EN Official Journal of the European Union L 158/1

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)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty on the Functioning of the European Union, and in particular Articles 114 and 168(4)(c) thereof,

Having regard to the proposal from the European Commission,

After transmission of the draft legislative act to the national parliaments,

Having regard to the opinion of the European Economic and Social Committee (1),

After consulting the Committee of the Regions,

Acting in accordance with the ordinary legislative procedure (2),

Whereas:

(1) In a clinical trial the rights, safety, dignity and well-being of subjects should be protected and the data generated should be reliable and robust. The interests of the subjects should always take priority over all other interests.

(2) In order to allow for independent control as to whether these principles are adhered to, a clinical trial should be subject to prior authorisation.

(3) The existing definition of a clinical trial as contained in Directive 2001/20/EC of the European Parliament and of the Council (3) should be clarified. For that purpose, the concept of clinical trial should be more precisely defined by introducing the broader concept of ‘clinical study’ of which the clinical trial is a category. That category should be defined on the basis of specific criteria. This approach takes due account of international guidelines, and is in line with the Union law governing medicinal products, which builds on the dichotomy of ‘clinical trial’ and ‘non-interventional study’.

(4) Directive 2001/20/EC aims to simplify and harmonise the administrative provisions governing clinical trials in the Union. However, experience shows that a harmonised approach to the regulation of clinical trials has only been partly achieved. This makes it in particular difficult to perform a given clinical trial in several Member States. Scientific development, however, suggests that future clinical trials will target more specific patient populations, such as subgroups identified through genomic information. In order to include a sufficient number of patients for such clinical trials it may be necessary to involve many, or all, Member States. The new procedures for the authorisation of clinical trials should stimulate the inclusion of as many Member States as possible. Therefore, in order to simplify the procedures for the submission of an application dossier for the authorisation of a clinical trial, the multiple submission of largely identical information should be avoided and replaced by the submission of one application dossier to all the Member States concerned through a single submission portal. Given that clinical trials carried out in a single Member State are equally important to European clinical research, the application dossier for such clinical trials should also be submitted through that single portal.

(5) As regards Directive 2001/20/EC, experience also indicates that the legal form of a Regulation would present advantages for sponsors and investigators, for example in the context of clinical trials taking place in more than one Member State, since they will be able to rely on its provisions directly, but also in the context of safety reporting and labelling of investigational medicinal products. Divergences of approach among different Member States will be therefore kept to a minimum.

(6) The Member States concerned should cooperate in assessing a request for authorisation of a clinical trial. This cooperation should not include aspects of an intrinsically national nature, such as informed consent.

(7) In order to avoid administrative delays for starting a clinical trial, the procedure to be used should be flexible and efficient, without compromising patient safety or public health.

(8) The timelines for assessing an application dossier for clinical trials should be sufficient to assess the file while, at the same time, ensuring quick access to new, innovative treatments and ensuring that the Union remains an attractive place for conducting clinical trials. Against this background, Directive 2001/20/EC introduced the concept of tacit authorisation. This concept should be maintained in order to ensure that timelines are adhered to. In the event of a public health crisis, Member States should have the possibility to assess and authorise a clinical trial application swiftly. No minimal timelines for approval should therefore be established.

(9) Clinical trials for the development of orphan medicinal products as defined in Regulation (EC) No 141/2000 of the European Parliament and of the Council (4) and of medicinal products addressed to subjects affected by severe, debilitating and often life-threatening diseases affecting no more than one person in 50 000 in the Union (ultra-rare diseases) should be fostered.

(10) Member States should efficiently assess all clinical trials applications within the given timelines. A rapid yet in-depth assessment is of particular importance for clinical trials concerning medical conditions which are severely debilitating and/or life threatening and for which therapeutic options are limited or non-existent, as in the case of rare and ultra-rare diseases.

