EXPLANATORY MEMORANDUM

1. CONTEXT OF THE PROPOSAL

Clinical trials as defined in Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use[1] are investigations of medicines in humans where the medicines are applied outside normal clinical practice on the basis of a research protocol.

Clinical trials are performed in many different contexts. Applications for marketing authorisation and publications in medical journals are based on data generated in clinical trials. Therefore, clinical trials are an indispensable part of clinical research which, in turn, is essential to develop medicinal products and improve medical treatment. Without clinical trials, there would be no new medicines, no further development of existing medicines, and no evidence-based improvement of treatments with medicines.

In the EU/EEA, approximately 4 400 clinical trials are applied for every year.[2] Approximately 60 % of clinical trials are sponsored by the pharmaceutical industry and 40 % by other stakeholders, such as academics.

Approximately 24 % of all clinical trials applied for in the EU are multinational clinical trials, i.e. clinical trials intended to be performed in at least two Member States. While this seems a relatively small proportion, these 24 % clinical trials involve approximately 67 % of all subjects enrolled in a clinical trial. This means that, on average, a clinical trial with more than 40 subjects is conducted in more than one Member State. Mono-national clinical trials are limited to small studies with low recruitment targets.

Directive 2001/20/EC has brought about important improvements in the safety and ethical soundness of clinical trials in the EU and in the reliability of clinical trials data. However, the Clinical Trials Directive is arguably the most heavily criticised piece of EU-legislation in the area of pharmaceuticals. This criticism is voiced by all stakeholders ‑ patients, industry, and academic research.

The data available support these criticisms:

· The number of applications for clinical trials fell by 25 % from 2007 to 2011.[3]

· The costs for conducting clinical trials have increased. Compared to the situation prior to the application of the Directive 2001/20/EC, the staff needs for industry sponsors to handle the clinical trial authorisation process have doubled (107 %); with small companies facing an even sharper increase. For non-commercial sponsors, the increase in administrative requirements due to the Directive 2001/20/EC has led to a 98% increase in administrative costs. In addition, since implementation of the Directive 2001/20/EC, insurance fees have increased by 800 % for industry sponsors.

· The average delay for launching a clinical trial has increased by 90 % to 152 days.

It would be wrong to attribute the fall in clinical trial activity solely and exclusively to the Directive 2001/20/EC. However, the Directive 2001/20/EC has had many direct effects on the cost and feasibility of conducting clinical trials which, in turn, have led to a decline in clinical trial activity in the EU. Moreover, other causes (such as salary costs and the need to conduct multinational studies to reach recruitment targets) have been aggravated through regulatory requirements and consequential costs of the Directive 2001/20/EC.

Thus, the existing provisions of Directive 2001/20/EC appear to have hampered the conduct of clinical trials in Europe. It is therefore necessary for the Commission to act.

2. RESULTS OF CONSULTATIONS WITH THE INTERESTED PARTIES AND IMPACT ASSESSMENT

In preparation of the impact assessment for this proposal, the Commission held two public consultations, the first from 9 October 2009 to 8 January 2010 and the second from 9 February to 13 May 2011.

In both public consultations, all the ‘General principles and minimum standards for consultation of interested parties by the Commission’ were met. The Commission has published the responses, and a summary of them.

In addition, since 2009 the Commission has held several meetings with stakeholders to hear their assessment of how the Clinical Trials Directive is working and to discuss the impact of potential policy options. A large stakeholder workshop was held on 31 March 2011 to clarify various points put forward in the concept paper submitted to public consultation.

The Commission conducted an impact assessment in accordance with its impact assessment guidelines and published the results in an impact assessment report.

3. LEGAL ASPECTS OF THE PROPOSAL

3.1. Scope (Chapters 1 and 2 of the proposed Regulation)

The scope of the proposed Regulation is essentially identical to that of Directive 2001/20/EC. The scope is limited to clinical research on medicinal products, but it is very wide in that it only excludes clinical studies that do not involve an ‘intervention’ (e.g. surveys amongst medical practitioners without additional intervention or ‘data mining’). For ‘non-interventional studies’ which are post-authorisation safety studies initiated, managed or financed by the marketing authorisation holder voluntarily or pursuant to obligations imposed by the competent authority for marketing authorisations, the rules are set out in Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use[4].

3.2 Authorisation procedure and Authorisation dossier (submission, assessment, decision; chapters 2, 3, 14 and 15 of the proposed Regulation)

The proposal introduces a new authorisation procedure for clinical trials based on the following concepts:

· A harmonised authorisation dossier, partly codifying the existing Commission guidance contained in EudraLex, Volume 10;

· A ‘single portal’ to submit an application for conducting a clinical trial linked to an EU database. This portal is managed by the European Commission and is free of charge for sponsors;

· A flexible and swift assessment procedure without establishing a new, central bureaucracy. This assessment is largely controlled by Member States. All Member States in which the sponsor intends to conduct the clinical trial are involved in the assessment;

· A clear mechanism to appoint a ‘reporting Member State’;

· Clear timelines with a concept of tacit approval in order to ensure compliance;

· A coordination and advisory forum to address issues which may arise in the authorisation procedure. This forum is managed and chaired by the Commission;

· A clear distinction between aspects where Member States cooperate in the assessment and aspects of an intrinsic ethical or national/local nature where the assessment is made by each Member State individually;

· The option, in certain well-defined cases, for a Member State to 'opt-out' of the conclusions of an assessment of an application for conducting a clinical trial ('qualified opt-out');

· It is left to each Member State to define the organisational setup and internal competences for assessing clinical trial authorisations, provided that international guidelines on the independence of the assessors are observed;

· A swift procedure to ‘extend’ a clinical trial to additional Member States;

· Where a clinical trial is modified after it has been authorised, this modification is subject to authorisation if, and only if, the modification has 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.

A crucial element of the rules for authorisation of a clinical trial is the clear distinction between aspects where Member States shall cooperate in the assessment of the application for authorisation of a clinical trial (Article 6 of the proposed Regulation) and those aspects where Member States conduct their assessment individually (Article 7 of the proposed Regulation). The latter includes aspects which are of an intrinsically national (for example, liability), ethical (for example, informed consent), or local (for example suitability of the clinical trial site) nature.

However, this distinction is without any prejudice as to the body which, in a Member State, performs the assessment. The proposal does not interfere with the Member State's internal organisation of the bodies involved in authorising (or not) a clinical trial. It is left to Member States to define the organisational set-up to comply with the authorisation procedure of this Regulation.

