# EUR-Lex - 52012PC0369 - EN

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# 52012PC0369

**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 /* COM/2012/0369 final - 2012/0192 (COD) */**

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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 use[1] are investigations of medicines
in humans where the medicines are applied outside normal clinical practice on
the basis of a research protocol.

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

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

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

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

The data available support these
criticisms:

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

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

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

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

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

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

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

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

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

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

3.           LEGAL ASPECTS OF THE PROPOSAL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

·
Where a clinical trial is modified after it has
been authorised, this modification is subject to authorisation if, and only if,
the modification has a substantial impact on the safety or rights of the
subjects or on the reliability and robustness of the data generated in the
clinical trial.

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

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

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

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

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

3.3.        Interface with 'scientific advice'

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3.10.  Inspections (Chapter 13 of the
proposed Regulation)

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

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

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

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

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

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

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

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

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

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

3.13. Legal form of a Regulation

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

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

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

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

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

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

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

3.14.  Competences, Double legal basis and
subsidiarity

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4.           BUDGETARY IMPLICATION

The budgetary implications of this proposal are
as follows:

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

·
Commission staff to manage the functioning of
the Regulation;

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

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

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

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

2012/0192 (COD)

Proposal for a

REGULATION OF THE EUROPEAN PARLIAMENT
AND OF THE COUNCIL

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

(Text with EEA relevance)

THE EUROPEAN PARLIAMENT AND THE
COUNCIL OF THE EUROPEAN UNION,

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

Having regard to the proposal from the
Commission[13],

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

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

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

After consulting the European Data
Protection Supervisor[16],

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

Whereas:

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

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

(3)       The existing definition of
a clinical trial as contained in Directive 2001/20/EC of the European
Parliament and of the Council of 4 April 2001 on the approximation of the laws,
regulations and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials on
medicinal products for human use[18]
should be clarified. For that purpose, the concept of clinical trial should be
more precisely defined by introducing the broader concept of 'clinical study'
of which the clinical trial is a category. That category should be defined on
the basis of specific criteria. This approach takes due account of
international guidelines, and is in line with the EU legislation governing
medicinal products, which builds on the dichotomy of 'clinical trial' and 'non-interventional
study'.

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

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

(6)       The Member States concerned
should cooperate in assessing a request for authorisation of a clinical trial.
This cooperation should not include aspects of an intrinsically national
nature, nor ethical aspects of a clinical trial, such as informed consent.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(39)     Medicinal products intended for research and development trials fall
outside the scope of Directive 2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code relating to medicinal products
for human use[19]. Such medicinal products include medicinal
products used in the context of a clinical trial. They should be covered by
specific rules taking account of their peculiarities. In establishing these
rules, a distinction should be made between investigational medicinal products
(the tested product and its reference products, including placebos) and
auxiliary medicinal products (medicinal products used in the context of a
clinical trial but not as investigational medicinal products), such as
medicinal products used for background treatment, challenge agents, rescue
medication, or used to assess end-points in a clinical trial. Auxiliary
medicinal products should not include concomitant medications, i.e. medications
unrelated to the clinical trial and not relevant for the design of the clinical
trial.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

HAVE ADOPTED THIS REGULATION:

Chapter I
General provisions

Article 1
Scope

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

It shall not apply to non-interventional
studies.

Article 2
Definitions

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

The following definitions shall also apply:

(1)
‘Clinical study’: any investigation in relation
to humans intended

(a)     to discover or verify the clinical,
pharmacological or other pharmacodynamic effects of one or more medicinal
products;

(b)     to identify any adverse reactions to
one or more medicinal products; or

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

with the objective of ascertaining their
safety or efficacy.

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

(a)     the investigational medicinal products
are not authorised;

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

(c)     the assignment of the subject to a
particular therapeutic strategy is decided in advance and does not fall within normal
clinical practice of the Member State concerned;

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

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

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

(a)     the investigational medicinal products
are authorised;

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

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

(4)
‘Non-interventional study’: a clinical study other
than a clinical trial;

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

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

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

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

(9)
‘Authorised investigational medicinal product’:
a medicinal product authorised in accordance with Regulation (EC) No 726/2004,
or, in any Member State concerned, in accordance with Directive 2001/83/EC, irrespective
of changes to the labelling of the medicinal product, which is used as an investigational
medicinal product;

(10)
'Authorised auxiliary medicinal product’: a
medicinal product authorised in accordance with Regulation (EC) No 726/2004,
or, in any Member State concerned, in accordance with Directive 2001/83/EC, irrespective
of changes to the labelling of the medicinal product, which is used as an
auxiliary medicinal product;

(11)
‘Member State concerned’: the Member State where
an application for authorisation of a clinical trial or of a substantial
modification has been submitted under Chapters II and III of this Regulation;

