Regulation 536/2014 on Clinical Trials
Recital 43: “The members of the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) have agreed on a detailed set
of guidelines on good clinical practice which is an internationally accepted standard for designing,
conducting, recording and reporting clinical trials, consistent with principles that have their origin in
the World Medical Association's Declaration of Helsinki. When designing, conducting, recording and
reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a
case, the ICH guidelines on good clinical practice should be taken appropriately into account for the
application of the rules set out in this Regulation, provided that there is no other specific guidance
issued by the Commission and that those guidelines are compatible with this Regulation”
CHAPTER I
Article 1: “Scope”
This Regulation applies to all clinical trials conducted in the Union.
It does not apply to non-interventional studies.
Article 2: “Definitions”
(1) For the purposes of this Regulation, the definitions of ‘medicinal product’,
‘radiopharmaceutical’, ‘adverse reaction’, ‘serious adverse reaction’, ‘immediate packaging’
and ‘outer packaging’ set out in points (2), (6), (11), (12), (23) and (24), respectively, of
Article 1 of Directive 2001/83/EC apply
(2) The following definitions also apply:
(1) ‘Clinical study’ means any investigation in relation to humans intended:
(a) to discover or verify the clinical, pharmacological or other
pharmacodynamic effects of one or more medicinal products;
(b) to identify any adverse reactions to one or more medicinal products; or
(c) to study the absorption, distribution, metabolism and excretion of one or
more medicinal products;
with the objective of ascertaining the safety and/or efficacy of those medicinal products
(2) ‘Clinical trial’ means a clinical study which fulfils any of the following conditions:
(a) the assignment of the subject to a particular therapeutic strategy is
decided in advance and does not fall within normal clinical practice of the
Member State concerned;
(b) the decision to prescribe the investigational medicinal products is taken
together with the decision to include the subject in the clinical study; or
(c) diagnostic or monitoring procedures in addition to normal clinical
practice are applied to the subjects
(3) ‘Low-intervention clinical trial’
(4) ‘Non-interventional study’
1
,(5) ‘Investigational medicinal product’
(6) ‘Normal clinical practice’
(7) ‘Advanced therapy investigational medicinal product’
(8) ‘Auxiliary medicinal product’
(9) ‘Authorised investigational medicinal product’
(10)‘Authorised auxiliary medicinal product’
(11)‘Ethics committee’ means an independent body established in a Member State in
accordance with the law of that Member State and empowered to give opinions for the
purposes of this Regulation, taking into account the views of laypersons, in particular
patients or patients' organisations
(12)‘Member State concerned’
(13)‘Substantial modification’ means any change to any aspect of the clinical trial which is made
after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to
have a substantial impact on the safety or rights of the subjects or on the reliability and
robustness of the data generated in the clinical trial
(14)‘Sponsor’ means an individual, company, institution or organisation which takes
responsibility for the initiation, for the management and for setting up the financing of the
clinical trial
(15)‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical
trial site
(16)‘Principal investigator’ means an investigator who is the responsible leader of a team of
investigators who conduct a clinical trial at a clinical trial site
(17)‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
investigational medicinal product or as a control
(18)‘Minor’
(19)‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal
competence to give informed consent, incapable of giving informed consent according to
the law of the Member State concerned
(20)‘Legally designated representative’ means a natural or legal person, authority or body
which, according to the law of the Member State concerned, is empowered to give informed
consent on behalf of a subject who is an incapacitated subject or a minor
(21)‘Informed consent’ means a subject's free and voluntary expression of his or her willingness
to participate in a particular clinical trial, after having been informed of all aspects of the
clinical trial that are relevant to the subject's decision to participate or, in case of minors and
of incapacitated subjects, an authorisation or agreement from their legally designated
representative to include them in the clinical trial
(22)‘Protocol’ means a document that describes the objectives, design, methodology, statistical
considerations and organisation of a clinical trial. The term ‘protocol’ encompasses
successive versions of the protocol and protocol modifications
(23)‘Investigator’s brochure’
(24)‘Manufacturing’
(25)‘Start of a clinical trial’ means the first act of recruitment of a potential subject for a specific
clinical trial, unless defined differently in the protocol