(11) The risk to subject safety in a clinical trial mainly stems from two sources: the investigational medicinal product and the intervention. Many clinical trials, however, pose only a minimal additional risk to subject safety compared to normal clinical practice. This is particularly the case where the investigational medicinal product is covered by a marketing authorisation, that is the quality, safety and efficacy has already been assessed in the course of the marketing authorisation procedure" or, if that product is not used in accordance with the terms of the marketing authorisation, that use is evidence- based and supported by published scientific evidence on the safety and efficacy of that product, and the intervention poses only very limited additional risk to the subject compared to normal clinical practice. Those low-intervention clinical trials are often of crucial importance for assessing standard treatments and diagnoses, thereby optimising the use of medicinal products and thus contributing to a high level of public health. Those clinical trials should be subject to less stringent rules, as regards monitoring, requirements for the contents of the master file and traceability of investigational medicinal products. In order to ensure subject safety they should however be subject to the same application procedure as any other clinical trial. The published scientific evidence supporting the safety and efficacy of an investigational medicinal product not used in accordance with the terms of the marketing authorisation could include high quality data published in scientific journal articles, as well as national, regional or institutional treatment protocols, health technology assessment reports or other appropriate evidence.

(12) The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in this Regulation.

(13) The assessment of the application for a clinical trial should address in particular the anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the subject. In respect of the relevance, various aspects should be taken into account, including whether the clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when they are used, are justified.

(14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent the population groups, for example gender and age groups, that are likely to use the medicinal product investigated in the clinical trial.

(15) In order to improve treatments available for vulnerable groups such as frail or older people, people suffering from multiple chronic conditions, and people affected by mental health disorders, medicinal products which are likely to be of significant clinical value should be fully and appropriately studied for their effects in these specific groups, including as regards requirements related to their specific characteristics and the protection of the health and well-being of subjects belonging to these groups.

(16) The authorisation procedure should provide for the possibility to extend the timelines for the assessment in order to allow the sponsor to address questions or comments raised during the assessment of the application dossier. Moreover, it should be ensured that, within the extension period, there is always sufficient time for assessing the additional information submitted.

(17) The authorisation to conduct a clinical trial should address all aspects of subject protection and data reliability and robustness. That authorisation should therefore be contained in a single administrative decision by the Member State concerned.

(18) It should be left to the Member State concerned to determine the appropriate body or bodies to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of ethics committees within the timelines for the authorisation of that clinical trial as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. When determining the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. In accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience. The persons assessing the application should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free from any other undue influence.

(19) The assessment of applications for the authorisation of clinical trials should be conducted on the basis of appropriate expertise. Specific expertise should be considered when assessing clinical trials involving subjects in emergency situations, minors, incapacitated subjects, pregnant and breastfeeding women and, where appropriate, other identified specific population groups, such as elderly people or people suffering from rare and ultra rare diseases.

(20) In practice, sponsors do not always have all the information needed for submitting a complete application for authorisation of a clinical trial in all of the Member States where a clinical trial is eventually going to be conducted. It should be possible for sponsors to submit an application solely on the basis of documents assessed jointly by those Member States where the clinical trial might be conducted.

(21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure the reliable functioning of the assessment procedure, however, an application for authorisation of a clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an application.

(22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An authorisation mechanism should be provided to allow for such extension, while avoiding the re-assessment of the application by all the Member States concerned which were involved in the initial authorisation of the clinical trial.

(23) Clinical trials are usually subject to many modifications after they have been authorised. Those modifications may relate to the conduct, the design, the methodology, the investigational or auxiliary medicinal product, or the investigator or clinical trial site involved. Where those modifications 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, they should be subject to an authorisation procedure similar to the initial authorisation procedure.

(24) The content of the application dossier for authorisation of a clinical trial should be harmonised in order to ensure that all Member States have the same information available and to simplify the application process for clinical trials.

(25) In order to increase transparency in the area of clinical trials, data from a clinical trial should only be submitted in support of a clinical trial application if that clinical trial has been recorded in a publicly accessible and free of charge database which is a primary or partner registry of, or a data provider to, the international clinical trials registry platform of the World Health Organization (WHO ICTRP). Data providers to the WHO ICTRP create and manage clinical trial records in a manner that is consistent with the WHO registry criteria. Specific provision should be made for data from clinical trials started before the date of application of this Regulation.

(26) It should be left to Member States to establish the language requirements for the application dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions smoothly, Member States should consider accepting a commonly understood language in the medical field as the language for the documentation not destined for the subject.

