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
Date: 2012-07-17
Institutions: European Commission
Subjects: administrative formalities, bio-ethics, experiment on humans, harmonisation of standards, market approval, medical research, medicinal product, testing

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} 

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EXPLANATORY MEMORANDUM 

1. 

CONTEXT OF THE PROPOSAL 

Clinical  trials  as  defined  in  Directive  2001/20/EC  of  the  European  Parliament  and  of  the 
Council  of  4  April  2001  on  the  approximation  of  the  laws,  regulations  and  administrative 
provisions of the Member States relating to the implementation of good clinical practice in the 
conduct of clinical trials on medicinal products for human 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  different  contexts.  Applications  for  marketing 
authorisation  and  publications  in  medical  journals  are  based  on  data  generated  in  clinical 
trials. Therefore, clinical trials are an indispensable part of clinical research which, in turn, is 
essential  to  develop  medicinal  products  and  improve  medical  treatment.  Without  clinical 
trials, there would be no new medicines, no further development of existing medicines, and no 
evidence-based improvement of treatments with medicines. 

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

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

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

The data available support these criticisms: 

• 

• 

1 
2 
3 

The number of applications for clinical trials fell by 25 % from 2007 to 2011.3 

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

OJ L 121, 1.5.2001, p. 34. 
Based on the figures for 2010. 
The decrease has been 12% from 2007 to 2010. 

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98%  increase  in  administrative  costs.  In  addition,  since  implementation  of  the 
Directive 2001/20/EC, insurance fees have increased by 800 % for industry sponsors. 

• 

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

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

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

2. 

RESULTS OF CONSULTATIONS WITH THE INTERESTED PARTIES AND 
IMPACT ASSESSMENT 

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

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

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

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

3. 

LEGAL ASPECTS OF THE PROPOSAL 

3.1.  SCOPE (CHAPTERS 1 AND 2 OF THE PROPOSED REGULATION) 

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

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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 authorisation procedure for clinical trials based on the 
following concepts: 

• 

• 

• 

• 

• 

• 

• 

• 

• 

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

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

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

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

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

A  coordination  and  advisory  forum  to  address  issues  which  may  arise  in  the 
authorisation  procedure.  This  forum 
the 
Commission; 

is  managed  and  chaired  by 

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

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

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

• 

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

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

4 

OJ L 311, 28.11.2001, p. 67. 

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impact on the safety or rights of the subjects or on the reliability and robustness 
of the data generated in the clinical trial. 

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

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

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

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

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

3.3. 

INTERFACE WITH 'SCIENTIFIC ADVICE' 

Independently  of  the  regulation  of  clinical  trials,  regulators  may  be  involved  in  the 
preparatory  phase  of  a  trial  in  the  context  of  protocol  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 medicinal products (OJ L 18, 22.1.2000, p. 1). 

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investigation plan6, scientific advice7, and post-authorisation safety/efficacy studies8 
(hereinafter referred to as 'scientific advice'). 

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

• 

• 

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

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

for  any  other  purpose 

3.4.  PROTECTION  OF  SUBJECTS  AND  INFORMED  CONSENT  (CHAPTER  5  OF  THE 
PROPOSED REGULATION) 

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

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Article  15  of  Regulation  (EC)  No  1901/2006  of  the  European  Parliament  and  of  the  Council  of  12 
December 2006 on medicinal products for paediatrics use (OJ L 378, 27.12.2006, p. 1). 
Article  56(3)  of  Regulation  (EC)  No  726/2004  of  the  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). 
Article 21a(b)(f) of Directive 2001/83/EC. 

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authorisation  procedure  have  been  moved  to  chapters  2  and  3  of  the  proposed 
Regulation,  and  provisions  related  to  damage  compensation  have  been  moved  to 
Chapter 12 of the proposed Regulation.  

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

Moreover  as  regards  the  protection  of  personal  data,  provisions  of  Directive 
95/46/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 investigators, which may be collected in the EU 
database, are kept in accordance with the exception foreseen in Article 17(3) (b) of 
the  proposal  for  a  regulation  of  the  European  Parliament  and  the  Council  on  the 
protection  of  individuals  with  regard  to  the  processing  of  personal  data  and  on  the 
free  movement  of  such  data  (General  Data  Protection  Regulation).  In  case  of 
detection  of  cases  of  misconduct  in  a  clinical  trial  it  would  be  important,  for 
example, to trace all the clinical trials in which the same investigators were involved, 
even several years after these clinical trials have ended. 

3.5.  SAFETY REPORTING (CHAPTER 7 OF THE PROPOSED REGULATION) 

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

• 

• 

• 

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

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

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

Details of the rules on safety reporting, which codify in parts  existing Commission 
guidance11 are contained in an annex to the proposed Regulation. This will facilitate 

9 
10 
11 

OJ L 281, 23.11.1995, p. 31. 
OJ L 8, 12.1.2001, p. 1. 
OJ C172, 11.6.2011, p. 1. 

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updating the existing rules, by way of delegated acts, in view of technical progress or 
global regulatory alignment. 

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

3.6.  CONDUCT OF THE TRIAL (CHAPTER 8 OF THE PROPOSED REGULATION) 

Directive  2001/20/EC  contains  relatively  few  rules  on  the  actual  conduct  of  trials. 
These  rules  are  partly  contained  in  Commission  Directive  2005/28/EC  of  8  April 
2005  laying  down  principles  and  detailed  guidelines  for  good  clinical  practice  as 
regards  investigational  medicinal  products  for  human  use,  as  well  as  the 
requirements  for  authorisation  of  the  manufacturing  or  importation  of  such 
products12, and partly contained in Commission guidance documents. The proposed 
Regulation brings together these rules. 

3.7.  INVESTIGATIONAL AND AUXILIARY MEDICINAL PRODUCTS, MANUFACTURING, 
LABELLING (CHAPTERS 9 TO 10 OF THE PROPOSED REGULATION) 

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

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

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

to 

in 

12 

OJ L 91, 9.4.2005, p. 13. 

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3.8.  SPONSORS,  CO-SPONSORSHIP,  EU  CONTACT  PERSON  (CHAPTER  11  OF  THE 
PROPOSED REGULATION) 

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

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

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

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

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

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

3.9.  COMPENSATION  FOR  DAMAGES 
REGULATION) 

(CHAPTER  12  OF  THE  PROPOSED 

'obligatory 
introduced  an 
insurance/indemnity  has  substantially 

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

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

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coverage  of  the  medical  practitioner,  the  institution,  or  product  liability  insurance 
provides sufficient coverage. 

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

3.10.  INSPECTIONS (CHAPTER 13 OF THE PROPOSED REGULATION) 

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

the 

3.11.  REPEALS  AND  ENTRY  INTO  FORCE  (CHAPTER  19  OF  THE  PROPOSED 
REGULATION) 

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

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

3.12  SIMPLIFICATION  OF  SUBSTANTIAL  RULES  FOR  CLINICAL  TRIALS  WITH 
AUTHORISED MEDICINAL PRODUCTS AND LOW-INTERVENTION CLINICAL TRIALS 

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

• 

• 

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

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

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

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

3.13. LEGAL FORM OF A REGULATION 

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

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

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

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

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

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

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

3.14.  COMPETENCES, DOUBLE LEGAL BASIS AND SUBSIDIARITY 

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

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

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

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

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

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

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

• 

• 

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

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

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

EN 

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• 

• 

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

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

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

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

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

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

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

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

• 

• 

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

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

EN 

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liability)  but  also  to  the  rules  on  the  burden  of  proof  and  on  calculating  the 
extent of damage. 

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

4. 

BUDGETARY IMPLICATION 

The budgetary implications of this proposal are as follows: 

• 

• 

• 

• 

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

Commission staff to manage the functioning of the Regulation; 

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

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

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

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

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2012/0192 (COD) 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 

on clinical trials on medicinal products for human use, and repealing Directive 
2001/20/EC 

(Text with EEA relevance) 

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, 

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

Having regard to the proposal from the Commission13, 

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

Having regard to the opinion of the European Economic and Social Committee14, 

Having regard to the opinion of the Committee of the Regions15, 

After consulting the European Data Protection Supervisor16, 

Acting in accordance with the ordinary legislative procedure17, 

Whereas: 

(1) 

(2) 

(3) 

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

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

The existing definition of a clinical trial as contained in Directive 2001/20/EC of the 
European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws,  regulations  and  administrative  provisions  of  the  Member  States  relating  to  the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 

13 
14 
15 
16 
17 

OJ C , , p. . 
OJ C , , p. . 
OJ C , , p. . 
XXX. 
OJ C , , p. . 

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(4) 

(5) 

(6) 

(7) 

(8) 

products for human use18 should be clarified. For that purpose, the concept of clinical 
trial should be more precisely defined by introducing the broader concept of 'clinical 
study' of which the clinical trial is a category. That category should be defined on the 
basis of specific criteria. This approach takes due account of international guidelines, 
and is in line with the EU legislation governing medicinal products, which builds on 
the dichotomy of 'clinical trial' and 'non-interventional study'.  

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

identified 

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

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.  

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

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

18 

OJ L 121, 1.5.2001, p. 34. 

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(9) 

The  risk  to  subject  safety  in  a  clinical  trial  mainly  stems  from  two  sources:  the 
investigational medicinal product and the intervention. Many clinical trials, however, 
pose  only  a  minimal  additional  risk  to  subject  safety  compared  to  normal  clinical 
practice. This is in particular  the case where the investigational medicinal product is 
covered by a marketing authorisation (i.e. the quality, safety and efficacy has already 
been assessed in the course of the marketing authorisation procedure) and where the 
intervention poses only very limited additional risk to the subject compared to normal 
clinical  practice.  Those  "low-intervention  clinical  trials"  are  often  of  crucial 
importance to assess standard treatments and diagnoses, thereby optimising the use of 
medicinal products and thus contributing to a high level of public health. They should 
be subject to less stringent rules, such as shorter deadlines for approval. 

(10)  The  assessment  of  the  application  for  a  clinical  trial  should  address  in  particular  the 
anticipated  therapeutic  and  public  health  benefits  ('relevance')  and  the  risk  and 
inconveniences for the subject. Regarding the relevance, numerous aspects should be 
taken  into  account,  including  whether  the  clinical  trial  has  been  recommended  or 
imposed by regulatory authorities in charge of the assessment and authorisation of the 
placing on the market of medicinal products. 

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

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

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

(14) 

It should be left to the Member State concerned to determine the appropriate body or 
bodies  to  be  involved  in  this  assessment.  This  decision  is  a  matter  of  internal 
organisation of each Member State. Member States, when determining the appropriate 
body  or  bodies,  should  ensure  the  involvement  of  lay  persons  and  patients.  They 
should also ensure that the necessary expertise is available. In any case, however, and 
in accordance with international guidelines, the assessment should be done jointly by a 
reasonable number of persons who collectively have the necessary qualifications and 
experience.  The  persons  assessing  the  application  should  be  independent  from  the 
sponsor, the institution of the trial site, and the investigators involved, as well as free 
of any other undue influence. 

(15) 

In  practice,  when  submitting  an  application  for  authorisation  of  a  clinical  trial, 
sponsors do not always have full certainty about the Member States where a clinical 
trial is eventually going to be conducted. It should be possible for sponsors to submit 
an application solely on the basis of the documents assessed jointly by those Member 
States where the clinical trial might be conducted. 

EN 

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

(17) 

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

(18)  Clinical  trials  are  usually  subject  to  many  modifications  after  they  have  been 
authorised.  Those  modifications  may  relate  to  the  conduct,  design,  methodology, 
investigational or auxiliary medicinal product, or the investigator or trial site involved. 
Where  those  modifications  have  a  substantial  impact  on  the  safety  or  rights  of  the 
subjects or on the reliability and robustness of the data generated in the clinical trial, 
they should be subject to an authorisation procedure similar to the initial authorisation 
procedure. 

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

(20) 

(21) 

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

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

(22)  The  human  dignity  and  right  to  the  integrity  of  the  person  are  recognized  in  the 
Charter  of  Fundamental  rights  of  the  European  Union.  In  particular,  the  Charter 
requires that any intervention in the field of biology and medicine cannot be performed 
without  free  and  informed  consent  of  the  person  concerned.  Directive  2001/20/EC 
contained an extensive set of rules for the protection of subjects. These rules should be 
upheld. Regarding the rules concerning the determination of the legal representative of 
incapacitated  persons  and  minors,  those  rules  diverge  in  Member  States.  It  should 
therefore  be  left  to  Member  States  to  determine  the  legal  representative  of 
incapacitated persons and minors. 

