EN    EN  
 EUROPEAN COMMISSION 
Brussels, 17.7.2012  
COM(2012) 369 final 
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) 
{SWD(2012) 200 final} 
{SWD(2012) 201 final}   
EN 2   EN EXPLANATORY MEMORANDUM  
1. CONTEXT  OF THE  PROPOSAL 
Clinical trials as defined in  Directive 2001/20/EC of the Eur opean 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 implem entation of good clinical practice in the 
conduct of clinical trials on me dicinal products for human use1 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 diff erent 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 furt her 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 sponsore d 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 importan t improvements in the safety and ethical 
soundness of clinical trials in the EU and in the re liability 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 fo r clinical trials fell by 25  % from 2007 to 2011.3 
• The costs for conducting clinical trials ha ve increased. Compared  to the situation 
prior to the application of the Direc tive 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 
                                                 
1 OJ L 121, 1.5.2001, p. 34. 
2 Based on the figures for 2010. 
3 The decrease has been 12% from 2007 to 2010.  
EN 3   EN 98% increase in administrative costs. In addition, since implementation of the 
Directive 2001/20/EC, insuran ce 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 th e fall in clinical tr ial activity sole ly 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 cl inical 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 targ ets) have been aggravated through regulatory 
requirements and consequential co sts 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 fo r 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 ‘Gener al principles and mi nimum 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 se veral meetings with stakeholders to hear 
their assessment of how the Clinical Trials Dir ective is working and to discuss the impact of 
potential policy options. A la rge stakeholder workshop was he ld on 31 March 2011 to clarify 
various points put forward in the con cept 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. S COPE (CHAPTERS 1 AND 2 OF THE PROPOSED REGULATION ) 
The scope of the proposed Regulation is esse ntially identical to that of Directive 
2001/20/EC. The scope is limited to clinical re search on medicinal products, but it is 
very wide in that it only excludes c linical studies that do not involve an 
‘intervention’ (e.g. survey s amongst medical practitio ners 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 aut horisations, the rules are se t out in Directive 2001/83/EC  
EN 4   EN of the European Parliament and of the Council of 6 November 2001 on the 
Community code relating to medicinal products for human use4. 
 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 au thorisation procedure for cl inical trials based on the 
following concepts: 
• A harmonised authorisation dossier, part ly codifying the existing Commission 
guidance contained in EudraLex, Volume 10; 
• A ‘single portal’ to submit an applica tion for conducting a clinical trial linked 
to an EU database. This portal is ma naged by the European  Commission and is 
free of charge for sponsors; 
• A flexible and swift assessment procedur e without establishing a new, central 
bureaucracy. This assessment is largely controlled by Member States. All Member States in which the sponsor in tends 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 a ddress issues which may arise in the 
authorisation procedure. This forum is managed and chaired by the Commission; 
• A clear distinction between aspects wh ere 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 a pplication for conducti ng a clinical trial 
('qualified opt-out'); 
• It is left to each Member State to defi ne the organisational setup and internal 
competences for assessing clinical tr ial authorisations, provided that 
international guidelines on the indepe ndence 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 
                                                
 
4 OJ L 311, 28.11.2001, p. 67.  
EN 5   EN impact on the safety or rights of the subj ects or on the reliabi lity 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 (Artic le 6 of the proposed 
Regulation) and those aspects where Me mber States conduct their assessment 
individually (Article  7 of the proposed Regulation). The latter includes aspects which 
are of an intrinsically nationa l (for example, liability), ethical (for example, informed 
consent), or local (for example suitabili ty 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 propos al does not interfere with the Member 
State's internal organisation of the bodies i nvolved in authorisi ng (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 Regulat ion 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 sy stematic 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 (s cience and ethics ca nnot be separated). 
Rather, the proposal leaves it up to Memb er States to organise, internally, the 
attribution of tasks to different bodies. Ind eed, what matters is that Member States 
ensure an independent, high-quality assessment  within the timelines  as set out in the 
legislation. Moreover, it is critic al to ensure clarity as to what issues are addressed in 
cooperation between Member St ates, and the issues which are addressed individually 
by each Member States because of their in trinsically 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, incl uding 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 a pplication for a clini cal trial throughout the 
EU, without trespassing on Member States' co mpetencies to organi se their internal 
decision-making on an application for au thorisation of a clinical trial. 
3.3. I
NTERFACE WITH 'SCIENTIFIC ADVICE ' 
Independently of the regulati on of clinical trials, regula tors may be involved in the 
preparatory phase of a trial in th e context of protocol assistance5, the paediatric 
                                                 
5 Article 6(1) of Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 
December 1999 on orphan me dicinal products (OJ L 18, 22.1.2000, p. 1).  
EN 6   EN investigation plan6, scientific advice7, and post-authorisation safety/efficacy studies8 
(hereinafter referred to as 'scientific advice'). 
The proposed Regulation does not 'mix' the asp ect of scientific ad vice with that of a 
clinical trial authorisation for two reasons: 
• The involvement of the regulator in the context of scie ntific 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 author isation 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 robustne ss. Indeed, it is perfectly conceivable 
(and has occasionally happened in the past ) that these two approaches come to 
conflicting results: while, from the poi nt of view of a future successful 
marketing authorisation, it may be desi rable 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 addre sses clinical trials in the abstract, i.e. 
independently from whether the results are intended to be used in a future 
marketing authorisation applicat ion, or for any other purpose (e.g. 
improvement of treatment strategies, comparing treatment with different 
medicines, etc.). This difference is  usually discusse d under the pattern 
'commercial' vs. 'academic' clinical tr ials. 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 th e proposal wants to stimulate. 
 3.4. P
ROTECTION 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 pe rformed without free 
and informed consent of the person concerne d. The EU law has to comply with this 
principle. The rules on the protection of s ubjects and on free and informed consent 
had been discussed extensively in the le gislative process leading to Directive 
2001/20/EC. The proposed Regulation does not, with the exception of the issue of 
clinical trials in emergency situations (s ee paragraph below), cha nge the substance of 
these rules. However, in terms of drafting, for the sake of clarity some provisions are 
re-arranged and, where possibl e, shortened. For example,  provisions related to the 
                                                 
6 Article 15 of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 
December 2006 on medicinal products for paed iatrics use (OJ L 378, 27.12.2006, p. 1). 
7 Article 56(3) of Regulation (EC) No 726/2004 of th e European Parliament and of the Council of 31 
March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 
30.4.2004, p. 1). 
8 Article 21a(b)(f) of Directive 2001/83/EC.  
EN 7   EN authorisation procedure have been move d to chapters 2 and 3 of the proposed 
Regulation, and provisions related to damage compensa tion 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 situa tion where, because of the urge ncy of the situation, it is 
impossible to obtain free and informed c onsent from the subject or the legal 
representative (‘clinical trials in emerge ncy 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/EC9 and Regulation (EC) No 45/200110 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 inve stigators, which may be collected in the EU 
database, are kept in accordance with the ex ception 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 Regul ation). In case of 
detection of cases of misconduct in a cl inical trial it woul d be important, for 
example, to trace all the clinical trials in  which the same inves tigators were involved, 
even several years after these clinical trials have ended. 
 3.5. S
AFETY REPORTING (CHAPTER 7 OF THE PROPOSED REGULATION ) 
The rules on safety reporting follow the pr inciples of the applicable international 
guidance documents. Compared to Dire ctive 2001/20/EC, the rules have been 
streamlined, simplified and modernised as follows: 
• The option to exclude reporting by the inve stigator to the sp onsor of adverse 
events, if this is provid ed for in the protocol; 
• Direct reporting of suspected unexpect ed serious adverse reactions by the 
sponsor to the European database EudraVigilance; 
• Simplified submission of the annual safe ty 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, wh ich codify in parts existing Commission 
guidance11 are contained in an a nnex to the proposed Regulat ion. This will facilitate 
                                                 
9 OJ L 281, 23.11.1995, p. 31. 
10 OJ L 8, 12.1.2001, p. 1. 
11 OJ C172, 11.6.2011, p. 1.  
EN 8   EN updating the existing rules, by way of delegate d acts, in view of technical progress or 
global regulatory alignment. 
Regarding the European database EudraVigilan ce, 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 ma intained and managed by the European 
Medicines Agency. Directive 2001/20/EC had already referred to this database and 
to the European Medicines Agency's ro le in administering it. The proposed 
Regulation does not introduce any changes in this respect. 
 3.6. C ONDUCT OF THE TRIAL (CHAPTER 8 OF THE PROPOSED REGULATION ) 
Directive 2001/20/EC contains relatively fe w rules on the actual conduct of trials. 
These rules are partly contained in Co mmission Directive 2005/ 28/EC of 8 April 
2005 laying down principles and detailed gu idelines for good clinical practice as 
regards investigational medicinal produc ts for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such 
products12, and partly contained in Commission guidance documents. The proposed 
Regulation brings together these rules. 
 3.7. I NVESTIGATIONAL AND AUXILIARY MEDICINAL PRODUCTS , MANUFACTURING , 
LABELLING (CHAPTERS 9 TO 10 OF THE PROPOSED REGULATION ) 
Medicinal products intended for research a nd development trials are excluded from 
the scope of Directiv e 2001/83/EC, including the rules on manufacturing, 
importation and labelling. The rules ar e contained in Directive 2001/20/EC, 
Directive 2005/28/EC and in  Commission guidelines. 
The proposed Regulation brings together thes e rules. The new rules continue to build 
on the concept of ‘investig ational medicinal product’. However, the proposed new 
rules reflect more clearly the fact that investigational medici nal products may be 
authorised, i.e. they have  already been placed on th e market in accordance with 
Directive 2001/83/EC. 
Moreover, experience with th e application of Directive 2001/20/EC shows the need 
for clarity on medicines used in the cont ext of a clinical trial that are not 
investigational medicinal products. These ‘auxiliary medicinal products’ (so far 
referred to in implementing Commissi on guidelines as ‘ non-investigational 
medicinal products’) will be subject to proportionate rules on manufacturing and 
labelling. 
                                                 
12 OJ L 91, 9.4.2005, p. 13.  
EN 9   EN  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 natio nal liability laws and are 
independent from the responsibility of a sponsor. 
Regarding ‘responsibility’, it is clearly pr eferable to have only one sponsor per 
clinical trial. A ‘single s ponsor’ is the best means to ensure that all information 
regarding the entire c linical trial are provided to the bodies supervising the clinical 
trial and all necessary  measures are taken. 
However, clinical trials are increasingly in itiated 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 ar e responsible for the en tire clinical trial. 
However, the proposed Regulatio n allows co-sponsors to ‘spl it’ the responsibility for 
the clinical trials amongst themselves. Ev en if co-sponsors spl it 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. Ho wever, if the sponsor is established in a 
third country, in order to ensu re an effective supervision of  a clinical trial, an EU 
contact person must be provided. Comm unication with that contact person is 
considered as communication with the sponsor. 
 3.9. C
OMPENSATION FOR DAMAGES (CHAPTER 12 OF THE PROPOSED 
REGULATION ) 
Directive 2001/20/EC introduced an 'obl igatory insurance/indemnity'. This 
obligatory insurance/indemnity has su bstantially increased the costs and 
administrative burden of conducting clinical trials, but there is no evidence that the 
number of damages, or the amount, has incr eased with the entry into force of the 
Directive. 
The proposed Regulation acknowledges that clini cal 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 necessa ry to provide a specific da mage compensation (be it an 
insurance or an indemnification) for the clin ical trial. In these cases, the insurance  
EN 10   EN coverage of the medical pr actitioner, 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 se t 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 possi ble compensations. These non-commercial 
sponsors have had, since the in troduction of the 'obligator y insurance/indemnity' with 
Directive 2001/20/EC, great difficultie s to obtain compensation coverage. 
 3.10. I NSPECTIONS (CHAPTER 13 OF THE PROPOSED REGULATION ) 
The provisions on inspections are largely based on Directive 2001/20/EC. Regarding 
inspection capacity, the proposed Regul ation provides the legal basis for 
Commission staff to perform c ontrols 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. R EPEALS AND ENTRY INTO FORCE (CHAPTER 19 OF THE PROPOSED 
REGULATION ) 
The proposed Regulation addresses the asp ects regulated in Di rective 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 ru les will apply in para llel 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 S IMPLIFICATION 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 ex perience 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 cr iticised for not taking  sufficiently into 
account these differences in risk. Instead, th e obligations and rest rictions laid down 
in the Directive 2001/20/EC apply largely irre spectively of the risk to subject safety.  
EN 11   EN This aspect is discussed extensively in th e impact assessment report. On the basis of 
this impact assessment, throughout the proposed Regulation aspects of risk-
proportionality have been car efully 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 ensu res that the Member States base their 
assessment of an application for authorisation of a clinical trial on an identical text, rather than on diverging nati onal transposition measures.  
The above holds not only for the entire auth orisation process, but also for all other 
issues addressed in this Regul ation, such as safety reporti ng during clinical  trials, and 
the requirements for labelling of the medi cinal products used in the context of a 
clinical trial. 
Moreover, experience has shown that Memb er States misused the transposition 
process in order to introduce addi tional procedural requirements.  
Finally, the legal form of a Regulation ha s an important simplification effect. The 
replacing of transposition measures at national level allows the relevant actors to plan and conduct the clinical trial, includi ng 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 transpos ing 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. C
OMPETENCES , DOUBLE LEGAL BASIS AND SUBSIDIARITY  
The proposed Regulation is, like Directiv e 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 author isation of their placing on the market. Finally, the 
proposed Regulation aims to harmonise the ru les for medicines used in the context of 
a clinical trial, thus allowing for their free movement within the Union.  
EN 12   EN 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 othe r 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 th e possibility of refe rring to the results 
and findings of clinical tria ls 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 medi cinal products used in  the context of a 
clinical trial , it has to be recalled that medici nal products intended for research and 
development trials are excluded from th e 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. T hus, these products do 
not benefit from secondary Union la w 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 safe ty for medicinal pr oducts. According to 
Articles 168(4) and 4(2)(k) TFEU this Union competence is – like Article 114 
TFEU - a shared competence which is exer cised with the adop tion of the proposed 
Regulation. 
The proposed Regulation aims at setting hi gh standards of quality and safety for 
medicinal products in two respects: 
• It ensures that data genera ted in clinical trials is reliable and robust, thus 
ensuring that treatments and medicines wh ich are supposed to be 'safer' for the 
patient build on reliable and robust clinic al data. Only if the data on which 
these decisions are taken is reliable a nd 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 proce dure, 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 ensu re the quality and safety of medicines 
administered to subjects in the contex t of a clinical tria l (while acknowledging 
that this assurance is only possible w ithin the limitations of the absence of 
knowledge, which characterises a clin ical trial): This is ensured inter alia  
through the authorisation procedure se t up with the proposed Regulation, as 
well as the rules on manufacturing of medi cinal 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:  
EN 13   EN • As set out above, the proposed Regula tion pursues equally as object the 
establishment and functioni ng of the internal market , and the setting of high 
standards of quality and safe ty for medicinal products; 
• The proposed Regulation pursues the se tting 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 receiv e an efficacious medicine/treatment. It also aims to 
ensure that the data generated in a clin ical trial is reliab le and robust not only 
regarding aspects of quality a nd safety, but also aspects of efficacy  of the 
medicinal product. This aspect of effi cacy, 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 mark eting authorisation holders to adapt their 
applications for authorisation to place th eir medicinal product on the market. They 
also hindered distribution of these produc ts. 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 complie d 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 Me mber States would conflict with the 
requirements of the Treaty, as only the Union can amend them. 
Having said this, for regulating clinical tr ials, the Treaty sets limits as regards 
harmonisation of ethical aspects of authoris ation and regulation of  clinical trials. 
Ethical aspects relate, in part icular, to the need to obtain ‘informed consent’ from the 
subject or the legal representative. Irrespectiv e of the risk that a clinical trial may 
pose to a patient, the mere fact that the trea tment 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 c onsent’ does not form 
part of the cooperation amongst Member St ates, but is assessed by each Member 
State individually. 
There are also several aspects of an intr insically 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  
EN 14   EN liability) but also to the rules on th e burden of proof and on calculating the 
extent of damage. 
Consequently, while regulation of clinical  trials and, in part icular, revision of 
Directive 2001/20/EC, is comp atible with the principle of subsidiarity, there are 
limits set by the Treaties whic h 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 Regulat ion functions properly; 
• Commission staff and othe r 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 envel ope of the Health for Growth Programme 
2014-2020.  
EN 15   EN 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 CO UNCIL 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 Commission13, 
After transmission of the draft legislative act to the national parliaments, Having regard to the opinion of the Eu ropean Economic and Social Committee
14, 
Having regard to the opinion of  the Committee of the Regions15, 
After consulting the European  Data Protection Supervisor16, 
Acting in accordance with the or dinary legislative procedure17, 
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 s ubject to prior authorisation. 
(3) The existing definition of a clinical tria l as contained in Dire ctive 2001/20/EC of the 
European Parliament and of the Council of  4 April 2001 on the approximation of the 
laws, regulations and administ rative provisions of the Memb er States relating to the 
implementation of good clinical practice in the conduct of cl inical trials on medicinal 
                                                
 
13 OJ C , , p. . 
14 OJ C , , p. . 
15 OJ C , , p. . 
16 XXX. 
17 OJ C , , p. .  
EN 16   EN products for human use18 should be clarified. For that pur pose, the concept of clinical 
trial should be more precisely defined by in troducing the broader concept of 'clinical 
study' of which the clinical trial is a category. That cate gory should be defined on the 
basis of specific criteria. This approach ta kes due account of international guidelines, 
and is in line with the EU  legislation governing medici nal 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 regul ation 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, Memb er States. The new procedures for the 
authorisation of clinical trials should stim ulate 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 thr ough 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 govern ing clinical trials in the Union cannot 
be achieved in the legal form of a Directiv e but can only be achieved with the legal 
form of a Regulation. Only the legal form of a Regulation ensure s that the Member 
States base their assessment of an applica tion for authorisation of a clinical trial on 
identical criteria, rather th an on diverging national trans position measures. This holds 
not only for the entire authorisation process, but also for all other issues addressed in 
this Regulation, such as safety reporting duri ng 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 efficien t, 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 th e 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 s hould therefore be established. 
                                                