As a consequence, the proposed Regulation does not, unlike Directive 2001/20/EC, establish which body or bodies within a Member State approves (or not) a clinical trial. The proposed Regulation does hence not regulate or harmonise the precise functioning of Ethics Committees, impose a systematic cooperation at an operational level between Ethics Committees in the EU, or limit the Ethics Committee's scope of the assessment to genuinely-ethical issue (science and ethics cannot be separated).

Rather, the proposal leaves it up to Member States to organise, internally, the attribution of tasks to different bodies. Indeed, what matters is that Member States ensure an independent, high-quality assessment within the timelines as set out in the legislation. Moreover, it is critical to ensure clarity as to what issues are addressed in cooperation between Member States, and the issues which are addressed individually by each Member States because of their intrinsically national, local or ethical character.

In pursuing this approach, however, the proposed Regulation maintains that any application of a clinical trial will have to be assessed jointly by a reasonable number of persons who are independent, who have collectively the necessary qualifications and experience in all relevant fields, including the view of lay persons. The proposal thus stays in tune with international guidance and ensures a thorough, independent, and high quality of the assessment of an application for a clinical trial throughout the EU, without trespassing on Member States' competencies to organise their internal decision-making on an application for authorisation of a clinical trial.

3.3. Interface with 'scientific advice'

Independently of the regulation of clinical trials, regulators may be involved in the preparatory phase of a trial in the context of protocol assistance[5], the paediatric investigation plan[6], scientific advice[7], and post-authorisation safety/efficacy studies[8] (hereinafter referred to as 'scientific advice').

The proposed Regulation does not 'mix' the aspect of scientific advice with that of a clinical trial authorisation for two reasons:

· The involvement of the regulator in the context of scientific advice is conceptually an entirely different matter than the authorisation of a clinical trial: while the former establishes which clinical data are desirable in order to possibly grant or uphold a marketing authorisation at a later stage, the latter establishes if a clinical trial is acceptable in view of patient rights and safety, as well as data reliability and robustness. Indeed, it is perfectly conceivable (and has occasionally happened in the past) that these two approaches come to conflicting results: while, from the point of view of a future successful marketing authorisation, it may be desirable to obtain certain clinical data on the basis of experiments on humans, those clinical trials may not be acceptable from the point of view of subject protection.

· Clinical trial legislation in the EU addresses clinical trials in the abstract, i.e. independently from whether the results are intended to be used in a future marketing authorisation application, or for any other purpose (e.g. improvement of treatment strategies, comparing treatment with different medicines, etc.). This difference is usually discussed under the pattern 'commercial' vs. 'academic' clinical trials. The latter form approximately 40% of clinical trials applied for in the EU. Therefore, the concept of 'mixing' scientific advice and the clinical trials authorisation would not be workable for more than one third of all clinical trials. It is in particular these 'academic' clinical trials, however, which the proposal wants to stimulate.

3.4. Protection of subjects and informed consent (chapter 5 of the proposed Regulation)

In line with Article 3(2)a of the Charter of Fundamental Rights of the EU any intervention in the field of medicine and biology can not be performed without free and informed consent of the person concerned. The EU law has to comply with this principle. The rules on the protection of subjects and on free and informed consent had been discussed extensively in the legislative process leading to Directive 2001/20/EC. The proposed Regulation does not, with the exception of the issue of clinical trials in emergency situations (see paragraph below), change the substance of these rules. However, in terms of drafting, for the sake of clarity some provisions are re-arranged and, where possible, shortened. For example, provisions related to the authorisation procedure have been moved to chapters 2 and 3 of the proposed Regulation, and provisions related to damage compensation have been moved to Chapter 12 of the proposed Regulation.

Regarding clinical trials in emergency situations, Directive 2001/20/EC does so far not address the specific situation where, because of the urgency of the situation, it is impossible to obtain free and informed consent from the subject or the legal representative (‘clinical trials in emergency situations’). To address this, specific provisions on clinical trials in emergency situations have been added in line with existing international guidance documents on this issue.

Moreover as regards the protection of personal data, provisions of Directive 95/46/EC[9] and Regulation (EC) No 45/2001[10] apply.

No personal data of data subjects participating in a trial will be collected in the EU database.

It is important that personal data of investigators, which may be collected in the EU database, are kept in accordance with the exception foreseen in Article 17(3) (b) of the proposal for a regulation of the European Parliament and the Council on the protection of individuals with regard to the processing of personal data and on the free movement of such data (General Data Protection Regulation). In case of detection of cases of misconduct in a clinical trial it would be important, for example, to trace all the clinical trials in which the same investigators were involved, even several years after these clinical trials have ended.

3.5. Safety reporting (Chapter 7 of the proposed Regulation)

The rules on safety reporting follow the principles of the applicable international guidance documents. Compared to Directive 2001/20/EC, the rules have been streamlined, simplified and modernised as follows:

· The option to exclude reporting by the investigator to the sponsor of adverse events, if this is provided for in the protocol;

· Direct reporting of suspected unexpected serious adverse reactions by the sponsor to the European database EudraVigilance;

· Simplified submission of the annual safety report by the sponsor. Moreover, the annual safety report is not submitted for authorised investigational medicinal products that are used within their authorised indication. For these products, the normal pharmacovigilance rules apply.

Details of the rules on safety reporting, which codify in parts existing Commission guidance[11] are contained in an annex to the proposed Regulation. This will facilitate updating the existing rules, by way of delegated acts, in view of technical progress or global regulatory alignment.

Regarding the European database EudraVigilance, this database exists already for the purposes of pharmacovigilance activities in accordance with Directive 2001/83/EC and Regulation (EC) No 726/2004 and is maintained and managed by the European Medicines Agency. Directive 2001/20/EC had already referred to this database and to the European Medicines Agency's role in administering it. The proposed Regulation does not introduce any changes in this respect.

3.6. Conduct of the trial (Chapter 8 of the proposed Regulation)

Directive 2001/20/EC contains relatively few rules on the actual conduct of trials. These rules are partly contained in Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products[12], and partly contained in Commission guidance documents. The proposed Regulation brings together these rules.

3.7. Investigational and auxiliary medicinal products, manufacturing, labelling (Chapters 9 to 10 of the proposed Regulation)

Medicinal products intended for research and development trials are excluded from the scope of Directive 2001/83/EC, including the rules on manufacturing, importation and labelling. The rules are contained in Directive 2001/20/EC, Directive 2005/28/EC and in Commission guidelines.