(27) Human dignity and the right to the integrity of the person are recognised in the Charter of Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any intervention in the field of biology and medicine cannot be performed without free and informed consent of the person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects. These rules should be upheld. Regarding the rules concerning the determination of the legally designated representatives of incapacitated persons and minors, those rules diverge in Member States. It should therefore be left to Member States to determine the legally designated representatives of incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require specific protection measures.

(28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be responsible for all medical care provided to the subject, including the medical care provided by other medical staff.

(29) It is appropriate that universities and other research institutions, under certain circumstances that are in accordance with the applicable law on data protection, be able to collect data from clinical trials to be used for future scientific research, for example for medical, natural or social sciences research purposes. In order to collect data for such purposes it is necessary that the subject gives consent to use his or her data outside the protocol of the clinical trial and has the right to withdraw that consent at any time. It is also necessary that research projects based on such data be made subject to reviews that are appropriate for research on human data, for example on ethical aspects, before being conducted.

(30) In accordance with international guidelines, the informed consent of a subject should be in writing. When the subject is unable to write, it may be recorded through appropriate alternative means, for instance through audio or video recorders. Prior to obtaining informed consent, the potential subject should receive information in a prior interview in a language which is easily understood by him or her. The subject should have the opportunity to ask questions at any moment. Adequate time should be provided for the subject to consider his or her decision. In view of the fact that in certain Member States the only person qualified under national law to perform an interview with a potential subject is a medical doctor while in other Member States this is done by other professionals, it is appropriate to provide that the prior interview with a potential subject should be performed by a member of the investigating team qualified for this task under the national law of the Member State where the recruitment takes place.

(31) In order to certify that informed consent is given freely, the investigator should take into account all relevant circumstances which might influence the decision of a potential subject to participate in a clinical trial, in particular whether the potential subject belongs to an economically or socially disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately influence her or his decision to participate.

(32) This Regulation should be 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, should himself or herself assent in order to participate in a clinical trial.

(33) It is appropriate to allow that informed consent be obtained by simplified means for certain clinical trials where the methodology of the trial requires that groups of subjects rather than individual subjects are allocated to receive different investigational medicinal products. In those clinical trials the investigational medicinal products are used in accordance with the marketing authorisations, and the individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data relating to him or her are not used for the clinical trial. Such clinical trials, which serve to compare established treatments, should always be conducted within a single Member State.

(34) Specific provisions should be defined for the protection of pregnant and breastfeeding women participating in clinical trials and in particular when the clinical trial does not have the potential to produce results of direct benefit to her or to her embryo, foetus or child after birth.

(35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical trials, and persons, who due to their age, disability or state of health are reliant on care and for that reason accommodated in residential care institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such assistance, are in a situation of subordination or factual dependency and therefore may require specific protective measures. Member States should be allowed to maintain such additional measures.

(36) This Regulation should provide for clear rules concerning informed consent in emergency situations. Such situations relate to cases where for example a patient has suffered a sudden life-threatening medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention. For such cases, intervention within an ongoing clinical trial, which has already been approved, may be pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the clinical trial under very strict conditions. In addition, the said clinical trial should relate directly to the 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. Any previously expressed objection by the patient should be respected, and informed consent from the subject or from his or her legally designated representative should be sought as soon as possible.

(37) In order to allow patients to assess possibilities to participate in a clinical trial, and to allow for effective supervision of a clinical trial by the Member State concerned, the start of the clinical trial, the end of the recruitment of subjects for the clinical trial and the end of the clinical trial should be notified. In accordance with international standards, the results of the clinical trial should be reported within one year from the end of the clinical trial.

(38) The date of the first act of recruitment of a potential subject is the date on which the first act of the recruitment strategy described in the protocol was performed, e. g. the date of a contact with a potential subject or the date of the publication of an advertisement for a particular clinical trial.

(39) The sponsor should submit a summary of the results of the clinical trial together with a summary that is understandable to a layperson, and the clinical study report, where applicable, within the defined timelines. Where it is not possible to submit the summary of the results within the defined timelines for scientific reasons, for example when the clinical trial is still ongoing in third countries and data from that part of the trial are not available, which makes a statistical analysis not relevant, the sponsor should justify this in the protocol and specify when the results are going to be submitted.