 
18 OJ L 121, 1.5.2001, p. 34.  
EN 17   EN (9) The risk to subject safety in a clinical  trial mainly stems from two sources: the 
investigational medicinal pr oduct and the intervention. Ma ny clinical tr ials, 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. th e quality, safety and efficacy has already 
been assessed in the course of the marke ting authorisation procedure) and where the 
intervention poses only very limited additi onal 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, su ch 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 th e relevance, numerous aspects should be 
taken into account, including whether the c linical trial has b een 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 pr ovide for the possibility to suspend the 
assessment in order to allow the sponsor to  address questions or comments raised 
during the assessment of the applicati on dossier. The maximum duration of the 
suspension should reflect whether the clinical tr ial is a low-intervention clinical trial or 
not. Moreover, it should be en sured 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 is sues should not be assessed in 
cooperation among all Member States concerned. 
(13) The authorisation of a c linical trial should address all aspects in relation to subject 
protection and data reliability  and robustness. The permi ssion to conduc t a clinical 
trial should therefore be contained in one single administra tive 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 involveme nt of lay persons and patients. They 
should also ensure that the necessary expert ise 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 collectiv ely have the necessary qualifications and 
experience. The persons assessing the app lication 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 applica tion 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 th e documents assessed jointly by those Member 
States where the clinical trial might be conducted.  
EN 18   EN (16) The sponsor should be allowed to withdr aw the application for authorisation of a 
clinical trial. To ensure the reliable func tioning of the assessment procedure, however, 
an application for authorisation of a clin ical trial should be withdrawn only for the 
entire clinical trial. It should be possibl e for the sponsor to submit a new application 
for authorisation of a clin ical trial following the wit hdrawal 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 tria l to an additional Member States after the 
initial authorisation of the clinical tria l. 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 we re 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 re late to the conduct, design, methodology, 
investigational or auxiliary medicinal product, or the investigator or  trial site involved. 
Where those modifications have a substant ial 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 pr ocedure similar to the initial authorisation 
procedure. 
(19) The content of the application dossier fo r authorisation of a cl inical trial should be 
harmonised in order to ensure  that all Member States have the same information 
available and to simplify the applicat ion process for clinical trials.  
(20) In order to increa se transparency in the area of c linical trials, clinical trial data 
submitted in support of a clinical trial appl ication 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 asse ssment of the application for authorisation 
of a clinical trial functions smoothly, Me mber States should consider accepting a 
commonly understood language in the medi cal field as the language for the 
documentation not destined to the subject. 
(22) The human dignity and ri ght to the integrity  of the person are recognized in the 
Charter of Fundamental rights of the Euro pean 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 th e 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 dete rmination of the lega l representative of 
incapacitated persons and minor s, those rules diverge in Member States. It should 
therefore be left to Member States to  determine the legal representative of 
incapacitated pers ons and minors. 
(23) This Regulation should provide for cl ear rules concerning informed consent in 
emergency situations. Such si tuations relate to cases where for example a patient has 
suffered a sudden life-threatening medical co ndition due to multiple traumas, strokes 
or heart attacks, necessitating immediat e medical intervention. For such cases, 
intervention within an ongoing clinical tria l, which has already been approved, may be 
pertinent. However, in certain circumstances , due to the unconsciousness of the patient  
EN 19   EN and the absence of an immediat ely available legal representa tive, it is not possible to 
obtain informed consent prior to the interv ention. The Regulation s hould therefore set 
clear rules whereby such patients may be enro lled in the clinical trial under very strict 
conditions. In addition, the sa id clinical trial should rela te directly to the medical 
condition which causes the impossibility of th e patient to give informed consent. Any 
previously expressed objection by the patient must be respected, and informed consent 
from the subject or the legal representati ve should be sought as soon as possible. 
(24) In accordance with international guidel ines, the free and informed consent of the 
subject should be in writing, save in excep tional 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 particip ate 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, th e end of recruitment for the clin ical 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 rele vant 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 informati on 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 cl inical practice which are now an 
internationally accepted sta ndard for designing, conducti ng, recording and reporting 
clinical trials, consistent with principles that have their origin in the World Medical 
Association’s Declaration of Helsinki. When designi ng, conducting, recording and 
reporting clinical trials, detailed questions  may arise as to the appropriate quality 
standard. In such a case, th e ICH guidelines on good clinic al practice should be used 
as guidance for the application of the rule s set out in this Re gulation, 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 m onitored by the sponsor in order 
to ensure the reliability a nd robustness of the results. M onitoring may also contribute 
to subject safety, taking into account the characteristics of th e 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 clin ical trial, in particular investigators and 
other healthcare staff, should be sufficiently  qualified to perfor m their tasks in a 
clinical trial and the faciliti es where the clinical trial is to be conducted should be 
suitable for the clinical trial.  
EN 20   EN (32) Depending on the circumstances of the clini cal trial, it should be  possible to trace the 
investigational and certain a uxiliary medicinal products in  order to ensure subject 
safety and data robustness a nd reliability. For the same r easons, 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 b ecome 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 take n 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 term s 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 clini cal 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 conduc t of the clinical trial with the protocol, and 
in order for investigators to be informed about the investigati onal medicinal products 
they administer, the sponsor should supply th e investigators with an investigator’s 
brochure. 
(37) The information generated in the clinical  trial should be record ed, handled and stored 
adequately for the purpose of ensuring s ubject rights and safet y, the robustness and 
reliability of the data generated in th e clinical trial, accurate reporting and 
interpretation, effective monitoring by th e sponsor and effec tive 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 s ponsor and inspection by Member States and 
the Commission), should be kept by the spons or and by the investigator. The clinical 
trial master file should be archived appropriate ly to allow for s upervision after the 
clinical trial has ended. 
(39) Medicinal products intended for research a nd 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 medici nal products used in  the context of a 
clinical trial. They shoul d be covered by specific rule s taking account of their 
peculiarities. In establishing these rule s, a distinction should be made between 
investigational medicinal products (the tested product and its reference products, 
including placebos) and auxiliary medicinal pr oducts (medicinal products used in the 
context of a clinical trial but not as i nvestigational medicina l 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 
                                                
 
19 OJ L 311, 28.11.2001, p. 67.  
EN 21   EN products should not include concomitant medi cations, i.e. medicati ons 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 th e distribution of inves tigational and auxiliary 
medicinal products to clinical trial sites throughout the Union, rules on the 
manufacturing and importation of both in vestigational and auxiliary medicinal 
products should be established. As is al ready the case for Dir ective 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 ru les in order to faci litate the conduct of a clinical trial. 
Therefore, the applicable rules should allo w 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 a nd auxiliary medicinal products shoul d be appropriately labelled in 
order to ensure subject safety  and the reliability and robustness of da ta 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 la belling should be adapte d to the risks to 
subject safety and the reliabili ty and robustness of data gene rated in a clinical trial. 
Where the investigational or auxiliary medi cinal product have already been placed on 
the market as an authorised medicina l product in accordan ce with Directive 
2001/83/EC, as a general rule no additional la belling 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 in troduced with Direct ive 2001/20/EC. This 
concept should be upheld. 
(43) In practice, there may be loose, info rmal networks of researchers or research 
institutions which run jointly a clinical trial. Th ose networks should be able to be co-
sponsors of a clinical trial. In order not to weaken the c oncept of responsibility in a 
clinical trial, where a clinic al trial has several sponsors, they should all be subject to 
the obligations of a sponsor under this Re gulation. 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 loca ted in a third country. In  order to facilitate 
supervision and control, a s ponsor located in a third country should establish a contact 
person in the Union to allow for the co mpetent 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, th e conditions for liability in 
such cases, including issues of causality and the level of damages and sanctions, 
should remain governed by national legislation.  
EN 22   EN (46) In clinical trials  with non-authorised investigational medicina l products, or where the 
intervention poses more than an insignifi cant risk to subject safety, compensation 
should be ensured for damages successfully claimed in accordance with the applicable 
laws. 
(47) At present, such damage compensatio n is provided by way of insurance. This 
insurance may cover damages to be paid to the subject by the spons or and investigator 
in the case of established liability. It may al so 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 diff er widely between Member 
States, it is difficult and burdensome for th e sponsor of a multinat ional trial to obtain 
insurance in accordance with those nationa l 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 give n the power to early terminate, suspend or 
modify a clinical trial. 
(49) In order to ensure comp liance with this Regu lation, Member States should be able to 
conduct inspections and should have adequate inspection capacities.  
(50) The Commission should be ab le to control whether Member  States correctly supervise 
compliance with this Regulation. Moreover, the Commission should be  able to control 
whether regulatory systems of third countri es ensure compliance with the specific 
provisions of this Regulati on and Directive 2001/83/EC con cerning clinical trials 
conducted in third countries. 
(51) In order to streamline a nd facilitate the flow of in formation 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 in formation as regards th e clinical trial. No 
personal data of data subjects participating in  a clinical trial shoul d 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 protecti on of personal data, 
recognised by Articles 7 and 8 of the Charte r of Fundamental Rights of the European 
Union. 
(53) Within a Member State, there may be se veral 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 procedur e set up in this Regulation is  largely controlled by Member 
States. Nevertheless, the Commission should support th e good functioning of this 
procedure, in accordance with this Regulation. 
(55) In order to carry out th e activities provided for in th is 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.  
EN 23   EN (56) In order to ensure un iform conditions for the implem entation of this Regulation, 
implementing powers should be conferred on the Commission to adopt implementing 
acts in relation to inspections. Those power s 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 ge neral principles concerning mechanisms 
for control by Member States of the Co mmission’s exercise of implementing powers20. 
(57) In order to ensure that information a nd documentation submitted in an application for 
authorisation of a clinical trial or a subs tantial 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 prot ection and reliability an d robustness of data 
generated in a clinical tr ial through a well-functioning safety reporting process and 
through detailed requirements for manufactur ing 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 clin ical trial or a substa ntial modification, to 
amend technical aspects for safe ty reporting in the context of a clinical trial, to adopt 
detailed requirements of good manufacturin g practice, and to amend the list of 
information to appear on the labelling of medici nal products used in the context of a 
clinical trial. It is of particular import ance that the Commission carry out appropriate 
consultations during its prepar atory work, including at expe rt level. The Commission, 
when preparing and drawing-up delegated acts, should ensure a simultaneous, timely 
and appropriate transmission of relevant doc uments to the European Parliament and 
Council. 
(58) Article 4(5) of Direct ive 2001/83/EC provides that nati onal legislation prohibiting or 
restricting the use of any speci fic type of human or animal cells should, in principle, 
not be affected by that Directive and all th e Regulations referred to therein. Likewise, 
this Regulation should not affect national le gislation 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 na tional provisions to the Commission. 
(59) Directive 95/46/EC of th e 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 supervis ion of the Member States competent 
authorities, in particular the public indepe ndent 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 indivi duals with regard to the processing of 
personal data by the Community institutions  and bodies and on th e free movement of 
such data22, 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. 
                                                 
20 OJ L 55, 28.2.2011, p. 13. 
21 OJ L 281, 23.11.1995, p. 31. 
22 OJ L 8, 12.1.2001, p. 1.  
EN 24   EN (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 aut horisation procedure. 
However, in order to allow the setting up at Union level of the extensive IT functionalities required for the authorisation procedure, it is appr opriate to provide for 
a reasonable period to elapse be fore 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 Direc tive 2001/20/EC during a transitional period.  
(63) This Regulation is in line with the majo r international guidance documents on clinical 
trials, such as the most recent (2008) ve rsion 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 doubl e 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 protecti on 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 produc ts. Both objectives 
are being pursued simultaneously. Both objec tives 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 en suring the functioning 
of the internal market in view of the c onduct of a clinical tria l in several Member 
States, the acceptability throughout the Union of  data generated in a clinical trial and 
submitted in the application for the authorisat ion of another clinical trial or of the 
placing on the market of a medicinal produc t, and the free movement of medicinal 
products used in the context of a clinical trial. Regarding Articl e 168(4)(c) TFEU, this 
Regulation sets high standards of the qual ity 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 Re gulation sets high 
standards of quality and safety of medicinal pr oducts 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 observe s 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 th e 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 achie ved at Union level, the Union may adopt 
measures, in accordance with the principle of subsidiarity as set out in Article 5 of the  
EN 25   EN Treaty on European Union. In accordance with the principle of proportionality, as set 
out in that Article, this Re gulation 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 clinic al trials conducted in the Union.  
It shall not apply to non- interventional studies. 
Article 2 
Definitions 
For the purposes of this Regulation, th e definitions of "medicinal product", 
"radiopharmaceutical", "adverse reaction", "serio us 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 c linical, 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 ascertai ning their safety or efficacy. 
(2) 'Clinical trial': a clinical study which fulfils any of the following conditions: 
(a) the investigational medicina l 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 th e 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;  
EN 26   EN (d) the decision to prescribe the inves tigational medicinal products is taken 
together with the decision to include  the subject in the clinical study;  
(e) diagnostic or monitoring procedur es 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 medici nal products are authorised; 
(b) according to the protocol of the clinical trial, the investigational 
medicinal products are used in a ccordance with th e terms of the 
marketing authorisation or their use is  a standard treatment in any of the 
Member States concerned; 
(c) the additional diagnostic or monitori ng 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 othe r than a clinical trial; 
(5) ‘Investigational medicinal pr oduct’: a medicinal product wh ich is being tested or 
used as a reference, including as  a placebo, in a clinical trial; 
(6) 'Normal clinical practice': the treatment regi me typically followed to treat, prevent, 
or diagnose a disease or a disorder; 
(7) ‘Advanced therapy investigational medicina l product’: an investigational medicinal 
product which is an advanced therapy medici nal product as defined in Article 2(1) of 
Regulation (EC) No 1394/2007 of the Eur opean Parliament and of the Council
23; 
(8) ‘Auxiliary medicinal product’: a medicinal pro duct used in the cont ext of a clinical 
trial, but not as an invest igational medicinal product; 
(9) ‘Authorised investig ational medicinal product’: a me dicinal product authorised in 
accordance with Regulation (EC) No 726/2004, or, in any Member State concerned, 
in accordance with Directive 2001/83/EC, irre spective of changes to the labelling of 
the medicinal product, which is used as  an investigationa l medicinal product; 
(10) 'Authorised auxiliary medicinal product’ : a medicinal produc t authorised in 
accordance with Regulation (EC) No 726/2004, or, in any Member State concerned, 
in accordance with Directive 2001/83/EC, irre spective of changes to the labelling of 
the medicinal product, which is used  as an auxiliary medicinal product; 
(11) ‘Member State concerned’: the Member Stat e 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; 
                                                