The proposed Regulation brings together these rules. The new rules continue to build on the concept of ‘investigational medicinal product’. However, the proposed new rules reflect more clearly the fact that investigational medicinal products may be authorised, i.e. they have already been placed on the market in accordance with Directive 2001/83/EC.

Moreover, experience with the application of Directive 2001/20/EC shows the need for clarity on medicines used in the context of a clinical trial that are not investigational medicinal products. These ‘auxiliary medicinal products’ (so far referred to in implementing Commission guidelines as ‘non-investigational medicinal products’) will be subject to proportionate rules on manufacturing and labelling.

3.8. Sponsors, co-sponsorship, EU contact person (Chapter 11 of the proposed Regulation)

Every clinical trial must have a ‘sponsor’, i.e. a legal or natural person responsible for initiating and managing the clinical trial.

This ‘responsibility’ must not be confused with issues of ‘liability’ for harm of a patient. The rules on liability depend on the applicable national liability laws and are independent from the responsibility of a sponsor.

Regarding ‘responsibility’, it is clearly preferable to have only one sponsor per clinical trial. A ‘single sponsor’ is the best means to ensure that all information regarding the entire clinical trial are provided to the bodies supervising the clinical trial and all necessary measures are taken.

However, clinical trials are increasingly initiated by loose networks of scientists or scientific institutions within one Member State or across several Member States. These networks have in some cases, for practical or legal reasons, difficulties in establishing who amongst them would act as ‘single sponsor’. These networks may also have practical or legal difficulties in forming, jointly, one legal entity to act as ‘single sponsor’.

To address this difficulty, while ensuring that the effective supervision of a clinical trial is not compromised, the proposed Regulation introduces the concept of ‘co-sponsorship’. At the outset, all co-sponsors are responsible for the entire clinical trial. However, the proposed Regulation allows co-sponsors to ‘split’ the responsibility for the clinical trials amongst themselves. Even if co-sponsors split responsibilities, however, all co‑sponsors remain responsible for establishing a sponsor who can take measures requested by a Member State, and who can give information on the clinical trial as a whole.

The sponsor’s obligations are independent from where the sponsor is established — whether in the EU or in a third country. However, if the sponsor is established in a third country, in order to ensure an effective supervision of a clinical trial, an EU contact person must be provided. Communication with that contact person is considered as communication with the sponsor.

3.9. Compensation for damages (Chapter 12 of the proposed Regulation)

Directive 2001/20/EC introduced an 'obligatory insurance/indemnity'. This obligatory insurance/indemnity has substantially increased the costs and administrative burden of conducting clinical trials, but there is no evidence that the number of damages, or the amount, has increased with the entry into force of the Directive.

The proposed Regulation acknowledges that clinical trials do not in all cases pose an additional risk to subjects compared to treatment in normal clinical practice. Consequently, where there is no additional risk, or where that additional risk is negligible, it is not necessary to provide a specific damage compensation (be it an insurance or an indemnification) for the clinical trial. In these cases, the insurance coverage of the medical practitioner, the institution, or product liability insurance provides sufficient coverage.

In cases where a clinical trial does pose an additional risk, the proposed Regulation obliges the sponsor to ensure compensation – be it through insurance, or through an indemnification mechanism. Regarding the latter, the proposed Regulation puts Member States under an obligation to set up a national indemnification mechanism which works on a not-for-profit basis. This shall help in particular 'non-commercial sponsors' to obtain coverage for possible compensations. These non-commercial sponsors have had, since the introduction of the 'obligatory insurance/indemnity' with Directive 2001/20/EC, great difficulties to obtain compensation coverage.

3.10. Inspections (Chapter 13 of the proposed Regulation)

The provisions on inspections are largely based on Directive 2001/20/EC. Regarding inspection capacity, the proposed Regulation provides the legal basis for Commission staff to perform controls in Member States and in third countries in the context of the EU acquis for medicinal products for human use and clinical trials.

3.11. Repeals and Entry into force (Chapter 19 of the proposed Regulation)

The proposed Regulation addresses the aspects regulated in Directive 2001/20/EC. That Directive is therefore repealed.

In order to allow for a smooth transition from the rules of the (transposed) Directive 2001/20/EC to this Regulation, both sets of rules will apply in parallel for three years after the date of application of this Regulation. This will facilitate the transition, in particular for aspects of the authorisation procedure.

3.12 Simplification of substantial rules for clinical trials with authorised medicinal products and low-intervention clinical trials

The regulation of clinical trials addresses two distinct risks: the risk to subject safety and the risk to data reliability. The former can vary widely, depending on a range of factors, in particular:

· The extent of knowledge and prior experience with the investigational medicinal product (in particular, whether or not the investigational medicinal product is authorised in the EU); and

· The type of intervention (which can range from a simple blood sample to a sophisticated biopsy).

The Directive 2001/20/EC is being heavily criticised for not taking sufficiently into account these differences in risk. Instead, the obligations and restrictions laid down in the Directive 2001/20/EC apply largely irrespectively of the risk to subject safety.

This aspect is discussed extensively in the impact assessment report. On the basis of this impact assessment, throughout the proposed Regulation aspects of risk-proportionality have been carefully taken into account.

3.13. Legal form of a Regulation

The proposed legal text takes the form of a Regulation and replaces the Directive 2001/20/EC.

The legal form of a Regulation ensures a coherent procedure for submission of applications for authorisations of clinical trials and their substantial modifications.

Indeed, experience shows the difficulties that are created if Member States, in their cooperation, base their work on 'similar, but different' transposing national laws. Only the legal form of a Regulation ensures that the Member States base their assessment of an application for authorisation of a clinical trial on an identical text, rather than on diverging national transposition measures.

The above holds not only for the entire authorisation process, but also for all other issues addressed in this Regulation, such as safety reporting during clinical trials, and the requirements for labelling of the medicinal products used in the context of a clinical trial.

Moreover, experience has shown that Member States misused the transposition process in order to introduce additional procedural requirements.

Finally, the legal form of a Regulation has an important simplification effect. The replacing of transposition measures at national level allows the relevant actors to plan and conduct the clinical trial, including multi-national clinical trials, on the basis of one regulatory framework, rather than on the basis of a 'patchwork' of 27 national frameworks in the transposing Member States laws.