(23)  This  Regulation  should  provide  for  clear  rules  concerning  informed  consent  in 
emergency situations. Such situations relate to cases where for example a patient has 
suffered a sudden life-threatening medical condition due to multiple traumas, strokes 
or  heart  attacks,  necessitating  immediate  medical  intervention.  For  such  cases, 
intervention within an ongoing clinical trial, which has already been approved, may be 
pertinent. However, in certain circumstances, due to the unconsciousness of the patient 

EN 

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and the absence of an immediately available legal representative, it is not possible to 
obtain informed consent prior to the intervention. The Regulation should therefore set 
clear rules whereby such patients may be enrolled in the clinical trial under very strict 
conditions.  In  addition,  the  said  clinical  trial  should  relate  directly  to  the  medical 
condition which causes the impossibility of the patient to give informed consent. Any 
previously expressed objection by the patient must be respected, and informed consent 
from the subject or the legal representative should be sought as soon as possible. 

(24) 

(25) 

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

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

(26) 

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

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

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

this information. 

(29)  The  members  of  the  International  Conference  on  Harmonisation  of  Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) have agreed 
on  a  detailed  set  of  guidelines  for  good  clinical  practice  which  are  now  an 
internationally  accepted  standard  for  designing,  conducting,  recording  and  reporting 
clinical  trials,  consistent  with  principles  that  have  their  origin  in  the  World  Medical 
Association’s  Declaration  of  Helsinki.  When  designing,  conducting,  recording  and 
reporting  clinical  trials,  detailed  questions  may  arise  as  to  the  appropriate  quality 
standard. In such a case, the ICH guidelines on good clinical practice should be used 
as  guidance  for  the  application  of  the  rules  set  out  in  this  Regulation,  provided  that 
there is no other specific guidance issued by the Commission and that those guidelines 
are without prejudice to this Regulation. 

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

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

EN 

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

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

(34)  Apart from the reporting of suspected unexpected serious adverse reactions, there may 
be other events which are relevant in terms of benefit-risk balance and which should 
be reported in a timely manner to the Member States concerned.  

(35)  Where unexpected events require an urgent modification of a clinical trial, it should be 
possible  for  the  sponsor  and  the  investigator  to  take  urgent  safety  measures  without 
awaiting prior authorisation.  

(36) 

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

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

(38) 

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

(39)  Medicinal products intended for research and development trials fall outside the scope 
of  Directive  2001/83/EC  of  the  European  Parliament  and  of  the  Council  of  6 
November  2001  on  the  Community  code  relating  to  medicinal  products  for  human 
use19.  Such  medicinal  products  include  medicinal  products  used  in  the  context  of  a 
clinical  trial.  They  should  be  covered  by  specific  rules  taking  account  of  their 
peculiarities.  In  establishing  these  rules,  a  distinction  should  be  made  between 
investigational  medicinal  products  (the  tested  product  and  its  reference  products, 
including placebos) and auxiliary medicinal products (medicinal products used in the 
context  of  a  clinical  trial  but  not  as  investigational  medicinal  products),  such  as 
treatment,  challenge  agents,  rescue 
medicinal  products  used  for  background 
medication,  or  used  to  assess  end-points  in  a  clinical  trial.  Auxiliary  medicinal 

19 

OJ L 311, 28.11.2001, p. 67. 

EN 

20 

   EN 

 
                                                 
(40) 

(41) 

(42) 

(43) 

products should not include concomitant medications, i.e. medications unrelated to the 
clinical trial and not relevant for the design of the clinical trial. 

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

Investigational  and  auxiliary  medicinal  products  should  be  appropriately  labelled  in 
order to ensure subject safety and the reliability and robustness of data generated in a 
clinical trial, and in order to allow for the distribution of those products to clinical trial 
sites  throughout  the  Union.  The  rules  for  labelling  should  be  adapted  to  the  risks  to 
subject  safety  and  the  reliability  and  robustness  of  data  generated  in  a  clinical  trial. 
Where the investigational or auxiliary medicinal product have already been placed on 
the  market  as  an  authorised  medicinal  product  in  accordance  with  Directive 
2001/83/EC, as a general rule no additional labelling should be required for open-label 
trials.  Moreover,  there  are  specific  products,  such  as  radiopharmaceuticals  used  as 
diagnostic investigational medicinal product, where the general rules on labelling are 
inappropriate in view of the very controlled setting of the use of radiopharmaceuticals 
in clinical trials. 

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

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

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

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

EN 

21 

   EN 

 
(46) 

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

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

is  small  and  costs  for 

insurance  market 

the 

(48)  The Member State concerned should be given the power to early terminate, suspend or 

modify a clinical trial. 

(49) 

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

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

(51) 

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

(52)  The  database  should  contain  all  relevant  information  as  regards  the  clinical  trial.  No 
personal data of data subjects participating in a clinical trial should be recorded in the 
database.  The  information  in  the  database  should  be  public,  unless  specific  reasons 
require that a piece of information should not be published, in order to protect the right 
of  the  individual  to  private  life  and  the  right  to  the  protection  of  personal  data, 
recognised by Articles 7 and 8 of the Charter of Fundamental Rights of the European 
Union. 

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

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

(55) 

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

EN 

22 

   EN 

 
(56) 

(57) 

In  order  to  ensure  uniform  conditions  for  the  implementation  of  this  Regulation, 
implementing powers should be conferred on the Commission to adopt implementing 
acts in relation to inspections. Those powers should be exercised in accordance with 
Regulation  (EU)  No  182/2011  of  the  European  Parliament  and  of  the  Council  of  16 
February  2011  laying  down  the  rules  and  general  principles  concerning  mechanisms 
for control by Member States of the Commission’s exercise of implementing powers20. 

In order to ensure that information and documentation submitted in an application for 
authorisation of a clinical trial or a substantial modification allows assessment of the 
application  in  view  of  technical  progress  and  global  regulatory  requirements,  and  in 
order to ensure a high level of subject protection and reliability and robustness of data 
generated  in  a  clinical  trial  through  a  well-functioning  safety  reporting  process  and 
through  detailed  requirements  for  manufacturing  and  labelling  of  medicinal  products 
used in the context of a clinical trial, the Commission should be empowered to adopt 
delegated acts in accordance with Article 290 of the Treaty on the Functioning of the 
European Union to amend the list of documentation and information to be submitted 
in  an  application  for  authorisation  of  a  clinical  trial  or  a  substantial  modification,  to 
amend technical aspects for safety reporting in the context of a clinical trial, to adopt 
detailed  requirements  of  good  manufacturing  practice,  and  to  amend  the  list  of 
information to appear on the labelling of medicinal products used in the context of a 
clinical trial. It is of particular importance that the Commission carry out appropriate 
consultations during its preparatory work, including at expert level. The Commission, 
when preparing and drawing-up delegated acts, should ensure a simultaneous, timely 
and  appropriate  transmission  of  relevant  documents  to  the  European  Parliament  and 
Council. 

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

(59)  Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 
on the protection of individuals with regard to the processing of personal data and on 
the free movement of such data21 applies to the processing of personal data carried out 
in  the  Member  States,  under  the  supervision  of  the  Member  States  competent 
authorities, in particular the public independent authorities designated by the Member 
States and Regulation (EC) No 45/2001 of the European Parliament and of the Council 
of 18 December 2000 on the protection of individuals with regard to the processing of 
personal data by the Community institutions and bodies and on the free movement of 
such  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 
21 
22 

OJ L 55, 28.2.2011, p. 13. 
OJ L 281, 23.11.1995, p. 31. 
OJ L 8, 12.1.2001, p. 1. 

EN 

23 

   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  authorisation  procedure. 
However,  in  order  to  allow  the  setting  up  at  Union  level  of  the  extensive  IT 
functionalities required for the authorisation procedure, it is appropriate to provide for 
a reasonable period to elapse before this Regulation applies. 

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

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

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

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

(66)  Since  the  objective  of  this  Regulation,  namely  to  ensure  that,  throughout  the  Union, 
clinical  trial  data  are  reliable  and  robust  while  ensuring  the  safety  and  rights  of 
subjects, cannot sufficiently be achieved by the Member States and can, by reason of 
the  scale  of  the  measure,  be  better  achieved  at  Union  level,  the  Union  may  adopt 
measures, in accordance with the principle of subsidiarity as set out in Article 5 of the 

EN 

24 

   EN 

 
Treaty on European Union. In accordance with the principle of proportionality, as set 
out in that Article, this Regulation does not go beyond what is necessary in order to 
achieve that objective, 

HAVE ADOPTED THIS REGULATION: 

Chapter I 
General provisions 

Article 1 
Scope 

This Regulation shall apply to clinical trials conducted in the Union.  

It shall not apply to non-interventional studies. 

Article 2 
Definitions 

the  purposes  of 

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

this  Regulation, 

The following definitions shall also apply: 

(1) 

‘Clinical study’: any investigation in relation to humans intended 

(a) 

to  discover  or  verify 
pharmacodynamic effects of one or more medicinal products; 

the  clinical,  pharmacological  or  other 

(b) 

to identify any adverse reactions to one or more medicinal products; or 

(c) 

to study the absorption, distribution, metabolism and excretion of one or 
more medicinal products; 

with the objective of ascertaining their safety or efficacy. 

(2) 

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

(a) 

the investigational medicinal products are not authorised; 

(b) 

(c) 

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

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 

25 

   EN 

 
(d) 

(e) 

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

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

(3) 

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

(a) 

the investigational medicinal products are authorised; 

(b) 

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

(c) 

the additional diagnostic or monitoring procedures do not pose more than 
minimal additional risk or burden to the safety of the subjects compared 
to normal clinical practice in any Member State concerned. 

(4) 

(5) 

(6) 

(7) 

(8) 

(9) 

(10) 

(11) 

‘Non-interventional study’: a clinical study other than a clinical trial; 

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

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

‘Advanced  therapy  investigational  medicinal  product’:  an  investigational  medicinal 
product which is an advanced therapy medicinal product as defined in Article 2(1) of 
Regulation (EC) No 1394/2007 of the European Parliament and of the Council23; 

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

‘Authorised  investigational  medicinal  product’:  a  medicinal  product  authorised  in 
accordance with Regulation (EC) No 726/2004, or, in any Member State concerned, 
in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of 
the medicinal product, which is used as an investigational medicinal product; 

'Authorised  auxiliary  medicinal  product’:  a  medicinal  product  authorised  in 
accordance with Regulation (EC) No 726/2004, or, in any Member State concerned, 
in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of 
the medicinal product, which is used as an auxiliary medicinal product; 

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

23 

OJ L 324, 10.12.2007, p. 121. 

EN 

26 

   EN 

 
                                                 
(12) 

(13) 

(14) 

(15) 

(16) 

(17) 

(18) 

(19) 

(20) 

(21) 

(22) 

(23) 

(24) 

(25) 

(26) 

‘Substantial  modification’:  any  change  to  any  aspect  of  the  clinical  trial  which  is 
made after notification of the decision referred to in Articles 8, 14, 19, 20 and 23 and 
which is likely to have a substantial impact on the safety or rights of the subjects or 
on the reliability and robustness of the data generated in the clinical trial; 

‘Sponsor’:  an 
responsibility for the initiation and management of the clinical trial; 

individual,  company, 

institution  or  organisation  which 

takes 

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

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

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

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

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

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

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

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

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

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

‘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; 

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

‘Good clinical practice’: a set of detailed ethical and scientific quality requirements 
for  designing,  conducting,  performing,  monitoring,  auditing,  recording,  analysing 
and reporting clinical trials ensuring that the rights, safety and well-being of subjects 
are protected, and that the data generated in the clinical trial are reliable and robust; 

EN 

27 

   EN 

 
(27) 

(28) 

(29) 

‘Inspection’:  the  act  by  a  competent  authority  of  conducting  an  official  review  of 
documents,  facilities,  records,  quality  assurance  arrangements,  and  any  other 
resources that are deemed by the competent authority to be related to the clinical trial 
and  that  may  be  located  at  the  site  of  the  trial,  at  the  sponsor's  and/or  contract 
research  organisation's  facilities,  or  at  other  establishments  which  the  competent 
authority sees fit to inspect; 

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

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

(30) 

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

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

Article 3 
General principle 

A clinical trial may be conducted only if 

– 

– 

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

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

Chapter II 
Authorisation procedure for a clinical trial 

Article 4 
Prior authorisation 

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

Article 5 
Submission of an application 

1. 