(12)
‘Substantial modification’: any change to any
aspect of the clinical trial which is made after notification of the decision referred
to in Articles 8, 14, 19, 20 and 23 and which is likely to have a substantial impact
on the safety or rights of the subjects or on the reliability and robustness of
the data generated in the clinical trial;

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

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

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

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

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

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

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

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

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

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

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

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

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

(26)
‘Good clinical practice’: a set of detailed ethical
and scientific quality requirements for designing, conducting, performing,
monitoring, auditing, recording, analysing and reporting clinical trials
ensuring that the rights, safety and well-being of subjects are protected, and
that the data generated in the clinical trial are reliable and robust;

(27)
‘Inspection’: the act by a competent authority
of conducting an official review of documents, facilities, records, quality
assurance arrangements, and any other resources that are deemed by the
competent authority to be related to the clinical trial and that may be located
at the site of the trial, at the sponsor's and/or contract research
organisation's facilities, or at other establishments which the competent
authority sees fit to inspect;

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

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

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

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

Article 3
General principle

A clinical trial may be conducted only if

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

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

Chapter II
Authorisation procedure for a clinical trial

Article 4
Prior authorisation

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

Article 5
Submission of an application

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

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

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

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

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

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

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

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

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

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

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

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

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

Article 6
Assessment report – Aspects covered by Part I

1.           The reporting Member State
shall assess the application with regard to the following aspects:

(a)
Compliance with Chapter V with respect to the
following:

(i)      The anticipated therapeutic and
public health benefits taking account of all of the following:

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

–
the relevance of the clinical trial, taking
account of the current state of scientific knowledge, and of whether the
clinical trial has been recommended or imposed by regulatory authorities in
charge of the assessment and authorisation of the placing on the market of
medicinal products;

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

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

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

–
the characteristics of the intervention compared
to normal clinical practice;

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

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

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

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

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

2.           The reporting Member State shall
draw up an assessment report. The assessment of the aspects referred to in
paragraph 1 shall constitute Part I of the assessment report.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article 7
Assessment report – Aspects covered by Part II

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

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

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

(c)
compliance of the arrangements for recruitment
of subjects with the requirements set out in Chapter V;

(d)
compliance with Directive 95/46/EC;

(e)
compliance with Article 46;

(f)
compliance with Article 47;

(g)
compliance with Article 72;

(h)
compliance with the applicable rules for the
collection, storage and future use of biological samples of the subject.

The assessment of the aspects referred to in
the first subparagraph shall constitute Part II of the assessment report.

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

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

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

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

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

Article 8
Decision on the clinical trial

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

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

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

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

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

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

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

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

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

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

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

Article 9
Persons assessing the application

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

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

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

Article 10
Specific considerations for vulnerable populations

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

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

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

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

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

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

Article 12
Withdrawal

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

Article 13
Resubmission

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

Article 14
Subsequent addition of a Member State concerned

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article 15
General principles

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

Article 16
Submission of application

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

5.           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.

6.           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

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

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

2.           Where the conclusion of
the reporting Member State is that the substantial modification is acceptable
or acceptable subject to conditions, the conclusion of the Member State
concerned shall be the same as that of the reporting Member State.

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:

(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.

2.           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.

3.           Where the Member State concerned
finds that the substantial modification does not concern an aspect covered by
Part II of the assessment report or that the application is not complete, it
shall inform the 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 concerning an aspect covered by
Part II of the assessment report and the application shall be considered as complete.

4.           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.

5.           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.

6.           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.

7.           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

1.           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.

2.           The aspects covered by
Part I of the assessment report shall be assessed in accordance with Article 18
and the aspects covered by Part II of the assessment report shall be assessed
in accordance with Article 22.

Article 22
Assessment of a substantial modification of aspects covered by Parts I and II
of the assessment report – Assessment of the aspects covered by Part II of the
assessment report

1.           Each Member State
concerned shall 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.

2.           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.

3.           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

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

Notification shall be done by way of 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.

2.           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.

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.

3.           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.

4.           Where the Member State
concerned has not notified the sponsor of its decision within the time periods
referred to in paragraph 1, the conclusion on 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.

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:

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

(b)
a clear description of the substantial
modification;

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

(d)
 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.

3.           Non-clinical data
submitted in an application dossier shall be based on studies complying with
Union legislation on the principles of good laboratory practice, as applicable
at the time of performance of those studies, or equivalent standards.

4.           Where reference is made in
the application dossier to data generated in a clinical trial, that clinical
trial shall have been conducted in accordance with this Regulation.

5.           Where the clinical trial
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.

6.           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.

7.           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.

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.

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

(d)     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.

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

3.           Any subject may, without
any resulting 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

1.           Informed consent shall be
written, dated and signed and given freely by the subject or his or her legal
representative after having been duly informed of the nature, significance,
implications and risks of the clinical trial. It shall be appropriately
documented. Where the subject is unable to 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.