Despite the legal form of a Regulation, however, there remain areas where the regulatory framework at EU level will be complemented by national laws: Examples are the rules on establishing who is a 'legal representative' of the subject, as well as the substantial rules of liability in the case of damages.

3.14. Competences, Double legal basis and subsidiarity

The proposed Regulation is, like Directive 2001/20/EC, based on Article 114 of the Treaty on the Functioning of the European Union (TFEU). In addition, the proposed Regulation is based on Article 168(4)(c) TFEU.

The proposed Regulation is based on Article 114 TFEU as it aims to harmonise the regulatory framework for clinical trials. In addition, the proposed Regulation aims to contributing to the harmonisation of the rules for pharmaceutical products placed on the market, including authorisation of their placing on the market. Finally, the proposed Regulation aims to harmonise the rules for medicines used in the context of a clinical trial, thus allowing for their free movement within the Union.

Regarding the harmonisation of the rules on clinical trials, practically every larger clinical trial is conducted in more than one Member State. Moreover, the results generated in a clinical trial may be used as basis for other clinical trials. In this respect, it is critical to ensure that the rules for patient rights and safety and data reliability and robustness are harmonised in order for them to be recognised throughout the Union.

Regarding the harmonisation of the rules for medicinal products in general, harmonised rules on clinical trials open up the possibility of referring to the results and findings of clinical trials in applications for an authorisation for placing a medicinal product on the Union market, including subsequent variations and extensions of the marketing authorisation.

Regarding the harmonisation of rules for medicinal products used in the context of a clinical trial, it has to be recalled that medicinal products intended for research and development trials are excluded from the Community Code for medicinal products for human use. Such medicinal products, however, may be produced in a different Member State from that where the clinical trial is conducted. Thus, these products do not benefit from secondary Union law ensuring their free movement while maintaining a high level of protection of human health.

In addition, the proposed Regulation is based on Article 168(4)(c) TFEU as it aims at setting high standards of quality and safety for medicinal products. According to Articles 168(4) and 4(2)(k) TFEU this Union competence is – like Article 114 TFEU ‑ a shared competence which is exercised with the adoption of the proposed Regulation.

The proposed Regulation aims at setting high standards of quality and safety for medicinal products in two respects:

· It ensures that data generated in clinical trials is reliable and robust, thus ensuring that treatments and medicines which are supposed to be 'safer' for the patient build on reliable and robust clinical data. Only if the data on which these decisions are taken is reliable and robust, regulators, scientists, industry and the public can take the right decisions to ensure a high standard of quality and safety of medicinal products. The provisions ensuring this relate in particular to the authorisation procedure, to the rules on the conduct of the clinical trial, including the rules on monitoring and supervision by Member States.

· It aims at setting high standards to ensure the quality and safety of medicines administered to subjects in the context of a clinical trial (while acknowledging that this assurance is only possible within the limitations of the absence of knowledge, which characterises a clinical trial): This is ensured inter alia through the authorisation procedure set up with the proposed Regulation, as well as the rules on manufacturing of medicinal products used in the context of a clinical trials, safety reporting, and inspections.

Article 168(4)(c) TFEU cannot serve as sole legal basis, but needs to be complemented with the legal basis of Article 114 TFEU for the following reasons:

· As set out above, the proposed Regulation pursues equally as object the establishment and functioning of the internal market, and the setting of high standards of quality and safety for medicinal products;

· The proposed Regulation pursues the setting of high standards as regards quality and safety, but also as regards efficacy of medicinal products for human use: It ensures, just as regards the aspect of safety, that subjects participating in a clinical trial may receive an efficacious medicine/treatment. It also aims to ensure that the data generated in a clinical trial is reliable and robust not only regarding aspects of quality and safety, but also aspects of efficacy of the medicinal product. This aspect of efficacy, however, is not explicitly addressed in Article 168(4)(c) TFEU. Rather, this aspect of public health is addressed through Article 114(3) TFEU (high level of health protection).

Situations like this were dealt with unsatisfactorily until Directive 2001/20/EC came into force. Laws, regulations and administrative acts differed from one Member State to another. These differences forced marketing authorisation holders to adapt their applications for authorisation to place their medicinal product on the market. They also hindered distribution of these products. This had a direct effect on the completion and operation of the internal market.

EU legislation on clinical trials attempts to meet this need. It lays down, at Union level, the rules of procedure to be complied with on aspects such as authorisation and performance of clinical trials, safety reporting, manufacturing and labelling of medicinal products used in a clinical trial.

In regulating clinical trials, the Union exercises its shared competence in accordance with Article 4(2) of the TFEU.

Any changes made to these rules by Member States would conflict with the requirements of the Treaty, as only the Union can amend them.

Having said this, for regulating clinical trials, the Treaty sets limits as regards harmonisation of ethical aspects of authorisation and regulation of clinical trials. Ethical aspects relate, in particular, to the need to obtain ‘informed consent’ from the subject or the legal representative. Irrespective of the risk that a clinical trial may pose to a patient, the mere fact that the treatment is part of an experiment renders it necessary — from an ethical viewpoint — to obtain the informed consent of the subject. Hence, the assessment of aspects related to ‘informed consent’ does not form part of the cooperation amongst Member States, but is assessed by each Member State individually.

There are also several aspects of an intrinsically national nature, in particular:

· Rules for establishing who is a ‘legal representative’ of a subject who cannot give informed consent (for example, because the subject is a child): these rules differ widely across the EU, depending on national tradition and practices;

· Rules on the extent of and prerequisites for liability for damages suffered by a subject: these rules are deeply rooted in national civil law on medical liability. This applies not only to the degree of negligence (e.g. no-fault or objective liability) but also to the rules on the burden of proof and on calculating the extent of damage.

Consequently, while regulation of clinical trials and, in particular, revision of Directive 2001/20/EC, is compatible with the principle of subsidiarity, there are limits set by the Treaties which have to be considered.

4. BUDGETARY IMPLICATION

The budgetary implications of this proposal are as follows:

· Costs for databases (one-off costs and maintenance);

· Commission staff to manage the functioning of the Regulation;

· Costs for meetings of Member States to ensure that the authorisation procedure set out in this Regulation functions properly;

· Commission staff and other costs to conduct Union controls and Union inspections.

Details of the costs are set out in the legislative financial statement. A thorough discussion on the costs is contained in the impact assessment report.

The costs will be covered with the envelope of the Health for Growth Programme 2014-2020.