(40) In order for the sponsor to assess all potentially relevant safety information, the investigator should, as a rule, report to him all serious adverse events.

(41) The sponsor should assess the information received from the investigator, and report safety information on serious adverse events which are suspected unexpected serious adverse reactions to the European Medicines Agency (‘the Agency’).

(42) The Agency should forward that information to the Member States for them to assess it.

(43) The members of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have agreed on a detailed set of guidelines on good clinical practice which is an internationally accepted standard for designing, conducting, recording and reporting clinical trials, consistent with principles that have their origin in the World Medical Association's Declaration of Helsinki. When designing, conducting, recording and reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a case, the ICH guidelines on good clinical practice should be taken appropriately into account for the application of the rules set out in this Regulation, provided that there is no other specific guidance issued by the Commission and that those guidelines are compatible with this Regulation.

(44) The conduct of a clinical trial should be adequately monitored by the sponsor in order to ensure the reliability and robustness of the results. Monitoring may also contribute to subject safety, taking into account the characteristics of the clinical trial and respect for fundamental rights of subjects. When establishing the extent of monitoring, the characteristics of the clinical trial should be taken into account.

(45) The individuals involved in conducting a clinical trial, in particular investigators and other healthcare professionals, should be sufficiently qualified to perform their tasks, and the facilities where a clinical trial is to be conducted should be suitable for that clinical trial.

(46) In order to ensure subject safety and the reliability and robustness of data from clinical trials, it is appropriate to provide that there should be arrangements for traceability, storage, return and destruction of investigational medicinal products, depending on the nature of the clinical trial. For the same reasons, there should also be such arrangements for unauthorised auxiliary medicinal products.

(47) During a clinical trial, a sponsor may become aware of serious breaches of the rules for the conduct of that clinical trial. This should be reported to the Member States concerned in order for action to be taken by those Member States, where necessary.

(48) Apart from the reporting of suspected unexpected serious adverse reactions, there may be other events which are relevant in terms of benefit-risk balance and which should be reported in a timely manner to the Member States concerned. It is important for subject safety that, in addition to serious adverse events and reactions, all unexpected events that might materially influence the benefit-risk assessment of the medicinal product or that would lead to changes in the administration of a medicinal product or in overall conduct of a clinical trial are notified to the Member States concerned. Examples of such unexpected events include an increase in the rate of occurrence of expected serious adverse reactions which may be clinically important, a significant hazard to the patient population, such as lack of efficacy of a medicinal product, or a major safety finding from a newly completed animal study (such as carcinogenicity).

(49) Where unexpected events require an urgent modification of a clinical trial, it should be possible for the sponsor and the investigator to take urgent safety measures without awaiting prior authorisation. If such measures constitute a temporary halt of the clinical trial, the sponsor should apply for a substantial modification before restarting the clinical trial.

(50) In order to ensure compliance of the conduct of a clinical trial with the protocol, and in order for investigators to be informed about the investigational medicinal products they administer, the sponsor should supply the investigators with an investigator's brochure.

(51) The information generated in a clinical trial should be recorded, handled and stored adequately for the purpose of ensuring subject rights and safety, the robustness and reliability of the data generated in the clinical trial, accurate reporting and interpretation, effective monitoring by the sponsor and effective inspection by Member States.

(52) In order to be able to demonstrate compliance with the protocol and with this Regulation, a clinical trial master file, containing relevant documentation to allow effective supervision (monitoring by the sponsor and inspection by Member States), should be kept by the sponsor and by the investigator. The clinical trial master file should be archived appropriately to allow for supervision after the clinical trial has ended.

(53) Where there are problems with respect to the availability of authorised auxiliary medicinal products, unauthorised auxiliary medicinal products may be used in a clinical trial in justified cases. The price of the authorised auxiliary medicinal product should not be considered as having an effect on the availability of such medicinal products.