2.           Written information given
to the subject and/or the legal representative for the purposes of obtaining
his or her informed consent shall be kept concise, clear, relevant, and
understandable to a lay person. It shall include both medical and legal
information. It shall inform the subject about his or her right to revoke his
or her informed consent.

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

Article 30
Clinical trials on incapacitated subjects

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

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

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

(c)     the explicit wish of an incapacitated
subject who is capable of forming an opinion and assessing this information to
refuse 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)     such research is essential to validate
data obtained in clinical trials on persons able to give informed consent or by
other research methods;

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

(g)     the clinical
trial has
been designed to minimise pain, 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:

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

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

(c)     the explicit wish of a minor who is
capable of forming an opinion and assessing this information to refuse
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)     such research is essential to validate
data obtained in clinical trials on persons able to give informed consent or by
other research methods;

(f)      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;

(g)     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.

2.           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

1.           By way of derogation from
points (c) and (d) of Article 28(1), from points (a) and (b) of Article 30(1)
and from points (a) and (b) of Article 31(1), informed consent may be obtained after
the start of the clinical trial to continue the clinical trial and information
on the clinical trial may be 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;

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

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

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

(a)
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;

(b)
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.           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.

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

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

2.           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.

3.           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.

4.           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.

5.           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.

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

1.           The investigator shall
report to the sponsor adverse events or laboratory abnormalities identified in
the protocol as critical to the safety evaluation in accordance with the reporting
requirements and within the time periods specified in the protocol.

2.           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.

3.           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.           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.

2.           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.

3.           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

1.           Regarding non-authorised investigational
medicinal products other than placebo, and authorised investigational medicinal
products which, according to the protocol, are not used in accordance with the
terms of the marketing authorisation, the sponsor shall submit annually by
electronic means to the Agency a report on the safety of each investigational
medicinal product used in a clinical trial for which it is the sponsor.

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

Article 40
Assessment by Member States

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

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

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

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

2.           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.

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.

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

1.           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.

2.           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

1.           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.

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

Article 50
Other reporting obligations relevant for subject safety

1.           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.

2.           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

1.           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.

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

3.           This Article is without
prejudice to Chapters II and VII.

Article 52
Investigator’s brochure

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

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

3.           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

1.           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.

2.           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.

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

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

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

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

(b)
it shall have permanently and continuously at its
disposal the services of 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 imported, the
manufacturing or import operations, the manufacturing process where relevant,
the site where the investigational medicinal products are to be manufactured,
and detailed information concerning the qualified person.

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

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

(a)
re-labelling, re-packaging or reconstitution
prior to use or packaging, where those processes are carried out in 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;

(b)
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.

6.           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

1.           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.

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

Article 60
Manufacturing and import

1.           Investigational medicinal
products shall be manufactured in applying manufacturing practice which ensures
the 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
investigational medicinal products, taking account of subject safety or data
reliability and robustness, technical progress and global regulatory
developments

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

3.           Investigational medicinal
products imported into the Union shall be manufactured by applying quality
standards at least equivalent to those laid down on the basis of this
Regulation.

Article 61
Modification of authorised 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.

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

Article 64
Authorised investigational and authorised auxiliary medicinal products

1.           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.

2.           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.

Chapter XI
Sponsor and investigator

Article 68
Sponsor

A clinical trial may have one or several
sponsors.

Any sponsor may delegate any or all of its
tasks to an 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.           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.

2.           By way of derogation from paragraph
1, all sponsors shall be responsible for establishing one sponsor responsible
for each of the following:

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

(b)     providing responses to all questions
from subjects, investigators or any Member State concerned 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.

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

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

3.           The use of the national
indemnification 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.

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

Article 75
Member State inspections

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

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

3.           Where a Member State concerned
intends to carry out an inspection with regard to one or several clinical 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.

4.           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.

5.           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.

6.           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.

Chapter XIV
IT Infrastructure

Article 77
EU portal

The Commission shall set up and maintain a
portal at Union level as a single entry point for the submission of data and
information relating to clinical trials in accordance with this Regulation.

Data and information submitted through the
EU portal shall be stored in the EU database referred to in Article 78.

Article 78
EU database

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

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

2.           The EU database shall be
established to enable the co-operation between the competent authorities of the
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.

3.           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.

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

5.           No personal data of
subjects shall be publicly accessible.

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

7.           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

1.           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.

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

2.           The CTAG shall have the
following tasks:

(a)     support the exchange of 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;

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

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

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.           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.

2.           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

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

2.           The delegation of power
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.

3.           The delegation of power
referred to in Articles 27, 42, 60 and 67 may be revoked at any time by the
European Parliament or by the Council. A decision of revocation shall put an
end to the delegation of the power specified in that decision. It shall take
effect the day following the publication of 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.

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

5.           A delegated act adopted
pursuant to 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/Euratom[24],
Council Directive 96/29/Euratom[25],
Directive 2001/18/EC of the European Parliament and of the Council[26], and Directive 2009/41/EC of
the European Parliament and of the Council.[27]

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

2.           Regulation (EC) No 45/2001
shall apply to the processing of personal data carried out by the Commission
and the European Medicines Agency pursuant to this Regulation.