(26)‘End of a clinical trial’ means the last visit of the last subject, or at a later point in time as
defined in the protocol
(27)‘Early termination of a clinical trial’
(28)‘Temporary halt of a clinical trial’
(29)‘Suspension of a clinical trial’
2
, (30)‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for
designing, conducting, performing, monitoring, auditing, recording, analysing and reporting
clinical trials ensuring that the rights, safety and well-being of subjects are protected, and
that the data generated in the clinical trial are reliable and robust
(31)‘Inspection’ means the act by a competent authority of conducting an official review of
documents, facilities, records, quality assurance arrangements, and any other resources that
are deemed by the competent authority to be related to the clinical trial and that may be
located at the clinical trial site, at the sponsor's and/or contract research organisation's
facilities, or at other establishments which the competent authority sees fit to inspect
(32)‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal
product is administered and which does not necessarily have a causal relationship with this
treatment
(33)‘Serious adverse event’ means any untoward medical occurrence that at any dose requires
inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or
significant disability or incapacity, results in a congenital anomaly or birth defect, is life-
threatening, or results in death
(34)‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature,
severity or outcome of which is not consistent with the reference safety information
(35)‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
accompanying an application for marketing authorisation
Article 3: “General principle”
A clinical trial may be conducted only if:
(a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other
interests; and
(b) it is designed to generate reliable and robust data.
CHAPTER II
Article 6: “Assessment report – Aspects covered by Part 1”
(1) The MS shall assess the application with regard to the following aspects:
(a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor
(b) Compliance with Chapter V with respect to:
(i) The anticipated therapeutic and public health benefits taking into account of all of
the following:
— the characteristics of and knowledge about the investigational medicinal
products;
— the relevance of the clinical trial, including whether the groups of subjects
participating in the clinical trial represent the population to be treated, or if not, the
explanation and justification provided in accordance with point (y) of paragraph 17
3
Recital 43: “The members of the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) have agreed on a detailed set
of guidelines on good clinical practice which is an internationally accepted standard for designing,
conducting, recording and reporting clinical trials, consistent with principles that have their origin in
the World Medical Association's Declaration of Helsinki. When designing, conducting, recording and
reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a
case, the ICH guidelines on good clinical practice should be taken appropriately into account for the
application of the rules set out in this Regulation, provided that there is no other specific guidance
issued by the Commission and that those guidelines are compatible with this Regulation”
CHAPTER I
Article 1: “Scope”
This Regulation applies to all clinical trials conducted in the Union.
It does not apply to non-interventional studies.
Article 2: “Definitions”
(1) For the purposes of this Regulation, the definitions of ‘medicinal product’,
‘radiopharmaceutical’, ‘adverse reaction’, ‘serious adverse reaction’, ‘immediate packaging’
and ‘outer packaging’ set out in points (2), (6), (11), (12), (23) and (24), respectively, of
Article 1 of Directive 2001/83/EC apply
(2) The following definitions also apply:
(1) ‘Clinical study’ means any investigation in relation to humans intended:
(a) to discover or verify the clinical, pharmacological or other
pharmacodynamic effects of one or more medicinal products;
(b) to identify any adverse reactions to one or more medicinal products; or
(c) to study the absorption, distribution, metabolism and excretion of one or
more medicinal products;
with the objective of ascertaining the safety and/or efficacy of those medicinal products
(2) ‘Clinical trial’ means a clinical study which fulfils any of the following conditions:
(a) the assignment of the subject to a particular therapeutic strategy is
decided in advance and does not fall within normal clinical practice of the
Member State concerned;
(b) the decision to prescribe the investigational medicinal products is taken
together with the decision to include the subject in the clinical study; or
(c) diagnostic or monitoring procedures in addition to normal clinical
practice are applied to the subjects
(3) ‘Low-intervention clinical trial’
(4) ‘Non-interventional study’
1
,(5) ‘Investigational medicinal product’
(6) ‘Normal clinical practice’
(7) ‘Advanced therapy investigational medicinal product’
(8) ‘Auxiliary medicinal product’
(9) ‘Authorised investigational medicinal product’