2012/0192 (COD)

Proposal for a

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

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 Commission[13],

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

Having regard to the opinion of the European Economic and Social Committee[14],

Having regard to the opinion of the Committee of the Regions[15],

After consulting the European Data Protection Supervisor[16],

Acting in accordance with the ordinary legislative procedure[17],

Whereas:

(1) In a clinical trial the safety and rights of subjects should be protected and the data generated should be reliable and robust.

(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 of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use[18] 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 EU legislation governing medicinal products, which builds on the dichotomy of 'clinical trial' and 'non-interventional study'.

(4) Directive 2001/20/EC aimed to simplify and harmonise the administrative provisions governing clinical trials in the European 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 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 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 submission procedures, the multiple submission of largely identical information should be avoided and replaced by the submission of one application dossier through a single submission portal to all the Member States concerned.

(5) Experience with Directive 2001/20/EC has also shown that the aim of simplifying and harmonising the administrative provisions governing clinical trials in the Union cannot be achieved in the legal form of a Directive but can only be achieved with the legal form of a Regulation. Only the legal form of a Regulation ensures that the Member States base their assessment of an application for authorisation of a clinical trial on identical criteria, rather than on diverging national transposition measures. This holds not only for the entire authorisation process, but also for all other issues addressed in this Regulation, such as safety reporting during clinical trials, and the requirements for labelling of the medicinal products used in the context of a clinical trial.

(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, nor ethical aspects of a clinical trial, such as informed consent.

(7) The procedure should be flexible and efficient, in order to avoid administrative delays for starting a clinical trial.

(8) The timelines for assessing an application dossier for clinical trials should be sufficiently long to assess the file, while 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) 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 in particular the case where the investigational medicinal product is covered by a marketing authorisation (i.e. the quality, safety and efficacy has already been assessed in the course of the marketing authorisation procedure) and where 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 to assess standard treatments and diagnoses, thereby optimising the use of medicinal products and thus contributing to a high level of public health. They should be subject to less stringent rules, such as shorter deadlines for approval.

(10) 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 inconveniences for the subject. Regarding the relevance, numerous aspects should be taken into account, including 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.

(11) The authorisation procedure should provide for the possibility to suspend the assessment in order to allow the sponsor to address questions or comments raised during the assessment of the application dossier. The maximum duration of the suspension should reflect whether the clinical trial is a low-intervention clinical trial or not. Moreover, it should be ensured that, following the end of the suspension, there is always sufficient time for assessing the additional information submitted.

(12) Some aspects in a clinical trial application relate to issues of an intrinsic national nature or to ethical aspects of a clinical trial. Those issues should not be assessed in cooperation among all Member States concerned.

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

(14) It should be left to the Member State concerned to determine the appropriate body or bodies to be involved in this assessment. This decision is a matter of internal organisation of each Member State. Member States, when determining the appropriate body or bodies, should ensure the involvement of lay persons and patients. They should also ensure that the necessary expertise is available. In any case, however, and 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 from the sponsor, the institution of the trial site, and the investigators involved, as well as free of any other undue influence.

(15) In practice, when submitting an application for authorisation of a clinical trial, sponsors do not always have full certainty about 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 the documents assessed jointly by those Member States where the clinical trial might be conducted.

(16) 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.

(17) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest to extend 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 this 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.

(18) Clinical trials are usually subject to many modifications after they have been authorised. Those modifications may relate to the conduct, design, methodology, investigational or auxiliary medicinal product, or the investigator or 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.

(19) 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.

(20) In order to increase transparency in the area of clinical trials, clinical trial data submitted in support of a clinical trial application should be based only on clinical trials recorded in a publicly accessible database.

(21) 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 to the subject.

(22) The human dignity and right to the integrity of the person are recognized in the Charter of Fundamental rights of the European Union. 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 contained an extensive set of rules for the protection of subjects. These rules should be upheld. Regarding the rules concerning the determination of the legal representative of incapacitated persons and minors, those rules diverge in Member States. It should therefore be left to Member States to determine the legal representative of incapacitated persons and minors.

(23) 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 circumstances, due to the unconsciousness of the patient and the absence of an immediately available legal representative, it is not possible to obtain informed consent prior to the intervention. The 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 which causes the impossibility of the patient to give informed consent. Any previously expressed objection by the patient must be respected, and informed consent from the subject or the legal representative should be sought as soon as possible.

(24) In accordance with international guidelines, the free and informed consent of the subject should be in writing, save in exceptional situations. It should be based on information which is clear, relevant and understandable to the subject.

(25) 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 recruitment 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 to the competent authorities within one year of the end of the clinical trial.

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

(27) 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 Agency.

(28) The Agency should forward this information to the Member States for them to assess this information.

(29) 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 for good clinical practice which are now 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 used as guidance 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 without prejudice to this Regulation.

(30) 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.

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

(32) Depending on the circumstances of the clinical trial, it should be possible to trace the investigational and certain auxiliary medicinal products in order to ensure subject safety and data robustness and reliability. For the same reasons, those products should be destroyed where necessary and, depending on the circumstances of the clinical trial, subject to specific storage conditions.

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

(34) 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.

(35) 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.

(36) In order to ensure compliance of the conduct of the 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.

(37) The information generated in the 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 or the Commission.

(38) 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 and the Commission), 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.

(39) 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 of 6 November 2001 on the Community code relating to medicinal products for human use[19]. 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, i.e. medications unrelated to the clinical trial and not relevant for the design of the clinical trial.

(40) 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 importation 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.

(41) Investigational and auxiliary medicinal products should be appropriately labelled 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 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 a clinical trial. 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, as a general rule no additional labelling should be required for open-label trials. 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.

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

(43) In practice, there may be loose, informal networks of researchers or research institutions which run jointly 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 responsibilies of the sponsor by contractual agreement.

(44) The sponsor of a clinical trial may be located in a third country. In order to facilitate supervision and control, a sponsor located in a third country should establish a contact person in the Union to allow for the competent authority of the Member State concerned to communicate with the sponsor. That contact person may be a legal or a natural person.

(45) 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 legislation.

(46) In clinical trials with non-authorised investigational medicinal products, or where the intervention poses more than an insignificant risk to subject safety, compensation should be ensured for damages successfully claimed in accordance with the applicable laws.