In order to obtain an authorisation, the sponsor shall submit an application dossier to 
the  intended  Member  States  concerned  through  the  portal  referred  to  in  Article  77 
(hereinafter 'EU portal'). 

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

EN 

28 

   EN 

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

2. 

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

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

concerned is the reporting Member State; 

3. 

4. 

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

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

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

the sponsor. 

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

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

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

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

5. 

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

EN 

29 

   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  whether  the  clinical trial  has  been 
recommended or imposed by regulatory authorities in charge of the 
assessment  and  authorisation  of  the  placing  on  the  market  of 
medicinal products; 

the  reliability  and  robustness  of  the  data  generated  in  the  clinical 
trial, taking account of statistical approaches, design of the trial and 
methodology 
randomisation, 
sample 
(including 
comparator and endpoints); 

size 

and 

(ii)  The risks and inconveniences for the subject, taking account of all of the 

following: 

– 

– 

– 

– 

the  characteristics  of  and  knowledge  about  the  investigational 
medicinal products and the auxiliary medicinal products; 

the  characteristics  of  the  intervention  compared  to  normal  clinical 
practice; 

the  safety  measures,  including  provisions  for  risk  minimisation 
measures, monitoring, safety reporting, and the safety plan;  

the risk to subject health posed by the medical condition for which 
the investigational medicinal product is being investigated; 

(b)  Compliance  with 

the  manufacturing  and 
importation  of  investigational  medicinal  products  and  auxiliary  medicinal 
products set out in Chapter IX; 

the  requirements  concerning 

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

(d)  The completeness and adequateness of the investigator’s brochure. 

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. 

The assessment report shall contain one of the following conclusions concerning the 
aspects addressed in Part I of the assessment report: 

30 

   EN 

2. 

3. 

EN 

 
(a) 

(b) 

the conduct of the clinical trial is acceptable in view of the requirements set out 
in this Regulation; 

the conduct of the clinical trial is acceptable in view of the requirements set out 
in  this  Regulation,  but  subject  to  compliance  with  specific  conditions  which 
shall be specifically listed in that conclusion; 

(c) 

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

4. 

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

5. 

6. 

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

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

 intervention clinical trials; 

(c)  within 30 days from the validation date for any clinical trial with an advanced

 therapy investigational medicinal product. 

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

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

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

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

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

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

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

EN 

31 

   EN 

 
7. 

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

Article 7 
Assessment report – Aspects covered by Part II 

1. 

Each Member State concerned shall assess, for its own territory, the application with 
respect to the following aspects: 

(a) 

compliance with the requirements for informed consent as set out in Chapter V; 

(b) 

(c) 

compliance  of  the  arrangements  for  rewarding  or  compensating  investigators 
and subjects with the requirements set out in Chapter V; 

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. 

3. 

Each Member State concerned shall complete its assessment within ten days from the 
validation  date.  It  may  request,  with  justified  reasons,  additional  explanations  from 
the  sponsor  regarding  the  aspects  referred  to  in  paragraph  1  only  within  that  time 
period. 

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

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

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

EN 

32 

   EN 

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

Article 8 
Decision on the clinical trial 

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

Notification  shall  be  done  by  way  of  one  single  decision  within  ten  days  from  the 
assessment date or the last day of the assessment referred to in Article 7, whichever 
is later. 

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

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

(a) 

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

(b) 

infringement of the national legislation referred to in Article 86. 

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

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. 

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

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

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

1. 

2. 

3. 

4. 

5. 

6. 

EN 

33 

   EN 

 
Article 9 
Persons assessing the application 

1. 

2. 

3. 

1. 

2. 

3. 

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

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

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

Article 10 
Specific considerations for vulnerable populations 

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

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

In  applications  for  authorisation  of  clinical  trials  referred  to  in  Article  32,  specific 
consideration shall be given to the circumstances of the conduct of the clinical trial.  

Article 11 
Submission and assessment of applications limited to aspects covered by Part I of the 
assessment report 

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

After the notification of the decision on the aspects covered by Part I of the assessment report, 
the  sponsor  may  apply  for  an  authorisation  limited  to  aspects  covered  by  Part  II  of  the 
assessment report. In this case, that application shall be assessed in accordance with Article 7 
and  the  Member  State  concerned  shall  notify  its  decision  with  regard  to  Part  II  of  the 
assessment report in accordance with Article 8.  

EN 

34 

   EN 

 
Article 12 
Withdrawal 

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

Article 13 
Resubmission 

This Chapter is without prejudice to the possibility for the sponsor  to submit,  following the 
refusal  to  grant  an  authorisation  or  the  withdrawal  of  an  application,  an  application  for 
authorisation to any intended Member State concerned. That application shall be considered 
as a new application for authorisation of another clinical trial. 

1. 

2. 

3. 

Article 14 
Subsequent addition of a Member State concerned 

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

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

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

The  additional  Member  State  concerned  shall  notify  the  sponsor  through  the  EU 
portal  by  way  of  one  single  decision  as  to  whether  the  clinical  trial  is  authorised, 
whether it is authorised subject to conditions, or whether the authorisation is refused 
within the following time periods: 

(a)  25 days from the date of submission of the application referred to in paragraph 

1 for low-intervention clinical trials; 

(b)  35 days from the date of submission of the application referred to in paragraph 

1 for clinical trials other than low-intervention clinical trials; 

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

4. 

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

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

EN 

35 

   EN 

 
(a) 

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

(b) 

infringement of the national legislation referred to in Article 86. 

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

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

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

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

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

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

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

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

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

5. 

6. 

7. 

8. 

EN 

36 

   EN 

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

9. 

10. 

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

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

11. 

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

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

Article 15 
General principles 

A  substantial  modification  may  only  be  implemented  if  it  has  been  approved  in  accordance 
with the procedure set out in this Chapter. 

Article 16 
Submission of application 

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

Article 17 
Validation of an application for authorisation of a substantial modification of an aspect 
covered by Part I of the assessment report 

1. 

2. 

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

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

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

the assessment report; 

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

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

EN 

37 

   EN 

 
3. 

4. 

5. 

1. 

2. 

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

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

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

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

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

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

The reporting Member State shall assess the application and draw up an assessment 
report.  

The assessment report shall contain one of the following conclusions concerning the 
aspects addressed in Part I of the assessment report: 

(a) 

(b) 

the substantial modification is acceptable in view of the requirements set out in 
this Regulation; 

the substantial modification is acceptable in view of the requirements set out in 
this Regulation, but subject to compliance with specific conditions which shall 
be specifically listed in that conclusion; 

(c) 

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

EN 

38 

   EN 

 
3. 

4. 

5. 

6. 

1. 

2. 

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

For the purposes of this Article and Articles 19 and 23, the assessment date shall be 
the date on which the assessment report is submitted to the sponsor and to the other 
Member States concerned. 

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

The reporting Member State, and only the reporting Member State, may, between the 
validation  date  and  the  assessment  date,  request  additional  explanations  from  the 
sponsor, taking into account the considerations referred to in paragraph 4.  

For  the  purpose  of  obtaining  those  additional  explanations,  the  reporting  Member 
State may suspend the period referred to in paragraph 4 for a maximum of 10 days.  

Where,  upon  receipt  of  the  additional  explanations,  the  remaining  time  period  for 
submitting Part I of the assessment report is less than five days, it shall be extended 
to five days.  

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

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

The  sponsor  may  at  its  own  initiative  change  the  content  of  the  application  only 
between  the  validation  date  and  the  assessment  date  and  only  for  duly  justified 
reasons. In this case, the reporting Member State may, depending on the extent of the 
change to the content of the application, suspend the period referred to in paragraph 3 
for up to 60 days. 

Article 19 
Decision on the substantial modification of an aspect covered by Part I of the assessment 
report 

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

Notification  shall  be  done  by  way  of  one  single  decision  within  ten  days  from  the 
assessment date. 

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 

39 

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

(b) 

infringement of the national legislation referred to in Article 86. 

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

3. 

Where  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 through the EU portal of the following: 

2. 

3. 

(a)  whether the substantial modification concerns an aspect covered by Part II of 

the assessment report; and 

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

Where  the  Member  State  concerned  has  not  notified  the  sponsor  within  the  time 
period  referred  to  in  paragraph  1  the  substantial  modification  applied  for  shall  be 
considered as concerning an aspect covered by Part II of the assessment report and 
the application shall be considered as complete. 

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 sponsor thereof through the EU portal and shall 
set a maximum of six days for the sponsor to comment or to complete the application 
through the EU portal.  

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

Where the 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  substantial  modification  shall  be  considered  as 

EN 

40 

   EN 

 
concerning an aspect covered by Part II of the assessment report and the application 
shall be considered as complete. 

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

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

Notification  shall  be  done  by  way  of  one  single  decision  within  ten  days  from  the 
validation date.  

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

For  the  purpose  of  obtaining  additional  explanations,  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  explanations,  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  additional  explanations  within  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. 

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

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

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

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.  

4. 

5. 

6. 

7. 

1. 

2. 

EN 

41 

   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. 

2. 

3. 

1. 

2. 

Each  Member  State  concerned  shall  assess,  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.  

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

For the purpose of obtaining additional explanations from the sponsor, the Member 
State concerned may suspend the time period referred to paragraph 1 for a maximum 
of ten days. 

Where, upon receipt of the additional explanations, 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  additional  explanations  within  the  time  period 
referred to in 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. 

Article 23 
Decision on the substantial modification of aspects covered by Parts I and II of the 
assessment report 

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

Notification  shall  be  done  by  way  of  one  single  decision  within  ten  days  from  the 
assessment date or the last day of the assessment referred to in Article 22, whichever 
is later. 

Where  the  conclusion  of  the  reporting  Member  State  is  that  the  substantial 
modification covered by Part I of  the assessment  report is acceptable or  acceptable 
subject  to  conditions,  the  conclusion  of  the  Member  State  concerned  shall  be  the 
same as that of the reporting Member State. 

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

(a) 

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

(b) 

infringement of the national legislation referred to in Article 86. 

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

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

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

3. 

4. 

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  the  authorisation  of  a  clinical  trial  shall  contain  all  the 
documentation and information necessary for 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 subjects, subjects, and trial sites; 

(c) 

the  investigational  medicinal  products  and,  where  necessary,  the  auxiliary 
medicinal products, in particular their properties, labelling, manufacturing and 
control; 

(d)  measures to protect subjects. 

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

2. 

The  application  dossier  for  the  authorisation  of  a  substantial  modification  shall 
contain all the following documentation and information necessary for the validation 
and assessment referred to in Chapter III: 

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(a) 

a  reference  to  the  clinical  trial  or  clinical  trials  which  are  substantially 
modified; 

(b) 

a clear description of the substantial modification; 

(c) 

(d) 

a presentation of data and additional information in support of the substantial 
modification, where necessary; 

 a  clear  description  of  the  consequences  of  the  substantial  modification  as 
regards  subject  right  and  safety  and  reliability  and  robustness  of  the  data 
generated in the clinical trial. 

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

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. 

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.  

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

Clinical trial data submitted in an application 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  trials  registry  platform  of  the  World  Health 
Organisation. 

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

3. 

4. 

5. 

6. 

7. 

Article 26 
Language requirements 

The language of the application dossier, or parts thereof, shall be determined by the Member 
State concerned.  

Member  States,  in  applying  the  first  paragraph,  shall  consider  accepting,  for  the 
documentation not addressed to the subject, a commonly understood language in the medical 
field. 

Article 27 
Update by way of delegated acts 

The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in 
order to amend Annexes I and II with the objective to adapt them to technical progress or to 
take account of global regulatory developments. 

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Chapter V 
Protection of subjects and informed consent 

Article 28 
General rules 

1. 

A clinical trial may be conducted only where all of the following conditions are met: 

(a) 

the  anticipated  therapeutic  and  public  health  benefits  justify  the  foreseeable 
risks and inconveniences; 

(b) 

compliance with point (a) is permanently observed; 

(c) 

(d) 

the subject or, where the subject is not able to give informed consent, his or her 
legal representative has given informed consent; 

the subject or, where the subject is not able to give informed consent, his or her 
legal  representative  has  had  the  opportunity,  in  a  prior  interview  with  the 
investigator  or  a  member  of  the  investigating  team,  to  understand  the 
objectives,  risks  and  inconveniences  of  the  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 integrity, to privacy and to the 
protection  of  the  data  concerning  him  or  her  in  accordance  with  Directive 
95/46/EC are safeguarded. 