(10)‘Authorised auxiliary medicinal product’
(11)‘Ethics committee’ means an independent body established in a Member State in
accordance with the law of that Member State and empowered to give opinions for the
purposes of this Regulation, taking into account the views of laypersons, in particular
patients or patients' organisations
(12)‘Member State concerned’
(13)‘Substantial modification’ means any change to any aspect of the clinical trial which is made
after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to
have a substantial impact on the safety or rights of the subjects or on the reliability and
robustness of the data generated in the clinical trial
(14)‘Sponsor’ means an individual, company, institution or organisation which takes
responsibility for the initiation, for the management and for setting up the financing of the
clinical trial
(15)‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical
trial site
(16)‘Principal investigator’ means an investigator who is the responsible leader of a team of
investigators who conduct a clinical trial at a clinical trial site
(17)‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
investigational medicinal product or as a control
(18)‘Minor’
(19)‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal
competence to give informed consent, incapable of giving informed consent according to
the law of the Member State concerned
(20)‘Legally designated representative’ means a natural or legal person, authority or body
which, according to the law of the Member State concerned, is empowered to give informed
consent on behalf of a subject who is an incapacitated subject or a minor
(21)‘Informed consent’ means a subject's free and voluntary expression of his or her willingness
to participate in a particular clinical trial, after having been informed of all aspects of the
clinical trial that are relevant to the subject's decision to participate or, in case of minors and
of incapacitated subjects, an authorisation or agreement from their legally designated
representative to include them in the clinical trial
(22)‘Protocol’ means a document that describes the objectives, design, methodology, statistical
considerations and organisation of a clinical trial. The term ‘protocol’ encompasses
successive versions of the protocol and protocol modifications
(23)‘Investigator’s brochure’
(24)‘Manufacturing’
(25)‘Start of a clinical trial’ means the first act of recruitment of a potential subject for a specific
clinical trial, unless defined differently in the protocol
(26)‘End of a clinical trial’ means the last visit of the last subject, or at a later point in time as
defined in the protocol
(27)‘Early termination of a clinical trial’
(28)‘Temporary halt of a clinical trial’
(29)‘Suspension of a clinical trial’
2
, (30)‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for
designing, conducting, performing, monitoring, auditing, recording, analysing and reporting
clinical trials ensuring that the rights, safety and well-being of subjects are protected, and
that the data generated in the clinical trial are reliable and robust
(31)‘Inspection’ means the act by a competent authority of conducting an official review of
documents, facilities, records, quality assurance arrangements, and any other resources that
are deemed by the competent authority to be related to the clinical trial and that may be
located at the clinical trial site, at the sponsor's and/or contract research organisation's
facilities, or at other establishments which the competent authority sees fit to inspect
(32)‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal
product is administered and which does not necessarily have a causal relationship with this
treatment
(33)‘Serious adverse event’ means any untoward medical occurrence that at any dose requires
inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or
significant disability or incapacity, results in a congenital anomaly or birth defect, is life-
threatening, or results in death
(34)‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature,
severity or outcome of which is not consistent with the reference safety information
(35)‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
accompanying an application for marketing authorisation
Article 3: “General principle”
A clinical trial may be conducted only if:
(a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other
interests; and
(b) it is designed to generate reliable and robust data.
CHAPTER II
Article 6: “Assessment report – Aspects covered by Part 1”
(1) The MS shall assess the application with regard to the following aspects:
(a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor
(b) Compliance with Chapter V with respect to:
(i) The anticipated therapeutic and public health benefits taking into account of all of
the following:
— the characteristics of and knowledge about the investigational medicinal
products;
— the relevance of the clinical trial, including whether the groups of subjects
participating in the clinical trial represent the population to be treated, or if not, the
explanation and justification provided in accordance with point (y) of paragraph 17
3