 
23 OJ L 324, 10.12.2007, p. 121.  
EN 27   EN (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 robust ness of the data generated in the clinical trial; 
(13) ‘Sponsor’: an individual, company, in stitution or organi sation 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 th e laws of the Member State concerned, 
under the age of legal competence to give informed consent; 
(17) ‘Incapacitated subject’: a subj ect who is, for other reason s 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 lega l 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 s ubject voluntarily confirms his or her 
willingness to participate in a particular tr ial, after having been informed of all 
aspects of the trial that ar e relevant to the subject's  decision to participate; 
(20) 'Protocol': a document that describes th e objectives, design, methodology, statistical 
considerations and organisa tion of a clinical trial; 
(21) ‘Manufacturing’: total and pa rtial manufacture, as well as  the various processes of 
dividing up, packaging, labell ing (including blinding); 
(22) ‘Start of the clinical trial’: the first act of recruitment of a pot ential subject, unless 
defined differently in the protocol; 
(23) ‘End of the clinical trial’: the last visit of  the last subject, unle ss 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 c onduct 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, mon itoring, 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 tr ial are reliable and robust;  
EN 28   EN (27) ‘Inspection’: the act by a competent authorit y of conducting an official review of 
documents, facilities, reco rds, quality assurance ar rangements, and any other 
resources that are deemed by the competent aut hority to be related to the clinical trial 
and that may be located at the site of th e trial, at the sponsor's and/or contract 
research organisation's facili ties, or at other establishments which the competent 
authority sees fit to inspect; 
(28) ‘Adverse event’: any untoward medical o ccurrence in a subject administered a 
medicinal product and which does not necessarily  have a causal rela tionship 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 disa bility or incapacity, or is a congenital anomaly or birth 
defect, is life-threatenin g or results in death; 
(30) ‘Unexpected serious adverse r eaction’: a serious adverse r eaction the natu re, 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 tria l are going to be re liable and robust. 
Chapter II 
Authorisation procedure for a clinical trial 
Article 4 
Prior authorisation 
A clinical trial shall be subject to aut horisation in accordance with this Chapter. 
Article 5 
Submission of an application 
1. In order to obtain an aut horisation, the sponsor shall subm it an application dossier to 
the intended Member States concerned th rough the portal referre d to in Article 77 
(hereinafter 'EU portal'). 
The sponsor shall propose one of the Member States conc erned as reporting Member 
State.  
EN 29   EN Where the proposed reporting Member Stat e 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 repor ting Member State shall be the reporting 
Member State. 
2. Within six days following submission of  the application do ssier, 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 repo rting Member State; 
(b) whether the clinical trial falls with in the scope of this Regulation; 
(c) whether the application is comple te in accordance with Annex I; 
(d) whether the clinical trial is a low-inte rvention clinical trial, where claimed by 
the sponsor. 
3. Where the proposed reporting Member Stat e has not notified the sponsor within the 
time period referred to in paragraph 2, th e clinical trial applied for shall be 
considered as falling within the scope of this Regulation, the application shall be 
considered complete, the clinical trial sha ll be considered a low-intervention clinical 
trial if this is claimed by the sponsor, and the proposed reporti ng Member State shall 
be the reporting Member State. 
4. Where the proposed reporting Member Stat e 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-in tervention clinical tr ial 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 firs t subparagraph, the application shall be 
considered as withdrawn.  
Where the proposed reporting Member Stat e has not notified th e sponsor according 
to points (a) to (d) of pa ragraph 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 consid ered as falling within the scope of this 
Regulation, the clinical trial shall be consid ered as a low-intervention clinical trial if 
this is claimed by the sponsor, and the pr oposed reporting Member State shall be the 
reporting Member State. 
5. For the purposes of this Chapter, the da te on which the spons or is notified in 
accordance with paragraph 2 shall be the va lidation date of the application. Where 
the sponsor is not notif ied, the validation date shall be the last day of the time periods 
referred to in paragraphs 2 and 4.  
EN 30   EN 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 whet her 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 th e 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 inconveni ences for the subject, ta king 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 interven tion compared to normal clinical 
practice; 
– the safety measures, including pr ovisions for risk minimisation 
measures, monitoring, safety re porting, 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 medicina l products and a uxiliary medicinal 
products set out in Chapter IX; 
(c) Compliance with the labelling requ irements 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:  
EN 31   EN (a) the conduct of the c linical trial is acceptable in view of the requirements set out 
in this Regulation; 
(b) the conduct of the c linical trial is acceptable in view of the requirements set out 
in this Regulation, but subject to comp liance with specific conditions which 
shall be specifically listed in that conclusion; 
(c) the conduct of the trial is not acceptabl e in view of the requirements set out in
 this Regulation. 
4. The reporting Member State shall submit Pa rt I of the assessmen t report, including 
its conclusion, to the sponsor and to the ot her Member States co ncerned 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 investigati onal medicinal product. 
For the purposes of this Chapter, the assessment date shall be the date on which the 
assessment report is submitted to the spons or 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 cons iderations duly into account.  
6. The reporting Member State, and only th e reporting Member State, may, between the 
validation date and the assessment date, re quest additional explanations from the 
sponsor, taking into account the consid erations referred to in paragraph 5. 
For the purpose of obtaining those additi onal explanations, th e reporting Member 
State may suspend the time period referred to in paragraph 4 for a maximum of 10 
days for low-intervention clinical trials a nd for a maximum of 20 days for trials other 
than low-intervention clinical trials. 
Where, upon receipt of the additional ex planations, 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 additiona l explanations with in the time period 
set by the reporting Member State in accord ance 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.   
EN 32   EN 7. The sponsor may at its own initiative cha nge the content of the application only 
between the validation date and the asse ssment 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, su spend 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 justif ied 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 e xplanations from the sponsor, the Member 
State concerned may suspend the period referr ed to in paragraph 2 for a maximum of 
ten days.  
Where, upon receiving the additional ex planations, the remaining time period for 
completing the assessment referred to in para graph 1 is less than five days, it shall be 
extended to five days.  
Where the sponsor does not provide additiona l explanations with in the time period 
set by the Member State in accordance with the first s ubparagraph, the application 
shall be considered as withdrawn. The wit hdrawal shall apply only with respect to 
the Member State concerned.  
EN 33   EN 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 si ngle 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 repo rt of the reporting 
Member State is that the conduct of the c linical trial is acceptable or acceptable 
subject to conditions, the c onclusion of the Member Stat e 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 Me mber State only on the following grounds: 
(a) significant differences in normal clinic al practice between the Member State 
concerned and the reporting Member St ate which would lead to a subject 
receiving an inferior treatment th an in normal clinical practice; 
(b) infringement of the national legi slation 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 sh all communicate its disa greement, together 
with a detailed justification based on scie ntific and socio-economic arguments, and a 
summary thereof, through th e EU portal to the Commissi on, 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 pa ragraph 1, the conclusi on 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 notif ied to the sponsor. Where the sponsor has 
not been notified in accordance with paragr aph 1, the notification date shall be the 
last day of the time period provided for in paragraph 1.  
EN 34   EN Article 9 
Persons assessing the application 
1. Member States shall ensure that the pe rsons validating and assessing the application 
do not have conflicts of interest, are indepe ndent of the sponsor, th e 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 ha ve 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. Th e view of at least one patient shall be 
taken into account. 
Article 10 
Specific considerations for vulnerable populations 
1. Where the subjects are minors, specifi c consideration shal l be given to the 
assessment of the application for authorisation of a clinical trial on the basis of paediatric expertise or after taking a dvice on clinical, ethical and psychosocial 
problems in the field of paediatrics. 
2. Where the subjects are incapacitated, speci fic 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 patien t population concerned. 
3. In applications for authoris ation of clinical trials refe rred to in Article 32, specific 
consideration shall be given to  the circumstances of the conduc t of the clinical trial.  
Article 11 
Submission and assessment of applications limite d to aspects covered by Part I of the 
assessment report 
Where the sponsor so requests, the application for authorisatio n of a clinical trial, its 
assessment and the decision shall be limited to th e aspects covered by Pa rt 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 li mited 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.   
EN 35   EN Article 12 
Withdrawal 
The sponsor may withdraw the a pplication at any time until the assessment date. In such a 
case, the application may only be withdrawn wi th respect to all Member States concerned. 
Article 13 
Resubmission 
This Chapter is without prejud ice to the possibility for the sponsor to submit, following the 
refusal to grant an authorisation or the withdr awal of an application, an application for 
authorisation to any intended Me mber State concerned. That appl ication shall be considered 
as a new application for authorisat ion of another clinical trial. 
Article 14 
Subsequent addition of a Member State concerned 
1. Where the sponsor wishes to extend an au thorised clinical trial to another Member 
State (hereinafter ‘additional Member State concerned’), the sponsor shall submit an 
application dossier to that Memb er 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 applicati on referred to in para graph 1 shall be the 
reporting Member State for the initial authorisation procedure. 
3. The additional Member State concerne d shall notify the s ponsor 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 adva nced therapy invest igational medicinal 
product. 
4. Where the conclusion as regards Part I of the assessment repo rt of the reporting 
Member State is that the conduct of the c linical trial is acceptable or acceptable 
subject to conditions, the conc lusion of the additional Me mber State concerned shall 
be the same as that of the reporting Memb er State referred to in Article 6(3). 
Notwithstanding the first subparagraph, an additional Member State concerned may 
disagree with the conclusion of the re porting Member State only on the following 
grounds:  
EN 36   EN (a) significant differences in normal clinic al practice between the Member State 
concerned and the reporting Member St ate which would lead to a subject 
receiving an inferior treatment th an in normal clinical practice; 
(b) infringement of the national legi slation referred to in Article 86. 
Where the additional Member State concer ned disagrees with the conclusion on the 
basis of point (a) of the second subparag raph, it shall communicate its disagreement, 
together with a detailed justification based on scie ntific 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 app lication 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 re porting Member State any considerations 
relevant to the application. 
6. The reporting Member State, and only th e reporting Member State, may, between the 
date of submission of the application referre d to in paragraph 1 and the expiry of the 
relevant time period referred to in paragr aph 3, request additiona l explanations from 
the sponsor concerning Part I of the a ssessment report, taking into account the 
considerations referred to in paragraph 5.  
For the purpose of obtaining those additi onal explanations, th e reporting Member 
State may suspend the relevant time period referred to in paragraph 3 for a maximum of 10 days for low-intervention clinical tria ls and for a maximum of 20 days for trials 
other than low-intervention clinical trials.  
Where, upon receipt of the additional ex planations, 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 ex tended to three and five days respectively. 
Where the sponsor does not provide additiona l explanations with in the time period 
set by the reporting Member State in accord ance 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 sh all 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 paragra ph 1. Within this time pe riod it may request, 
with justified reasons, add itional explanations from the sponsor regarding aspects 
relating to Part II of the assessment repor t as far as its territory is concerned.  
8. For the purpose of obtaining the additio nal explanations, the additional Member 
State concerned may suspend the period referr ed 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.  
EN 37   EN 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 addi tional Member State concerned shall 
include in its decision its conclusion on Part II of the assessment report. 
10. Where the additional Member State concer ned has not notified the sponsor of its 
decision within the relevant time period re ferred to in paragraph 3, the conclusion on 
Part I of the assessment report shall be c onsidered as the decision of the additional 
Member State concerned on the application fo r authorisation of the clinical trial. 
11. A sponsor shall not submit an application in accordance with th is Article where a 
procedure referred to in Chapter III as re gards 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 implemen ted if it has been a pproved in accordance 
with the procedure set out in this Chapter. 
Article 16 
Submission of application 
In order to obtain an authoris ation, the sponsor shall submit an application dossier to the 
Member States concerne d through the EU portal. 
Article 17 
Validation of an application for authorisation of a substantial mod ification of an aspect 
covered by Part I of the assessment report 
1. The reporting Member State for the author isation of a substan tial modification shall 
be the reporting Member State for th e initial authorisation procedure. 
2. Within four days following submission of the application do ssier, the reporting 
Member State shall notify the sponsor through the EU portal of the following: 
(a) whether the substantial modification con cerns an aspect covered by Part I of 
the assessment report; 
(b) whether the application is comple te in accordance with Annex II; 
(c) where the clinical trial is a low-inte rvention clinical trial, whether it will 
remain a low-intervention clinical tr ial after its substantial modification.  
EN 38   EN 3. Where the reporting Member State has not notified the sponsor within the time 
period referred to in paragraph 2, the subs tantial modification applied for shall be 
considered as concerning an aspect covere d 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 th at the application does not concern an 
aspect covered by Part I of the assessmen t report, that the application is not 
complete, or that the clinical trial will no longer be a low-interv ention clinical trial 
after the substantial modificat ion, contrary to what the s ponsor claims, it shall inform 
the sponsor thereof through th e EU portal and shall set a maximum of six days for 
the sponsor to comment or to complete the application throug h the EU portal.  
Where the sponsor has not provided comments  nor completed the application within 
the time-period referred to in the firs t 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 cl inical trial, that it will remain a low-
intervention clinical trial afte r 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 th e validation date of the application. Where 
the sponsor is not notif ied, 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 as pect covered by Part I of the assessment 
report   
1. The reporting Member State shall assess th e application and dr aw 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 complian ce 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.  
EN 39   EN 3. The reporting Member State shall submit Pa rt I of the assessmen t report, including 
its conclusion, to the sponsor and to the ot her Member States concerned within 15 
days from the validation date. 
For the purposes of this Article and Artic les 19 and 23, the assessment date shall be 
the date on which the assessment report is s ubmitted to the sponsor and to the other 
Member States concerned. 
4. 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 c onsiderations duly into account. 
5. The reporting Member State, and only th e reporting Member State, may, between the 
validation date and the assessment date, re quest additional explanations from the 
sponsor, taking into account the consider ations referred to in paragraph 4.  
For the purpose of obtaining those additi onal explanations, th e reporting Member 
State may suspend the period referred to in paragraph 4 for a maximum of 10 days.  
Where, upon receipt of the additional ex planations, the remaining time period for 
submitting Part I of the assessment report is le ss than five days, it shall be extended 
to five days.  
Where the sponsor does not provide additiona l explanations with in the time period 
determined by the reporting Member State in accordance with the second subparagraph, the applic ation shall be considered as withdrawn. 
The request and the additional explanations shall be submitted through the EU portal.  
6. The sponsor may at its own initiative cha nge the content of the application only 
between the validation date and the asse ssment 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, su spend the period referred to in paragraph 3 
for up to 60 days. 
Article 19 
Decision on the substantial modification of an as pect covered by Part I of the assessment 
report 
1. Each Member State concerned shall notif y the sponsor through th e EU portal as to 
whether the substantial modification is author ised, whether it is authorised subject to 
conditions, or whether aut horisation is refused.  
Notification shall be done by way of one si ngle decision within ten days from the 
assessment date. 
2. Where the conclusion of the reporting Member State is that the substantial 
modification 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.  
EN 40   EN Notwithstanding the first subparagraph, a Member State concerned may disagree 
with that conclusion of the reporting Member State only on the following grounds: 
(a) significant differences in normal clinic al practice between the Member State 
concerned and the reporting Member St ate which would lead to a subject 
receiving an inferior treatment th an in normal clinical practice; 
(b) infringement of the national legi slation 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 sh all communicate its disa greement, together 
with a detailed justification based on scie ntific and socio-economic arguments, and a 
summary thereof, through th e EU portal to the Commissi on, to all Member States, 
and to the sponsor. 
3. Where the Member State concerned has not notified the sponsor of its decision 
within the time period referred to in paragraph 1, the conclusion of the assessment report shall be considered as the decision in the Member State concerned on the application for authorisation of  the substantial modification. 
Article 20 
Validation, assessment and decision regarding a substantial modification of an aspect 
covered by Part II of the assessment report 
1. Within four days following submission of the application dossier, the Member State 
concerned shall notify the sponsor th rough the EU portal of the following: 
(a) whether the substantial modification concer ns an aspect covered by Part II of 
the assessment report; and 
(b) whether the application is comple te in accordance with Annex II. 
2. Where the Member State concerned has not notified the spons or within the time 
period referred to in paragraph 1 the subs tantial modification applied for shall be 
considered as concerning an aspect cove red by Part II of the assessment report and 
the application shall be considered as complete. 
3. Where the Member State concerned finds that the substantial modification does not 
concern an aspect covered by Part II of the assessment report or that the application 
is not complete, it shall inform the spons or 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 firs t subparagraph, the application shall be 
considered as withdrawn. 
Where the Member State concerned has not notified the sponsor according to points 
(a) and (b) of paragraph 1 within three days following receipt of the comments or of the completed application, the substantia l modification shall be considered as  
EN 41   EN concerning an aspect covered by Part II of the assessmen t report and the application 
shall be considered as complete. 
4. For the purpose of this Article, the da te on which the spons or is notified in 
accordance with paragraph 1 shall be the va lidation date of the application. Where 
the sponsor is not notif ied, the validation date shall be the last day of the time periods 
referred to in paragraphs 1 and 3. 
5. The Member State concerned shall assess th e application and shal l notify the sponsor 
through the EU portal as to whether the substantial modification is authorised, 
whether it is authorised s ubject to conditions, or whethe r authorisation is refused. 
Notification shall be done by way of one si ngle decision within ten days from the 
validation date.  
6. During the time period referred to in th e second subparagraph of paragraph 5 the 
Member State concerned may request, with justified reasons, addi tional explanations 
from the sponsor regarding the substantial modification as far as its territory is 
concerned.  
For the purpose of obtaining additional expl anations, the Member State concerned 
may suspend the time period referred to in  the second subparagraph of paragraph 5 
for a maximum of ten days. 
Where, upon receipt of the additional ex planations, the remaining time period for 
notifying the decision referred to in in the second subparagraph of paragraph 5 is less 
than five days, it shall be extended to five days.  
Where the sponsor does not provide additiona l explanations with in the time period 
set by the Member State in accordance with the first and second subparagraph, the application shall be considered as withdrawn. 
The request and the additional explanations shall be submitted through the EU portal. 
7. Where the Member State concerned has not  notified the sponsor of its decision 
within the time periods set out in paragr aphs 5 and 6, the s ubstantial modification 
shall be considered as authorised. 
Article 21 
Substantial modification of aspects covered by Parts I and II of the assessment report 
1. Where a substantial modificat ion relates to aspects cove red by Parts I and II of the 
assessment report, the application for author isation of that subs tantial modification 
shall be validated in accordance with Article 17. 
2. The aspects covered by Part I of the assessment report shall be assessed in 
accordance with Article 18 and the aspects covered by Part II of the assessment 
report shall be assessed in accordance with Article 22.   
EN 42   EN Article 22 
Assessment of a substantial modification of  aspects covered by Parts I and II of the 
assessment report – Assessment of the aspects covered by Part II of the assessment report 
1. Each Member State concerned shall asse ss, for its territory, the aspects of the 
substantial modification which are covered by Part II of the assessment report within 
ten days from the validation date.  
2. During the time period referred to in pa ragraph 1 the Member State concerned may 
request, with justified reasons, additional explanations from the sponsor regarding 
this substantial modification as fa r as its territory is concerned. 
3. For the purpose of obtaining additional e xplanations from the sponsor, the Member 
State concerned may suspend the time peri od referred to paragraph 1 for a maximum 
of ten days. 
Where, upon receipt of the additional expl anations, the remaining time period for 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 additiona l explanations with in the time period 
referred to in the first and second subparagr aph, the application shall be considered 
as withdrawn. 
The request and the additional explanations shall be submitted through the EU portal. 
Article 23 
Decision on the substantial modification of aspects covered by Parts I and II of the 
assessment report 
1. Each Member State concerned shall notify the sponsor through the EU Portal as to 
whether the substantial modification is author ised, whether it is authorised subject to 
conditions, or whether au thorisation is refused. 
Notification shall be done by way of one si ngle decision within ten days from the 
assessment date or the last day of the assessment referred to in Article 22, whichever 
is later. 
2. Where the conclusion of the reporting Member State is that the substantial 
modification covered by Part I of the asse ssment report is acceptable or acceptable 
subject to conditions, the c onclusion of the Member Stat e 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 Me mber State only on the following grounds: 
(a) significant differences in normal clinic al practice between the Member State 
concerned and the reporting Member St ate which would lead to a subject 
receiving an inferior treatment th an in normal clinical practice; 
(b) infringement of the national legi slation referred to in Article 86.  
EN 43   EN Where the Member State concerned disagr ees with the conclusion regarding the 
substantial modification of aspects covered by Part I of the a ssessment report on the 
basis of point (a) of the second subparag raph, it shall communicate its disagreement, 
together with a detailed justification based on scie ntific 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 the substantial modificat ion of aspects covere d by Part I of the 
assessment report, the substantial modification is acceptable or acceptable subject to conditions, the Member State concerned sha ll include in its decision its conclusion 
on the substantial modification of aspects cove red by Part II of th e assessment report. 
4. Where the Member State concerned has not  notified the sponsor of its decision 
within the time periods referred to in pa ragraph 1, the conclusion on the substantial 
modification of aspects covered by Part I of  the assessment report shall be considered 
as the decision of the Member State concerne d on the application for authorisation of 
the substantial modification. 
Article 24 
Persons assessing the application 
Article 9 applies to the assessments made under this Chapter 
Chapter IV 
Application dossier 
Article 25 
Data submitted in the application dossier 
1. The application dossier for th e authorisation of a clinical trial shall contain all the 
documentation and information necessary fo r the validation and assessment referred 
to in Chapter II and relating to:  
(a) the conduct of the trial, including the scientific context and arrangements 
taken,  
(b) sponsor, investigators, potential su bjects, subjects, and trial sites; 
(c) the investigational medi cinal products and, where necessary, the auxiliary 
medicinal products, in particular their properties, labelling, manufacturing and 
control; 
(d) measures to protect subjects. 
The list of documentation and information is set out in Annex I. 
2. The application dossier for the authoris ation of a substantial modification shall 
contain all the following documentation and information necessary for the validation 
and assessment referred to in Chapter III:  
EN 44   EN (a) a reference to the clinical trial or cl inical trials which are substantially 
modified; 
(b) a clear description of the substantial modification; 
(c) a presentation of data and additional in formation in support of the substantial 
modification, where necessary; 
(d)  a clear description of the consequen ces of the substan tial modification as 
regards subject right and safety and re liability and robustness of the data 
generated in the clinical trial. 
The list of documentation and information is set out in Annex II. 
3. Non-clinical data submitted  in an application dossier  shall be based on studies 
complying with Union legislation on the principles of good laboratory practice, as 
applicable at the time of performance of those studies,  or equivalent standards. 
4. Where reference is made in the application dossier to data generated in a clinical 
trial, that clinical trial shall have been conducted in accordance with this Regulation.  
5. Where the clinical trial ha s been conducted outside the Union, it shall comply with 
principles equivalent to thos e of this Regulation as rega rds subject rights and safety 
and reliability and robustness of data generated in the cl inical trial.  
6. Clinical trial data submitted in an applica tion dossier shall be based on clinical trials 
which have been registered prior to their start in a public register which is a primary registry of the international clinical tria ls registry platform of the World Health 
Organisation. 
7. Data submitted in an application dossier wh ich do not comply with paragraphs 3 to 6 
shall not be considered in the assessment of an application fo r authorisation of a 
clinical trial or of a substantial modification. 
Article 26 
Language requirements 
The language of the application do ssier, or parts thereof, shal l be determined by the Member 
State concerned.  
Member States, in applying the first para graph, shall consider accepting, for the 
documentation not addressed to the subject, a commonly understood lan guage in the medical 
field. 
Article 27 
Update by way of delegated acts 
The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in 
order to amend Annexes I and II with the objective to adapt them  to technical progress or to 
take account of global regulatory developments.  
EN 45   EN Chapter V 
Protection of subjects and informed consent 
Article 28 
General rules 
1. A clinical trial may be conducted only wher e all of the following conditions are met: 
(a) the anticipated therapeutic and public health benefits jus tify the foreseeable 
risks and inconveniences; 
(b) compliance with point (a ) is permanently observed; 
(c) the subject or, where the subject is not ab le to give informed consent, his or her 
legal representative has given informed consent; 
(d) the subject or, where the subject is not ab le to give informed consent, his or her 
legal representative has had the opport unity, in a prior interview with the 
investigator or a member of the i nvestigating team, to understand the 
objectives, risks and inconveniences of th e clinical trial, and the conditions 
under which it is to be conducted and has also been informed of the right to 
withdraw from the clinical trial at any time without any resulting detriment; 
(e) the rights of the subject to physical and mental integr ity, to privacy and to the 
protection of the data concerning him or her in accordance with Directive 95/46/EC are safeguarded. 
2. The rights, safety and well-being of the subjects shall prevail over the interests of 
science and society. 
3. Any subject may, without any resulting detrimen t, withdraw from the clinical trial at 
any time by revoking his or her informed cons ent. The withdrawal  of consent shall 
not affect the activities carried out based on consen t before its withdrawal. 
Article 29 
Informed consent 
1. Informed consent shall be written, dated and signed and given freely by the subject 
or his or her legal representative after having been duly informed of the nature, 
significance, implications and risks of the clinical trial. It shall be appropriately documented. Where the subject is unable to wr ite, oral consent in the presence of at 
least one impartial witness ma y be given in exceptional case s. The subject or his or 
her legal representative shall be provi ded with a copy of the document by which 
informed consent has been given. 
2. Written information given to the subject and/or the legal representative for the 
purposes of obtaining his or her informed consent shall be kept  concise, clear, 
relevant, and understandable to a lay pers on. It shall include both medical and legal  
EN 46   EN information. It shall inform the subject a bout his or her right to revoke his or her 
informed consent.  
3. The subject shall be provided with a cont act point where he or she may obtain further 
information.  
Article 30 
Clinical trials on incapacitated subjects 
1. In the case of incapacitated subjects who have  not given, or have not refused to give, 
informed consent before the onset of th eir incapacity, a clinical trial may be 
conducted only where, in addition to the c onditions set out in Ar ticle 28, all of the 
following conditions are met: 
(a) the informed consent of the legal representative has been obtained, whereby 
consent shall represent the subject’s presumed will; 
(b) the incapacitated subject has received ad equate information in relation to his or 
her capacity for understanding regarding th e trial, the risks and the benefits; 
(c) the explicit wish of an incapacitated subject who is capable of forming an 
opinion and assessing this information to  refuse participa tion in, or to be 
withdrawn from, the clinical trial at any time is considered by the investigator; 
(d) no incentives or financial inducemen ts are given except compensation for 
participation in the clinical trial; 
(e) such research is essential to validate data obtained in clinical trials on persons 
able to give informed consen t or by other research methods; 
(f) such research relates directly to a life-threatening or debilitating medical 
condition from which the subject suffers; 
(g) the clinical trial has been designed to  minimise pain, disc omfort, fear and any 
other foreseeable risk in relation to the disease and developmental stage and 
both the risk threshold and the degree of distress are specially defined and 
constantly observed;  
(h) there are grounds for expecting that pa rticipation in the c linical trial will 
produce a benefit to the incapacitated subject outweighing the risks or will produce no risk at all. 
2. The subject shall as far as possible take part in the consent procedure. 
Article 31 
Clinical trials on minors 
1. A clinical trial on minors may be conducte d only where, in addition to the conditions 
set out in Article 28, all of the following conditions are met:  
EN 47   EN (a) the informed consent of the legal representative has been obtained, whereby 
consent shall represent the minor’s presumed will; 
(b) the minor has received all relevant information in a way adapted to his or her 
age and maturity, from professionals tr ained or experience d in working with 
children, regarding the trial, the risks and the benefits; 
(c) the explicit wish of a minor who is capable of forming an opinion and 
assessing this information to refuse part icipation in, or to be withdrawn from, 
the clinical trial at any time, is duly ta ken into consideration by the investigator 
in accordance with his or her age and maturity; 
(d) no incentives or financial inducemen ts are given except compensation for 
participation in the clinical trial; 
(e) such research is essential to validate data obtained in clinical trials on persons 
able to give informed consen t or by other research methods; 
(f) such research either relates direct ly to a medical condition from which the 
minor concerned suffers or is of such a nature that it can only be carried out on minors; 
(g) the clinical trial has been designed to  minimise pain, disc omfort, fear and any 
other foreseeable risk in relation to the disease and developmental stage and 
both the risk threshold and the degree of distress are specially defined and 
constantly observed; 
(h) some direct benefit for the group of patie nts is obtained from the clinical trial. 
2. The minor shall take part in the consent procedure in a manner ad apted to his or her 
age and maturity. 
Article 32 
Clinical trials in emergency situations 
1. By way of derogation from points (c) and (d ) of Article 28(1), from points (a) and (b) 
of Article 30(1) and from points (a) and (b) of Article 31(1), informed consent may 
be obtained after the start of the clinical trial to continue the clinical trial and 
information on the clinical trial may be gi ven after the start of the clinical trial 
provided that all of the following conditions are fulfilled: 
(a) due to the urgency of the situation, caused by a sudden life-threatening or other 
sudden serious medical condition, it is impossible to obtain prior informed 
consent from the subject an d it is impossible to suppl y prior information to the 
subject; 
(b) no legal representative is available; 
(c) the subject has not previously expresse d objections known to the investigator;  
EN 48   EN (d) the research relates di rectly to a medical condition which causes the 
impossibility to obtain prior informed c onsent and to supply prior information; 
(e) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the 
subject. 
2. The informed consent referred to in para graph 1 shall be obtained, and information 
on the clinical trial shall be given, in accordance with the following requirements: 
(a) regarding incapacitated subjec ts and minors, the informed consent referred to 
in paragraph 1 shall be obtained as  soon as possible from the legal 
representative and the information referre d to in paragraph 1 shall be given as 
soon as possible to the subject; 
(b) regarding other subjects, the informed c onsent referred to in  paragraph 1 shall 
be obtained as soon as possible from th e legal representative or the subject, 
whichever is sooner and the information referred to in paragraph 1 shall be 
given as soon as possible to the legal re presentative or the subject, whichever is 
sooner. 
For the purposes of point (b ), where informed consent has been obtained from the 
legal representative, informed consent to c ontinue the trial shall be obtained from the 
subject as soon as it is capabl e of giving informed consent. 
Chapter VI 
Start, end, suspension, temporary halt, and early termination of a 
clinical trial 
Article 33 
Notification of the start of the clinical trial and of the end of  the recruitment of subjects 
1. The sponsor shall notify each Member State concerned of th e start of a clinical trial 
in relation to that Member State through the EU portal. 
That notification shall be made within 15 days from the start of the clinical trial in 
relation to that Member State. 
2. The sponsor shall notify each Member State concerned of the end of the recruitment 
of subjects for a clinical trial in that  Member State thr ough the EU portal.  
That notification shall be made within 15 days from the end of the recruitment of 
subjects. In case of re-start of re cruitment, paragraph 1 shall apply.  
Article 34 
End of the clinical trial, early termination of the clinical trial 
1. The sponsor shall notify each Member State co ncerned of the end of a clinical trial in 
relation to that Member State through the EU portal.  
EN 49   EN That notification shall be made within 15 da ys from the end of the clinical trial in 
relation to that Member State.  
2. The sponsor shall notify each Member State co ncerned of the end of  the clinical trial 
through the EU portal. 
That notification shall be made within 15 days from the end of the clinical trial. 
3. Within one year from the end of a clinical  trial, the sponsor shall submit to the EU 
database a summary of the resu lts of the clinical trial.  
However, where, for scientific reasons, it is not possible to submit a summary of the 
results within one year, the summary of re sults shall be submitted as soon as it is 
available. In this case, the protocol sha ll specify when the results are going to be 
submitted, together with an explanation. 
4. For the purpose of this Regulation, if a susp ended or temporarily halted clinical trial 
is not restarted, the date of the decision of the sponsor not to restart the clinical trial 
shall be considered as the end of the clini cal trial. In the case of early termination, the 
date of the early termination shall be consider ed as the date of th e end of the clinical 
trial. 
5. Without prejudice to paragraph 3, where th e clinical trial provides for a primary 
completion date prior to the end of the trial,  and the respective results of the clinical 
trial are available, a summary of those results shall be submitted to the EU database within one year of the primary completion date. 
Article 35 
Temporary halt or early termination by the sponsor for reasons of subject safety  
For the purposes of this Regulati on, the temporary halt or early termination of a clinical trial 
for reasons of a change of the benefit-risk balance and the restart following such temporary 
halt of a clinical trial shall be considered as a substantial modification of a clinical trial. 
Chapter VII 
Safety reporting in the co ntext of a clinical trial 
Article 36 
Electronic database for safety reporting 
The European Medicines Agency established by Regulation (EC) No  726/2004 (hereinafter, 
the "Agency") shall set up and maintain an elec tronic database for the reporting provided for 
in Articles 38 and 39.  
EN 50   EN Article 37 
Reporting of adverse events and serious adverse events by the investigator to the sponsor 
1. The investigator shall report to the sponsor adverse events or laboratory 
abnormalities identified in the protocol as  critical to the safety evaluation in 
accordance with the reporting requirements a nd within the time periods specified in 
the protocol. 
2. The investigator shall immediately repor t serious adverse events to the sponsor 
unless the protocol provides, for certain a dverse events, that no reporting is required. 
The investigator shall record all seri ous adverse events. Where necessary, the 
investigator shall send a fo llow-up report to the sponsor. 
3. The sponsor shall keep detailed records of  all adverse events re ported to it by the 
investigator. 
Article 38 
Reporting of suspected unexpected serious adve rse reactions by the sponsor to the Agency 
1. The sponsor shall report electronically and without delay to the electronic database 
referred to in Article 36 all relevant info rmation about suspected unexpected serious 
adverse reactions to investigational medi cinal products insofar as the suspected 
unexpected serious adverse r eaction occurred in  a clinical tria l conducted by the 
sponsor, or occurred in a clinical  trial related to the sponsor.  
2. The time period for reporting shall take acco unt of the severity  of the reaction. 
Where necessary to ensure timely reportin g, the sponsor may submit an initial 
incomplete report followed up by a complete report. 
3. Where a sponsor, due to a lack of resources , does not have the possibility to report to 
the electronic database referred to in Ar ticle 36, it may report to the Member State 
where the suspected unexpected serious adverse reaction occurred. That Member State shall report the suspected unexpected  serious adverse reaction in accordance 
with paragraph 1. 
Article 39 
Annual reporting by the sponsor to the Agency 
1. Regarding non-authorised investigational medicinal products other than placebo, and 
authorised investigational medicinal products which, according to the protocol, are not used in accordance with the terms of the marketing authorisation, the sponsor 
shall submit annually by electronic means to the Agency a report on the safety of 
each investigational medicinal product used in a clinical trial for which it is the 
sponsor. 
2. The obligation referred to in paragraph 1 starts with the first authorisation of a 
clinical trial in accordance with this Regul ation. It ends with the end of the last 
clinical trial conducted by the sponsor w ith the investigationa l medicinal product.  
EN 51   EN Article 40 
Assessment by Member States 
1. The Agency shall, by electronic means, forward to the relevant Member States the 
information reported in accordance with Article 38 and 39 
2. Member States shall cooperate in asse ssing the information reported in accordance 
with Articles 38 and 39. 
Article 41 
Annual reporting by the sponsor to  the marketing authorisation holder 
1. Regarding authorised medicinal products which, according to the protocol, are used 
in accordance with the terms of the marketing authorisati on, the sponsor shall inform 
annually the marketing aut horisation holder of all su spected serious adverse 
reactions. 
2. The obligation referred to in paragraph 1 starts with the first authorisation of a 
clinical trial in accordance with this Regula tion. It ends with the end of the clinical 
trial. 
Article 42 
Technical aspects 
Technical aspects for safety reporting in acco rdance with Articles 37 to 41 are contained in 
Annex III. The Commission shall be empowered to  adopt delegated acts in accordance with 
Article 85 in order to amend Annex III for any of the following purposes: 
– ensuring a high level of protection of subjects; 
– improving the information on the safety of medicinal products; 
– adapting technical requirement s to technical progress; 
– setting up or modifying detailed rules on cooperation on the assessment of the 
information reported in accordance with Articles 38 and 39; 
– taking account of global regulatory developm ents in the field of clinical trials. 
Article 43 
Reporting with regard to auxil iary medicinal products 
Safety reporting with regard to auxiliary medi cinal products shall be made in accordance with 
Chapter 3 of Directive 2001/83/EC.   
EN 52   EN Chapter VIII 
Conduct of the trial, supervision by the sponsor, training and 
experience, auxiliary medicinal products 
Article 44 
Compliance with the protocol  and good clinical practice 
A clinical trial shall be conducte d in accordance with the protocol. 
Without prejudice to Union legislation and speci fic guidelines of the Commission the sponsor 
and the investigator, when draw ing up the protocol and when a pplying this Regulation and the 
protocol, shall take due account of the quality standards set by the detailed international 
guidelines on good clinical practice of the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
The Commission shall make the detailed inte rnational guidelines on good clinical practice 
referred to in the second pa ragraph publicly available. 
Article 45 
Monitoring 
The sponsor shall adequately monitor the conduct of  a clinical trial. The extent and nature of 
the monitoring shall be determined by the sponsor  on the basis of all characteristics of the 
clinical trial, including the following characteristics: 
(a) whether the clinical trial is a low-intervention clinical trial; 
(b) the objective and methodology of the clinical trial; 
(c) the degree of deviation of the interven tion from normal clinical practice. 
Article 46 
Suitability of individuals involved  in conducting the clinical trial 
The investigator shall be a medical doctor as defined in national law, or a person following a 
profession which is recognised in the Memb er State concerned as qualifying for an 
investigator because of the necessary scientific  knowledge and experience in patient care.  
Other individuals involved in conducting a clinical trial shall be suitably qualified by 
education, training and experien ce to perform their tasks. 
Article 47 
Suitability of trial sites 
The facilities where the clin ical trial is to be conducted shall be suitable for the clinical trial.  
EN 53   EN Article 48 
Tracking, storing, destruction and return of medicinal products 
1. Investigational medicinal pr oducts shall be traceable, stor ed, destroyed and returned 
as appropriate and proportionate to ensure  subject safety and the reliability and 
robustness of the data generated in the clin ical trial, taking into account whether the 
investigational medicinal product is authoris ed, and whether the cl inical trial is a 
low-intervention clinical trial. 
The first subparagraph shall also apply to  unauthorised auxiliary medicinal products. 
2. The relevant information regarding the trace ability, storage, destruction and return of 
medicinal products referred to in paragraph 1 shall be contained in the application 
dossier. 
Article 49  
Reporting of serious breaches  
1. Where the sponsor is aware, with respect to a c linical trial for which it is a sponsor, 
of a serious breach of this Re gulation or of the version of the protocol applicable at 
the time of the breach, it shall notify the Member States concerned, through the EU 
portal, of that breach within seven da ys of becoming aware of that breach. 
2. For the purposes of this Article, a ‘serious  breach’ means a breach likely to affect to 
a significant degree the safety and rights of the subjects or the reliability and robustness of the data genera ted in the clinical trial. 
Article 50 
Other reporting obligations re levant for subject safety 
1. The sponsor shall notify the Member St ates concerned through the EU portal and 
without undue delay, of all unexpected events  which affect the benefit-risk balance 
of the clinical trial, but are not suspected unexpected serious adverse reactions as 
referred to in Article 38. 
2. The sponsor shall submit to the Member States concerned, through the EU portal, all 
inspection reports of third country authori ties concerning a clinical trial conducted by 
that sponsor. 
Article 51 
Urgent safety measures 
1. Where an unexpected event is likely to seri ously affect the benef it-risk balance, the 
sponsor and the investigator sh all take appropriate urgent safety measures to protect 
the subjects. 
2. The sponsor shall without delay inform the Member States concerned, through the 
EU portal, of the event and the measures taken. 
3. This Article is without prej udice to Chapters II and VII.  
EN 54   EN Article 52 
Investigator’s brochure 
1. The sponsor shall provide the investigat or with the inves tigator’s brochure. 
2. The investigator’s brochure shall contain all clinical and non-clinical data on the 
investigational medicinal products re levant to the clinical trial. 
3. The investigator’s brochure shall be upda ted where new safety information becomes 
available, and at least once per year. 
Article 53 
Recording, processing, handling an d storage of information 
1. All clinical trial information shall be reco rded, processed, handled, and stored in such 
a way that it can be accurately reporte d, interpreted and verified while the 
confidentiality of records a nd the personal data of the s ubjects remain protected in 
accordance with the applicable legi slation on personal data protection. 
2. Appropriate technical and organisational m easures shall be implemented to protect 
information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, altera tion, or destruction or acci dental loss, in particular 
where the processing involves the transmission over a network. 
Article 54 
Clinical trial master file 
The sponsor and the investigator shall keep a clinical trial master file. 
The content of the clinic al trial master file sh all allow verification of the conduct of a clinical 
trial, taking account of all characteristics of the clinical trial, including whether the clinical 
trial is a low-intervention clinical trial. 
The clinical trial master file ke pt by the investigator and that kept by the sponsor may have a 
different content if this is justified by the di fferent nature of the responsibilities of the 
investigator and the sponsor.  
Article 55 
Archiving of the clinical trial master file 
Unless other Union legislation requires archiving for a longe r period, the sponsor and the 
investigator shall archive the content of the clinical trial master file for at least five years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national legislation. 
The content of the clinical trial master file shal l be archived in a way that ensures that it is 
readily available, upon request, to the competent authorities. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. 
The new owner shall assume the responsibilities set out in this Article.  
EN 55   EN The sponsor shall appoint individuals within it s organisation to be re sponsible for archives. 
Access to archives shall be re stricted to those individuals. 
The media used to archive the content of the clin ical trial master file shall be such that the 
content remains complete and legible through out the time period refe rred to in the first 
paragraph. 
Any alteration to the content of the clinical  trial master file shall be traceable. 
Article 56 
Auxiliary medicinal products  
1. Only authorised auxiliary medicinal pr oducts may be used in a clinical trial.  
2. Paragraph 1 shall not apply where no au thorised auxiliary medicinal product is 
available in the Union or where the sponsor cannot reasonably be expected to use an 
authorised auxiliary medicinal product. A justification to this effect shall be included 
in the protocol. 
Chapter IX 
Manufacturing and import of inve stigational medicinal products 
and auxiliary medicinal products  
Article 57 
Scope 
Notwithstanding Article 1, this Chapter sha ll apply to the manufacture and import of 
investigational medicinal products and auxiliary medicinal products. 
Article 58 
Manufacturing and import authorisation 
1. The manufacturing and import of investig ational medicinal products in the Union 
shall be subject to the hold ing of an authorisation.  
2. In order to obtain the authorisation refe rred to in paragraph 1, the applicant shall 
meet the following requirements: 
(a) it shall have at its disposal, for manufact ure or import, suitable and sufficient 
premises, technical equipment and cont rol facilities complying with the 
requirements set out in this Regulation; 
(b) it shall have permanently and continuously  at its disposal the services of a 
person who fulfils the conditi ons set out in Article 49 (2) and (3) of Directive 
2001/83/EC (hereinafter ‘qualified person’). 
3. The applicant shall specify, in the re quest for authorisation, the types and 
pharmaceutical forms of the investigati onal medicinal product manufactured or  
EN 56   EN imported, the manufacturing or import opera tions, the manufacturing process where 
relevant, the site where the investig ational medicinal products are to be 
manufactured, and detailed informa tion concerning the qualified person. 
4. Articles 42 to 46(e) of Directive 2001/83/ EC shall apply to the manufacturing and 
importation authorisation re ferred to in paragraph 1. 
5. Paragraph 1 shall not apply to any of the following processes: 
(a) re-labelling, re-packaging or reconstitution prior to use or packaging, where 
those processes are carried out in hosp itals, health centres or clinics, by 
pharmacists or other persons legally aut horised in the Member State to carry 
out such processes, and if the investigational medicinal products are intended to be used exclusively by those institutions; 
(b) the manufacture or import of radi opharmaceuticals used as diagnostic 
investigational medicinal products where those proce sses are carr ied out in 
hospitals, health centres or clinics, by pharmacists or other persons legally 
authorised in the Member State concerne d to carry out such processes, and if 
the investigational medicinal products are intended to be used exclusively in 
those institutions;  
(c) the preparation of medicinal products refe rred to in Article 3(1) and (2) of 
Directive 2001/83/EC. 
6. Member States shall make the processes se t out in paragraph 5 s ubject to appropriate 
and proportionate requirements to ensure s ubject safety and reliability and robustness 
of the data generated in the clinical trial.  They shall subject the processes to regular 
inspections.  
Article 59 
Responsibilities of the qualified person 
1. The qualified person shall ensure that each batch of inves tigational medicinal 
products manufactured in or imported into the Union complies with the requirements 
set out in Article 60 and shall certify that those requirements are fulfilled. 
2. The certification referred to in paragraph 1 shall be made available by the sponsor at 
the request of the Member State concerned. 
Article 60 
Manufacturing and import 
1. Investigational medicinal products shall be manufactured in applying manufacturing 
practice which ensures the qual ity of such medicinal produc ts in order to safeguard 
subject safety and the reliab ility and robustness of clinic al data generated in the 
clinical trial (hereinafter 'good manufacturing practice' ). The Commission shall be 
empowered to adopt delegated acts in accord ance with Article 85 in order to specify 
the detailed requirements of good manufactur ing practice for ensu ring the quality of  
EN 57   EN investigational medicinal products, taking accoun t of subject safety or data reliability 
and robustness, technical progress an d global regulatory developments 
2. Paragraph 1 shall not apply to the pr ocesses referred to in Article 58(5). 
3. Investigational medicinal products imported into the Union shall be manufactured by 
applying quality standards at least equivalent to those laid down on the basis of this 
Regulation. 
Article 61 
Modification of authorised inves tigational medicinal products  
Articles 58, 59 and 60 shall apply to authorised  investigational medicinal products only as 
regards any modification of such products not covered by a marke ting authorisation. 
Article 62 
Manufacturing of auxiliary medicinal products 
Where the auxiliary medicinal product is not au thorised, and where an authorised auxiliary 
medicinal product is modified while this modification is not covered by a marketing 
authorisation, it shall be ma nufactured by applying the necessary standards to ensure 
appropriate quality. 
Chapter X 
Labelling 
Article 63 
Unauthorised investigational and unauthoris ed auxiliary medicinal products 
1. The following information shall appear on the outer packaging and on the immediate 
packaging of unauthorised investigationa l medicinal products and unauthorised 
auxiliary medicinal products: 
(a) Information to identify contact persons or persons involved in the clinical trial; 
(b) Information to identify the clinical trial; 
(c) Information to identify the medicinal product; 
(d) Information related to the us e of the medicinal product. 
2. The information to appear on the outer packaging and immediate packaging shall 
ensure subject safety and reliability and robustness of the data generated in the 
clinical trial, while taking account of the design of the tr ial, whether the products are 
investigational or auxiliary medicinal pr oduct, and whether they are products with 
particular characteristics.   
EN 58   EN A list of information appearing on the out er packaging and immediate packaging is 
set out in Annex IV.  
Article 64 
Authorised investigational and authori sed auxiliary medicinal products 
1. Authorised investigational medicinal pr oducts and authorised auxiliary medicinal 
products shall be labelled  
(a) in accordance with Article 63(1); or 
(b) in accordance with Title V of Directive 2001/83/EC. 
2. Notwithstanding paragraph 1(b), where the sp ecific circumstances of a clinical trial 
so require in order to ensure subject safety  or the reliability and robustness of data 
generated in a clinical trial, additional part iculars relating to the identification of the 
trial and of the contact person shall appear  on the outer packaging and the immediate 
packaging of authorised inve stigational medicinal products . A list of these additional 
particulars appearing on the outer packagi ng and immediate packaging is set out in 
Annex IV.  
Article 65 
Radiopharmaceutical used as investigational medicinal product fo r a medical diagnosis 
Articles 63 and 64 shall not apply to radiopharm aceuticals used as investigational medicinal 
product for a medical diagnosis. 
The products referred to in the first paragraph shall be labelled appropriately in order to 
ensure subject safety and the reliability and robus tness of data generated in the clinical trial. 
Article 66 
Language 
The language of the information on the label shall be determined by the Member State 
concerned. The medicinal product may be labelled in several languages. 
Article 67 
Delegated act 
The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in 
order to amend Annex IV to ensure subject safe ty and the reliability and robustness of data 
generated in a clinical trial or to  take account of technical progress.  
EN 59   EN Chapter XI 
Sponsor and investigator 
Article 68 
Sponsor 
A clinical trial may have one or several sponsors. 
Any sponsor may delegate any or all of its tasks to an individu al, a company, an institution or 
an organisation. Such delegati on shall be without prejudice to the responsibility of the 
sponsor. 
The investigator and the sponsor may be the same person. 
Article 69 
Co-sponsorship 
1. Where a clinical trial has more than one sponsor, all sponsors shall be subject to the 
responsibilities of a spons or under this Regulation, unless the sponsors decide 
otherwise in a contract setting out thei r respective responsib ilities. Where the 
contract does not specify to  which sponsor a given respons ibility is attributed, that 
responsibility shall lie  with all sponsors. 
2. By way of derogation from paragraph 1, all sponsors shall be responsible for 
establishing one sponsor responsible for each of the following: 
(a) compliance with the obligations of a sponsor in the authorisation procedures 
set out in Chapters II and III; 
(b) providing responses to all questions from subjects, investigators or any 
Member State concerned rega rding the clinical trial;  
(c) implementing measures taken in accordance with Article 74. 
Article 70 
Contact person of the sponsor in the Union 
Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure 
that a contact person is established in the Un ion. That contact person shall be the addressee 
for all communications with the sponsor provided fo r in this Regulation. Any communication 
to that contact person shall be consid ered as communication to the sponsor. 
Article 71 
Liability 
This Chapter shall not affect th e civil and criminal liability of  the sponsor, investigator, or 
persons to whom the sponsor has delegated tasks.  
EN 60   EN Chapter XII 
Damage compensation, insurance and national indemnification 
mechanism 
Article 72 
Damage compensation 
For clinical trials other than low-intervention clinical trials, the sponsor shall ensure that 
compensation in accordance with the applicable  laws on liability of the sponsor and the 
investigator is provided for any damage suffered by the subject . This damage compensation 
shall be provided independently of the financia l capacity of the sponsor  and the investigator. 
Article 73 
National indemnification mechanism 
1. Member States shall provide for a national indemnification mechanism for 
compensating damage as referred to in Article 72. 
2. The sponsor shall be deemed to comply with Article 72 where it makes use of the 
national indemnification mechanism in the Member State concerned. 
3. The use of the national indemnification mech anism shall be free of charge where, for 
objective reasons, the clinical trial was not intended, at the time of submission of the application for authorisation of that clinical  trial, to be used for obtaining a marketing 
authorisation for a medicinal product. 
For all other clinical trials, the use of the national indemnification mechanism may 
be subject to a fee. Member States shall establish that fee on a not-for-profit basis, 
taking into account the risk of the clini cal trial, the potential damage, and the 
likelihood of the damage. 
Chapter XIII 
Supervision by Member States, Union inspections and controls 
Article 74 
Corrective measures to be taken by Member States 
1. Where a Member State concerned has obj ective grounds for cons idering that the 
requirements set out in this Regulation are no longer met, it may take the following 
measures: 
(a) it may terminate early the clinical trial; (b) it may suspend the clinical trial; (c) it may modify any aspect of the clinical trial.  
EN 61   EN 2. The measures referred to in paragraph 1 shall be communicated to all Member States 
concerned through the EU portal. 
Article 75 
Member State inspections 
1. Member States shall appoint inspectors to supervise compliance with this Regulation. 
They shall ensure that those inspectors are adequately qualified and trained. 
2. Inspections shall be conducted under the responsibility of the Member State where 
the inspection takes place. 
3. Where a Member State concerned intends to carry out an inspection with regard to 
one or several clinical tria ls which are conducted in mo re than one Member State 
concerned, it shall notify its  intention to the other Member States concerned, the 
Commission and the Agency, through the EU portal, and shall inform them of its 
findings after the inspection. 
4. The Agency shall coordinate cooperati on on inspections between Member States, 
inspections conducted by Member States in third countries , and inspections 
conducted in the framework of a mark eting authorisati on application under 
Regulation (EC) No 726/2004. 
5. Following an inspection, the Member State under whose responsibility the inspection 
has been conducted shall draw up an insp ection report. That Member State shall 
make the inspection report available to the sponsor of the relevant clinical trial and 
shall submit the inspection report through the EU portal to the EU database.  
When making the inspection report available to the sponsor, the Member State 
referred to in the first subparagraph shall ensure that confidentiality is protected. 
6. The Commission shall specify  the modalities for the inspection procedures by the 
way of implementing acts. Those implementi ng acts shall be adopt ed in accordance 
with the examination procedure referred to in Article 84(2). 
Article 76 
Union controls and Union inspections 
1. The Commission may conduct cont rols in order to verify 
(a) whether Member States correctly supe rvise compliance with this Regulation; 
(b) whether the regulatory system applicable  to clinical trials conducted outside the 
Union ensures that point 8 of Annex I to Directive 2001/8 3/EC is complied 
with; 
(c) whether the regulatory system applicable  to clinical trials conducted outside the 
Union ensures that Article 25(3) of  this Regulation is complied with. 
2. The Commission may conduct inspecti ons where it considers necessary.  
EN 62   EN Chapter XIV 
IT Infrastructure 
Article 77 
EU portal 
The Commission shall set up and maintain a portal  at Union level as a single entry point for 
the submission of data and information relating to clinical trials in accordance with this 
Regulation. 
Data and information submitted through the EU portal shall be stored in the EU database 
referred to in Article 78. 
Article 78 
EU database 
1. The Commission shall set up and maintain a database at Union level (hereinafter, the 
‘EU database’). The Commission shall be c onsidered controller of the database. 
The EU database shall contain the data a nd information submitted in accordance with 
this Regulation.  
2. The EU database shall be established to enable the co-operation between the 
competent authorities of the Me mber States to the extent that it is necessary for the 
application of this Regulation and to search for specific clinical trials. It shall also enable sponsors to refer to previous subm issions of an application for authorisation 
of a clinical trial or a substantial modification. 
3. The EU database shall be publicly accessible unless, for all or parts of the data and 
information contained therein, confidential ity is justified on any of the following 
grounds: 
– protecting personal data in accordance  with Regulation (EC) No 45/2001; 
– protecting commercially c onfidential information; 
– ensuring effective supervision of the conduct of a clinical trial by Member 
States. 
4. The EU database shall contain personal data only insofar as this is necessary for the 
purposes of paragraph 2. 
5. No personal data of subjects  shall be publicly accessible. 
6. The sponsor shall permanently update in the EU database information on any 
changes to the clinical trials which are not  substantial modificati ons but are relevant 
for the supervision of the clinical trial by the Member States.  
EN 63   EN 7. The Commission and Member States sha ll ensure that the data subject may 
effectively exercise his or he r rights to information, to acce ss, to rectify and to object 
in accordance with Regulation (EC) No  45/2001 and national data protection 
legislation implementing Direc tive 95/46/EC respectively. They shall ensure that the 
data subject may effectively ex ercise the right of access to da ta relating to him or her, 
and the right to have inaccurate or incomple te data corrected and erased. Within their 
respective responsibilities, the Commission and Member States shall ensure that 
inaccurate and unlawfully processed data  is deleted, in accordance with the 
applicable legislation. Corrections and de letions shall be carried out as soon as 
possible, but no later than within 60 days af ter a request is made by a data subject. 
Chapter XV 
Cooperation between Member States 
Article 79 
National contact points 
1. Each Member State shall designate one natio nal contact point in order to facilitate 
the functioning of the procedures set out in Chapters II and III. 
2. Each Member State shall communicate th e contact point to the Commission. The 
Commission shall publish a list of the contact points.  
Article 80 
Support by the Commission 
The Commission shall support the functioning of th e cooperation of the Member States in the 
framework of the authorisation procedures referr ed to in Chapters II and III of this Regulation 
and the functioning of th e cooperation referred to in Article 40(2).  
Article 81 
Clinical Trials Coordination and Advisory Group 
1. A Clinical Trials Coordination and A dvisory Group (CTAG), composed of the 
national contact points referred to in Article 79 is hereby established. 
2. The CTAG shall have the following tasks: 
(a) support the exchange of informati on between the Member States and the 
Commission on the experience acquired with  regard to the implementation of 
this Regulation; 
(b) assist the Commission in providing for the support referred to in Article 80; 
3. The CTAG shall be chaired by a representative of the Commission. 4. The CTAG shall meet at regular interval s and whenever the situation requires, on a 
request from the Commission or a Member State.  
EN 64   EN 5. The secretariat shall be  provided by the Commission 
Chapter XVI 
Fees 
Article 82 
General principle 
This Regulation shall be without prejudice to th e possibility for Member States to levy a fee 
for the activities set out in this Regulation, pr ovided that the level of  the fee is set in a 
transparent manner and on the basis of cost recovery principles. 
Article 83 
One fee per activity per Member State 
A Member State shall not require, for an assessment as referred to in Chapters II and III, 
multiple payments to different bodies involved in this assessment. 
Chapter XVII 
Implementing acts and Delegated acts  
Article 84 
Committee 
1. The Commission shall be assisted by th e Standing Committee on Medicinal Products 
for Human Use established by Directive 2001/83/EC. That committee shall be a committee within the meaning of Regulation (EU) No 182/2011. 
2. Where reference is made to this para graph, Article 5 of Regulation (EU) No 
182/2011 shall apply. 
Where the opinion of the committee is to be  obtained by writte n procedure, that 
procedure shall be terminated without re sult when, within the time-limit for delivery 
of the opinion, the chair of the committee so decided or a simple majority of 
committee members so request. 
Article 85 
Exercise of the delegation 
1. The power to adopt delegated acts is conferred on the Commission subject to the 
conditions laid down in  this Article.  
2. The delegation of power refe rred to in Articles 27, 42, 60 and 67 shall be conferred 
on the Commission for an indeterminate period  of time from the date of entry into 
force of this Regulation.  
EN 65   EN 3. The delegation of power referred to in  Articles 27, 42, 60 and 67 may be revoked at 
any time by the European Parliament or by the Council. A decision of revocation shall put an end to the delegation of the power  specified in that decision. It shall take 
effect the day following the publication of th e decision in the Official Journal of the 
European Union or at a later date specified therein. It shall not affect the validity of 
any delegated acts already in force. 
4. As soon as it adopts a delegated act, the Commission shall notify it simultaneously to 
the European Parliament and to the Council. 
5. A delegated act adopted pursuant to Artic les 27, 42, 60 and 67 shal l enter into force 
only if no objection has been expressed eith er by the European Parliament or the 
Council within a period of 2 months of no tification of that ac t to the European 
Parliament and the Council or if, before the expiry of that period, the European 
Parliament and the Council have both informed the Commission that they will not object. That period shall be extended by 2 m onths at the initiative of the European 
Parliament or the Council. 
Chapter XVIII 
Miscellaneous provisions 
Article 86 
Medicinal products containing, consis ting of or derived from cells 
This Regulation shall not affect the applic ation of national legislation prohibiting or 
restricting the use of any specific type of human or animal cells, or the sale, supply or use of 
medicinal products containing, consisting of or derived from those cells, on grounds not dealt 
with in this Regulation. The Member Stat es shall communicate the national legislation 
concerned to the Commission. 
Article 87 
Relation with other legislation 
This Regulation shall be without prej udice to, Council Dire ctive 97/43/Euratom24, Council 
Directive 96/29/Euratom25, Directive 2001/18/EC of the European Parliament and of the 
Council26, and Directive 2009/41/EC of the Eur opean Parliament and of the Council.27 
                                                 