Article 90
Civil and criminal liability

This Regulation is without 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.           Directive 2001/20/EC is repealed
as of [please set a specific date - two years after publication of this
Regulation].

2.           By way of derogation from the
paragraph 1, where the request for authorisation of a clinical trial has been
submitted before the date provided for in Article 92(2) [application date]
pursuant to Directive 2001/20/EC, that clinical trial shall continue to be
governed by that Directive until [please set a specific date – five years
after publication of this Regulation].

3.           References to Directive
2001/20/EC shall be construed as references to this Regulation and shall be
read in 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 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                       For
the Council

The President                                                 The
President

ANNEX I
Application dossier for initial application

1.           Introduction and general principles

1.           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.

2.           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.

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

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

2.           Cover
letter

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

6.           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 use[28] (if the Agency has already
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.           The cover letter shall
indicate where the relevant information is contained in the application
dossier.

8.           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.

9.           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.           Protocol

11.         The protocol shall describe
the objective, design, methodology, statistical considerations and organisation
of a trial.

12.         The protocol shall be identified
by the title, the sponsor’s protocol code number specific for all versions of
it (if available), the date and number of the version, to be updated when it is
amended, and a 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;

· 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; in particular organisational and
technical arrangements that will be implemented to avoid unauthorised access,
disclosure, dissemination, alteration or loss of information and personal data
processed;

· 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.

5.           Investigator’s
brochure (IB)

18.         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 protocol, such as the dose, dose frequency/interval,
methods of administration, and safety monitoring procedures.

19.         The information in the IB shall
be presented in a concise, simple, objective, balanced and non-promotional form
that enables a 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.

20.         If the investigational
medicinal product is authorised, and is used according to the terms of the
marketing authorisation, the approved summary of product characteristics (SmPC)
shall be the IB. If the conditions of use in the clinical trial differ from
those authorised, the SmPC 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.

21.         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.

22.         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').

6.           Documentation relating to compliance
with good manufacturing practice (GMP) for the investigational medicinal
product (IMP)

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

24.         In the following cases, no
documentation needs to be submitted:

· the IMP is authorised, is not modified, and is manufactured in the
EU; or

· the IMP is not manufactured in the EU, but is authorised and is not
modified.

25.         If the IMP is not
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:

· a copy of the importation authorisation as referred to in Article 58;
and

· certification by the qualified person in the EU that the
manufacturing complies with GMP at least equivalent to the GMP in the EU,
unless there are specific arrangements provided for in mutual recognition agreements
between the EU and third countries.

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

27.         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.

7.           IMP dossier (IMPD)

28.         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.

7.1.1.     Data relating to the IMP

7.1.1.1.  Introduction

29.         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.

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

31.         The information in the IMPD
shall be 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.

35.         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.

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

37.         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.         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.

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

40.         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.         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.

42.         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 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 || SmPC

- outside the conditions of the SmPC || SmPC || If appropriate || If appropriate

- after modification (e.g. blinding) || P+A || SmPC || SmPC

Another pharmaceutical form or strength of the IMP is authorised or has a marketing authorisation in an ICH country and the IMP is supplied by the marketing authorisation holder || SmPC+P+A || Yes || Yes

The IMP is not authorised and has no marketing authorisation in an ICH country but the active substance is contained in an authorised medicinal product and || || ||

- is supplied by the same manufacturer || SmPC+P+A || Yes || Yes

- is supplied by another manufacturer || SmPC+S+P+A || Yes || Yes

The IMP was subject to a previous clinical 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 || Reference to previous submission

- new data are available since last amendment to the CTA || New data || New data || New data

- is used under different conditions || If appropriate || If appropriate || If appropriate

(S: Data relating to the active substance;
P: Data relating to the IMP; A: Additional information on Facilities and
Equipment, 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 for each active
substance/active substance pertaining to that ATC group. 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.

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

8.           Auxiliary
medicinal product dossier

48.         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.

9.           Scientific advice and Paediatric
investigation plan (PIP)

49.         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.

50.         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.         Recruitment arrangements (information per
Member State concerned)

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

52.         Where the recruitment of
subjects is done through advertisement, copies of the advertising material shall
be submitted, including any printed materials, and audio or visual recordings.
The procedures 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.

12.         Subject information and informed consent
procedure (information per Member State concerned)

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

54.         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;

–
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.

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

13.         Suitability of the investigator
(information per Member State concerned)

56.         A list of the planned
clinical trial sites, the name and position of the investigators responsible
for a team of investigators conducting a clinical trial at a clinical trial
site ('principal investigator') and the number of subjects at the sites shall
be submitted.