(47) At present, such damage compensation is provided by way of insurance. This insurance may cover damages to be paid to the subject by the sponsor and investigator in the case of established liability. It may also compensate the subject directly without prior establishment of the liability of the sponsor or investigator. Experience shows that the insurance market is small and costs for insurance coverage are disproportionately high. Moreover, as liability regimes differ widely between Member States, it is difficult and burdensome for the sponsor of a multinational trial to obtain insurance in accordance with those national laws. Therefore, each Member State should establish a national indemnification mechanism which compensates subjects in accordance with the laws of that Member State.

(48) The Member State concerned should be given the power to early terminate, suspend or modify a clinical trial.

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

(50) 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.

(51) In order to streamline and facilitate the flow of information between sponsors and Member States as well as between Member States, the Commission should set up and maintain a database, accessed through a portal.

(52) The database should contain all relevant information as regards the clinical trial. No personal data of data subjects participating in a clinical trial should be recorded in the database. The information in the 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 of Fundamental Rights of the European Union.

(53) 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.

(54) The authorisation procedure set up in this Regulation is largely controlled by Member States. Nevertheless, the Commission should support the good functioning of this procedure, in accordance with this Regulation.

(55) 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 assessing, in a given Member State, an application for authorisation of a clinical trial.

(56) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission to adopt implementing acts in relation to inspections. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the rules and general principles concerning mechanisms for control by Member States of the Commission’s exercise of implementing powers[20].

(57) In order to ensure that information and documentation submitted in an application for authorisation of a clinical trial or a substantial modification allows assessment of the application in view of technical progress and global regulatory requirements, and in order to ensure a high level of subject protection and reliability and robustness of data generated in a clinical trial through a well-functioning safety reporting process and through detailed requirements for manufacturing and labelling of medicinal products used in the context of a clinical trial, the Commission should be empowered to adopt delegated acts in accordance with Article 290 of the Treaty on the Functioning of the European Union to amend the list of documentation and information to be submitted in an application for authorisation of a clinical trial or a substantial modification, to amend technical aspects for safety reporting in the context of a clinical trial, to adopt detailed requirements of good manufacturing practice, and to amend the list of information to appear on the labelling of medicinal products used in the context of a clinical trial. 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 Council.

(58) Article 4(5) of Directive 2001/83/EC provides that national legislation prohibiting or restricting the use of any specific type of human or animal cells should, in principle, not be affected by that Directive and all the Regulations referred to therein. Likewise, this Regulation should not affect national legislation prohibiting or restricting the use of any specific type of human or animal cells. As in Directive 2001/83/EC, Member States should communicate those national provisions to the Commission.

(59) Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data[21] applies to the processing of personal data carried out in the Member States, 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 of 18 December 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data[22], which 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.

(60) Without prejudice to the national systems for the cost and reimbursement of medical treatments, subjects should not have to pay for investigational medicinal products.

(61) The authorisation procedure set up in this Regulation should apply as soon as possible, in order for sponsors to reap the benefits of a streamlined authorisation procedure. However, in order to allow the setting up at Union level of the extensive IT functionalities required for the authorisation procedure, it is appropriate to provide for a reasonable period to elapse before this Regulation applies.

(62) 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.

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

(64) 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 to meet common safety concerns as regards these products. Both objectives are being pursued simultaneously. Both 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 EU 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 the quality and safety of medicinal products by ensuring that data generated in clinical trials is reliable and robust, thus ensuring that treatments and medicines which are supposed 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.

(65) This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter of Fundamental Rights of the European Union 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.

(66) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are reliable and robust while ensuring the safety and rights of subjects, cannot sufficiently be achieved by the Member States and can, by reason of the scale of the measure, 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 shall apply to clinical trials conducted in the Union.

It shall not apply to non-interventional studies.

Article 2 Definitions

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

The following definitions shall also apply:

(1) ‘Clinical study’: 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 their safety or efficacy.

(2) 'Clinical trial': a clinical study which fulfils any of the following conditions:

(a) the investigational medicinal products are not authorised;

(b) according to the protocol of the clinical study, the investigational medicinal products are not used in accordance with the terms of the marketing authorisation of the Member State concerned;

(c) 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;

(d) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study;

(e) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.

(3) ‘Low-intervention clinical trial’: a clinical trial which fulfils all of the following conditions:

(a) the investigational medicinal products are authorised;

(b) according to the protocol of the clinical trial, the investigational medicinal products are used in accordance with the terms of the marketing authorisation or their use is a standard treatment in any of the Member States concerned;

(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’: a clinical study other than a clinical trial;

(5) ‘Investigational medicinal product’: a medicinal product which is being tested or used as a reference, including as a placebo, in a clinical trial;

(6) 'Normal clinical practice': the treatment regime typically followed to treat, prevent, or diagnose a disease or a disorder;

(7) ‘Advanced therapy investigational medicinal product’: an investigational medicinal product which is an advanced therapy medicinal product as defined in Article 2(1) of Regulation (EC) No 1394/2007 of the European Parliament and of the Council[23];

(8) ‘Auxiliary medicinal product’: a medicinal product used in the context of a clinical trial, but not as an investigational medicinal product;

(9) ‘Authorised investigational medicinal product’: 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’: 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) ‘Member State concerned’: the Member State where an application for authorisation of a clinical trial or of a substantial modification has been submitted under Chapters II and III of this Regulation;

(12) ‘Substantial modification’: any change to any aspect of the clinical trial which is made after notification of the decision referred to in Articles 8, 14, 19, 20 and 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;

(13) ‘Sponsor’: an individual, company, institution or organisation which takes responsibility for the initiation and management of the clinical trial;

(14) ‘Investigator’: an individual responsible for the conduct of a clinical trial at a clinical trial site;

(15) ‘Subject’: an individual who participates in a clinical trial, either as recipient of an investigational medicinal product or as a control;

(16) ‘Minor’: a subject who is, according to the laws of the Member State concerned, under the age of legal competence to give informed consent;

(17) ‘Incapacitated subject’: a subject who is, for other reasons than the age of legal competence to give informed consent, legally incapable of giving informed consent according to the laws of the Member State concerned;

(18) ‘Legal representative’: a natural or legal person, authority or body which, according to the national law of the Member State concerned, gives informed consent for a subject who is incapacitated or a minor;

(19) 'Informed consent': a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate;

(20) 'Protocol': a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial;

(21) ‘Manufacturing’: total and partial manufacture, as well as the various processes of dividing up, packaging, labelling (including blinding);

(22) ‘Start of the clinical trial’: the first act of recruitment of a potential subject, unless defined differently in the protocol;

(23) ‘End of the clinical trial’: the last visit of the last subject, unless defined differently in the protocol;

(24) ‘Temporary halt of the clinical trial’: interruption of the conduct of a clinical trial by the sponsor with the intention of the sponsor to resume it;

(25) 'Suspension of the clinical trial': interruption of the conduct of a clinical trial by a Member State;

(26) ‘Good clinical practice’: 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;

(27) ‘Inspection’: 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 site of the trial, at the sponsor's and/or contract research organisation's facilities, or at other establishments which the competent authority sees fit to inspect;

(28) ‘Adverse event’: any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment;

(29) ‘Serious adverse event’: any untoward medical occurrence that at any dose requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect, is life-threatening or results in death;

(30) ‘Unexpected serious adverse reaction’: a serious adverse reaction the nature, severity or outcome of which is not consistent with the reference safety information.