The  rights,  safety  and  well-being  of  the  subjects  shall  prevail  over  the  interests  of 
science and society. 

Any subject may, without any resulting detriment, withdraw from the clinical trial at 
any time by revoking his or her informed consent. The withdrawal of consent shall 
not affect the activities carried out based on consent before its withdrawal. 

Article 29 
Informed consent 

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 write, oral consent in the presence of at 
least one impartial witness may be given in exceptional cases. The subject or his or 
her  legal  representative  shall  be  provided  with  a  copy  of  the  document  by  which 
informed consent has been given. 

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 person. It shall include both medical and legal 

2. 

3. 

1. 

2. 

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3. 

1. 

information.  It  shall  inform  the  subject  about  his  or  her  right  to  revoke  his  or  her 
informed consent.  

The subject shall be provided with a contact point where he or she may obtain further 
information. 

Article 30 
Clinical trials on incapacitated subjects 

In the case of incapacitated subjects who have not given, or have not refused to give, 
informed  consent  before  the  onset  of  their  incapacity,  a  clinical  trial  may  be 
conducted  only where, in  addition to the conditions set out in Article 28, all of the 
following conditions are met: 

(a) 

(b) 

(c) 

the  informed  consent  of  the  legal  representative  has  been  obtained,  whereby 
consent shall represent the subject’s presumed will; 

the incapacitated subject has received adequate information in relation to his or 
her capacity for understanding regarding the trial, the risks and the benefits; 

the  explicit  wish  of  an  incapacitated  subject  who  is  capable  of  forming  an 
opinion  and  assessing  this  information  to  refuse  participation  in,  or  to  be 
withdrawn from, the clinical trial at any time is considered by the investigator; 

(d)  no  incentives  or  financial  inducements  are  given  except  compensation  for 

participation in the clinical trial; 

(e) 

(f) 

(g) 

such research is essential to validate data obtained in clinical trials on persons 
able to give informed consent or by other research methods; 

such  research  relates  directly  to  a  life-threatening  or  debilitating  medical 
condition from which the subject suffers; 

the clinical trial has been designed to minimise pain, discomfort, 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  participation  in  the  clinical  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 conducted only where, in addition to the conditions 
set out in Article 28, all of the following conditions are met: 

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(a) 

(b) 

(c) 

the  informed  consent  of  the  legal  representative  has  been  obtained,  whereby 
consent shall represent the minor’s presumed will; 

the minor has received all relevant information in a way adapted to his or her 
age  and  maturity,  from  professionals  trained  or  experienced  in  working  with 
children, regarding the trial, the risks and the benefits; 

the  explicit  wish  of  a  minor  who  is  capable  of  forming  an  opinion  and 
assessing this information to refuse participation in, or to be withdrawn from, 
the clinical trial at any time, is duly taken into consideration by the investigator 
in accordance with his or her age and maturity; 

(d)  no  incentives  or  financial  inducements  are  given  except  compensation  for 

participation in the clinical trial; 

(e) 

(f) 

(g) 

such research is essential to validate data obtained in clinical trials on persons 
able to give informed consent or by other research methods; 

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

the clinical trial has been designed to minimise pain, discomfort, 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 patients is obtained from the clinical trial. 

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

Article 32 
Clinical trials in emergency situations 

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  given  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 and it is impossible to supply prior information to the 
subject; 

(b)  no legal representative is available; 

(c) 

the subject has not previously expressed objections known to the investigator; 

2. 

1. 

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(d) 

(e) 

the  research  relates  directly  to  a  medical  condition  which  causes  the 
impossibility to obtain prior informed consent and to supply prior information; 

the clinical trial poses a minimal risk to, and imposes a minimal burden on, the 
subject. 

2. 

The informed consent referred to in paragraph 1 shall be obtained, and information 
on the clinical trial shall be given, in accordance with the following requirements: 

(a) 

(b) 

regarding  incapacitated  subjects  and  minors,  the  informed  consent  referred  to 
in  paragraph  1  shall  be  obtained  as  soon  as  possible  from  the  legal 
representative and the information referred to in paragraph 1 shall be given as 
soon as possible to the subject; 

regarding other subjects, the informed consent referred to in paragraph 1 shall 
be  obtained  as  soon  as  possible  from  the  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 representative 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 continue the trial shall be obtained from the 
subject as soon as it is capable 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. 

2. 

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

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

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

That  notification  shall  be  made  within  15  days  from  the  end  of  the  recruitment  of 
subjects. In case of re-start of recruitment, paragraph 1 shall apply.  

Article 34 
End of the clinical trial, early termination of the clinical trial 

1. 

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

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2. 

3. 

4. 

5. 

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

The sponsor shall notify each Member State concerned of the end of the clinical trial 
through the EU portal. 

That notification shall be made within 15 days from the end of the clinical trial. 

Within one year from the end of a clinical trial, the sponsor shall submit to the EU 
database a summary of the results 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  results  shall  be  submitted  as  soon  as  it  is 
available.  In  this  case,  the  protocol  shall  specify  when  the  results  are  going  to  be 
submitted, together with an explanation. 

For the purpose of this Regulation, if a suspended 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 clinical trial. In the case of early termination, the 
date of the early termination shall be considered as the date of the end of the clinical 
trial. 

Without  prejudice  to  paragraph  3,  where  the  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 Regulation, 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 context 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 electronic database for the reporting provided for 
in Articles 38 and 39. 

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Article 37 
Reporting of adverse events and serious adverse events by the investigator to the sponsor 

1. 

2. 

3. 

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 and within the time periods specified in 
the protocol. 

The  investigator  shall  immediately  report  serious  adverse  events  to  the  sponsor 
unless the protocol provides, for certain adverse events, that no reporting is required. 
The  investigator  shall  record  all  serious  adverse  events.  Where  necessary,  the 
investigator shall send a follow-up report to the sponsor. 

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

Article 38 
Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency 

1. 

2. 

3. 

1. 

2. 

The sponsor shall  report electronically and without delay to the electronic database 
referred to in Article 36 all relevant information about suspected unexpected serious 
adverse  reactions  to  investigational  medicinal  products  insofar  as  the  suspected 
unexpected  serious  adverse  reaction  occurred  in  a  clinical  trial  conducted  by  the 
sponsor, or occurred in a clinical trial related to the sponsor.  

The  time  period  for  reporting  shall  take  account  of  the  severity  of  the  reaction. 
Where  necessary  to  ensure  timely  reporting,  the  sponsor  may  submit  an  initial 
incomplete report followed up by a complete report. 

Where a sponsor, due to a lack of resources, does not have the possibility to report to 
the electronic database referred to in Article 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 

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. 

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

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Article 40 
Assessment by Member States 

1. 

2. 

1. 

2. 

The  Agency  shall,  by  electronic  means,  forward  to  the  relevant  Member  States  the 
information reported in accordance with Article 38 and 39 

Member  States  shall  cooperate  in  assessing  the  information  reported  in  accordance 
with Articles 38 and 39. 

Article 41 
Annual reporting by the sponsor to the marketing authorisation holder 

Regarding authorised medicinal products which, according to the protocol, are used 
in accordance with the terms of the marketing authorisation, the sponsor shall inform 
annually  the  marketing  authorisation  holder  of  all  suspected  serious  adverse 
reactions. 

The  obligation  referred  to  in  paragraph  1  starts  with  the  first  authorisation  of  a 
clinical trial in accordance with this Regulation. It ends with the end of the clinical 
trial. 

Article 42 
Technical aspects 

Technical aspects  for safety reporting  in accordance 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 requirements 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 developments in the field of clinical trials. 

Article 43 
Reporting with regard to auxiliary medicinal products 

Safety reporting with regard to auxiliary medicinal products shall be made in accordance with 
Chapter 3 of Directive 2001/83/EC.  

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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 conducted in accordance with the protocol. 

Without prejudice to Union legislation and specific guidelines of the Commission the sponsor 
and the investigator, when drawing up the protocol and when applying 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  international  guidelines  on  good  clinical  practice 
referred to in the second paragraph 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 intervention 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  Member  State  concerned  as  qualifying  for  an 
investigator because of the necessary scientific knowledge and experience in patient care.  

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

Article 47 
Suitability of trial sites 

The facilities where the clinical trial is to be conducted shall be suitable for the clinical trial. 

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Article 48 
Tracking, storing, destruction and return of medicinal products 

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

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

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

Article 49 
Reporting of serious breaches 

Where the sponsor is aware, with respect to a clinical trial for which it is a sponsor, 
of a serious breach of this Regulation 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 days of becoming aware of that breach. 

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

Article 50 
Other reporting obligations relevant for subject safety 

The  sponsor  shall  notify  the  Member  States  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. 

The sponsor shall submit to the Member States concerned, through the EU portal, all 
inspection reports of third country authorities concerning a clinical trial conducted by 
that sponsor. 

Article 51 
Urgent safety measures 

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

The  sponsor  shall  without  delay  inform  the  Member  States  concerned,  through  the 
EU portal, of the event and the measures taken. 

This Article is without prejudice to Chapters II and VII. 

1. 

2. 

1. 

2. 

1. 

2. 

1. 

2. 

3. 

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Article 52 
Investigator’s brochure 

1. 

2. 

3. 

1. 

2. 

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

The  investigator’s  brochure  shall  contain  all  clinical  and  non-clinical  data  on  the 
investigational medicinal products relevant to the clinical trial. 

The investigator’s brochure shall be updated where new safety information becomes 
available, and at least once per year. 

Article 53 
Recording, processing, handling and storage of information 

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

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

Article 54 
Clinical trial master file 

The sponsor and the investigator shall keep a clinical trial master file. 

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

Article 55 
Archiving of the clinical trial master file 

Unless  other  Union  legislation  requires  archiving  for  a  longer  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 shall 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. 

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

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

2. 

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

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

Chapter IX 
Manufacturing and import of investigational medicinal products 
and auxiliary medicinal products  

Article 57 
Scope 

Notwithstanding  Article  1,  this  Chapter  shall  apply  to  the  manufacture  and  import  of 
investigational medicinal products and auxiliary medicinal products. 

Article 58 
Manufacturing and import authorisation 

1. 

2. 

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

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

(a) 

(b) 

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

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

3. 

The  applicant  shall  specify,  in  the  request  for  authorisation,  the  types  and 
pharmaceutical  forms  of  the  investigational  medicinal  product  manufactured  or 

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imported, the manufacturing or import operations, the manufacturing process where 
to  be 
relevant, 
manufactured, and detailed information concerning the qualified person. 

investigational  medicinal  products  are 

the  site  where 

the 

4. 

5. 

6. 

1. 

2. 

1. 

Articles  42  to  46(e)  of  Directive  2001/83/EC  shall  apply  to  the  manufacturing  and 
importation authorisation referred to in paragraph 1. 

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

(a) 

(b) 

re-labelling,  re-packaging  or  reconstitution  prior  to  use  or  packaging,  where 
those  processes  are  carried  out  in  hospitals,  health  centres  or  clinics,  by 
pharmacists  or  other  persons  legally  authorised  in  the  Member  State  to  carry 
out such processes, and if the investigational medicinal products are intended 
to be used exclusively by those institutions; 

the  manufacture  or  import  of  radiopharmaceuticals  used  as  diagnostic 
investigational  medicinal  products  where  those  processes  are  carried  out  in 
hospitals,  health  centres  or  clinics,  by  pharmacists  or  other  persons  legally 
authorised in the Member State concerned to carry out such processes, and if 
the  investigational  medicinal  products  are  intended  to  be  used  exclusively  in 
those institutions;  

(c) 

the  preparation  of  medicinal  products  referred  to  in  Article  3(1)  and  (2)  of 
Directive 2001/83/EC. 

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

Article 59 
Responsibilities of the qualified person 

The  qualified  person  shall  ensure  that  each  batch  of  investigational  medicinal 
products manufactured in or imported into the Union complies with the requirements 
set out in Article 60 and shall certify that those requirements are fulfilled. 

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

Article 60 
Manufacturing and import 

Investigational medicinal products shall be manufactured in applying manufacturing 
practice which ensures the quality of such medicinal products in order to safeguard 
subject  safety  and  the  reliability  and  robustness  of  clinical  data  generated  in  the 
clinical  trial  (hereinafter  'good  manufacturing  practice').  The  Commission  shall  be 
empowered to adopt delegated acts in accordance with Article 85 in order to specify 
the detailed requirements of good manufacturing practice for ensuring the quality of 

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2. 