57.         Description of the
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.

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

14.         Suitability of the facilities
(information per Member State concerned)

59.         A written statement on the
suitability of the trial sites by the head of the clinic/institution at the
trial site or by some other responsible person, according to the system in the
Member State shall be submitted.

15.         Proof of insurance cover or indemnification
(information per Member State concerned)

16.         Financial arrangements (information per Member
State concerned)

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

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

17.         Proof of payment of fee (information per
Member State concerned)

ANNEX II
Application dossier for substantial modification

1.           Introduction and general principles

1.           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.

2.           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.

2.           cover letter

3.           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).

3.           Modification application Form

4.           description of the modification

4.           The modification shall be
described as follows:

–       an extract from the amended documents
showing previous and new wording in track changes, as well as an 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).

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

5.           Supporting information

6.           Additional supporting
information shall include where applicable:

–       summaries of data;

–       an updated overall risk/benefit
assessment;

–       possible consequences for subjects
already included in the trial;

–       possible consequences for the
evaluation of the results.

6.           Update of EU application form

7.           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.

ANNEX III
Safety reporting

1.           Reporting
of serious adverse events by the investigator to the sponsor

1.           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.

2.           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.

3.           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.

4.           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.

2.           Reporting of suspected unexpected
serious adverse reactions (SUSARs) by the sponsor to the Agency

2.1.        Serious event, ‘reaction’

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

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

7.           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.

8.           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.

2.2.        ‘Expectedness’/‘unexpectedness’

9.           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.

10.         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.

11.         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.

12.         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.

2.4.        Time limits for reporting fatal
or life-threatening SUSARs

16.         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.

17.         If
the initial report is incomplete, e.g. if the sponsor has not provided all the
information/assessment within seven days, the sponsor shall submit a completed
report based on the initial information within an additional eight days.

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

19.         If
significant new information on an already reported case is received by the
sponsor, the clock starts again at day zero, i.e. the date of receipt of new
information. This information shall be reported as a follow-up report within 15
days.

2.5.        Time limits for reporting non-fatal or
non-life-threatening SUSARs

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

21.         If a SUSAR turns out to be
fatal or life-threatening, whereas initially it was considered as non-fatal or
not life-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.         Only SUSARs on which the treatment allocation of the subject is unblinded
shall be reported by the sponsor.

24.         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.

25.         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 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.

27.         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.

3.           Annual
safety reporting by the sponsor

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

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

30.         If there are significant
changes to the 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.

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

(e)     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)      period of use (use-by date, expiry
date or re-test date as applicable), in month/year format and in a manner that
avoids any ambiguity;

(k)     ‘Keep out of reach of children’,
except when the product is for use in trials where the product is not taken
home by subjects.

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

3.           The address and telephone
number of the 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.

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

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

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

2.           Unauthorised auxiliary medicinal
products

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

a)      name of the main contact;

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

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

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

3.           Additional labelling for authorised investigational
medicinal products

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

a)      name of the main contact;

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

4.           Replacing of information

8.           Any of the particulars listed
in sections 1, 2, and 3 may be omitted and replaced by other means (e.g. use of
a centralised 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.

ANNEX V
Correlation table

Directive 2001/20/EC || This Regulation

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

Article 1(2) || Article 2, 2nd paragraph (26)

Article 1(3), 1st subparagraph || -

Article 1(3), 2nd subparagraph || Article 44, 3rd subparagraph

Article 1(4) || Article 44, 2nd subparagraph

Article 2 || Article 2

Article 3(1) || -

Article 3(2) || Article 4, 28, 29(1), 72

Article 3(3) || -

Article 3(4) || Article 29(3)

Article 4 || Articles 28, 31, 10(1)

Article 5 || Articles 28, 30, 10(2)

Article 6 || Articles 4 to 14

Article 7 || Articles 4 to 14

Article 8 || -

Article 9 || Articles 4 to 14

Article 10(a) || Articles 15 to 24

Article 10(b) || Article 51

Article 10(c) || Articles 34, 35

Article 11 || Article 78

Article 12 || Article 74

Article 13(1) || Article 58(1) to (4)

Article 13(2) || Article 58 (2)

Article 13(3), 1st subparagraph || Article 59(1), 60(1), (3)

Article 13(3), 2nd subparagraph || Article 60(1)

Article 13(3), 3rd subparagraph || -

Article 13(4) || Article 59(2)

Article 13(5) || -

Article 14 || Article 63-67

Article 15 || Article 75

Article 16 || Article 37

Article 17(1)(a) to (c) || Article 38

Article 17(1)(d) || -

Article 17(2) || Article 39

Article 17(3)(a) || -

Article 17(3)(b) || Article 40(1)

Article 18 || -

Article 19, 1st paragraph, 1st sentence || Article 71

Article 19, 1st paragraph, 2nd sentence || Article 70

Article 19, 2nd paragraph || Article 88

Article 19, 3rd paragraph || -

Article 20 || -

Article 21 || Article 84

Article 22 || -

Article 23 || -

Article 24 || -

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

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 structure[29]

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

 ̈ The
proposal/initiative relates to a new action following a pilot
project/preparatory action[30]

 ̈ The proposal/initiative relates to the
extension of an existing action

 ̈ The
proposal/initiative relates to an action redirected towards a new action

1.4.        Objectives

1.4.1.     The Commission's
multiannual 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.

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

ABM/ABB activity(ies) concerned

Public health

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.