24 OJ L 180, 9.7.1997, p. 22.  
25 OJ L 159, 29.6.1996, p. 1. 
26 OJ L 106, 17.4.2001, p. 1. 
27 OJ L 125, 21.5.2009, p. 75.  
EN 66   EN Article 88 
Investigational medicinal products free of charge for the subject 
Without prejudice to the Member States’ compet ence for the definition of their health policy 
and for the organisation and delivery of heal th services and medical care, the costs for 
investigational medicinal products sh all not be borne by the subject.  
Article 89 
Data Protection 
1. Member States shall apply Directive 95/ 46/EC to the processing of personal data 
carried out in the Member States  pursuant to this Regulation.  
2. Regulation (EC) No 45/2001 shall apply to the processing of personal data carried 
out by the Commission and the European Medicines Agency pursuant to this 
Regulation. 
Article 90 
Civil and criminal liability 
This Regulation is without prej udice to national and Union ru les on the civil and criminal 
liability of the sponsor or the investigator . 
Chapter XIX 
Final provisions 
Article 91 
Repeal 
1. Directive 2001/20/EC is  repealed as of [ please set a specific date - two years after 
publication of this Regulation ]. 
2. By way of derogation from the paragraph 1, where the request for authorisation of a 
clinical trial has been submitted before the date provided for in Article 92(2) [application date] pursuant to Directive 2001/20/EC, that clin ical trial shall continue 
to be governed by that Directive until [ please set a specific date – five years after 
publication of this Regulation ]. 
3. References to Directive 2001/20/EC shall be construed as references to this 
Regulation and shall be read in accordan ce with the correlation table laid down in 
Annex V. 
Article 92 
Transitional provision 
By way of derogation from Article 91(1), where the request for auth orisation of a clinical trial 
is submitted between [ please set a specific date - two years from the publication of this  
EN 67   EN Regulation ] and [ please set a specific date - three years after publication ] that clinical trial 
may be started in accordance with Articles 6,  7 and 9 of Directive 2001/2 0/EC. That clinical 
trial shall continue to be gove rned by that Di rective until [ please set a specific date – five 
years after publication of this Regulation ]. 
Article 93 
Entry into force 
This Regulation shall enter into force on the twentieth day following that of its publication in 
the Official Journal of  the European Union. 
It shall apply as from [ please set a specific date - two years after its publication ]. 
This Regulation shall be binding in  its entirety and directly applicable in all Member States. 
Done at Brussels,  
For the European Parliament For the Council 
The President The President    
EN 68   EN ANNEX I  
Application dossier for initial application  
1. I NTRODUCTION AND GENERAL PRINCIPLES  
1. The sponsor shall, where appropriate, re fer to previous applications. If these 
applications have been submitted by another sponsor, a written agreement from that sponsor shall be submitted. 
2. The application shall be signed by the s ponsor. This signature confirms that the 
sponsor is satisfied that: 
• the information provided is complete; 
• the attached documents contain an accurate account of the information 
available; 
• the clinical tria l will be conducted in accord ance with the protocol. 
3. The application dossier for an application referred to in Article 11 shall be limited to 
sections 2 to 10 of this Annex. 
4. Without prejudice to Article  26, the application dossier fo r an application referred to 
in Article 14 shall be limited to sections 11 to 17 of this Annex. 
2. C
OVER LETTER  
5. The cover letter shall draw attenti on to peculiarities of the trial. 
6. However, in the cover letter it is not n ecessary to reproduce information already 
contained in the EU application fo rm, with the following exceptions: 
• specific features of the trial population, such as subjects not able to give 
informed consent or minors; 
• whether the trial involves the first administration of a new active substance to 
humans; 
• whether scientific advice relating to th e trial or investigational medicinal 
product has been given by the Agency, th e national competent authority of a 
Member State or third country; and 
• whether the trial is part or is intended to be part of a Paediatric Investigation 
Plan (PIP) as referred to in Title II, Chapter 3, of Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 
2006 on medicinal products for paediatric use28 (if the Agency has already 
                                                 