3. 

investigational medicinal products, taking account of subject safety or data reliability 
and robustness, technical progress and global regulatory developments 

Paragraph 1 shall not apply to the processes referred to in Article 58(5). 

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 investigational 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 marketing authorisation. 

Article 62 
Manufacturing of auxiliary medicinal products 

Where  the  auxiliary  medicinal  product  is  not  authorised,  and  where  an  authorised  auxiliary 
medicinal  product  is  modified  while  this  modification  is  not  covered  by  a  marketing 
authorisation,  it  shall  be  manufactured  by  applying  the  necessary  standards  to  ensure 
appropriate quality. 

Chapter X 
Labelling 

Article 63 
Unauthorised investigational and unauthorised auxiliary medicinal products 

1. 

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

(a) 

Information to identify contact persons or persons involved in the clinical trial; 

(b) 

Information to identify the clinical trial; 

(c) 

Information to identify the medicinal product; 

(d) 

Information related to the use 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 trial, whether the products are 
investigational  or  auxiliary  medicinal  product,  and  whether  they  are  products  with 
particular characteristics.  

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A list of information appearing on the outer packaging and immediate packaging is 
set out in Annex IV. 

1. 

2. 

Article 64 
Authorised investigational and authorised auxiliary medicinal products 

Authorised  investigational  medicinal  products  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. 

Notwithstanding paragraph 1(b), where the specific 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 particulars relating to the identification of the 
trial and of the contact person shall appear on the outer packaging and the immediate 
packaging of authorised investigational medicinal products. A list of these additional 
particulars appearing on the outer packaging and immediate packaging is set out in 
Annex IV.  

Article 65 
Radiopharmaceutical used as investigational medicinal product for a medical diagnosis 

Articles 63 and 64 shall not apply to radiopharmaceuticals 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 robustness 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 safety and the reliability and robustness of data 
generated in a clinical trial or to take account of technical progress. 

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Chapter XI 
Sponsor and investigator 

A clinical trial may have one or several sponsors. 

Article 68 
Sponsor 

Any sponsor may delegate any or all of its tasks to an individual, a company, an institution or 
an  organisation.  Such  delegation  shall  be  without  prejudice  to  the  responsibility  of  the 
sponsor. 

The investigator and the sponsor may be the same person. 

Article 69 
Co-sponsorship 

1. 

2. 

Where a clinical trial has more than one sponsor, all sponsors shall be subject to the 
responsibilities  of  a  sponsor  under  this  Regulation,  unless  the  sponsors  decide 
otherwise  in  a  contract  setting  out  their  respective  responsibilities.  Where  the 
contract  does  not  specify  to  which  sponsor  a  given  responsibility  is  attributed,  that 
responsibility shall lie with all sponsors. 

By  way  of  derogation  from  paragraph  1,  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 regarding 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 Union. That contact person shall be the addressee 
for all communications with the sponsor provided for in this Regulation. Any communication 
to that contact person shall be considered as communication to the sponsor. 

Article 71 
Liability 

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

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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 financial capacity of the sponsor and the investigator. 

Article 73 
National indemnification mechanism 

1. 

2. 

3. 

Member  States  shall  provide  for  a  national  indemnification  mechanism  for 
compensating damage as referred to in Article 72. 

The  sponsor  shall  be  deemed  to  comply  with  Article  72  where  it  makes  use  of  the 
national indemnification mechanism in the Member State concerned. 

The use of the national indemnification mechanism 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  clinical  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  objective  grounds  for  considering  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. 

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2. 

1. 

2. 

3. 

4. 

5. 

6. 

The measures referred to in paragraph 1 shall be communicated to all Member States 
concerned through the EU portal. 

Article 75 
Member State inspections 

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

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

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

The  Agency  shall  coordinate  cooperation  on  inspections  between  Member  States, 
inspections  conducted  by  Member  States  in  third  countries,  and  inspections 
conducted  in  the  framework  of  a  marketing  authorisation  application  under 
Regulation (EC) No 726/2004. 

Following an inspection, the Member State under whose responsibility the inspection 
has  been  conducted  shall  draw  up  an  inspection  report.  That  Member  State  shall 
make the inspection report available to the 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. 

The  Commission  shall  specify  the  modalities  for  the  inspection  procedures  by  the 
way of implementing acts. Those implementing acts shall be adopted in accordance 
with the examination procedure referred to in Article 84(2). 

Article 76 
Union controls and Union inspections 

1. 

The Commission may conduct controls in order to verify 

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

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

(c)  whether the regulatory system applicable to clinical trials conducted outside the 

Union ensures that Article 25(3) of this Regulation is complied with. 

2. 

The Commission may conduct inspections where it considers necessary. 

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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. 

2. 

3. 

4. 

5. 

6. 

The Commission shall set up and maintain a database at Union level (hereinafter, the 
‘EU database’). The Commission shall be considered controller of the database. 

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

The  EU  database  shall  be  established  to  enable  the  co-operation  between  the 
competent authorities of the Member 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 submissions of an application for authorisation 
of a clinical trial or a substantial modification. 

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

– 

– 

– 

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

protecting commercially confidential information; 

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

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

No personal data of subjects shall be publicly accessible. 

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

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7. 

1. 

2. 

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

Chapter XV 
Cooperation between Member States 

Article 79 
National contact points 

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

Each  Member  State  shall  communicate  the  contact  point  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 the cooperation of the Member States in the 
framework of the authorisation procedures referred to in Chapters II and III of this Regulation 
and the functioning of the cooperation referred to in Article 40(2).  

Article 81 
Clinical Trials Coordination and Advisory Group 

1. 

2. 

3. 

4. 

A  Clinical  Trials  Coordination  and  Advisory  Group  (CTAG),  composed  of  the 
national contact points referred to in Article 79 is hereby established. 

The CTAG shall have the following tasks: 

(a) 

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

(b) 

assist the Commission in providing for the support referred to in Article 80; 

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

The CTAG shall meet at regular intervals and whenever the situation requires, on a 
request from the Commission or a Member State. 

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5. 

The secretariat shall be provided by the Commission 

Chapter XVI 
Fees 

Article 82 
General principle 

This Regulation shall be without prejudice to the possibility for Member States to levy a fee 
for  the  activities  set  out  in  this  Regulation,  provided  that  the  level  of  the  fee  is  set  in  a 
transparent manner and on the basis of cost recovery principles. 

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. 

2. 

1. 

2. 

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

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

Where  the  opinion  of  the  committee  is  to  be  obtained  by  written  procedure,  that 
procedure shall be terminated without result 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 

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

The delegation of power referred 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. 

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3. 

4. 

5. 

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 the decision in the Official Journal of the 
European Union or at a later date specified therein. It shall not affect the validity of 
any delegated acts already in force. 

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

A delegated act adopted pursuant to Articles 27, 42, 60 and 67 shall enter into force 
only  if  no  objection  has  been  expressed  either  by  the  European  Parliament  or  the 
Council  within  a  period  of  2  months  of  notification  of  that  act  to  the  European 
Parliament  and  the  Council  or  if,  before  the  expiry  of  that  period,  the  European 
Parliament  and  the  Council  have  both  informed  the  Commission  that  they  will  not 
object.  That  period  shall  be  extended  by  2  months at the initiative of the European 
Parliament or the Council. 

Chapter XVIII 
Miscellaneous provisions 

Article 86 
Medicinal products containing, consisting of or derived from cells 

This  Regulation  shall  not  affect  the  application  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  States  shall  communicate  the  national  legislation 
concerned to the Commission. 

Article 87 
Relation with other legislation 

This  Regulation  shall  be  without  prejudice  to,  Council  Directive  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 European Parliament and of the Council.27 

24 
25 
26 
27 

OJ L 180, 9.7.1997, p. 22.  
OJ L 159, 29.6.1996, p. 1. 
OJ L 106, 17.4.2001, p. 1. 
OJ L 125, 21.5.2009, p. 75. 

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Article 88 
Investigational medicinal products free of charge for the subject 

Without prejudice to the Member States’ competence for the definition of their health policy 
and  for  the  organisation  and  delivery  of  health  services  and  medical  care,  the  costs  for 
investigational medicinal products shall not be borne by the subject.  

Article 89 
Data Protection 

1. 

2. 

Member  States  shall  apply  Directive  95/46/EC  to  the  processing  of  personal  data 
carried out in the Member States pursuant to this Regulation.  

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  prejudice  to  national  and  Union  rules  on  the  civil  and  criminal 
liability of the sponsor or the investigator. 

Chapter XIX 
Final provisions 

Article 91 
Repeal 

1. 

2. 

3. 

Directive  2001/20/EC is repealed as of [please set a specific date - two years after 
publication of this Regulation]. 

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 clinical trial shall continue 
to  be  governed  by  that  Directive  until  [please  set  a  specific  date  –  five  years  after 
publication of this Regulation]. 

References  to  Directive  2001/20/EC  shall  be  construed  as  references  to  this 
Regulation  and  shall  be  read  in  accordance  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 authorisation of a clinical trial 
is  submitted  between  [please  set  a  specific  date  -  two  years  from  the  publication  of  this 

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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 2001/20/EC. That clinical 
trial  shall  continue  to  be  governed  by  that  Directive  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 
The President 

For the Council 
The President 

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1. 

1. 

2. 

3. 

4. 

2. 

5. 

6. 

ANNEX I 
Application dossier for initial application 

INTRODUCTION AND GENERAL PRINCIPLES 

The  sponsor  shall,  where  appropriate,  refer  to  previous  applications.  If  these 
applications have been submitted by another sponsor, a written agreement from that 
sponsor shall be submitted. 

The  application  shall  be  signed  by  the  sponsor.  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 trial will be conducted in accordance with the protocol. 

The application dossier for an application referred to in Article 11 shall be limited to 
sections 2 to 10 of this Annex. 

Without prejudice to Article 26, the application dossier for an application referred to 
in Article 14 shall be limited to sections 11 to 17 of this Annex. 

COVER LETTER 

The cover letter shall draw attention to peculiarities of the trial. 

However,  in  the  cover  letter  it  is  not  necessary  to  reproduce  information  already 
contained in the EU application form, 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  the  trial  or  investigational  medicinal 
product  has  been  given  by  the  Agency,  the  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. 

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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 orphan designation for the investigational 
medicinal product or the disease. 

• 

• 

7. 

8. 

9. 

The  cover  letter  shall  indicate  where  the  relevant  information  is  contained  in  the 
application dossier. 

The  cover  letter  shall  indicate  where  in  the  application  dossier  the  reference  safety 
information  is  contained  for  assessing  whether  an  adverse  reaction  is  a  suspected 
unexpected serious adverse reaction. 

In  the  case  of  a  resubmission,  the  cover  letter  shall  highlight  the  changes  as 
compared to the previous submission. 

3. 

EU APPLICATION FORM 

10. 

The EU application form, duly filled in. 

4. 

11. 

12. 

PROTOCOL 

The  protocol  shall  describe 
considerations and organisation of a trial. 

the  objective,  design,  methodology,  statistical 

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 short title or name assigned to it. 

13. 

In particular, the protocol shall include: 

•  a clear and unambiguous definition of the end of the clinical 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  anticipated  benefits  and  risks  to  allow  assessment  in 

accordance with Article 6; 

•  inclusion and exclusion 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  from  the  clinical  trial,  an  explanation 

and justification for these exclusion criteria; 

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•  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 the publication policy; 

•  a  description  of  the  arrangements  for  taking  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  the  arrangements,  if  any,  for  tracing,  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; 
technical 
arrangements  that  will  be  implemented  to  avoid  unauthorised  access,  disclosure, 
dissemination, alteration or loss of information and personal data processed; 

in  particular  organisational  and 

•  a  description  of  measures  that  will  be  implemented  to  ensure  confidentiality  of 

records and personal data of subjects concerned in clinical trials; 

•  a description of measures that will be implemented 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-authorised auxiliary medicinal products. 

14. 

If  a  clinical  trial  is  conducted  with  an  active  substance  available  in  the  European 
Union under different trade names in a number of authorised medicinal products, the 
protocol  may  define  the  treatment  in  terms  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 adverse 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  unblinding  of  investigational  medicinal  products 
shall be addressed in the protocol, where necessary. 

17. 

The protocol shall be accompanied by a synopsis of the protocol. 

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5. 

18. 

19. 

20. 

21. 

22. 

6. 

23. 

24. 

25. 