For the purposes of this Regulation, a subject who falls under the definition of both “minor” and “incapacitated subject” shall be considered as an incapacitated subject.

Article 3 General principle

A clinical trial may be conducted only if

– the rights, safety and well-being of subjects are protected; and

– the data generated in the clinical trial are going to be reliable and robust.

Chapter II Authorisation procedure for a clinical trial

Article 4 Prior authorisation

A clinical trial shall be subject to authorisation in accordance with this Chapter.

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 77 (hereinafter 'EU portal').

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

Where the proposed reporting Member State does not wish to be the reporting Member State, it shall agree with another Member State concerned that the latter will be the reporting Member State. If no Member State concerned accepts to be the reporting Member State, the proposed reporting Member State shall be the reporting Member State.

2. Within six days following submission of the application dossier, the proposed reporting Member State shall notify the sponsor through the EU portal of the following:

(a) whether it is the reporting Member State or which other Member State concerned is the reporting Member State;

(b) whether the clinical trial falls within the scope of this Regulation;

(c) whether the application is complete in accordance with Annex I;

(d) whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor.

3. Where the proposed reporting Member State has not notified the sponsor within the time period referred to in paragraph 2, the clinical trial applied for shall be considered as falling within the scope of this Regulation, the application shall be considered complete, the clinical trial shall be considered a low-intervention clinical trial if this is claimed by the sponsor, and the proposed reporting Member State shall be the reporting Member State.

4. Where the proposed reporting Member State finds that the application is not complete, that the clinical trial applied for does not fall within the scope of this Regulation, or that the clinical trial is not a low-intervention clinical trial while this is claimed by the sponsor, it shall inform the sponsor thereof through the EU portal and shall set a maximum of six days for the sponsor to comment or to complete the application through the EU portal.

Where the sponsor has not provided comments nor completed the application within the time-period referred to in the first subparagraph, the application shall be considered as withdrawn.

Where the proposed reporting Member State has not notified the sponsor according to points (a) to (d) of paragraph 2 within three days following receipt of the comments or of the completed application, the application shall be considered complete, the clinical trial shall be considered as falling within the scope of this Regulation, the clinical trial shall be considered as a low-intervention clinical trial if this is claimed by the sponsor, and the proposed reporting Member State shall be the reporting Member State.

5. For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 2 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the time periods referred to in paragraphs 2 and 4.

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) 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, taking account of the current state of scientific knowledge, and of 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;

– the reliability and robustness of the data generated in the clinical trial, taking account of statistical approaches, design of the 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;

(b) Compliance with the requirements concerning the manufacturing and importation of investigational medicinal products and auxiliary medicinal products set out in Chapter IX;

(c) Compliance with the labelling requirements set out in Chapter X;

(d) 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;

(c) the conduct of the trial is not acceptable in view of the requirements set out in this Regulation.

4. The reporting Member State shall submit Part I of the assessment report, including its conclusion, to the sponsor and to the other Member States concerned within the following time periods:

(a) within 10 days from the validation date for low-intervention clinical trials;

(b) within 25 days from the validation date for clinical trials other than low- intervention clinical trials;

(c) within 30 days from the validation date for any clinical trial with an advanced therapy investigational medicinal product.

For the purposes of this Chapter, the assessment date shall be the date on which the assessment report is submitted to the sponsor and to the other Member States concerned.

5. Until the assessment date, any Member State concerned may communicate to the reporting Member State any considerations relevant to the application. The reporting Member State shall take those considerations duly into account.

6. The reporting Member State, and only the reporting Member State, may, between the validation date and the assessment date, request additional explanations from the sponsor, taking into account the considerations referred to in paragraph 5.

For the purpose of obtaining those additional explanations, the reporting Member State may suspend the time period referred to in paragraph 4 for a maximum of 10 days for low-intervention clinical trials and for a maximum of 20 days for trials other than low-intervention clinical trials.

Where, upon receipt of the additional explanations, the remaining time period for submitting Part I of the assessment report is less than three days in the case of low-intervention clinical trials, and less than five days for other than low-intervention clinical trials, it shall be extended to three and five days respectively.

Where the sponsor does not provide additional explanations within the time period set by the reporting Member State in accordance with the second subparagraph, the application shall be considered as withdrawn.

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

7. The sponsor may at its own initiative change the content of the application only between the validation date and the assessment date and only for duly justified reasons. In this case, the reporting Member State may, depending on the extent of the change to the content of the application, suspend the period referred to in paragraph 4 for a maximum of 60 days.

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 investigators and subjects with the requirements set out in Chapter V;

(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 46;

(f) compliance with Article 47;

(g) compliance with Article 72;

(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 ten days from the validation date. It may request, with justified reasons, additional explanations from the sponsor regarding the aspects referred to in paragraph 1 only within that time period.

3. For the purpose of obtaining additional explanations from the sponsor, the Member State concerned may suspend the period referred to in paragraph 2 for a maximum of ten days.

Where, upon receiving the additional explanations, the remaining time period for completing the assessment referred to in paragraph 1 is less than five days, it shall be extended to five days.

Where the sponsor does not provide additional explanations within the time period set by the Member State in accordance with the first subparagraph, the application shall be considered as withdrawn. The withdrawal shall apply only with respect to the Member State concerned.

The request and the additional explanations 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 ten days from the assessment date or the last day of the assessment referred to in Article 7, whichever is later.

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

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

(a) significant differences in normal clinical practice between the Member State concerned and the reporting Member State which would lead to a subject receiving an inferior treatment than in normal clinical practice;

(b) infringement of the national legislation referred to in Article 86.