(54) Medicinal products intended for research and development trials fall outside the scope of Directive 2001/83/EC of the European Parliament and of the Council (5). Such medicinal products include medicinal products used in the context of a clinical trial. They should be covered by specific rules taking account of their peculiarities. In establishing these rules, a distinction should be made between investigational medicinal products (the tested product and its reference products, including placebos) and auxiliary medicinal products (medicinal products used in the context of a clinical trial but not as investigational medicinal products), such as medicinal products used for background treatment, challenge agents, rescue medication, or used to assess end-points in a clinical trial. Auxiliary medicinal products should not include concomitant medications, that is medications unrelated to the clinical trial and not relevant for the design of the clinical trial.

(55) In order to ensure subject safety and the reliability and robustness of data generated in a clinical trial, and in order to allow for the distribution of investigational and auxiliary medicinal products to clinical trial sites throughout the Union, rules on the manufacturing and import of both investigational and auxiliary medicinal products should be established. As is already the case for Directive 2001/20/EC, those rules should reflect the existing rules of good manufacturing practices for products covered by Directive 2001/83/EC. In some specific cases, it should be possible to allow deviations from those rules in order to facilitate the conduct of a clinical trial. Therefore, the applicable rules should allow for some flexibility, provided that subject safety, as well as reliability and robustness of the data generated in the clinical trial are not compromised.

(56) The requirement to hold an authorisation for manufacture or import of investigational medicinal products should not apply to the preparation of investigational radiopharmaceuticals from radionuclide generators, kits or radionuclide precursors in accordance with the manufacturer's instructions for use in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State.

(57) Investigational and auxiliary medicinal products should be appropriately labelled in order to ensure subject safety and the reliability and robustness of data generated in clinical trials, and in order to allow for the distribution of those products to clinical trial sites throughout the Union. The rules for labelling should be adapted to the risks to subject safety and the reliability and robustness of data generated in clinical trials. Where the investigational or auxiliary medicinal product have already been placed on the market as an authorised medicinal product in accordance with Directive 2001/83/EC and Regulation (EC) No 726/2004 of the European Parliament and of the Council (6), as a general rule no additional labelling should be required for clinical trials that do not involve the blinding of the label. Moreover, there are specific products, such as radiopharmaceuticals used as diagnostic investigational medicinal product, where the general rules on labelling are inappropriate in view of the very controlled setting of the use of radiopharmaceuticals in clinical trials.

(58) In order to ensure clear responsibilities, the concept of a ‘sponsor’ of a clinical trial, in line with international guidelines, was introduced by Directive 2001/20/EC. This concept should be upheld.

(59) In practice, there may be loose, informal networks of researchers or research institutions which jointly conduct a clinical trial. Those networks should be able to be co-sponsors of a clinical trial. In order not to weaken the concept of responsibility in a clinical trial, where a clinical trial has several sponsors, they should all be subject to the obligations of a sponsor under this Regulation. However, the co-sponsors should be able to split up the responsibilities of the sponsor by contractual agreement.

(60) In order to ensure that enforcement action may be taken by Member States and that legal proceedings may be brought in appropriate cases, it is appropriate to provide that sponsors that are not established in the Union should be represented by a legal representative in the Union. However in view of the divergent approaches of the Member States as regards civil and criminal liability, it is appropriate to leave to each Member State concerned, as regards its territory, the choice as to whether or not to require such a legal representative, provided that at least a contact person is established in the Union.

(61) Where, in the course of a clinical trial, damage caused to the subject leads to the civil or criminal liability of the investigator or the sponsor, the conditions for liability in such cases, including issues of causality and the level of damages and sanctions, should remain governed by national law.

(62) In clinical trials compensation should be ensured for damages successfully claimed in accordance with the applicable laws. Therefore Member States should ensure that systems for compensation for damages suffered by a subject are in place which are appropriate to the nature and the extent of the risk.

(63) The Member State concerned should be given the power to revoke the authorisation of a clinical trial, suspend a clinical trial or require the sponsor to modify a clinical trial.

(64) In order to ensure compliance with this Regulation, Member States should be able to conduct inspections and should have adequate inspection capacities.

(65) The Commission should be able to control whether Member States correctly supervise compliance with this Regulation. Moreover, the Commission should be able to control whether regulatory systems of third countries ensure compliance with the specific provisions of this Regulation and Directive 2001/83/EC concerning clinical trials conducted in third countries.