INVESTIGATOR’S BROCHURE (IB) 

The purpose of the IB is to provide the investigators and others involved in the trial 
with  information  to  facilitate  their  understanding  of  the  rationale  for,  and  their 
compliance  with,  key  features  of 
the  dose,  dose 
frequency/interval, methods of administration, and safety monitoring procedures. 

the  protocol,  such  as 

The information in the IB shall be presented in a concise, simple, objective, balanced 
and non-promotional form that enables a clinician 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  clinical  trial  and  the  safe  use  of  the 
investigational  medicinal  product  in  the  trial  and  be  presented  in  the  form  of 
summaries. 

the  marketing  authorisation, 

If  the  investigational  medicinal  product  is  authorised,  and  is  used  according  to  the 
the  approved  summary  of  product 
terms  of 
characteristics  (SmPC)  shall  be  the  IB.  If  the  conditions  of  use  in  the  clinical  trial 
differ  from  those  authorised,  the  SmPC  shall  be  supplemented  with  a  summary  of 
relevant  non-clinical  and  clinical  data  that  support  the  use  of  the  investigational 
medicinal product in the clinical trial. Where the investigational medicinal product is 
identified  in  the  protocol  only  by  its  active  substance,  the  sponsor  shall  select  one 
SmPC  as  equivalent  to  the  IB  for  all  medicinal  products  that  contain  that  active 
substance and are used at any clinical trial site. 

For  a  multinational  trial  where  the  medicinal  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  choose  one  SmPC  for  the  whole  clinical  trial.  This  SmPC 
shall be the one best suited to ensure patient safety. 

If  the  IB  is  not  a  SmPC,  it  shall  contain  a  clearly  identifiable  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'). 

DOCUMENTATION  RELATING  TO  COMPLIANCE  WITH  GOOD  MANUFACTURING 
PRACTICE (GMP) FOR THE INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 

As regards documentation relating to GMP compliance, the following shall apply. 

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. 

If the IMP is not authorised, and does not have a marketing authorisation from a third 
country that is party to the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH), and is not 
manufactured in the EU, the following documentation shall be submitted: 

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•  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. 

In all other cases, a copy of the manufacturing/importing authorisation as referred to 
in Article 58 shall be submitted. 

For  IMPs  the  manufacturing  or  importation  of  which  is  not  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. 

IMP DOSSIER (IMPD) 

The  IMPD  shall  give  information  on  the  quality  of  any  IMP,  the  manufacture  and 
control of the IMP, and data from non-clinical studies and from its clinical use. 

26. 

27. 

7. 

28. 

7.1.1.  Data relating to the IMP 

7.1.1.1.  Introduction 

29. 

30. 

31. 

Regarding  data,  the  IMPD  may  be  replaced  by  other  documentation  which  may  be 
submitted alone or with a simplified IMPD. The details of this ‘simplified IMPD’ are 
set out in section 7.1.2. 

The IMPD shall be prefaced with a detailed table of contents and a glossary of terms. 

The information in the IMPD shall be concise. 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 submitted in a logical structure. 

7.1.1.3.  Non-clinical pharmacology and toxicology data 

33. 

The  IMPD  shall  also  contain  summaries  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 appropriate literature references. Wherever 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. 

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35. 

36. 

37. 

The  IMPD  shall  provide  a  critical  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. 

The  IMPD  shall  contain  a  statement  of  the  good  laboratory  practice  status  or 
equivalent standards, as referred to in Article 25(3). 

The test material used in toxicity studies shall be representative of that of the clinical 
trial use in terms of qualitative and quantitative impurity profiles. The preparation of 
the  test  material  shall  be  subject  to  the  controls  necessary  to  ensure  this  and  thus 
support the validity of the study. 

7.1.1.4.  Previous clinical trial and human experience data 

38. 

39. 

40. 

Clinical  trial  and  human  experience  data  shall  be  submitted  in  a  logical  structure, 
such  as  the  headings  of  the  current  version  of  Module  5  of  the  Common  Technical 
Document, or of the eCTD format. 

This  section  shall  provide  summaries  of  all  available  data  from  previous  clinical 
trials and human experience with the IMPs. 

It shall contain a statement of the GCP compliance 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. 

42. 

This section shall provide a brief integrated summary that critically analyses the non-
clinical and clinical data in relation to the potential risks and benefits of the proposed 
trial unless this information is already provided 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  benefits  for  studies  on  minors  or  incapacitated 
adults shall take account of the specific provisions set out in this Regulation. 

Where  appropriate,  safety  margins  shall  be  discussed  in  terms  of  relative  systemic 
exposure to the IMP, preferably based on ‘area under the curve’ (AUC) data, or peak 
concentration  (Cmax)  data,  whichever  is  considered  more  relevant,  rather  than  in 
terms of applied dose. The clinical relevance of any findings in the non-clinical and 
clinical  studies  along  with  any  recommendations  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-alone 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  assessors  to  reach  a  decision  on  the  potential 

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toxicity  of  the  IMP  and  the  safety  of  its  use  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 would usually be included in the IB, the pre-
clinical and clinical information shall 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 requirements 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  marketing
authorisation in an ICH country and is used in
the trial:  
- within the conditions of the SmPC 
- outside the conditions of the SmPC 
- after modification (e.g. blinding) 

Another pharmaceutical form or strength of the
is  authorised  or  has  a  marketing
IMP 
authorisation in an ICH country and the IMP is
supplied by the marketing authorisation holder

The  IMP 
is  not  authorised  and  has  no
marketing authorisation in an ICH country but
the  active  substance 
in  an
authorised medicinal product and 
- is supplied by the same manufacturer 
- is supplied by another manufacturer 

is  contained 

The IMP was subject to a previous clinical trial
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 
- new data are available since last amendment 
to the CTA 
- is used under different conditions 

SmPC 
P+A 

SmPC 
If appropriate 
SmPC 

If appropriate 
SmPC 

SmPC+P+A 

Yes 

Yes 

SmPC+P+A 
SmPC+S+P+A

Yes 
Yes 

Yes 
Yes 

Reference to previous submission 

New data 

New data 

New data 

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,  Adventitious  Agents  Safety  Evaluation,  Novel 
Excipients, and Solvents for Reconstitution and Diluents) 

46. 

If the IMP is defined in the protocol in terms of active substance or ATC code (see 
above, section 4), the applicant may replace the IMPD by one representative SmPC 
that  ATC  group. 
for  each  active  substance/active  substance  pertaining 
Alternatively, the applicant may provide a collated document containing information 
equivalent to that in the representative SmPCs for each active substance that could be 
used as an IMP in the clinical trial. 

to 

7.1.3. 

IMPD in cases of placebo 

47. 

If the IMP is a placebo, the information requirements shall be limited to quality data. 
No additional documentation is required if the placebo has the same composition as 

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8. 

48. 

9. 

49. 

50. 

the  tested  investigational  medicinal  product,  is  manufactured  by  the  same 
manufacturer, and is not sterile. 

AUXILIARY MEDICINAL PRODUCT DOSSIER 

Without prejudice to Article 62, the documentation requirements set out in sections 6 
and  7  shall  also  apply  also  for  auxiliary  medicinal  products.  However,  where  the 
auxiliary  medicinal  product  is  authorised  in  the  Member  State  concerned,  no 
additional information is submitted. 

SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP) 

If  available,  a  copy  of  the  summary  of  scientific  advice  of  the  Agency  or  of  any 
Member State or third country with regard to the clinical trial shall be submitted. 

If the clinical trial is part of an agreed 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 cover letter is sufficient (see section 2). 

10. 

CONTENT OF THE LABELLING OF THE IMPS 

11. 

51. 

52. 

12. 

53. 

54. 

RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED) 

Unless  described  in  the  protocol,  a  separate  document  shall  describe  in  detail  the 
procedures for enrolment of subjects. 

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  proposed  for  handling  responses  to  the 
advertisement  shall  be  outlined.  This  includes  the  planned  arrangements  for 
information or advice to the respondents found not to be suitable for inclusion in the 
trial. 

SUBJECT  INFORMATION AND  INFORMED  CONSENT PROCEDURE (INFORMATION PER 
MEMBER STATE CONCERNED) 

All  information  to  the  subjects  (or,  where  applicable,  the  parents  or  legal 
representative) before their decision to participate or abstain from participation shall 
be submitted together with the form for written informed consent. 

Description of procedures relating to informed 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; 

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– 

– 

– 

if a procedure with witnessed consent is to be used, relevant information on the 
reason for using a witness, on the selection of the witness and on the procedure 
for obtaining informed consent shall be provided. 

in  the  case  of  clinical  trials  as  referred  to  in  Article  32,  the  procedure  for 
obtaining  the  informed  consent  of  the  legal  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 urgency situation and to document it. 

In  these  cases,  the  information  given  to  the  subject  and  to  the  parents  or  legal 
representative shall be provided. 

SUITABILITY  OF  THE  INVESTIGATOR  (INFORMATION  PER  MEMBER  STATE 
CONCERNED) 

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. 

Description of the qualification 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 experience obtained from work with clinical trials and patient 
care shall be described. 

Any conditions, such as economic interests, that might be suspected to influence the 
impartiality of the principal investigators shall be presented. 

SUITABILITY OF THE FACILITIES (INFORMATION PER MEMBER STATE CONCERNED) 

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 responsible person, according to the 
system in the Member State shall be submitted. 

PROOF  OF  INSURANCE  COVER  OR  INDEMNIFICATION (INFORMATION  PER MEMBER 
STATE CONCERNED) 

FINANCIAL ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED) 

Information  on  financial  transactions  and  compensation  paid  to  subjects  and 
investigator/site for participating in the clinical trial shall be submitted. 

55. 

13. 

56. 

57. 

58. 

14. 

59. 

15. 

16. 

60. 

61. 

Description of any agreement between the sponsor and the site shall be submitted. 

17. 

PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED) 

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1. 

1. 

2. 

2. 

3. 

ANNEX II 
Application dossier for substantial modification 

INTRODUCTION AND GENERAL PRINCIPLES 

Where  a  substantial  modification  concerns  more  than  one  clinical  trial  of  the  same 
sponsor and the same IMP, the sponsor may make a single request for authorisation. 
The cover letter and the notification contain a list of all clinical trials affected with 
their official identification numbers and respective modification code numbers. 

The  application  shall  be  signed  by  the  sponsor.  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 

trial  will  be  conducted 

in  accordance  with 

the  amended 

documentation. 

COVER LETTER 

A cover letter with the following information 

– 

– 

– 

– 

– 

– 

in  its  subject  line  the  EU  trial  number  and  the  sponsor  protocol  number  (if 
available) with the title of the trial and the sponsor’s modification code number 
allowing unique identification of the substantial modification, whereby care is 
taken to use the code number consistently; 

identification of the applicant; 

identification  of  the  modification  (sponsor’s  substantial  modification  code 
number and date), whereby one modification could refer to several changes in 
the protocol or scientific supporting documents; 

a highlighted  indication  of  any special issues relating to the modification and 
an  indication  as  to  where  the  relevant  information  or  text  is  in  the  original 
application dossier; 

identification of any information not contained in the modification application 
form that might impact on the risk to subjects; 

where applicable, a list of all affected clinical trials with official identification 
numbers and respective modification code numbers (see above). 

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3. 

4. 

4. 

5. 

5. 

6. 

6. 

7. 

MODIFICATION APPLICATION FORM 

DESCRIPTION OF THE MODIFICATION 

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 extract 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, whereby identical changes can be grouped). 

The new version shall be identified by the date and an updated version number. 

SUPPORTING INFORMATION 

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. 

UPDATE OF EU APPLICATION FORM 

If a substantial modification involves changes 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. 

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ANNEX III 
Safety reporting 

1. 

1. 

2. 

3. 

4. 

2. 

REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE SPONSOR 

An  adverse  event  can  be  any  unfavourable  and  unintended  sign  (including  an 
abnormal  laboratory  finding,  for  example),  symptom  or  disease  temporally 
associated with the use of a medicinal product. 

The  investigator  shall  report  the  serious  adverse  events  referred  to  in  Article  37(2) 
immediately  following  knowledge  of  the  serious  adverse  event.  If  necessary,  a 
follow-up report shall be sent to allow the sponsor to determine whether the serious 
adverse event requires reassessment of the benefit-risk balance of the clinical trial. 

The investigator shall be responsible for reporting to the sponsor all serious adverse 
events  in  relation  to  subjects  treated  by  him  or  her  in  the  clinical  trial.  The 
investigator  does  not  need  to  actively  monitor  subjects  for  adverse  events  once  the 
trial has ended with regard to the subjects treated by him, unless otherwise provided 
for in the protocol. 