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.

1.6.        Duration and financial
impact

 ̈ Proposal/initiative of limited
duration

–
 ̈  Proposal/initiative in effect from [DD/MM]YYYY to [DD/MM]YYYY

–
 ̈  Financial impact from YYYY to YYYY

X Proposal/initiative of unlimited
duration

–
Implementation with a start-up period 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) envisaged[31]

X Centralised direct management
by the Commission

 ̈ Centralised indirect management with the delegation of implementation tasks to:

–
 ̈  executive agencies

–
 ̈  bodies set up by the Communities[32]

–
 ̈  national public-sector bodies/bodies with public-service mission

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

 ̈ Shared management with the Member States

 ̈ Decentralised management with third countries

 ̈ Joint management with international organisations (to be specified)

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

Comments

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

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.

Heading of multiannual financial framework || Budget line || Type of expenditure || Contribution

Number [Description: Public Health Program] || Diff./non-diff. ([33]) || from EFTA[34] countries || from candidate countries[35] || from third countries || within the meaning of Article 18(1)(aa) of the Financial Regulation

3B || 17.03.XX || Diff/non-diff. || YES/NO || 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/NO || YES/NO || YES/NO || YES/NO

3.2.        Estimated impact on
expenditure

3.2.1.     Summary of estimated impact
on expenditure

EUR

Heading of multiannual financial framework: || Number 3B || Public Health Program

DG: SANCO || || || Year 2014[36] || Year 2015 || Year 2016 || Year 2017 || Year 2018 || Year 2019 || Year 2020 and following years || TOTAL

Ÿ Operational appropriations || || || || || || || ||

Number of budget line: 17.03.XX || Commitments || (1) || 895.000 || 1.082.000 || 238.000 || 193.000 || 180.000 || 184.000 || 187.000 || 2.959.000

Payments || (2) || 447.000 || 998.000 || 671.000 || 232.000 || 175.000 || 184.000 || 187.000 + 65.000 || 2.959.000

Number of budget line || Commitments || (1a) || || || || || || || ||

Payments || (2a) || || || || || || || ||

Appropriations of an administrative nature financed  from the envelope for specific programmes[37] || || || || || || || ||

Number of budget line: 17.01.04.02 || || (3) || 57.000 || 58.000 || 119.000 || 121.000 || 124.000 || 126.000 || 129.000 || 734.000

TOTAL appropriations for DG SANCO || Commitments || =1+1a +3 || 952.000 || 1.140.000 || 357.000 || 314.000 || 304.000 || 310.000 || 316.000 || 3.693.000

Payments || =2+2a+3 || 504.000 || 1.056.000 || 790.000 || 353.000 || 299.000 || 310.000 || 316.000 + 65.000 || 3.693.000

Ÿ TOTAL operational appropriations || Commitments || (4) || 895.000 || 1.082.000 || 238.000 || 193.000 || 180.000 || 184.000 || 187.000 || 2.959.000

Payments || (5) || 447.000 || 998.000 || 671.000 || 232.000 || 175.000 || 184.000 || 187.000 + 65.000 || 2.959.000

Ÿ TOTAL appropriations of an administrative nature financed from the envelope for specific programmes || (6) || 57.000 || 58.000 || 119.000 || 121.000 || 124.000 || 126.000 || 129.000 || 734.000

TOTAL appropriations under HEADING SANCO of the multiannual financial framework || Commitments || || 952.000 || 1.140.000 || 357.000 || 314.000 || 304.000 || 310.000 || 316.000 || 3.693.000

Payments || || 504.000 || 1.056.000 || 790.000 || 353.000 || 299.000 || 310.000 || 316.000 + 65.000 || 3.693.000

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

Ÿ TOTAL operational appropriations || Commitments || (4) || || || || || || || ||

Payments || (5) || || || || || || || ||

Ÿ TOTAL appropriations of an administrative nature financed from the envelope for specific programmes || (6) || || || || || || || ||

TOTAL appropriations under HEADINGS 1 to 4 of the multiannual financial framework (Reference amount) || Commitments || =4+ 6 || || || || || || || ||

Payments || =5+ 6 || || || || || || || ||

Heading of multiannual financial framework: || 5 || " Administrative expenditure "

EUR

|| || || Year 2014 || Year 2015 || Year 2016 || Year 2017 || Year 2018 || Year 2019 || Year 2020 and following years || TOTAL