28 OJ L 378, 27.11.2006, p. 1.  
EN 69   EN issued a decision on the PIP, the cover letter contains the link to the decision of 
the Agency on its website); 
• whether investigational medicinal products  or auxiliary medicinal products are 
a narcotic and psychotropic; 
• whether the sponsor has obtained an or phan designation for the investigational 
medicinal product or the disease. 
7. The cover letter shall indicat e where the relevant information is contained in the 
application dossier. 
8. The cover letter shall indicate where in th e application dossier the reference safety 
information is contained for assessing wh ether an adverse reac tion is a suspected 
unexpected serious adverse reaction. 
9. In the case of a resubmission, the cove r letter shall highlight the changes as 
compared to the previous submission. 
3. EU  APPLICATION FORM  
10. The EU application form, duly filled in. 
4. P ROTOCOL  
11. The protocol shall describe the objective, design, methodology, statistical 
considerations and organisation of a trial. 
12. The protocol shall be identified by the title, the sponsor’s protocol code number 
specific for all versions of it (if available), the date and number of the version, to be 
updated when it is amended, and a shor t title or name assigned to it. 
13. In particular, the protocol shall include: 
• a clear and unambiguous defini tion of the end of the clin ical trial in question (in 
most cases this will be the date of the last visit of the last subject; any exceptions to this are justified in the protocol);  
• a discussion of the relevance of the clinical  trial and its design to allow assessment 
in accordance with Article 6; 
• an evaluation of the anticip ated benefits and risks to allow assessment in 
accordance with Article 6; 
• inclusion and excl usion criteria; 
• a justification for including subjects who are incapable of giving informed consent 
or other special populations, such as minors;  
• if elderly persons or women are excluded fr om the clinical trial, an explanation 
and justification for these exclusion criteria;  
EN 70   EN • a detailed description of the recruitment and informed-consent procedure, 
especially when subjects are incapable of giving informed consent; 
• a summary of monitoring arrangements; 
• a description of th e publication policy; 
• a description of the arrangements for ta king care of the subjects after their 
participation in the trial has ended, where such additional care is necessary 
because of the subjects’ participation in the trial and where it differs from that 
normally expected for the medical condition in question; 
• a description of th e arrangements, if any, for tr acing, storing, destroying and 
returning the investigational medicinal product and auxiliary medicinal product in 
accordance with Article 48; 
• a description of the arrangements to comply with the applicable rules on the 
protection of personal data; in par ticular organisational and technical 
arrangements that will be implemented to  avoid unauthorised access, disclosure, 
dissemination, alteration or loss of info rmation and personal data processed; 
• a description of measures that will be implemented to ensure confidentiality of 
records and personal data of subject s concerned in clinical trials; 
• a description of measures that will be im plemented in case of data security breach 
in order to mitigate the possible adverse effects; 
• duly substantiated reasons for submission of the summary of the results of the 
clinical trials after more than one year; 
• a justification for the use of non-aut horised auxiliary medicinal products. 
14. If a clinical trial is con ducted with an active substan ce available in the European 
Union under different trade names in a numbe r of authorised medicinal products, the 
protocol may define the treatment in term s of the active substance or Anatomical 
Therapeutic Chemical (ATC) code (level 3-5)  only and not specify the trade name of 
each product. 
15. With regard to the notification of adve rse events, the protocol shall identify 
• adverse events or laboratory anomalies that  are critical to safety evaluations and 
are to be reported to the sponsor; and 
• serious adverse events which do not require reporting by the investigator. 
16. Issues regarding labelling and the unbli nding of investigational medicinal products 
shall be addressed in the protocol, where necessary. 
17. The protocol shall be accompanied by a synopsis of the protocol.  
EN 71   EN 5. I NVESTIGATOR ’S BROCHURE (IB) 
18. The purpose of the IB is to provide the inve stigators and others involved in the trial 
with information to facilitate their unders tanding of the rationale for, and their 
compliance with, key features of th e protocol, such as the dose, dose 
frequency/interval, methods of administ ration, and safety monitoring procedures. 
19. The information in the IB shall be presented in a concise, simple, objective, balanced 
and non-promotional form that enables a clin ician or investigator  to understand it and 
make an unbiased risk-benefit assessment of the appropriateness of the proposed 
clinical trial. It shall be prepared from all available information and evidence that 
supports the rationale for the proposed c linical trial and the safe use of the 
investigational medicinal pr oduct in the trial and be pr esented in the form of 
summaries.  
20. If the investigational medici nal product is authorised, and is used according to the 
terms of the marketing authorisa tion, the approved summary of product 
characteristics (SmPC) shall be the IB. If the conditions of use in the clinical trial 
differ from those authorised, the SmPC sh all be supplemented with a summary of 
relevant non-clinical and c linical data that support the use of th e investigational 
medicinal product in the clini cal trial. Where the investig ational medicinal product is 
identified in the protocol only by its active substance, th e sponsor shall select one 
SmPC as equivalent to the IB for all me dicinal products that contain that active 
substance and are used at any clinical trial site. 
21. For a multinational trial where the medici nal product to be used in each Member 
State is the one authorised at national level, and the SmPC varies among Member 
States, the sponsor shall choos e one SmPC for the whole cl inical trial. This SmPC 
shall be the one best suited  to ensure patient safety. 
22. If the IB is not a SmPC, it shall contai n a clearly identifiabl e section determining 
what adverse reactions are to be considered  as expected adverse reactions, including 
information on the frequency and nature of the adverse reactions ('reference safety 
information'). 
6. D OCUMENTATION RELATING TO COMPLI ANCE WITH GOOD MANUFACTURING 
PRACTICE (GMP)  FOR THE INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
23. As regards documentation relating to GMP compliance, the following shall apply. 
24. In the following cases, no documentation needs to be submitted: 
• the IMP is authorised, is not modified, and is manufactured in the EU; or 
• the IMP is not manufactured in the EU, but  is authorised and is not modified. 
25. If the IMP is not au thorised, and does not have a mark eting authorisation from a third 
country that is party to the Internationa l Conference on Harm onisation of Technical 
Requirements for Registration of Pharmaceu ticals for Human Use (ICH), and is not 
manufactured in the EU, the following documentation shall be submitted:  
EN 72   EN • a copy of the importation authorisation as referred to in Article 58; and 
• certification by the qualified person in the EU that the manufacturing complies 
with GMP at least equivalent to the GMP in the EU, unless there are specific 
arrangements provided for in mutual recognition agreements between the EU and third countries. 
26. In all other cases, a copy of the manufactur ing/importing authorisat ion as referred to 
in Article 58 shall be submitted. 
27. For IMPs the manufacturing or importa tion of which is no t subject to an 
authorisation in accordance with Article 58, documentation to demonstrate compliance with the requirements referred to in Article 58(6) shall be submitted. 
7. IMP
 DOSSIER (IMPD) 
28. The IMPD shall give information on th e quality of any IMP, the manufacture and 
control of the IMP, and data from non-cl inical studies and from its clinical use. 
7.1.1. Data relating to the IMP 
7.1.1.1. Introduction 
29. Regarding data, the IMPD may be repla ced by other documentation which may be 
submitted alone or with a simplified IMPD. Th e details of this ‘simplified IMPD’ are 
set out in section 7.1.2. 
30. The IMPD shall be prefaced with a detailed table of contents and a glossary of terms. 
31. The information in the IMPD shall be c oncise. The IMPD must  not be unnecessarily 
voluminous. It is preferable to present data in tabular  form accompanied by a brief 
narrative highlighting the main salient points. 
7.1.1.2. Quality data 32. Quality data shall be subm itted in a logical structure. 
7.1.1.3. Non-clinical pharmacology and toxicology data 33. The IMPD shall also contain summar ies of non-clinical  pharmacology and 
toxicology data for any IMP used  in the clinical trial. It shall contain a reference list 
of studies conducted and appropr iate literature references. Wh erever appropriate, it is 
preferable to present data in tabular form accompanied by a brief narrative highlighting the main salient points. The summaries of the studies conducted shall allow an assessment of the adequacy of  the study and whether the study has been 
conducted according to an acceptable protocol. 
34. Non-clinical pharmacology and toxicology data shall be submitted in a logical 
structure, such as the headings of the current version of Module 4 of the Common 
Technical Document , or the eCTD format.  
EN 73   EN 35. The IMPD shall provide a cr itical analysis of  the data, including  justification for 
omissions of data, and an assessment of the safety of the product in the context of the 
proposed clinical trial rather than a mere  factual summary of the studies conducted. 
36. The IMPD shall contain a statement of  the good laboratory practice status or 
equivalent standards, as re ferred to in Article 25(3). 
37. The test material used in toxicity studies sh all be representative of that of the clinical 
trial use in terms of qualitative and quantita tive impurity profiles. The preparation of 
the test material shall be subject to the co ntrols necessary to ensure this and thus 
support the validity of the study. 
7.1.1.4. Previous clinical tria l and human experience data  
38. Clinical trial and human experience data shall be submitted in a logical structure, 
such as the headings of the cu rrent version of Module 5 of the Common Technical 
Document , or of the eCTD format. 
39. This section shall provide summaries of al l available data from previous clinical 
trials and human experience with the IMPs. 
40. It shall contain a statement of the GCP comp liance of the clinical trials referred to, as 
well as a reference to the public entry referred to in Article 25(4) to (6). 
7.1.1.5. Overall risk and benefit assessment 41. This section shall provide a brief integrated summary that  critically analyses the non-
clinical and clinical data in  relation to the potential risk s and benefits of the proposed 
trial unless this information is already provide d in the protocol. In the latter case, it 
shall cross-refer to the relevant section in the protocol. The text shall identify any studies that were terminated prematurely and discuss the reasons. Any evaluation of 
foreseeable risks and anticipated benef its for studies on minors or incapacitated 
adults shall take account of  the specific provisions set out in this Regulation. 
42. Where appropriate, safety margins shall be discussed in terms of relative systemic 
exposure to the IMP, preferably based on ‘a rea under the curve’ (AUC) data, or peak 
concentration (C
max) data, whichever is considered more relevant, rather than in 
terms of applied dose. The c linical relevance of any findi ngs in the non-clinical and 
clinical studies along with any recommendati ons for further monitoring of effects 
and safety in the clinical trials shall also be discussed. 
7.1.2. Simplified IMPD by referring to other documentation 
43. The applicant may refer to other documentation submitted alone or with a simplified 
IMPD. 
7.1.2.1. Possibility to refer to the IB 44. The applicant may either provide a stand-al one IMPD or cross-refer to the IB for the 
pre-clinical and clinical parts of the IMPD . In the latter case, the summaries of pre-
clinical information and clinical information shall include data, preferably in tables, providing sufficient detail to allow assesso rs to reach a decision on the potential  
EN 74   EN toxicity of the IMP and the safety of its us e in the proposed trial. If there is some 
special aspect of the pre-clinical data or clinical data that requires a detailed expert 
explanation or discussion beyond what woul d usually be included in the IB, the pre-
clinical and clinical information shal l be submitted as part of the IMPD. 
7.1.2.2. Possibility to refer to the SmPC 45. The applicant may submit the current version of the SmPC as the IMPD if the IMP is 
authorised. The exact requireme nts are detailed in Table 1. 
Table 1: Content of simplified IMPD 
Types of previous assessment  Quality data Non-clinical data Clinical data 
The IMP is authorised or has a marketin g
authorisation in an ICH country and is used i n
the trial:     
- within the conditions of the SmPC SmPC 
- outside the conditions of the SmPC SmPC If appropriate If appropriate 
- after modification (e.g. blinding)  P+A SmPC SmPC 
Another pharmaceuti cal form or strength of the
IMP is authorised or has a marketingauthorisation in an ICH country and the IMP is
supplied by the marketing authorisation holderSmPC+P+A Yes Yes 
The IMP is not authorised and has no
marketing authorisation in an ICH country bu t
the active substance is contained in a n
authorised medicinal product and    
- is supplied by the same manufacturer  SmPC+P+A Yes Yes 
- is supplied by another manufacturer  SmPC+S+P+A Yes Yes 
The IMP was subject to a previous clinical tria l
application and authorised  in the Member State
concerned and has not been modified  and    
- no new data are available since last 
amendment to the CTA Reference to previous submission 
- new data are available since last amendment 
to the CTA New data New data New data 
- is used under different conditions If appropriate If appropriate If appropriate 
(S: Data relating to the active substance; P:  Data relating to the IMP; A: Additional 
information on Facilities and Equipment, Ad ventitious Agents Safety Evaluation, Novel 
Excipients, and Solvents for Reconstitution and Diluents) 
46. If the IMP is defined in th e protocol in terms of active substance or ATC code (see 
above, section 4), the applicant may repl ace the IMPD by one representative SmPC 
for each active substance/active substa nce pertaining to  that ATC group. 
Alternatively, the applicant may provide a collated document containing information 
equivalent to that in the representative Sm PCs for each active substance that could be 
used as an IMP in the clinical trial. 
7.1.3. IMPD in cases of placebo 
47. If the IMP is a placebo, the information re quirements shall be lim ited to quality data. 
No additional documentation is required if  the placebo has the same composition as  
EN 75   EN the tested investigational medicinal product, is manufactured by the same 
manufacturer, and is not sterile. 
8. A UXILIARY MEDICINAL PRODUCT DOSSIER  
48. Without prejudice to Article 62, the documentation requirements set out in sections 6 
and 7 shall also apply also for auxiliar y medicinal products. However, where the 
auxiliary medicinal product is authorised in the Member State concerned, no 
additional information is submitted. 
9. S CIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP) 
49. If available, a copy  of the summary of scientific ad vice of the Agency or of any 
Member State or third country with regard  to the clinical trial shall be submitted. 
50. If the clinical trial is part of an agr eed PIP, a copy of the Agency’s decision on the 
agreement on the PIP, and the opinion of the Paediatric Committee, unless these 
documents are fully accessible via the internet shall be submitted. In the latter case, a link to this documentation in the cove r letter is sufficient (see section 2). 
10. C
ONTENT OF THE LABELLING OF THE IMP S 
11. R ECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED ) 
51. Unless described in the prot ocol, a separate document sh all describe in detail the 
procedures for enrolment of subjects. 
52. Where the recruitment of subjects is done  through advertisement, copies of the 
advertising material shall be submitted, including any printed materials, and audio or visual recordings. The procedures pr oposed for handling responses to the 
advertisement shall be outlined. This in cludes the planned arrangements for 
information or advice to the respondents f ound not to be suitable for inclusion in the 
trial. 
12. S
UBJECT INFORMATION AND INFORMED CONSENT PROCEDURE (INFORMATION PER 
MEMBER STATE CONCERNED ) 
53. All information to the subjects (or, where applicable, the parents or legal 
representative) before their decision to part icipate or abstain from participation shall 
be submitted together with the form for written informed consent. 
54. Description of procedures relating to info rmed consent in specific circumstances to 
be submitted: 
– in trials with minors or incapacitated subjects, the procedures to obtain 
informed consent from the parent(s) or legal representative, and the involvement of the minor or incapacitated subject  shall be described;  
EN 76   EN – if a procedure with witnessed consent is to be used, relevant information on the 
reason for using a witness, on the select ion of the witness and on the procedure 
for obtaining informed consent shall be provided. 
– in the case of clinical trials as re ferred to in Article 32, the procedure for 
obtaining the informed consent of the le gal representative and the subject to 
continue the clinical trial shall be described. 
– in the case of clinical trials in emergency situations, description of the 
procedures followed to identify the ur gency situation and to document it. 
55. In these cases, the information given to  the subject and to the parents or legal 
representative shall be provided. 
13. S UITABILITY OF THE INVESTIGATOR (INFORMATION PER MEMBER STATE 
CONCERNED ) 
56. A list of the planned clinical trial sites,  the name and position of the investigators 
responsible for a team of investigators conducting  a clinical trial at a clinical trial site 
('principal investigator') and the number of subjects at the sites shall be submitted. 
57. Description of the qualificati on of the principal investigators in a current curriculum 
vitae and other relevant documents shall be submitted. Any previous training in the 
principles of GCP or experi ence obtained from work with clinical trials and patient 
care shall be described. 
58. Any conditions, such as economic interests, that might be suspect ed to influence the 
impartiality of the principal investigators shall be presented. 
14. S UITABILITY OF THE FACILITIES (INFORMATION PER MEMBER STATE CONCERNED ) 
59. A written statement on the suitability of the trial sites by the head of the 
clinic/institution at the trial site or by some other respons ible person, acco rding to the 
system in the Member State shall be submitted. 
15. P ROOF OF INSURANCE COVE R OR INDEMNIFICATION (INFORMATION PER MEMBER 
STATE CONCERNED ) 
16. F INANCIAL ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED ) 
60. Information on financial transactions and compensation paid to subjects and 
investigator/site for participating in the clinical trial shall be submitted. 
61. Description of any agreement between th e sponsor and the site shall be submitted. 
17. P ROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED )  
EN 77   EN ANNEX II  
Application dossier for substantial modification  
1. I NTRODUCTION AND GENERAL PRINCIPLES  
1. Where a substantial modification concerns mo re than one clinical trial of the same 
sponsor and the same IMP, the sponsor ma y make a single request for authorisation. 
The cover letter and the notifica tion contain a list of all clinical trials affected with 
their official identification numbers a nd respective modification code numbers. 
2. The application shall be signed by the s ponsor. This signature confirms that the 
sponsor is satisfied that: 
• the information provided is complete; 
• the attached documents contain an accura te account of the information available; 
• the clinical trial will be conducte d in accordance with the amended 
documentation. 
2. COVER LETTER  
3. A cover letter with the following information 
– in its subject line the EU trial number and the s ponsor protocol number (if 
available) with the title of  the trial and the sponsor’s modification code number 
allowing unique identification of the subs tantial modification, whereby care is 
taken to use the code number consistently; 
– identification of the applicant; – identification of the m odification (sponsor’s substa ntial modification code 
number and date), whereby one modificat ion could refer to several changes in 
the protocol or scientif ic supporting documents; 
– a highlighted indication of any special issues relating to the modification and 
an indication as to where the relevant in formation or text is in the original 
application dossier; 
– identification of any information not c ontained in the modification application 
form that might impact on the risk to subjects; 
– where applicable, a list of a ll affected clinical trials with official identification 
numbers and respective modificatio n code numbers (see above).  
EN 78   EN 3. M ODIFICATION APPLICATION FORM  
4. DESCRIPTION OF THE MODIFICATION  
4. The modification shall be described as follows: 
– an extract from the amended documents showing previous and new wording in 
track changes, as well as an extr act showing only the new wording; 
– notwithstanding the previous point, if the changes are so widespread or far-
reaching that they justify an entirely new version of the document, a new version of the entire document (in such cases, an additional table lists the amendments to the documents, where by identical changes can be grouped). 
5. The new version shall be identified by  the date and an updated version number. 
5. S
UPPORTING INFORMATION  
6. Additional supporting information shall include where applicable: 
– summaries of data; – an updated overall risk/benefit assessment; – possible consequences for subjects  already included in the trial; 
– possible consequences for the evaluation of the results. 
6. U
PDATE OF EU APPLICATION FORM  
7. If a substantial modification involves cha nges to entries on the EU application form, 
a revised version of that form shall be submitted. The fields affected by the substantial modification shall be highlighted in the revised form.  
EN 79   EN ANNEX III  
Safety reporting  
1. R EPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE SPONSOR  
1. An adverse event can be any unfavour able and unintended sign (including an 
abnormal laboratory finding, for example) , symptom or disease temporally 
associated with the use of a medicinal product. 
2. The investigator shall repor t the serious adverse events referred to in Article 37(2) 
immediately following knowledge of the se rious adverse event. If necessary, a 
follow-up report shall be sent to allow the sponsor to de termine whether the serious 
adverse event requires reassessment of the benefit-risk balance of the clinical trial. 
3. The investigator shal l be responsible for reporting to the sponso r all serious adverse 
events in relation to subjects treated by him or her in the clinical trial. The investigator does not need to actively m onitor subjects for adverse events once the 
trial has ended with regard to the subject s treated by him, unless otherwise provided 
for in the protocol. 
4. Serious adverse events occurring to a subjec t after the end of the trial with regard to 
the subjects treated by him shall be repor ted to the sponsor if the investigator 
becomes aware of them. 
2. R
EPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSAR S) 
BY THE SPONSOR TO THE AGENCY  
2.1. Serious event, ‘reaction’ 
5. A medical event which requires an intervention to prevent one of the 
characteristics/consequences referred to in point 29 of the second paragraph of 
Article 2 is a serious adverse event. 
6. The definition of adverse reaction covers also medication errors and uses outside 
what is foreseen in the protocol, incl uding misuse and abuse of the product. 
7. The definition implies a reasonable possibi lity of a causal relationship between the 
event and the IMP. This means that ther e are facts (evidence)  or arguments to 
suggest a causal relationship. 
8. In the absence of information on causa lity from the reporting investigator, the 
sponsor shall consult the reporting inves tigator and encourage him to express an 
opinion on this aspect. The causality assessmen t given by the investigator shall not 
be downgraded by the sponsor. If the spons or disagrees with the investigator’s 
causality assessment, the opinion of both th e investigator and th e sponsor shall be 
provided with the report.  
EN 80   EN 2.2. ‘Expectedness’/‘unexpectedness’ 
9. Regarding unexpectedness, reports whic h add significant information on the 
specificity, increase of o ccurrence, or severity of  a known, already documented 
serious adverse reaction shall c onstitute unexpected events.  
10. The expectedness of an adverse reaction sh all be determined by the sponsor in the 
reference safety information (‘RSI’). This is done from the perspective of events previously observed, not on the basis of what might be anticipated from the 
pharmacological properties of a medicinal product. 
11. The RSI is contained in the Summary of  product characteristics (‘SmPC’) or the 
investigator's brochure (IB). The coveri ng letter which is submitted with the 
application dossier shall refer to the RSI. If  the IMP is authorised in several Member 
States concerned with different SmPCs, the sponsor shall select the most appropriate 
SmPC, with reference to subject safety, as RSI. 
12. The RSI may change during the conduct of  a clinical trial.  For the purpose of 
reporting of suspected unexpected serious ad verse reactions (SUSARs) the version of 
the RSI at the moment of occurrence of the SUSAR shall apply. Thus, a change of 
the RSI impacts on the number of adverse reactions to be reported as SUSARs. 
Regarding the applicable RSI for the purpose of the annual safety report, see section 
3. 
13. If information on expectedness has been made available by the reporting 
investigator, this shall be taken into consideration by the sponsor. 
2.3. Detailed scope of SUSARs to be reported 
14. The sponsor of a clinical tr ial performed in at least one Member State shall report the 
following SUSARs: 
• all SUSARs occurring in that clinical tr ial, irrespective of whether the SUSAR has 
occurred at a trial site in a Member State or third country concerned; and 
• all SUSARs related to the same active substance (regardless  of pharmaceutical 
form and strength or indication inves tigated) in a clinical trial performed 
exclusively in a third country, if that clinical trial is 
– sponsored by the same sponsor; or 
– sponsored by another sponsor who is either part of the same mother 
company or who develops a medicina l product jointly, on the basis of a 
formal agreement, with that other sponsor. Provision of the IMP or information to a future potential ma rketing authorisation holder on safety 
matters should not be consid ered a joint development. 
15. SUSARs identified after the end of the trial sha ll be reported as well.   
EN 81   EN 2.4. Time limits for reporting fa tal or life-threatening SUSARs 
16. For fatal and life-threateni ng SUSARs the sponsor shall re port at least the minimum 
information as soon as possible and in any case no later than seven days after being 
made aware of the case. 
17. If the initial report is incomplete, e.g. if the sponsor has not provided all the 
information/assessment within seven days , the sponsor shall submit a completed 
report based on the initial information within an additional eight days. 
18. The clock for initial reporting (day 0 = Di  0) starts as soon as the information 
containing the minimum reporting criteri a has been received by the sponsor. 
19. If significant new information on an already reported case is received by the sponsor, 
the clock starts again at day zero, i.e. the date of receipt of new information. This 
information shall be reported as a follow-up report within 15 days. 
2.5. Time limits for reporting non-fa tal or non-life-threatening SUSARs 
20. SUSARs which are not fatal and not life-t hreatening shall be re ported within 15 
days. 
21. If a SUSAR turns out to be fatal or life-threatening, whereas initially it was 
considered as non-fatal or not life-threat ening, the non-fatal or  non-life-threatening 
SUSAR shall be reported as soon as possibl e, but within 15 days. The fatal or life-
threatening SUSAR follow-up report shall be made as soon as possible, but within a 
maximum of seven days after first knowle dge of the reaction being fatal or life-
threatening. Regarding the follo w-up report, see section 2.4. 
22. In cases where a SUSAR turn s out to be fatal or life-t hreatening, whereas initially it 
was considered as non-fatal or not life-thre atening, while the initial report has not yet 
been submitted, a combined report shall be created. 
2.6. Unblinding treatment allocation 
23. Only SUSARs on which the treatment alloca tion of the subject is unblinded shall be 
reported by the sponsor.  
24. The investigator shal l only unblind the treatme nt allocation in the co urse of a clinical 
trial if this is relevant to the safety of the subject. 
25. As regards the sponsor, when an event ma y be a SUSAR the blind shall be broken by 
the sponsor only for that specific subject. Th e blind shall be main tained for persons 
responsible for the ongoing c onduct of the trial (such as the management, monitors, 
investigators) and thos e responsible for data analysis and interpretation of results at 
the conclusion of the trial, such as biomet rics personnel. Unblinded information shall 
only be accessible to those who need to be involved in the safety reporting to the 
Agency, Data Safety Monitoring Boards (‘DSMB’), or persons performing ongoing 
safety evaluations during the trial. 
26. However, for trials in high morbidity or  high mortality disease, where efficacy end-
points could also be SUSARs or when mortality or anot her ‘serious’ outcome (that  
EN 82   EN may potentially be reported as a SUSAR) is the efficacy end-point in a clinical trial, 
the integrity of the clinical trial may be compromised if the blind is systematically broken. Under these and similar circumstance s, the sponsor shall highlight in the 
protocol which serious events would be treat ed as disease-related and not subject to 
systematic unblinding and expedited reporting. 
27. In all cases, following unblinding, if the even t turns out to be a SUSAR (for example 
as regards expectedness), the repor ting rules for SUSARs shall apply. 
3. A
NNUAL SAFETY REPORTING BY THE SPONSOR  
28. The report shall contain, in an appendix, th e RSI in effect at th e start of the reporting 
period. 
29. The RSI in effect at the start of the reporting period shall serve as RSI during the 
reporting period. 
30. If there are significant changes to the RS I during the reporting pe riod they shall be 
listed in the annual safety report. Moreover,  in this case the revised RSI shall be 
submitted as an appendix to the report, in addition to the RSI in effect at the start of the reporting period. Desp ite the change to the RSI, the RSI in effect at the start of 
the reporting period serves as RSI during the reporting period.  
EN 83   EN ANNEX IV  
IMP and AMP labelling  
1. U NAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS  
1.1. General rules 
1. The following particulars shall appear on the immediate and the outer packaging: 
(a) name, address and telephone number of the main contact for information on the 
product, clinical trial and emergency unblinding; this may be the sponsor, 
contract research organisation or inves tigator (for the purpose of this Annex 
this is referred to as the ‘main contact’); 
(b) pharmaceutical form, route of administra tion, quantity of dosage units, and, in 
the case of open label trials, the name/identifier and strength/potency; 
(c) the batch or code number identifying  the contents and packaging operation; 
(d) a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 
(e) the subject identification number/tr eatment number and, where relevant, the 
visit number; 
(f) the name of the i nvestigator (if not incl uded in (a) or (d)); 
(g) directions for use (reference may be made to a leaflet or other explanatory 
document intended for the subject or  person administering the product); 
(h) ‘For clinical trial use only’ or similar wording; (i) the storage conditions; (j) period of use (use-by date, expiry date  or re-test date as applicable), in 
month/year format and in a manner that avoids any ambiguity; 
(k) ‘Keep out of reach of children’, except when the product is for use in trials 
where the product is not taken home by subjects. 
2. Symbols or pictograms may be included to  clarify certain information mentioned 
above. Additional information, warnings or handling instructions may be displayed. 
3. The address and telephone number of the ma in contact need not appear on the label 
where subjects have been given a leaflet or card which provid es these details and 
have been instructed to keep this in their possession at all times.  
EN 84   EN 1.2. Limited labelling of immediate packaging 
1.2.1. Immediate and outer pack aging provided together 
4. When the product is provided to the s ubject or the person administering the 
medication in an immediate package a nd outer packaging intended to remain 
together, and the outer packaging carries the particulars listed in section 1.1., the 
following particulars shall a ppear on the immediate pack aging (or any sealed dosing 
device that contains the immediate package): 
(a) name of the main contact; (b) pharmaceutical form, route of administ ration (may be excluded for oral solid 
dose forms), quantity of dosage units and, in the case of open label trials, the name/identifier and strength/potency; 
(c) batch and/or code number identifying  the contents and packaging operation; 
(d) a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 
(e) the subject identification number/tr eatment number and, where relevant, the 
visit number. 
1.2.2. Small immediate packaging 
5. If the immediate packaging takes the form of blister packs or small units such as 
ampoules on which the particulars required in section 1.1. cannot be displayed, the 
outer packaging is provided bearing a labe l with those particulars. The immediate 
packaging shall contain the following: 
(a) name of the main contact; (b) route of administration (may be exclude d for oral solid dose forms) and, in the 
case of open label trials, the name/identifier and strength/potency; 
(c) batch or code number identifying th e contents and packaging operation; 
(d) a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 
(e) the subject identification number/tr eatment number and, where relevant, the 
visit number. 
2. U
NAUTHORISED AUXILIARY MEDICINAL PRODUCTS  
6. The following particulars shall appear on the immediate and the outer packaging: 
a) name of the main contact; b) name of the medicinal product, fo llowed by its strength and pharmaceutical 
form;  
EN 85   EN c) statement of the active substances expressed qualitativ ely and quantitatively 
per dosage unit; 
d) trial reference code allowing identificat ion of the trial site , investigator and 
subject. 
3. A DDITIONAL LABELLING FOR AUTHORISED INVESTIGATIONAL MEDICINAL 
PRODUCTS  
7. The following particulars shall appear on the immediate and the outer packaging: 
a) name of the main contact; b) trial reference code allowing identificat ion of the trial site , investigator and 
subject. 
4. R
EPLACING OF INFORMATION  
8. Any of the particulars listed in sections  1, 2, and 3 may be omitted and replaced by 
other means (e.g. use of a centralised el ectronic randomisation system, use of a 
centralised information system) provided th at subject safety a nd the reliability and 
robustness of data are not compromised. Th is shall be justified in the protocol.  
EN 86   EN ANNEX V  
Correlation table  
Directive 2001/20/EC This Regulation 
Article 1(1) Articles 1, 2, 1st paragraph, 2nd paragraph (1), 
(2), (4) 
Article 1(2) Article 2, 2nd paragraph (26) 
Article 1(3), 1st subparagraph - 
Article 1(3), 2nd subparagraph Article 44, 3rd subparagraph 
Article 1(4) Article 44, 2nd subparagraph 
Article 2 Article 2 
Article 3(1) - 
Article 3(2) Article 4, 28, 29(1), 72 
Article 3(3) - 
Article 3(4) Article 29(3) 
Article 4 Articles 28, 31, 10(1) 
Article 5 Articles 28, 30, 10(2) 
Article 6 Articles 4 to 14 
Article 7 Articles 4 to 14 
Article 8 - 
Article 9 Articles 4 to 14 
Article 10(a) Articles 15 to 24 
Article 10(b) Article 51 
Article 10(c) Articles 34, 35 
Article 11 Article 78 
Article 12 Article 74 
Article 13(1) Article 58(1) to (4) 
Article 13(2) Article 58 (2)  
EN 87   EN Article 13(3), 1st subparagraph Article 59(1), 60(1), (3) 
Article 13(3), 2nd subparagraph Article 60(1) 
Article 13(3), 3rd subparagraph - 
Article 13(4) Article 59(2) 
Article 13(5) - 
Article 14 Article 63-67 
Article 15 Article 75 
Article 16 Article 37 
Article 17(1)(a) to (c) Article 38 
Article 17(1)(d) - 
Article 17(2) Article 39 
Article 17(3)(a) - 
Article 17(3)(b) Article 40(1) 
Article 18 - 
Article 19, 1st paragraph, 1st sentence Article 71 
Article 19, 1st paragraph, 2nd sentence Article 70 
Article 19, 2nd paragraph Article 88 
Article 19, 3rd paragraph - 
Article 20 - 
Article 21 Article 84 
Article 22 - 
Article 23 - 
Article 24 -  
EN 88   EN LEGISLATIVE FINANCIAL STATEMENT 
1. FRAMEWORK  OF THE  PROPOSAL/INITIATIVE   
 1.1. Title of the proposal/initiative  
 1.2. Policy area(s) concerned in the ABM/ABB structure  1.3. Nature of the proposal/initiative  
 1.4. Objective(s)   1.5. Grounds for the proposal/initiative   1.6. Duration and financial impact   1.7. Management method(s) envisaged  
2. MANAGEMENT
 MEASURES   
 2.1. Monitoring and reporting rules  
 2.2. Management and control system   2.3. Measures to prevent fraud and irregularities  
3. ESTIMATED
 FINANCIAL  IMPACT  OF THE  PROPOSAL/INITIATIVE   
 3.1. Heading(s) of the multiannual fina ncial framework and expenditure budget 
line(s) affected  
 3.2. Estimated impact on expenditure   
 3.2.1. Summary of estimated impact on expenditure  
 3.2.2. Estimated impact on ope rational appropriations  
 3.2.3. Estimated impact on appropriati ons of an administrative nature 
 3.2.4. Compatibility with the current  multiannual financial framework 
 3.2.5. Third-party participation in financing  
 3.3. Estimated impact on revenue 
EN 89   EN LEGISLATIVE FINANCIAL STATEMENT  
1. FRAMEWORK  OF THE  PROPOSAL/INITIATIVE   
1.1. Title of the proposal/initiative  
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 
1.2. Policy area(s) concerned in the ABM/ABB structure29  
Public health. 
The costs will be covered with the envel ope of the Health for Growth Programme 
2014-2020. 
1.3. Nature of the proposal/initiative  
X The proposal/initiative relates to  a new action   
 The proposal/initiative relates to a new action following a pilot project/preparatory 
action30  
 The proposal/initiative relates to the extension of an existing action   
 The proposal/initiative relates to an action redirected towards a new action   
1.4. Objectives 
1.4.1. The Commission's multiannual strategi c objective(s) targeted by the 
proposal/initiative  
The proposal aims to promote public health  and research acro ss the EU through 
providing for harmonized rules on the author isation and conduct of clinical trials. 
1.4.2. Specific objective(s) and ABM /ABB activity(ies) concerned  
Specific objective No. 1:  Electronic 'EU portal' and "EU database"  for submission for 
requests for authorisation of clinical trials, and follow-up. 
Specific objective No.  2: Update of the 'Clinical trial module' of  the existing 
EudraVigilance database to ensure processing of safety reports during clinical trials. 
Specific objective No. 3:  A cooperation system amongst Member States in assessing 
an application for the authorisation of a clinical trial. 
                                                 