Where the Member State concerned disagrees with the conclusion on the basis of point (a) of the second subparagraph, it shall communicate its disagreement, together with a detailed justification based on scientific and socio-economic arguments, and a summary thereof, through the EU portal to the Commission, to all Member States, and to the sponsor.

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

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

5. The Member States concerned shall not request additional explanations from the sponsor after the assessment date.

6. 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 the last day of the time period provided for in paragraph 1.

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, the institution of the trial site and the investigators involved, as well as free of any other undue influence.

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. In the assessment, the view of at least one person whose primary area of interest is non-scientific shall be taken into account. The view of at least one patient shall be taken into account.

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, 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. In applications for authorisation of clinical trials referred to in Article 32, 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 of the assessment report

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

After the notification of the decision on the aspects covered by Part I of the assessment report, the sponsor may apply for an authorisation limited to aspects covered by Part II 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 with regard to Part II of the assessment report in accordance with Article 8.

Article 12 Withdrawal

The sponsor may withdraw the application at any time until the assessment date. In such a case, the application may only be withdrawn with respect to all Member States concerned.

Article 13 Resubmission

This Chapter is without prejudice to the possibility for the sponsor to submit, 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 considered as 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 (hereinafter ‘additional Member State concerned’), the sponsor shall submit an application dossier to that Member State through the EU portal.

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

2. The reporting Member State for the application 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 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 within the following time periods:

(a) 25 days from the date of submission of the application referred to in paragraph 1 for low-intervention clinical trials;

(b) 35 days from the date of submission of the application referred to in paragraph 1 for clinical trials other than low-intervention clinical trials;

(c) 40 days from the date of submission of the application referred to in paragraph 1 for any clinical trial with an advanced therapy investigational medicinal product.

4. Where the conclusion as regards Part I of the assessment report of the reporting Member State is that the conduct of the clinical trial is acceptable or acceptable subject to conditions, the conclusion of the additional Member State concerned shall be the same as that of the reporting Member State referred to in Article 6(3).

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

(a) significant differences in normal clinical practice between the Member State concerned and the reporting Member State which would lead to a subject receiving an inferior treatment than in normal clinical practice;

(b) infringement of the national legislation referred to in Article 86.

Where the additional Member State concerned disagrees with the conclusion on the basis of point (a) of the second subparagraph, it shall communicate its disagreement, together with a detailed justification based on scientific and socio-economic arguments, and a summary thereof, through the EU portal to the Commission, to all Member States, and to the sponsor.

5. Between the date of submission of the application referred to in paragraph 1 and the expiry of the relevant time period referred to in paragraph 3, the additional Member State concerned may communicate to the reporting Member State any considerations relevant to the application.

6. The reporting Member State, and only the reporting Member State, may, between the date of submission of the application referred to in paragraph 1 and the expiry of the relevant time period referred to in paragraph 3, request additional explanations from the sponsor concerning Part I of the assessment report, taking into account the considerations referred to in paragraph 5.

For the purpose of obtaining those additional explanations, the reporting Member State may suspend the relevant time period referred to in paragraph 3 for a maximum of 10 days for low-intervention clinical trials and for a maximum of 20 days for trials other than low-intervention clinical trials.

Where, upon receipt of the additional explanations, the remaining time period for notifying the decision referred to in paragraph 4 is less than three days in the case of low-intervention clinical trials, and less than five days for other than low-intervention clinical trials, it shall be extended to three and five days respectively.

Where the sponsor does not provide additional explanations within the time period set by the reporting Member State in accordance with the second subparagraph, the application shall be considered as withdrawn.

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

7. The additional Member State concerned shall assess, for its territory, the aspects relating to Part II of the assessment report within ten days of the date of submission of the application referred to in paragraph 1. Within this time period it may request, with justified reasons, additional explanations from the sponsor regarding aspects relating to Part II of the assessment report as far as its territory is concerned.

8. For the purpose of obtaining the additional explanations, the additional Member State concerned may suspend the period referred to in paragraph 7 for a maximum of ten days. Where, upon receipt of the additional explanations, the remaining time period for assessing the aspects relating to Part II of the assessment report is less than five days, it shall be extended to five days.

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

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

10. Where the additional Member State concerned has not notified the sponsor of its decision within the relevant time period referred to in paragraph 3, the conclusion on Part I of the assessment report shall be considered as the decision of the additional Member State concerned on the application for authorisation of the clinical trial.

11. A sponsor shall not submit an application in accordance with this Article where a procedure referred to in Chapter III as regards that clinical trial is pending.

Chapter III Authorisation procedure for a substantial modification of a clinical trial

Article 15 General principles

A substantial modification 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 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.

2. Within four days following submission of the application dossier, the reporting Member State shall notify the sponsor through the EU portal of the following:

(a) whether the substantial modification concerns an aspect covered by Part I of the assessment report;

(b) whether the application is complete in accordance with Annex II;

(c) where the clinical trial is a low-intervention clinical trial, whether it will remain a low-intervention clinical trial after its substantial modification.

3. Where the reporting Member State has not notified the sponsor within the time period referred to in paragraph 2, the substantial modification applied for shall be considered as concerning an aspect covered by Part I of the assessment report, the application shall be considered as complete and, where the clinical trial is a low-intervention clinical trial, it shall be considered as remaining a low-intervention clinical trial after its substantial modification.

4. Where the reporting Member State finds that the application does not concern an aspect covered by Part I of the assessment report, that the application is not complete, or that the clinical trial will no longer be a low-intervention clinical trial after the substantial modification, contrary to what the sponsor claims, it shall inform the sponsor thereof through the EU portal and shall set a maximum of six days for the sponsor to comment or to complete the application through the EU portal.

Where the sponsor has not provided comments nor completed the application within the time-period referred to in the first subparagraph, the application shall be considered as withdrawn.

Where the reporting Member State has not notified the sponsor according to points (a) to (c) of paragraph 2 within three days following receipt of the comments or of the completed application, the application shall be considered complete and, where the clinical trial is a low-intervention clinical trial, that it will remain a low-intervention clinical trial after its substantial modification.

5. For the purposes of Articles 18, 19 and 22, the date on which the sponsor is notified in accordance with paragraph 2 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the time 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 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;

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

3. The reporting Member State shall submit Part I of the assessment report, including its conclusion, to the sponsor and to the other Member States concerned within 15 days from the validation date.

For the purposes of this Article and Articles 19 and 23, the assessment date shall be the date on which the assessment report is submitted to the sponsor and to th