DG: SANCO ||

Ÿ Human resources[38] || 222.000 || 222.000 || 857.000 || 857.000 || 857.000 || 857.000 || 857.000 || 4.730.000[39]

Ÿ Other administrative expenditure || || || 87.000 || 88.000 || 90.000 || 92.000 || 94.000 || 451.000

TOTAL DG SANCO[40] || Appropriations || || || 87.000 || 88.000 || 90.000 || 92.000 || 94.000 || 451.000

TOTAL appropriations under HEADING 5 of the multiannual financial framework[41] || (Total commitments = Total payments) || || || 87.000 || 88.000 || 90.000 || 92.000 || 94.000 || 451.000

EUR

|| || || Year 2014 || Year 2015 || Year 2016 || Year 2017 || Year 2018 || Year 2019 || Year 2020 and following years || TOTAL

TOTAL appropriations under HEADINGS 1 to 5 of the multiannual financial framework || Commitments || 952.000 || 1.140.000 || 444.000 || 402.000 || 394.000 || 402.000 || 410.000 || 4.144.000

Payments || 504.000 || 1.056.000 || 877.000 || 441.000 || 389.000 || 402.000 || 410.000 + 65.000 || 4.144.000

3.2.2.     Estimated impact on
operational appropriations

–
 ̈  The proposal/initiative does not require the use of operational
appropriations

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

Commitment appropriations in EUR

Indicate objectives and outputs ò || || || Year 2014 || Year 2015 || Year 2016 || Year 2017 || Year 2108 || Year 2019 || Year 2020 and following years || TOTAL

OUTPUTS

Type of output || Average cost of the output || Number of outputs || Cost || Number of outputs || Cost || Number of outputs || Cost || Number of outputs || Cost || Number of outputs || Cost || Number of outputs || Cost || Number of outputs || Cost || Total number of outputs || Total cost

SPECIFIC OBJECTIVE No 1 Electronic 'EU portal' and "EU database" for submission for requests for authorisation of clinical trials, and follow-up || || || || || || || || || || || || || || || ||

- Output || IT Portal || || 1 || 595.000 || 1 || 782.000 || 1 || 238.000 || 1 || 193.000 || 1 || 180.000 || 1 || 184.000 || 1 || 187.000 || 7 || 2.359.000

Sub-total for specific objective N°1 || 1 || 595.000 || 1 || 782.000 || 1 || 238.000 || 1 || 193.000 || 1 || 180.000 || 1 || 184.000 || 1 || 187.000 || 7 || 2.359.000

SPECIFIC OBJECTIVE No 2 Update of the 'Clinical trial module' of the existing EudraVigilance database to ensure processing of safety reports during clinical trials. || || || || || || || || || || || || || || || ||

- Output || IT update || || 1 || 300.000 || 1 || 300.000 || || || || || || || || || || || 2 || 600.000

Sub-total for specific objective N°2 || 1 || 300.000 || 1 || 300.000 || || || || || || || || || || || 2 || 600.000

|| || || || || || || || || || || || || || || ||

- Output || Meetings || || || || || || || || || || || || || || || || ||

|| || || || || || || || || || || || || || || ||

|| || || || || || || || || || || || || || || ||

- Output || System inspectoins || || || || || || || || || || || || || || || || ||

|| || || || || || || || || || || || || || || ||

TOTAL COST || 2 || 895.000 || 2 || 1.082.000 || 1 || 238.000 || 1 || 193.000 || 1 || 180.000 || 1 || 184.000 || 1 || 187.000 || 9 || 2.959.000

3.2.3.     Estimated impact on
appropriations of an administrative nature

3.2.3.1.  Summary

–
 ̈  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 || Year 2019 || Year 2020 and following years || TOTAL

HEADING 5 of the multiannual financial framework || || || || || || || ||

Human resources [42] || 222.000 || 222.000 || 857.000 || 857.000 || 857.000 || 857.000 || 857.000 || 4.730.000[43]

Other administrative expenditure || || || 87.000 || 88.000 || 90.000 || 92.000 || 94.000 || 451.000

Subtotal HEADING 5 of the multiannual financial framework[44] || || || 87.000 || 88.000 || 90.000 || 92.000 || 94.000 || 451.000

Outside HEADING 5[45] of the multiannual financial framework || || || || || || || ||

Human resources || || || || || || || ||

Other expenditure of an administrative nature || 57.000 || 58.000 || 119.000 || 121.000 || 124.000 || 126.000 || 129.000 || 734.000

Subtotal outside HEADING 5 of the multiannual financial framework || 57.000 || 58.000 || 119.000 || 121.000 || 124.000 || 126.000 || 129.000 || 734.000

TOTAL[46] || 57.000 || 58.000 || 206.000 || 209.000 || 214.000 || 218.000 || 223.000 || 1.185.000

3.2.3.2.  Estimated requirements of human
resources

–
X  The proposal/initiative does not require the
use of human resources[47]

–
 ̈  The proposal/initiative requires the use of human resources, as
explained below:

– || Year 2014 || Year 2015 || Year 2016 || Year 2017 || Year 2018 || Year 2019 || Year 2020 and following years || TOTAL

17 01 01 01 (Headquarters and Commission’s Representation Offices) [48] || 1.75 FTEc || 1.75 FTE || 6.75 FTE || 6.75 FTE || 6.75 FTE || 6.75 FTE || 6.75 FTE ||

XX 01 01 02 (Delegations) || || || || || || || ||

XX 01 05 01 (Indirect research) || || || || || || || ||

10 01 05 01 (Direct research) || || || || || || || ||

XX 01 02 01 (CA, INT, SNE from the "global envelope") || || || || || || || ||

XX 01 02 02 (CA, INT, JED, LA and SNE in the delegations) || || || || || || || ||

XX 01 04 yy [49] || - at Headquarters[50] || || || || || || || ||

- 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 ||

3.2.4.     Compatibility with the
current multiannual financial framework

–
X  Proposal/initiative is compatible the 2014-2020
multiannual financial framework.

–
 ̈  Proposal/initiative will entail reprogramming of the relevant
heading in the multiannual financial framework.

Explain what reprogramming is required,
specifying the budget lines concerned and the corresponding amounts.

–
 ̈  Proposal/initiative requires application of the flexibility
instrument or revision of the multiannual financial framework[51].

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 || || || || || || || ||

3.3.        Estimated impact on
revenue

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

[1]               OJ L 121, 1.5.2001, p. 34.

[2]               Based on the figures for 2010.

[3]               The decrease has been 12% from 2007 to 2010.

[4]               OJ L 311, 28.11.2001, p. 67.

[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).

[6]               Article 15 of Regulation (EC) No 1901/2006 of the
European Parliament and of the Council of 12 December 2006 on medicinal products
for paediatrics use (OJ L 378, 27.12.2006, p. 1).

[7]               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).

[8]               Article 21a(b)(f) of Directive 2001/83/EC.

[9]               OJ L 281, 23.11.1995, p. 31.

[10]             OJ L 8, 12.1.2001, p. 1.

[11]             OJ C172, 11.6.2011, p. 1.

[12]             OJ L 91, 9.4.2005, p. 13.

[13]             OJ C , , p. .

[14]             OJ C , , p. .

[15]             OJ C , , p. .

[16]             XXX.

[17]             OJ C , , p. .

[18]             OJ L 121, 1.5.2001, p. 34.

[19]             OJ L 311, 28.11.2001, p. 67.

[20]             OJ L 55, 28.2.2011, p. 13.

[21]             OJ L 281, 23.11.1995, p. 31.

[22]             OJ L 8, 12.1.2001, p. 1.

[23]             OJ L 324, 10.12.2007, p. 121.

[24]             OJ L 180, 9.7.1997, p. 22.

[25]             OJ L 159, 29.6.1996, p. 1.

[26]             OJ L 106, 17.4.2001, p. 1.

[27]             OJ L 125, 21.5.2009, p. 75.

[28]             OJ L 378, 27.11.2006, p. 1.

[29]             ABM: Activity-Based Management – ABB: Activity-Based
Budgeting.

[30]             As referred to in Article 49(6)(a) or (b) of the
Financial Regulation.

[31]             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

[32]             As referred to in Article 185 of the Financial
Regulation.

[33]             Diff. = Differentiated appropriations / Non-diff. =
Non-Differentiated Appropriations

[34]             EFTA: European Free Trade Association.

[35]             Candidate countries and, where applicable, potential
candidate countries from the Western Balkans.

[36]             All prices are current prices.

[37]             Technical and/or administrative assistance and
expenditure in support of the implementation of EU programmes and/or actions
(former "BA" lines), indirect research, direct research.

[38]             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.

[39]             In accordance with the impact assessment report, the
necessary additional human ressources (1.75 FTE + 5 FTE) are going to be
re-deployed from within DG SANCO. Consequently, the costs for human resources
are not added in the 'total' for Heading 5.

[40]             In accordance with the impact assessment report, the
necessary additional human ressources (1.75 FTE + 5 FTE) are going to be
re-deployed from within DG SANCO. Consequently, the costs for human resources
are not added in the 'total DG SANCO'.

[41]             In accordance with the impact assessment report, the
necessary additional human ressources (1.75 FTE + 5 FTE) are going to be
re-deployed from within DG SANCO. Consequently, the costs for human resources
are not added in the 'total' for Heading 5.

[42]             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.

[43]             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.

[44]             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.

[45]             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.

[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.

[47]             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.

[48]             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.

[49]             Under
the ceiling for external personnel from operational
appropriations (former "BA" lines).

[50]             Essentially for Structural Funds, European Agricultural
Fund for Rural Development (EAFRD) and European Fisheries Fund (EFF).

[51]             See points 19 and 24 of the Interinstitutional
Agreement.