manufactured by applying quality standards at least equivalent to those laid down pursuant to paragraph 1.

The Member States shall ensure compliance with the requirements of this Article by means of inspections.

Article 64

Modification of authorised investigational medicinal products

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

Article 65

Manufacturing of auxiliary medicinal products

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

CHAPTER X LABELLING

Article 66

Unauthorised investigational and unauthorised auxiliary medicinal products

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

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

(b) information to identify the clinical trial;

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

The information which is to appear on the outer packaging and immediate packaging shall ensure subject safety and reliability and robustness of the data generated in the clinical trial, while taking account of the design of the clinical trial, whether the products are investigational or auxiliary medicinal product, and whether they are products with particular characteristics.

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

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

Article 67

Authorised investigational and authorised auxiliary medicinal products

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

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

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

Notwithstanding point (b) of paragraph 1, where the specific circumstances, provided for in the protocol, of a clinical trial so require in order to ensure the safety of the subject or the reliability and robustness of data generated in a clinical trial, additional particulars relating to the identification of the clinical trial and of the contact person shall appear on the outer packaging and the immediate packaging of authorised investigational medicinal products. A list of these additional particulars appearing on the outer packaging and immediate packaging is set out in section C of Annex VI.

Article 68

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

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

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

Article 69

Language

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

Article 70

Delegated act

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

Article 71

A clinical trial may have one or several sponsors.

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

The investigator and the sponsor may be the same person.

Article 72

Co-sponsorship

Without prejudice to Article 74, where a clinical trial has more than one sponsor, all sponsors shall have the responsibilities of a sponsor set out in this Regulation, unless the sponsors decide otherwise in a written contract setting out their respective responsibilities. Where the contract does not specify to which sponsor a given responsibility is attributed, that responsibility shall lie with all sponsors.

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

(a) a sponsor responsible for compliance with the obligations of a sponsor in the authorisation procedures set out in Chapters II and III;

(b) a sponsor responsible for being a contact point for receiving all questions from subjects, investigators or any Member State concerned regarding the clinical trial and providing answers to them;

Article 73

Principal investigator

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

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

Article 74

Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

Article 75

Liability

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

CHAPTER XII DAMAGE COMPENSATION

Article 76

Damage compensation

Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical trial conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk.

The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State concerned where the clinical trial is conducted.

Member States shall not require any additional use of the system referred to in paragraph 1 from the sponsor for low-intervention clinical trials, if any possible damage that could be suffered by a subject resulting from the use of the investigational medicinal product in accordance with the protocol of that specific clinical trial on the territory of that Member State is covered by the applicable compensation system already in place.

CHAPTER XIII SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS

Article 77

Corrective measures to be taken by Member States

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

(a) revoke the authorisation of a clinical trial;

(b) suspend a clinical trial;

Before the Member State concerned takes any of the measures referred to in paragraph 1 it shall, except where immediate action is required, ask the sponsor and/or the investigator for their opinion. That opinion shall be delivered within seven days.

The Member State concerned shall immediately after taking a measure referred to in paragraph 1 inform all Member States concerned through the EU portal.

Each Member State concerned may consult the other Member States concerned before taking any of the measures referred to in paragraph 1.

Article 78

Member State inspections

Member States shall appoint inspectors to perform inspections in order to supervise compliance with this Regulation. They shall ensure that those inspectors are adequately qualified and trained.

Inspections shall be conducted under the responsibility of the Member State where the inspection takes place.

Where a Member State concerned intends to carry out an inspection on its territory or in a third country with regard to one or several clinical trials which are conducted in more than one Member State concerned, it shall notify its intention to the other Member States concerned, the Commission and the Agency, through the EU portal, and shall inform them of its findings after the inspection.

Inspections fees, if any, may be waived for non-commercial sponsors.

In order to efficiently use the resources available and to avoid duplications, the Agency shall coordinate the cooperation between Member States concerned on inspections conducted in Member States, in third countries, and inspections conducted in the framework of an application for a marketing authorisation under Regulation (EC) No 726/2004.

Following an inspection, the Member State under whose responsibility the inspection has been conducted shall draw up an inspection report. That Member State shall make the inspection report available to the inspected entity and the sponsor of the relevant clinical trial and shall submit the inspection report through the EU portal.

The Commission shall specify, by means of implementing acts, the detailed arrangements for the inspection procedures including the qualification and training requirements for inspectors. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 88(2).

Article 79

Union controls

The Commission may conduct controls in order to verify:

(a) whether Member States correctly supervise compliance with this Regulation;

(b) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that point 8 of the Introduction and general principles contained in Annex I to Directive 2001/83/EC is complied with;

(c) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that Article 25(5) of this Regulation is complied with.

The Union controls referred to in point (a) of paragraph 1 shall be organised in cooperation with the Member States concerned.

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

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

CHAPTER XIV IT INFRASTRUCTURE

Article 80

EU portal

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

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

Article 81

EU database

The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a EU database at Union level. The Agency shall be considered to be the controller of the EU database and shall be responsible for avoiding unnecessary duplication between the EU database and the EudraCT and Eudravigilance databases.

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

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

The EU database shall be established to enable cooperation between the competent authorities of the Member States concerned to the extent that it is necessary for the application of this Regulation and to search for specific clinical trials. It shall also facilitate the communication between sponsors and Member States concerned and enable sponsors to refer to previous submissions of an application for authorisation of a clinical trial or a substantial modification. It shall also enable citizens of the Union to have access to clinical information about medicinal products. To this end all data held in the EU database shall be in an easily searchable format, all related data shall be grouped together by way of the EU trial number, and hyperlinks shall be provided to link together related data and documents held on the EU database and other databases managed by the Agency.