29 ABM: Activity-Based Management – ABB: Activity-Based Budgeting. 
30 As referred to in Article 49(6)(a) or (b) of the Financial Regulation.  
EN 90   EN Specific objective No. 4:  A mechanism of 'system insp ections' of third countries' 
regulatory systems for clinical trials. 
ABM/ABB activity(ies) concerned  
Public health  
EN 91   EN 1.4.3. Expected result(s) and impact 
Specify the effects which the proposal/initiative should have on the beneficiaries/groups targeted. 
Effects on sponsors of clinical trials ( both 'industry sponsors' and 'non-commercial 
sponsors'): Reduction in administrative burdens for submitting applications for 
clinical trials and substantial modifications. 
Effects on patients and health systems:  Quicker access to new and innovative 
medicines and treatments. 
1.4.4. Indicators of results and impact  
Specify the indicators for monitoring implementation of the proposal/initiative. 
• Number of clinical trials a pplied for in the EU, as well as the number of subjects; 
• Number of multinational clinical trials applied for in the EU, as well as the 
number of subjects; 
• Number of days between fi nalisation of the protocol and 'first patient in'; 
• Level of administrative costs presen ting administrative burdens, and of 
operational costs of clinical tr ials conducted in the EU; and 
• Number of clinical trials conducted outside the EU for generating data referred to 
in the request for authorisation of a clinical trial or a medicinal product. 
1.5. Grounds for the proposal/initiative  
1.5.1. Requirement(s) to be met in the short or long term  
The Clinical Trials Directive is criticis ed by all stakeholders (ranging from patients 
to researchers and industry) for having caused a significan t decline in the 
attractiveness of patient-oriented research and related studies in the EU. Indeed, the 
number of clinical trials applied for in the EU ha s fallen from 5028 (2007) to 3800 in 
2011. This trend greatly reduces Europe’s competitiveness in the field of clinical 
research and, thus, has a ne gative impact on the devel opment of new and innovative 
treatments and medicines.  
It is required to address this trend and these criticisms. 
1.5.2. Added value of EU involvement 
Harmonised rules open up the po ssibility of referring to the results and findings of 
clinical trials in applicati ons for an authorisation for pl acing a medicinal product on 
the Union market, including subsequent vari ations and extensions of the marketing 
authorisation. 
This is critically important in the case of  clinical trials because practically every 
larger clinical trial is performed in more than one Member State.  
EN 92   EN An additional factor is that medicinal products intended for research and 
development trials are excluded from th e Community Code for medicinal products 
for human use. These products may have b een produced in a diffe rent Member State 
from that where the clinical trial is c onducted. Thus, these products do not benefit 
from the secondary Union law ensuring th eir free movement while maintaining a 
high level of protection of human health. 
1.5.3. Lessons learned from sim ilar experiences in the past 
In the area of regulation of medicines, si nce 1975 there are mechanisms in place to 
facilitate the authorisation of a medicinal product in the internal market. This 
experience has proven highly su ccessful. Some elements of  the present initiative 
build on the experiences made in the ar ea of the authorisat ion of medicines. 
On the other hand, the Clinical Trials Di rective of 2001, which has not provided for 
any cooperation mechanism between Member States, has been in parts a negative 
example not to be followed. 
1.5.4. Coherence and possible synergy wi th other relevant instruments 
Synergy expected with the revision of th e legislation on 'medical devices': this 
legislation provides for a similar 'EU portal' for 'clinical investigations' (clinical 
research with medical devices) as is planned for clinical trials.  
EN 93   EN 1.6. Duration and financial impact  
 Proposal/initiative of limited duration  
–  Proposal/initiative in effect fr om [DD/MM]YYYY to [DD/MM]YYYY  
–  Financial impact from YYYY to YYYY  
X Proposal/initiative of unlimited duration  
– Implementation with a start-up period fr om 2014 to 2016 (the  start-up period is 
the time between date of entry into force of the Regulation, i.e. 20 days after its publication, and the date of application of the Regulation: During this time all 
implementation measures have to be take n by the Commission in order to ensure 
that the Regulation can function on the da y of application of the Regulation), 
– followed by full-scale operation. 
1.7. Management mode(s) envisaged
31  
X Centralised direct management  by the Commission  
 Centralised indirect management  with the delegation of implementation tasks 
to: 
–  executive agencies  
–  bodies set up by the Communities32  
–  national public-sector bodies/bodies with public-service mission  
–  persons entrusted with the implementation of specific actions pursuant to Title 
V of the Treaty on European Union and iden tified in the relevant basic act within 
the meaning of Article 49 of  the Financial Regulation  
 Shared management with the Member States  
 Decentralised management with third countries   
 Joint management with international organisations (to be specified) 
If more than one management mode is indicated, pl ease provide details in the "Comments" section. 
Comments  
                                                 