Serious adverse events occurring to a subject after the end of the trial with regard to 
the  subjects  treated  by  him  shall  be  reported  to  the  sponsor  if  the  investigator 
becomes aware of them. 

REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
BY THE SPONSOR TO THE AGENCY 

2.1. 

Serious event, ‘reaction’ 

5. 

6. 

7. 

8. 

the 
A  medical  event  which  requires  an 
characteristics/consequences  referred  to  in  point  29  of  the  second  paragraph  of 
Article 2 is a serious adverse event. 

to  prevent  one  of 

intervention 

The  definition  of  adverse  reaction  covers  also  medication  errors  and  uses  outside 
what is foreseen in the protocol, including misuse and abuse of the product. 

The  definition  implies  a  reasonable  possibility  of  a  causal  relationship  between  the 
event  and  the  IMP.  This  means  that  there  are  facts  (evidence)  or  arguments  to 
suggest a causal relationship. 

In  the  absence  of  information  on  causality  from  the  reporting  investigator,  the 
sponsor  shall  consult  the  reporting  investigator  and  encourage  him  to  express  an 
opinion on this aspect. The causality assessment given by the investigator shall not 
be  downgraded  by  the  sponsor.  If  the  sponsor  disagrees  with  the  investigator’s 
causality  assessment,  the  opinion  of  both  the  investigator  and  the  sponsor  shall  be 
provided with the report. 

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2.2. 

‘Expectedness’/‘unexpectedness’ 

9. 

10. 

11. 

12. 

Regarding  unexpectedness,  reports  which  add  significant  information  on  the 
specificity,  increase  of  occurrence,  or  severity  of  a  known,  already  documented 
serious adverse reaction shall constitute unexpected events.  

The  expectedness  of  an  adverse  reaction  shall  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. 

The  RSI  is  contained  in  the  Summary  of  product  characteristics  (‘SmPC’)  or  the 
investigator's  brochure  (IB).  The  covering  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. 

The  RSI  may  change  during  the  conduct  of  a  clinical  trial.  For  the  purpose  of 
reporting of suspected unexpected serious adverse 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 trial performed in at least one Member State shall report the 
following SUSARs: 

•  all SUSARs occurring in that clinical trial, 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  investigated)  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 medicinal product jointly, on the basis of a 
formal  agreement,  with  that  other  sponsor.  Provision  of  the  IMP  or 
information to a future potential marketing authorisation holder on safety 
matters should not be considered a joint development. 

15. 

SUSARs identified after the end of the trial shall be reported as well.  

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2.4. 

Time limits for reporting fatal or life-threatening SUSARs 

16. 

17. 

18. 

19. 

For fatal and life-threatening SUSARs the sponsor shall report 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. 

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. 

The  clock  for  initial  reporting  (day  0  =  Di  0)  starts  as  soon  as  the  information 
containing the minimum reporting criteria has been received by the sponsor. 

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-fatal or non-life-threatening SUSARs 

20. 

21. 

SUSARs  which  are  not  fatal  and  not  life-threatening  shall  be  reported  within  15 
days. 

If  a  SUSAR  turns  out  to  be  fatal  or  life-threatening,  whereas  initially  it  was 
considered  as  non-fatal  or  not  life-threatening,  the  non-fatal  or  non-life-threatening 
SUSAR shall be reported as soon as possible, 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  knowledge  of  the  reaction  being  fatal  or  life-
threatening. Regarding the follow-up report, see section 2.4. 

22. 

In cases where a SUSAR turns out to be fatal or life-threatening, whereas initially it 
was considered as non-fatal or not life-threatening, while the initial report has not yet 
been submitted, a combined report shall be created. 

2.6. 

Unblinding treatment allocation 

23. 

24. 

25. 

Only SUSARs on which the treatment allocation of the subject is unblinded shall be 
reported by the sponsor.  

The investigator shall only unblind the treatment allocation in the course of a clinical 
trial if this is relevant to the safety of the subject. 

As regards the sponsor, when an event may be a SUSAR the blind shall be broken by 
the sponsor only for that specific subject. The blind shall be maintained for persons 
responsible for the ongoing conduct of the trial (such as the management, monitors, 
investigators) and those responsible for data analysis and interpretation of results at 
the conclusion of the trial, such as biometrics 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 another ‘serious’ outcome (that 

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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  circumstances,  the  sponsor  shall  highlight  in  the 
protocol which serious events would be treated as disease-related and not subject to 
systematic unblinding and expedited reporting. 

In all cases, following unblinding, if the event turns out to be a SUSAR (for example 
as regards expectedness), the reporting rules for SUSARs shall apply. 

ANNUAL SAFETY REPORTING BY THE SPONSOR 

The report shall contain, in an appendix, the RSI in effect at the start of the reporting 
period. 

The  RSI  in  effect  at  the  start  of  the  reporting  period  shall  serve  as  RSI  during  the 
reporting period. 

If there are significant changes to the RSI during the reporting period 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. Despite the change to the RSI, the RSI in effect at the start of 
the reporting period serves as RSI during the reporting period. 

27. 

3. 

28. 

29. 

30. 

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ANNEX IV 
IMP and AMP labelling 

1. 

UNAUTHORISED 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  investigator  (for  the  purpose  of  this  Annex 
this is referred to as the ‘main contact’); 

(b)  pharmaceutical form, route of administration, 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) 

(e) 

a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 

the  subject  identification  number/treatment  number  and,  where  relevant,  the 
visit number; 

(f) 

the name of the investigator (if not included 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) 

(k) 

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; 

‘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. 

3. 

Symbols  or  pictograms  may  be  included  to  clarify  certain  information  mentioned 
above. Additional information, warnings or handling instructions may be displayed. 

The address and telephone number of the main contact need not appear on the label 
where  subjects  have  been  given  a  leaflet  or  card  which  provides  these  details  and 
have been instructed to keep this in their possession at all times. 

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1.2. 

Limited labelling of immediate packaging 

1.2.1. 

Immediate and outer packaging provided together 

4. 

When  the  product  is  provided  to  the  subject  or  the  person  administering  the 
medication  in  an  immediate  package  and  outer  packaging  intended  to  remain 
together,  and  the  outer  packaging  carries  the  particulars  listed  in  section  1.1.,  the 
following particulars shall appear on the immediate packaging (or any sealed dosing 
device that contains the immediate package): 

(a) 

name of the main contact; 

(b)  pharmaceutical  form,  route  of  administration  (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) 

(e) 

a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 

the  subject  identification  number/treatment  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  label  with  those  particulars.  The  immediate 
packaging shall contain the following: 

(a) 

name of the main contact; 

(b) 

route of administration (may be excluded 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 the contents and packaging operation; 

(d) 

(e) 

a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere; 

the  subject  identification  number/treatment  number  and,  where  relevant,  the 
visit number. 

2. 

6. 

UNAUTHORISED AUXILIARY MEDICINAL PRODUCTS 

The following particulars shall appear on the immediate and the outer packaging: 

a) 

b) 

name of the main contact; 

name  of  the  medicinal  product,  followed  by  its  strength  and  pharmaceutical 
form; 

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c) 

d) 

statement  of  the  active  substances  expressed  qualitatively  and  quantitatively 
per dosage unit; 

trial  reference  code  allowing  identification  of  the  trial  site,  investigator  and 
subject. 

ADDITIONAL  LABELLING  FOR  AUTHORISED 
PRODUCTS 

INVESTIGATIONAL  MEDICINAL 

The following particulars shall appear on the immediate and the outer packaging: 

a) 

b) 

name of the main contact; 

trial  reference  code  allowing  identification  of  the  trial  site,  investigator  and 
subject. 

REPLACING OF INFORMATION 

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  electronic  randomisation  system,  use  of  a 
centralised  information  system)  provided  that  subject  safety  and  the  reliability  and 
robustness of data are not compromised. This shall be justified in the protocol. 

3. 

7. 

4. 

8. 

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ANNEX V 
Correlation table 

Directive 2001/20/EC 

This Regulation 

Article 1(1) 

Article 1(2) 

Articles 1, 2, 1st paragraph, 2nd paragraph (1), 
(2), (4) 

Article 2, 2nd paragraph (26) 

Article 1(3), 1st subparagraph 

- 

Article 1(3), 2nd subparagraph 

Article 44, 3rd subparagraph 

Article 1(4) 

Article 2 

Article 3(1) 

Article 3(2) 

Article 3(3) 

Article 3(4) 

Article 4 

Article 5 

Article 6 

Article 7 

Article 8 

Article 9 

Article 10(a) 

Article 10(b) 

Article 10(c) 

Article 11 

Article 12 

Article 13(1) 

Article 13(2) 

Article 44, 2nd subparagraph 

Article 2 

- 

Article 4, 28, 29(1), 72 

- 

Article 29(3) 

Articles 28, 31, 10(1) 

Articles 28, 30, 10(2) 

Articles 4 to 14 

Articles 4 to 14 

- 

Articles 4 to 14 

Articles 15 to 24 

Article 51 

Articles 34, 35 

Article 78 

Article 74 

Article 58(1) to (4) 

Article 58 (2) 

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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 13(5) 

Article 14 

Article 15 

Article 16 

Article 17(1)(a) to (c) 

Article 17(1)(d) 

Article 17(2) 

Article 17(3)(a) 

Article 17(3)(b) 

Article 18 

Article 19, 1st paragraph, 1st sentence 

Article 19, 1st paragraph, 2nd sentence 

Article 19, 2nd paragraph 

Article 19, 3rd paragraph 

Article 20 

Article 21 

Article 22 

Article 23 

Article 24 

Article 59(2) 

- 

Article 63-67 

Article 75 

Article 37 

Article 38 

- 

Article 39 

- 

Article 40(1) 

- 

Article 71 

Article 70 

Article 88 

- 

- 

Article 84 

- 

- 

- 

87 

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   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  financial  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 operational appropriations  

3.2.3. Estimated impact on appropriations 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 

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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  envelope  of  the  Health  for  Growth  Programme 
2014-2020. 

1.3. 

Nature of the proposal/initiative  

X The proposal/initiative relates to a new action  

(cid:133)  The  proposal/initiative  relates  to  a  new  action  following  a  pilot  project/preparatory 
action30  

(cid:133) The proposal/initiative relates to the extension of an existing action  

(cid:133) The proposal/initiative relates to an action redirected towards a new action  

1.4. 

Objectives 

1.4.1.  The  Commission's  multiannual 

strategic  objective(s) 

targeted  by 

the 

proposal/initiative  

The  proposal  aims  to  promote  public  health  and  research  across  the  EU  through 
providing for harmonized rules on the authorisation 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 
30 

ABM: Activity-Based Management – ABB: Activity-Based Budgeting. 
As referred to in Article 49(6)(a) or (b) of the Financial Regulation. 

EN 

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Specific  objective  No.  4:  A  mechanism  of  'system  inspections'  of  third  countries' 
regulatory systems for clinical trials. 

ABM/ABB activity(ies) concerned 

Public health 

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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 applied 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 finalisation of the protocol and 'first patient in'; 

•  Level  of  administrative  costs  presenting  administrative  burdens,  and  of 

operational costs of clinical trials 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 criticised by all stakeholders (ranging from patients 
to  researchers  and  industry)  for  having  caused  a  significant  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 has 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 negative impact on the development 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  possibility  of  referring  to  the  results  and  findings  of 
clinical trials in applications for an authorisation for placing a medicinal product on 
the  Union  market,  including  subsequent  variations  and  extensions  of  the  marketing 
authorisation. 

This  is  critically  important  in  the  case  of  clinical  trials  because  practically  every 
larger clinical trial is performed in more than one Member State. 

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An  additional  factor  is  that  medicinal  products  intended  for  research  and 
development  trials  are  excluded  from  the  Community  Code  for  medicinal  products 
for human use. These products may have been produced in a different Member State 
from  that  where  the  clinical  trial  is  conducted.  Thus,  these  products  do  not  benefit 
from  the  secondary  Union  law  ensuring  their  free  movement  while  maintaining  a 
high level of protection of human health. 

1.5.3.  Lessons learned from similar experiences in the past 

In the area of regulation of medicines, since 1975 there are mechanisms in place to 
facilitate  the  authorisation  of  a  medicinal  product  in  the  internal  market.  This 
experience  has  proven  highly  successful.  Some  elements  of  the  present  initiative 
build on the experiences made in the area of the authorisation of medicines. 