The EU database shall support the recording and submission to the Medicinal Product Dictionary, contained in the Eudravigilance database, of all the data on medicinal products without a marketing authorisation in the Union and substances not authorised as part of a medicinal product in the Union, that are necessary for the maintenance of that dictionary. To this effect and also with the purpose of enabling the sponsor to cross-refer to prior applications, an EU medicinal product number shall be issued for every medicinal product without a marketing authorisation and an EU active substances code shall be issued for each new active substance not previously authorised as part of a medicinal product in the Union. This shall be done before or during the application for authorisation of the first clinical trial with that product or active substance submitted in accordance with this Regulation. Those numbers shall be mentioned in all subsequent applications for clinical trials and for substantial modifications.

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

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

(a) protecting personal data in accordance with Regulation (EC) No 45/2001;

(b) protecting commercially confidential information, in particular through taking into account the status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in disclosure;

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

Without prejudice to paragraph 4, unless there is an overriding public interest in disclosure, data contained in the application dossier shall not be publicly accessible before the decision on the clinical trial has been made.

The EU database shall contain personal data only insofar as this is necessary for the purposes of paragraph 2.

No personal data of subjects shall be publicly accessible.

The user interface of the EU database shall be available in all official languages of the Union.

The sponsor shall permanently update in the EU database information on any changes to the clinical trials which are not substantial modifications but are relevant for the supervision of the clinical trial by the Member States concerned.

10.

The Agency, the Commission and Member States shall ensure that the data subject may effectively exercise his or her rights to information, to access, to rectify and to object in accordance with Regulation (EC) No 45/2001 and national data protection legislation implementing Directive 95/46/EC, respectively. They shall ensure that the data subject may effectively exercise the right of access to data relating to him or her, and the right to have inaccurate or incomplete data corrected or erased. Within their respective responsibilities, the Agency, the Commission and Member States shall ensure that inaccurate and unlawfully processed data are deleted, in accordance with the applicable law. Corrections and deletions shall be carried out as soon as possible, but no later than 60 days of a request being made by a data subject.

Article 82

Functionality of the EU portal and the EU database

The Agency shall, in collaboration with the Member States and the Commission, draw up the functional specifications for the EU portal and the EU database, together with the time frame for their implementation.

The Management Board of the Agency shall, on the basis of an independent audit report, inform the Commission when it has verified that the EU portal and the EU database have achieved full functionality and the systems meet the functional specifications drawn up pursuant to paragraph 1.

The Commission shall, when it is satisfied that the conditions referred to in paragraph 2 have been fulfilled, publish a notice to that effect in the Official Journal of the European Union.

CHAPTER XV COOPERATION BETWEEN MEMBER STATES

Article 83

National contact points

Each Member State shall designate one national contact point in order to facilitate the functioning of the procedures set out in Chapters II and III.

Each Member State shall communicate the contact point referred to in paragraph 1 to the Commission. The Commission shall publish a list of the national contact points.

Article 84

Support by the Agency and the Commission

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

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

Article 85

Clinical Trials Coordination and Advisory Group

A Clinical Trials Coordination and Advisory Group (CTAG), composed of the national contact points referred to in Article 83 is hereby established.

The CTAG shall have the following tasks:

(a) to support the exchange of information between the Member States and the Commission on the experience acquired with regard to the implementation of this Regulation;

(b) to assist the Commission in providing the support referred to in the second paragraph of Article 84;

The CTAG shall be chaired by a representative of the Commission.

The CTAG shall meet at regular intervals and whenever the situation requires, on a request from the Commission or a Member State. Any item of the agenda of the meeting shall be placed at the request of the Commission or a Member State.

The secretariat shall be provided by the Commission.

The CTAG shall draw up its rules of procedure. The rules of procedure shall be made public.

CHAPTER XVI FEES

Article 86

General principle

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

Article 87

One payment per activity per Member State

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

CHAPTER XVII IMPLEMENTING ACTS AND DELEGATED ACTS

Article 88

Committee procedure

The Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use established by Directive 2001/83/EC. That committee shall be a committee within the meaning of Regulation (EU) No 182/2011.

Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply.

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

Article 89

Exercise of the delegation

The power to adopt delegated acts is conferred on the Commission subject to the conditions laid down in this Article.

The power to adopt delegated acts referred to in Articles 27, 39, 45, 63(1) and 70 shall be conferred on the Commission for a period of five years from the date referred to in the second paragraph of Article 99. The Commission shall draw up a report in respect of the delegated powers not later than six months before the end of the five year period. The delegation of powers shall be tacitly extended for periods of an identical duration, unless the European Parliament or the Council opposes such extension not later than three months before the end of each period.

The delegation of power referred to in Articles 27, 39, 45, 63(1) and 70 may be revoked at any time by the European Parliament or by the Council. A decision of revocation shall put an end to the delegation of the power specified in that decision. It shall take effect the day following the publication of the decision in the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity of any delegated acts already in force.

As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament and to the Council.

A delegated act adopted pursuant to Articles 27, 39, 45, 63(1) and 70 shall enter into force only if no objection has been expressed either by the European Parliament or the Council within a period of two months from notification of that act to the European Parliament and the Council or if, before the expiry of that period, the European Parliament and the Council have both informed the Commission that they will not object. That period shall be extended by two months at the initiative of the European Parliament or the Council.

CHAPTER XVIII MISCELLANEOUS PROVISIONS

Article 90

Specific requirements for special groups of medicinal products

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