31 Details of management modes and references to the Financial Regulation may be found on the 
BudgWeb site: http://www.cc.cec/budg/man/b udgmanag/budgmanag_en.html  
32 As referred to in Article 185 of the Financial Regulation.  
EN 94   EN 2. MANAGEMENT  MEASURES   
2.1. Monitoring and reporting rules  
Specify frequency and conditions. 
The Commission has established mechanisms for working with the Member States to 
monitor implementation of th e EU acquis in the area of pharmaceutical and clinical 
trials regulation. Notably, the 'Pharmaceuti cal Committee' is going to provide the 
forum to monitor and assess the ap plication of the new Regulation. 
2.2. Management and control system  
2.2.1. Risk(s) identified  
The EU portal becomes too complex and does not meet the require ments of the users 
(Member States and sponsors). Thus, the EU portal would not have the simplifying 
effect it intends to achieve. 
2.2.2. Control method(s) envisaged  
Close and regular contacts with th e developers of the EU portal. 
Repeated meetings with stakeholders and Me mber States to ensure that the EU portal 
meets users' needs. 
2.3. Measures to prevent fraud and irregularities  
Specify existing or envisaged prevention and protection measures. 
In addition to the application of all regulat ory control mechanisms, DG SANCO will devise 
an anti-fraud strategy in line with the Comm ission's new anti-fraud strategy (CAFS) adopted 
on 24 June 2011 in order to ensure inter alia  that its internal anti-fraud related controls are 
fully aligned with the CASF and that its fraud risk management approach is geared to identify 
fraud risk areas and adequate responses. Wh ere necessary, networking groups and adequate 
IT tools dedicated to analysing fraud cases rela ted to the financing implementing activities of 
the Clinical Trials Regulation will  be set up. In particul ar a series of measur es will be put in 
place such as:  
 