On the other hand, the Clinical Trials Directive 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 with other relevant instruments 

Synergy  expected  with  the  revision  of  the  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. 

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1.6. 

Duration and financial impact  

(cid:133) Proposal/initiative of limited duration  

–  (cid:133)  Proposal/initiative in effect from [DD/MM]YYYY to [DD/MM]YYYY  

–  (cid:133)  Financial impact from YYYY to YYYY  

X Proposal/initiative of unlimited duration 

–  Implementation  with  a  start-up  period  from  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 taken by the Commission in order to ensure 
that the Regulation can function on the day of application of the Regulation), 

–  followed by full-scale operation. 

1.7.  Management mode(s) envisaged31  

X Centralised direct management by the Commission  

(cid:133)  Centralised  indirect  management  with  the  delegation  of  implementation  tasks 
to: 

–  (cid:133)  executive agencies  

–  (cid:133)  bodies set up by the Communities32  

–  (cid:133)  national public-sector bodies/bodies with public-service mission  

–  (cid:133)  persons entrusted with the implementation of specific actions pursuant to Title 
V of the Treaty on European Union and identified in the relevant basic act within 
the meaning of Article 49 of the Financial Regulation  

(cid:133) Shared management with the Member States  

(cid:133) Decentralised management with third countries  

(cid:133) Joint management with international organisations (to be specified) 

If more than one management mode is indicated, please provide details in the "Comments" section. 

Comments  

31 

32 

Details  of  management  modes  and  references  to  the  Financial  Regulation  may  be  found  on  the 
BudgWeb site: http://www.cc.cec/budg/man/budgmanag/budgmanag_en.html 
As referred to in Article 185 of the Financial Regulation. 

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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 the EU acquis in the area of pharmaceutical and clinical 
trials  regulation.  Notably,  the  'Pharmaceutical  Committee'  is  going  to  provide  the 
forum to monitor and assess the application 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 requirements 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 the developers of the EU portal. 

Repeated meetings with stakeholders and Member 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 regulatory control mechanisms, DG SANCO will devise 
an anti-fraud strategy in line with the Commission'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.  Where  necessary,  networking  groups  and  adequate 
IT tools dedicated to analysing fraud cases related to the financing implementing activities of 
the Clinical Trials Regulation will be set up. In particular a series of measures will be put in 
place such as:   

- decisions, agreements and contracts resulting from the financing implementing activities of 
the Clinical Trials Regulation will expressly entitle the Commission, including OLAF, and the 
Court of Auditors to conduct audits, on-the-spot checks and inspections; 

-  during  the  evaluation  phase  of  a  call  for  proposals/tender,  the  proposers  and  tenderers  are 
checked against the published exclusion criteria based on declarations 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 related to fraud and irregularities is given to all staff involved in 

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contract  management  as  well  as  to  auditors  and  controllers  who  verify  the  beneficiaries' 
declarations on the spot. 

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3. 

ESTIMATED FINANCIAL IMPACT OF THE PROPOSAL/INITIATIVE  

3.1. 

Heading(s)  of  the  multiannual  financial  framework  and  expenditure  budget 
line(s) affected  

•  Existing expenditure budget lines  

In order of multiannual financial framework headings and budget lines. 

Budget line 

Type of  
expenditure

Contribution  

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  

Heading of 
multiannual 
financial 
framework 

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. 

Heading of 
multiannual 
financial 
framework 

Budget line 

Type of 
expenditure

Contribution  

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 
34 
35 

Diff. = Differentiated appropriations / Non-diff. = Non-Differentiated Appropriations 
EFTA: European Free Trade Association.  
Candidate countries and, where applicable, potential candidate countries from the Western Balkans. 

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3.2. 

Estimated impact on expenditure  

3.2.1. 

Summary of estimated impact on expenditure  

Heading of multiannual financial 
framework:  

Number 
3B 

Public Health Program 

EUR  

DG: SANCO 

(cid:121) Operational appropriations  

Number of budget line: 17.03.XX 

Number of budget line 

Appropriations 
administrative 
 from the envelope for specific programmes37  

an 

of 

Year 
201436 

Year 
2015 

Year 
2016 

Year 
2017  

Year 
2018  

Year 
2019  

Year 
2020 and 
following 
years 

TOTAL 

895.000 

1.082.0
00 

238.000  193.000 

447.000  998.000  671.000  232.000 

180.000 

184.000 

187.000 

175.000 

184.000 

187.000 + 
65.000 

2.959.000 

2.959.000 

Commitments 

Payments 

Commitments 

Payments 

(1) 

(2) 

(1a) 

(2a) 

nature 

financed 

Number of budget line: 17.01.04.02 

(3) 

57.000 

58.000 

119.000  121.000 

124.000 

126.000 

129.000 

TOTAL appropriations 

Commitments 

=1+1a 
+3 

952.000 

1.140.0
00 

357.000  314.000 

304.000 

310.000 

316.000 

734.000 

3.693.000 

36 
37 

All prices are current prices. 
Technical and/or administrative assistance and expenditure in support of the implementation of EU programmes and/or actions (former "BA" lines), indirect research, 
direct research. 

EN 

97 

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 

(cid:121) TOTAL operational appropriations  

Commitments 

Payments 

(4) 

(5) 

895.000 

1.082.0
00 

238.000  193.000 

447.000  998.000  671.000  232.000 

(cid:121)  TOTAL  appropriations  of  an  administrative  nature 
financed from the envelope for specific programmes  

(6) 

57.000 

58.000 

119.000  121.000 

180.000 

184.000 

187.000 

175.000 

184.000 

124.000 

126.000 

187.000 + 
65.000 

129.000 

TOTAL appropriations  
under HEADING SANCO 
of the multiannual financial framework 

Commitments 

  952.000 

Payments 

  504.000 

1.140.0
00 
1.056.0
00 

357.000  314.000 

304.000 

310.000 

316.000 

790.000  353.000 

299.000 

310.000 

316.000 + 
65.000 

2.959.000 

2.959.000 

734.000 

3.693.000 

3.693.000 

If more than one heading is affected by the proposal / initiative: 

(cid:121) TOTAL operational appropriations  

Commitments 

Payments 

(cid:121)  TOTAL  appropriations  of  an  administrative  nature 
financed from the envelope for specific programmes  

(4) 

(5) 

(6) 

TOTAL appropriations  
under HEADINGS 1 to 4 
of the multiannual financial framework 
(Reference amount) 

Commitments 

=4+ 6 

Payments 

=5+ 6 

EN 

98 

EN 

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heading of multiannual financial 
framework:  

5 

" Administrative expenditure " 

Year 
2014 

Year 
2015 

Year 
2016 

Year 
2017  

Year 
2018 

Year 
2019 

Year 
2020 
and 
followi
ng 
years 

DG: SANCO 

(cid:121) Human resources38 
(cid:121) Other administrative expenditure  

222.000  222.000  857.000  857.000 

857.000 

857.000 

857.000 

87.000 

88.000 

90.000 

92.000 

94.000 

EUR  

TOTAL 

4.730.00039 
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 
= Total payments) 

commitments 

87.000 

88.000 

90.000 

92.000 

94.000 

451.000 

38 

39 

40 

41 

In accordance with the impact assessment report, the necessary additional human ressources (1.75 FTE + 5 FTE with date of application) are going to be 
re-deployed from within DG SANCO. 
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. 
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'. 
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 

99 

EN 

 
  
 
 
 
 
 
 
 
 
 
 
 
                                                 
Year 
2014 

Year 
2015 

Year 
2016 

Year 
2017  

Year 
2018 

Year 
2019 

EUR 

Year 2020
and 
following 
years 

TOTAL 

TOTAL appropriations  
under HEADINGS 1 to 5 
of the multiannual financial framework  

Commitments 

952.000 

Payments 

504.000 

1.140.0
00 

1.056.0
00 

444.000  402.000 

394.000 

402.000 

410.000 

877.000  441.000 

389.000 

402.000 

410.000 + 
65.000 

4.144.000 

4.144.000 

EN 

100 

EN 

 
  
 
 
 
3.2.2.  Estimated impact on operational appropriations  

–  (cid:133)  The proposal/initiative does not require the use of operational appropriations  

–  X  The proposal/initiative requires the use of operational appropriations, as explained below:  

Year 
2014 

Year 
2015 

Year 
2016 

Year 
2017 

Year 
2108 

Year 
2019 

Commitment appropriations in EUR  

Year 
2020 and 
following 
years 

TOTAL 

OUTPUTS 

Cost 

r
e
b
m
u
N

f

s Cost 

t
u
p
t
u
o

f
o

r
e
b
m
u
N

  Cost 
s
t
u
p
t
u
o

f
o

r
e
b
m
u
N

r
e
b
m
u
N

s
t
u
p
t
u
o

f
o

Cost 

s Cost 

t
u
p
t
u
o

f
o

r
e
b
m
u
N

  Cost 

r
e
b
m
u
N

s Cost 

t
u
p
t
u
o

f
o

r
e
b
m
u
N

Total  
cost 

Total 
numbe
r of 
output
s 

Indicate 
objectives and 
outputs  

Type 
of 
output 

(cid:216) 

Avera
ge 
cost  
of the 
output 

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
Sub-total for specific objective N°2 

1 

300.00

1 

300.00

1 

300.00

1 

300.00

2 

600.000 

2 

600.000 

EN 

101 

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 

102 

EN 

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.3.  Estimated impact on appropriations of an administrative nature 

3.2.3.1.  Summary  

–  (cid:133)  The  proposal/initiative  does  not 

require 

the  use  of  administrative 

appropriations  

–  X  The  proposal/initiative  requires  the  use  of  administrative  appropriations,  as 

explained below: 

Year 
2014 

Year 
2015 

Year 
2016 

Year 
2017  

Year 
2018 

TOTAL 

Year 
2019 

Year 
2020 and 
following 
years 

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  

Subtotal HEADING 5 
of the multiannual 
financial framework

44

Outside HEADING 545 
of the multiannual 
financial framework  

Human resources  

Other expenditure  
of an administrative 
nature 

Subtotal  
outside HEADING 5 
of the multiannual 
financial framework  

87.000 

88.000 

90.000 

92.000 

94.000 

451.000 

87.000 

88.000 

90.000 

92.000 

94.000 

451.000 

57.000 

58.000 

119.000 

121.000 

124.000 

126.000 

129.000 

57.000 

58.000 

119.000 

121.000 

124.000 

126.000 

129.000 

734.000 

734.000 

42 

43 

44 

45 

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. 
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 'subtotal' for Heading 5. 
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 'subtotal' for Heading 5. 
Technical  and/or  administrative  assistance  and  expenditure  in  support  of  the  implementation  of  EU 
programmes and/or actions (former "BA" lines), indirect research, direct research. 

EN 

103 

   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  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' of administrative expenditure. 

EN 

104 

   EN 

 
                                                 
3.2.3.2.   Estimated requirements of human resources  

–  X  The proposal/initiative does not require the use of human resources47 

–  (cid:133)  The  proposal/initiative  requires  the  use  of  human  resources,  as  explained 

Year 
2014 

Year 
2015 

Year 
2016 

Year 
2017  

Year 
2018 

Year 
2019 

1.75 
FTEc 

1.75 
FTE 

6.75 
FTE 

6.75 FTE 

6.75 
FTE 

6.75 
FTE 

TO

Year 
2020 and 
following 
years 
6.75 FTE 

below: 

–   

17 01 01 01 (Headquarters and Commission’s 
Representation Offices) 48 
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) 
XX 01 04 yy 49 

- at Headquarters50 

- 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  relation  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 

48 

49 
50 

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. 
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. 
Under the ceiling for external personnel from operational appropriations (former "BA" lines). 
Essentially  for  Structural  Funds,  European  Agricultural  Fund  for  Rural  Development  (EAFRD)  and 
European Fisheries Fund (EFF). 

EN 

105 

   EN 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
3.2.4.  Compatibility with the current multiannual financial framework  

–  X  Proposal/initiative 

is  compatible 

the  2014-2020  multiannual 

financial 

framework. 

–  (cid:133)  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. 

–  (cid:133)  Proposal/initiative requires application of the flexibility instrument 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 million (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  co-financing 
body  

TOTAL appropriations 
cofinanced  

51 

See points 19 and 24 of the Interinstitutional Agreement. 

EN 

106 

   EN 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
3.3. 

Estimated impact on revenue  

–  X  Proposal/initiative has no financial impact on revenue. 

EN 

107 

   EN