(66) In order to streamline and facilitate the flow of information between sponsors and Member States as well as between Member States, the Agency should, in collaboration with Member States and the Commission, set up and maintain an EU database, accessed through an EU portal.

(67) In order to ensure a sufficient level of transparency in the clinical trials, the EU database should contain all relevant information as regards the clinical trial submitted through the EU portal. The EU database should be publicly accessible and data should be presented in an easily searchable format, with related data and documents linked together by the EU trial number and with hyperlinks, for example linking together the summary, the layperson's summary, the protocol and the clinical study report of one clinical trial, as well as linking to data from other clinical trials which used the same investigational medicinal product. All clinical trials should be registered in the EU database prior to being started. As a rule, the start and end dates of the recruitment of subjects should also be published in the EU database. No personal data of data subjects participating in a clinical trial should be recorded in the EU database. The information in the EU database should be public, unless specific reasons require that a piece of information should not be published, in order to protect the right of the individual to private life and the right to the protection of personal data, recognised by Articles 7 and 8 of the Charter. Publicly available information contained in the EU database should contribute to protecting public health and fostering the innovation capacity of European medical research, while recognising the legitimate economic interests of sponsors.

(68) For the purposes of this Regulation, in general the data included in a clinical study report should not be considered commercially confidential once a marketing authorisation has been granted, the procedure for granting themarketing authorisation has been completed, the application for marketing authorisation has been withdrawn. In addition, the main characteristics of a clinical trial, the conclusion on Part I of the assessment report for the authorisation of a clinical trial, the decision on the authorisation of a clinical trial, the substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and early termination, in general, should not be considered confidential.

(69) Within a Member State, there may be several bodies involved in the authorisation of clinical trials. In order to allow for effective and efficient cooperation between Member States, each Member State should designate one contact point.

(70) The authorisation procedure set out in this Regulation is largely controlled by Member States. Nevertheless, the Commission and the Agency should support the good functioning of that procedure, in accordance with this Regulation.

(71) In order to carry out the activities provided for in this Regulation, Member States should be allowed to levy fees. However, Member States should not require multiple payments to different bodies involved in the assessment, in a given Member State, of an application for authorisation of a clinical trial.

(72) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission in respect of the establishment and modification of rules on cooperation between the Member States when assessing the information provided by the sponsor on the Eudravigilance database and the specification of detailed arrangements for inspection procedures. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council (7).

(73) In order to supplement or amend certain non-essential elements of this Regulation, the power to adopt acts in accordance with Article 290 of the Treaty on the Functioning of the European Union (TFEU) should be delegated to the Commission in respect of: the amendment of Annexes I, II, IV and V to this Regulation 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; the amendment of Annex III in order to improve the information on the safety of medicinal products, to adapt technical requirements to technical progress or to take 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; the specification of the principles and guidelines of good manufacturing practice and the detailed arrangements for inspection for ensuring the quality of investigational medicinal products; the amendment of 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. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level. The Commission, when preparing and drawing-up delegated acts, should ensure a simultaneous, timely and appropriate transmission of relevant documents to the European Parliament and to the Council.

(74) Directive 2001/83/EC provides that that Directive does not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products as abortifacients. Directive 2001/83/EC provides that national legislation prohibiting or restricting the use of any specific type of human or animal cells is not, in principle, affected by either that Directive or any of the Regulations referred to therein. Likewise, this Regulation should not affect national law prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products used as abortifacients. In addition, this Regulation should not affect national law prohibiting or restricting the sale, supply or use of medicinal products containing narcotic substances within the meaning of the relevant international conventions in force such as the Single Convention on Narcotic Drugs of 1961 of the United Nations. Member States should communicate those national provisions to the Commission.

(75) Directive 2001/20/EC provides that no gene therapy trials may be carried out which result in modifications to the subject's germ line genetic identity. It is appropriate to maintain that provision.