- decisions, agreements and cont racts resulting from the financ ing implementing activities of 
the Clinical Trials Regulation will expressly entitle the Co mmission, including OLAF, and the 
Court of Auditors to conduct audits , on-the-spot checks and inspections;  
 
- during the evaluation phase of a call for pr oposals/tender, the propos ers and tenderers are 
checked against the published ex clusion criteria based on declar ations and the Early Warning 
System (EWS);  
 
- the rules governing the eligibility of costs will be simplified in accordance with the 
provisions of the Financial Regulation;  
 
- regular training on issues relate d to fraud and irregularities is given to all staff involved in  
EN 95   EN contract management as well as to auditors and controllers who verify the beneficiaries' 
declarations on the spot.  
EN 96   EN 3. ESTIMATED  FINANCIAL  IMPACT  OF THE  PROPOSAL/INITIATIVE   
3.1. Heading(s) of the multiannual financ ial framework and expenditure budget 
line(s) affected  
• Existing expenditure budget lines  
In order  of multiannual financial framewor k headings and budget lines. 
Budget line  Type of  
expenditureContribution  
Heading of 
multiannual 
financial 
framework Number  
[Description: Public Health Program]  Diff./non-
diff. 
(33) from 
EFTA34 
countries from 
candidate 
countries35 from third 
countries within the 
meaning of Article 
18(1)(aa) of the 
Financial 
Regulation  
3B 17.03.XX Diff/non
-diff. YES /N
O YES  
/NO YES  / 
NO YES  / NO 
• New budget lines requested  
In order  of multiannual financial framework headings and budget lines. 
Budget line  Type of 
expenditureContribution  
Heading of 
multiannual 
financial 
framewor k Number  
[Heading……………………………………..]  Diff./non-
diff. from 
EFTA 
countries from 
candidate 
countries from third 
countries within the 
meaning of Article 
18(1)(aa) of the 
Financial 
Regulation  
[…] [XX.YY.YY.YY] 
[…] […] YES/N
O YES/N
O YES/N
O YES/NO 
                                                 
33 Diff. = Differentiated appropriations / Non- diff. = Non-Differentiated Appropriations 
34 EFTA: European Free Trade Association.  
35 Candidate countries and, where applicable, poten tial candidate countries from the Western Balkans.  
EN 97   EN 3.2. Estimated impact on expenditure  
3.2.1. Summary of estimated impact on expenditure  
EUR  
Heading of multiannual financial 
framework:  Number 
3B Public Health Program 
 
DG: SANCO   
Year 
201436 Year 
2015 Year 
2016 Year 
2017  Year 
2018  Year 
2019  Year 
2020 and 
following 
years  TOTAL 
y Operational appropriations          
Commitments (1) 895.000 1.082.0
00 238.000 193.000 180.000 184.000  187.000  2.959.000 
Number of budget line: 17.03.XX  
Payments (2) 447.000 998.000 671.000 232.000 175.000 184.000 187.000 + 
65.000 2.959.000 
Commitments (1a)         Number of budget line  Payments (2a)         
Appropriations of an administrative nature financed 
 from the envelope for specific programmes37          
Number of budget line: 17.01.04.02   (3) 57.000 58.000 119.000 121.000 124.000 126.000 129.000 734.000 
TOTAL appropriations Commitments =1+1a 
+3 952.000 1.140.0
00 357.000 314.000 304.000  310.000  316.000  3.693.000 
                                                 
36 All prices are current prices. 
37 Technical and/or administrative assistance and expenditure in support of the implementation of EU programmes and/or actions (f ormer "BA" lines), indirect research, 
direct research.  
EN 98   EN for DG SANCO Payments =2+2a
+3 504.000 1.056.0
00 790.000 353.000 299.000 310.000 316.000 + 
65.000 3.693.000 
 
  
Commitments (4) 895.000 1.082.0
00 238.000 193.000 180.000 184.000  187.000  2.959.000 
y TOTAL operational appropriations  
Payments (5) 447.000 998.000 671.000 232.000 175.000 184.000 187.000 + 
65.000 2.959.000 
y TOTAL appropriations of an administrative nature 
financed from the envelope for specific programmes  (6) 57.000 58.000 119.000 121.000 124.000 126.000 129.000 734.000 
Commitments  952.000 1.140.0
00 357.000 314.000  304.000  310.000  316.000  3.693.000 TOTAL appropriations  
under HEADING SANCO 
of the multiannual financial framework  Payments  504.000 1.056.0
00 790.000 353.000 299.000 310.000 316.000 + 
65.000  3.693.000 
If more than one heading is affected by the proposal / initiative:  
Commitments (4)         
y TOTAL operational appropriations  
Payments (5)         
y TOTAL appropriations of an administrative nature 
financed from the envelope for specific programmes  (6)         
Commitments =4+ 6         TOTAL appropriations  
under HEADINGS 1 to 4 
of the multiannual financial framework 
(Reference amount)  Payments =5+ 6         
  
EN 99   EN  
Heading of multiannual financial 
framework:  5 " Administrative expenditure "  
EUR  
   
Year 
2014 Year 
2015 Year 
2016 Year 
2017  Year 
2018 Year 
2019 Year 
2020 
and 
followi
ng 
years TOTAL 
DG: SANCO 
y Human resources38 222.000 222.000 857.000 857.000 857.000  857.000  857.000  4.730.00039 
y Other administrative expenditure    87.000 88.000 90.000 92.000 94.000 451.000 
TOTAL DG SANCO40 Appropriations    87.000 88.000 90.000 92.000 94.000 451.000 
 
TOTAL appropriations 
under HEADING 5 
of the multiannual financial framework41  (Total commitments 
= Total payments)   87.000 88.000 90.000 92.000 94.000 451.000 
                                                 
38 In accordance with the impact assessment report, the necessary additional human ressources (1.75 FTE + 5 FTE with date of appl ication) are going to be 
re-deployed from within DG SANCO.  
39 In accordance with the impact assessment report, the necessary additional human ressources (1.75 FTE + 5 FTE) are going to be re-deployed from within 
DG SANCO. Consequently, the costs for human resources are not added in the 'total' for Heading 5.  
40 In accordance with the impact assessment report, the necessary additional human ressources (1.75 FTE + 5 FTE) are going to be re-deployed from within 
DG SANCO. Consequently, the costs for human resources are not added in the 'total DG SANCO'.  
41 In accordance with the impact assessment report, the necessary additional human ressources (1.75 FTE + 5 FTE) are going to be re-deployed from within 
DG SANCO. Consequently, the costs for human resources are not added in the 'total' for Heading 5.   
EN 100   EN EUR 
   
Year 
2014 Year 
2015 Year 
2016 Year 
2017  Year 
2018 Year 
2019 Year 2020
and 
following 
years TOTAL 
Commitments  952.000 1.140.0
00 444.000 402.000 394.000 402.000 410.000 4.144.000  TOTAL appropriations  
under HEADINGS 1 to 5 
of the multiannual financial framework   Payments  504.000 1.056.0
00 877.000 441.000 389.000 402.000 410.000 + 
65.000 4.144.000   
EN 101   EN 3.2.2. Estimated impact on opera tional appropriations  
–  The proposal/initiative does not requir e the use of operational appropriations  
– X The proposal/initiative requires the use of opera tional appropriations, as explained below:  
Commitment appropriations in EUR  
  Year 
2014 Year 
2015 Year 
2016 Year 
2017 Year 
2108  Year 
2019  Year 
2020 and 
following 
years  TOTAL  
OUTPUTS  Indicate 
objectives and 
outputs  
 
Ø Type 
of 
output Avera
ge 
cost  
of the 
output 
Number 
fCost 
Number 
of ou tputsCost 
Number 
of outputs Cost 
Number 
of outputs Cost 
Number 
of ou tputsCost 
Numbe r Cost 
Number 
of ou tputsCost Total 
numbe
r of 
output
s Total  
cost 
SPECIFIC OBJECTIVE No 1 
Electronic 'EU portal' and "EU 
database" for submission for 
requests for authorisation of clinical 
trials, and follow-up                 
- Output IT Portal  1 595.00 1 782.00 1 238.00 1 193.00 1 180.0 1 184.00 1 187.00 7 2.359.00
Sub-total for specific objective N°1 1 595.00
0 1 782.00
0 1 238.00
0 1 193.00
0 1 180.0
00 1 184.00
0 1 187.00
0 7 2.359.00
0 
SPECIFIC OBJECTIVE No 2 
Update of the 'Clinical trial module' 
of the existing EudraVigilance 
database to ensure processing of 
safety reports during clinical trials.                 
- Output IT 
update 1 300.00 1 300.00           2 600.000 
Sub-total for specific objective N°2 1 300.00 1 300.00           2 600.000  
EN 102   EN 0 0 
                 
- Output Meetings                  
                 
                 
- Output System 
inspectoi                 
                 
TOTAL COST  2 895.00
0 2 1.082.
000 1 238.00
0 1 193.00
0 1 180.0
00 1 184.00
0 1 187.00
0 9 2.959.00
0 
  
EN 103   EN 3.2.3. Estimated impact on appropriations  of an administrative nature 
3.2.3.1. Summary  
–  The proposal/initiative does not re quire the use of administrative 
appropriations  
– X The proposal/initiative requires the us e of administrative appropriations, as 
explained below: 
 
Year 
2014 Year 
2015 Year 
2016 Year 
2017  Year 
2018 Year 
2019 Year 
2020 and 
following 
years  TOTAL 
 
HEADING 5 
of the multiannual 
financial framework        
 
Human resources 42 222.000 222.000 857.000 857.000 857.000  857.000  857.000  4.730.000
43 
Other administrative 
expenditure    87.000  88.000  90.000  92.000  94.000  451.000 
Subtotal HEADING 5 
of the multiannual 
financial framework44    87.000  88.000  90.000  92.000  94.000  451.000 
 
Outside HEADING 545 
of the multiannual 
financial framework         
 
Human resources          
Other expenditure  
of an administrative nature 57.000  58.000  119.000  121.000  124.000  126.000  129.000  
734.000 
Subtotal  
outside HEADING 5 
of the multiannual 
financial framework  57.000  58.000  119.000  121.000  124.000  126.000  129.000  
734.000 
 
                                                 
42 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed from within DG SANCO.  
43 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed fr om within DG SANCO. Consequently, the costs 
for human resources are not added in the 'subtotal' for Heading 5.  
44 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed fr om within DG SANCO. Consequently, the costs 
for human resources are not added in the 'subtotal' for Heading 5.  
45 Technical and/or administrative assistance and expenditure in support of the implementation of EU 
programmes and/or actions (former "BA" li nes), indirect research, direct research.  
EN 104   EN TOTAL46 57.000 58.000 206.000 209.000 214.000 218.000 223.000 1.185.000 
                                                 
46 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed fr om within DG SANCO. Consequently, the costs 
for human resources are not added in the 'total' of administrative expenditure.   
EN 105   EN 3.2.3.2.  Estimated requirements of human resources  
– X The proposal/initiative does not require the use of human resources47 
–  The proposal/initiative re quires the use of human resources, as explained 
below: 
–  Year 
2014 Year 
2015 Year 
2016 Year 
2017  Year 
2018 Year 
2019 Year 
2020 and 
following 
years TO
17 01 01 01 (Headquarters and Commission’s 
Representation Offices) 48 1.75 
FTEc 1.75 
FTE 6.75 
FTE 6.75 FTE 6.75 
FTE 6.75 
FTE 6.75 FTE 
XX 01 01 02 (Delegations)        
XX 01 05 01 (Indirect research)        10 01 05 01 (Direct research)        
XX 01 02 01 (CA, INT, SNE from the 
"global envelope")         
XX 01 02 02 (CA, INT, JED, LA and SNE in 
the delegations)        
- at Headquarters
50        XX 01 04 yy 49 
- in delegations         
XX 01 05 02 (CA, INT, SNE - Indirect 
research)        
10 01 05 02 (CA, INT, SNE - Direct 
research)        
Other budget lines (specify)        
TOTAL         
XX is the policy area or budget title concerned. 
The human resources required will be met by staff from the DG who are already 
assigned to management of the action and/or have been redeployed within the DG, together if necessary with any additional allocation which may be granted to the managing DG under the annual allocation procedure and in the light of budgetary 
constraints. 
Description of tasks to be carried out: 
Officials and temporary agents General questions in rela tion to the authorisation procedure for clinical trials. 
Preparation, chairing and follow-up of the relevant expert group. 'System inspections' 
in third countries. 
External personnel  
                                                 
47 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed from within DG SANCO.  
48 In accordance with the impact assessment rep ort, the necessary additional human ressources 
(1.75 FTE + 5 FTE) are going to be re-deployed from within DG SANCO.  
49 Under the ceiling for external personnel from operational appropriations (former "BA" lines). 
50 Essentially for Structural Funds , European Agricultural Fund for Rural Development (EAFRD) and 
European Fisheries Fund (EFF).  
EN 106   EN 3.2.4. Compatibility with the current multiannual financial framework  
– X Proposal/initiative is compatible the 2014-2020 multiannual financial 
framework. 
–  Proposal/initiative will entail reprogramming of the relevant heading in the 
multiannual financial framework. 
Explain what reprogramming is required, specifying the budget lines concerned and the corresponding 
amounts. 
–  Proposal/initiative requires application of  the flexibility inst rument or revision 
of the multiannual financial framework51. 
Explain what is required, specifying the headings and budget lines concerned and the corresponding 
amounts. 
3.2.5. Third-party contributions  
– X The proposal/initiative does not provide for co-financing by third parties  
– The proposal/initiative provides for the co-financing estimated below: 
Appropriations in EUR m illion (to 3 decimal places) 
 
Year 
N Year 
N+1 Year 
N+2 Year 
N+3 … enter as many years as 
necessary to show the duration 
of the impact (see point 1.6)  Total 
Specify the c o-financing 
body          
TOTAL appropriations 
cofinanced          
 
 
                                                 
51 See points 19 and 24 of the Interinstitutional Agreement.  
EN 107   EN 3.3. Estimated impact on revenue  
– X Proposal/initiative has no financial impact on revenue.