(76) Directive 95/46/EC of the European Parliament and of the Council (8) applies to the processing of personal data carried out in the Member States within the framework of this Regulation, under the supervision of the Member States competent authorities, in particular the public independent authorities designated by the Member States and Regulation (EC) No 45/2001 of the European Parliament and of the Council (9) applies to the processing of personal data carried out by the Commission and the Agency within the framework of this Regulation, under the supervision of the European Data Protection Supervisor. Those instruments strengthen personal data protection rights, encompassing the right to access, rectification and withdrawal, as well as specify the situations when restriction on those rights may be imposed. With a view to respecting those rights, while safeguarding the robustness and reliability of data from clinical trials used for scientific purposes and the safety of subjects participating in clinical trials, it is appropriate to provide that, without prejudice to Directive 95/46/EC, the withdrawal of informed consent should not affect the results of activities already carried out, such as the storage and use of data obtained on the basis of informed consent before withdrawal.

(77) Subjects should not have to pay for investigational medicinal products, auxiliary medicinal products, medical devices used for their administration and procedures specifically required by the protocol, unless the law of the Member State concerned provides otherwise.

(78) The authorisation procedure set out in this Regulation should apply as soon as possible, in order for sponsors to reap the benefits of a streamlined authorisation procedure. However, in view of the importance of the extensive IT functionalities required for the authorisation procedure, it is appropriate to provide that this Regulation should only become applicable once it has been verified that the EU portal and the EU database are fully functional.

(79) Directive 2001/20/EC should be repealed to ensure that only one set of rules applies to the conduct of clinical trials in the Union. In order to facilitate the transition to the rules set out in this Regulation, sponsors should be allowed to start and conduct a clinical trial in accordance with Directive 2001/20/EC during a transitional period.

(80) This Regulation is in line with the major international guidance documents on clinical trials, such as the 2008 version of the World Medical Association's Declaration of Helsinki and good clinical practice, which has its origins in the Declaration of Helsinki.

(81) As regards Directive 2001/20/EC, experience also shows that a large proportion of clinical trials are conducted by non-commercial sponsors. Non-commercial sponsors frequently rely on funding which comes partly or entirely from public funds or charities. In order to maximise the valuable contribution of such non-commercial sponsors and to further stimulate their research but without compromising the quality of clinical trials, measures should be taken by Member States to encourage clinical trials conducted by those sponsors.

(82) This Regulation is based on the double legal basis of Articles 114 and 168(4)(c) TFEU. It aims at achieving an internal market as regards clinical trials and medicinal products for human use, taking as a base a high level of protection of health. At the same time, this Regulation sets high standards of quality and safety for medicinal products in order to meet common safety concerns as regards these products. Both objectives are being pursued simultaneously. These two objectives are inseparably linked and one is not secondary to another. Regarding Article 114 TFEU, this Regulation harmonises the rules for the conduct of clinical trials in the Union, therefore ensuring the functioning of the internal market in view of the conduct of a clinical trial in several Member States, the acceptability throughout the Union of data generated in a clinical trial and submitted in the application for the authorisation of another clinical trial or of the placing on the market of a medicinal product, and the free movement of medicinal products used in the context of a clinical trial. Regarding Article 168(4)(c) TFEU, this Regulation sets high standards of quality and safety for medicinal products by ensuring that data generated in clinical trials are reliable and robust, thus ensuring that treatments and medicines which are intended to be an improvement of a treatment of patients build on reliable and robust data. Moreover, this Regulation sets high standards of quality and safety of medicinal products used in the context of a clinical trial, thus ensuring the safety of subjects in a clinical trial.

(83) This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter and notably human dignity, the integrity of the person, the rights of the child, respect for private and family life, the protection of personal data and the freedom of art and science. This Regulation should be applied by the Member States in accordance with those rights and principles.

(84) The European Data Protection Supervisor has given an opinion (10) pursuant to Article 28(2) of Regulation (EC) No 45/2001.

(85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects, cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve that objective,

HAVE ADOPTED THIS REGULATION:

CHAPTER I

GENERAL PROVISIONS

Article 1

Scope

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

It does not apply to non-interventional studies.

Article 2

Definitions

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.

CHAPTER II

AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL

Article 4

Prior authorisation

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

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

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

Article 5

Submission of an application

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.

CHAPTER III

AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL

Article 15

General principles

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

Article 16

Submission of application

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

Article 17

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

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 subpa