The document discusses clinical research regulations in the European Union. It provides information on the aim of the European Medicines Agency (EMA) in regulating clinical trials to protect subjects' rights and safety. It describes the EMA's role in ensuring good clinical practice standards across the European Economic Area. It also summarizes key points of the new Clinical Trials Regulation, including requirements for authorization, informed consent, and conducting trials on vulnerable groups. Finally, it discusses the Clinical Trials Information System that will support application and oversight of trials under the new Regulation.

1. Clinical Research regulations in the
European Union (ema)
Submitted by:-
Mr. Shantanu S. Thakre
M-Pharm 1st – Year
Department of Pharmaceutics
Pharmaceutical Regulatory Affairs Group
JSS College of Pharmacy, Mysuru
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2.  Contents:-
 Aim of EMA (European Medicines Agency)
 Role of EMA
 Clinical Research Regulations
 Clinical Research Regulations conducted in countries outside the EU
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3.  Aim of EMA (European Medicines Agency):-
The regulation of clinical trials aims to ensure that the rights, safety, and well-being
of trial subjects are protected and the results of clinical trials are credible.
Regardless of where they are conducted, all clinical trials included in applications
for authorization for human medicines in the EEA must have been carried out by
the requirements set out in Annex 1 of Directive 2001/83/EC. This means that:
 Clinical trials conducted in the EEA (European Economic Area) have to comply
with EU clinical trial legislation (Directive 2001/20/EC)
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4. • Clinical trials conducted outside the EEA have to comply with ethical
principles equivalent to those set out in the EEA, including adhering
to International good clinical practice and the Declaration of Helsinki.
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5. In the EEA, approximately 4,000 clinical trials are authorized each year. This
equals approximately 8,000 clinical-trial applications, with each trial involving two
Member States on average.
Approximately 61% of clinical trials are sponsored by the pharmaceutical
industry and 39% by non-commercial sponsors, mainly academia.
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6.  Role of EMA:-
 The European Medicines Agency (EMA) relies on the results of clinical
trials carried out by pharmaceutical companies to reach its opinions on the
authorization of medicines.
 Although the authorization of clinical trials occurs at the national level,
EMA plays a key role in ensuring the standards of good clinical
practice (GCP) are applied across the European Economic Area (EEA) in
cooperation with the Member States. It also manages a database of clinical
trials carried out in the European Union (EU).
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7.  EMA's Committee for Medicinal Products for Human Use (CHMP) is
responsible for conducting the assessment of human medicine for which EU-
wide authorization is sought. As part of its scientific evaluation work,
the CHMP reviews the clinical trial data included in the application.
 Clinical trial data is included in clinical-study reports that form a large part of
the application dossiers submitted by pharmaceutical companies applying
for authorization via the Agency.
 Assessments are based on purely scientific criteria and determine whether or
not the medicines concerned meet the necessary quality, safety,
and efficacy requirements by EU legislation, particularly Directive 2001/83/EC 7

8.  Clinical Research Regulations:-
Brief Information:
 On 16 April 2014, the European Commission adopted the new Clinical Trial
Regulation (EU No 536/2014), repealing Directive 2001/20/EC.
 Although the Clinical Trial Regulation was adopted and entered into force in
2014, the timing of its application depends on confirmation of full functionality
of the Clinical Trials Information System (CTIS) through an independent audit.
 The Regulation becomes applicable six months after the European Commission
publishes notice of this confirmation.
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9.  Clinical Trial Regulation (EU No 536/2014):-
1) Scope:
This Regulation applies to all clinical trials conducted in the Union. It does not
apply to non-interventional studies.
2) 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.
GENERAL PROVISION:-
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10. 1) Prior authorization
 A clinical trial shall be subject to scientific and ethical review and shall be
authorized by this Regulation.
 The ethical review shall be performed by an ethics committee by the law
of the Member State concerned.
 The Member States shall ensure that the timelines and procedures for
the review by the ethics committees are compatible with the timelines
and procedures set out in this Regulation for the assessment of the
application for authorization of a clinical trial.
AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
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11. 2) Submission of an application
1. To obtain authorization, the sponsor shall submit an application dossier
to the intended Member States concerned through the portal (the ‘EU
portal’).
2. The sponsor shall propose one of the Member States concerned as
reporting Member State.
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12. 3) If a Member State concerned other than the proposed reporting Member State
is willing to be the reporting Member State or where the proposed reporting
Member State does not wish to be the reporting Member State, this shall be
notified through the EU portal to all Member States concerned not later than
three days after the application dossier is submitted.
4) The sponsor shall when apply for a low-intervention clinical trial, where the
investigational medicinal product is not used by the terms of the marketing
authorization but the use of that product is evidence-based and supported by
published scientific evidence on the safety and efficacy of that product,
propose one of the Member States concerned where the use is evidence-
based, as reporting Member State.
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13. 5) Within 10 days from the submission of the application dossier, the reporting
Member State shall validate the application taking into account
considerations expressed by the other Member States concerned and notify
the sponsor, through the EU portal, of the following
(a) whether the clinical trial applied for falls within the scope of this
Regulation;
(b) whether the application dossier is complete.
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14. 6) Where the reporting Member State, taking into account considerations
expressed by the other Member States concerned, finds that the application
dossier is not complete, or that the clinical trial applied for does not fall within
the scope of this Regulation, it shall inform the sponsor thereof through the EU
portal and shall set a maximum of 10 days for the sponsor to comment on the
application or to complete the application dossier through the EU portal.
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15.  EU portal:
 The Agency shall, in collaboration with the Member States and the
Commission, 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.
 The EU portal shall be technically advanced and user-friendly so as to
avoid unnecessary work.
 Data and information submitted through the EU portal shall be stored in
the EU database.
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16.  EU database:
 The EU database shall be established to enable cooperation between the
competent authorities of the Member States concerned to the extent that it
is necessary for the application of this Regulation and to search for specific
clinical trials.
 The EU database shall support the recording and submission to the
Medicinal Product Dictionary, contained in the Eudravigilance database, of
all the data on medicinal products without a marketing authorization in the
Union and substances not authorized as part of a medicinal product in the
Union, that are necessary for the maintenance of that dictionary.
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17.  The user interface of the EU database shall be available in all official
languages of the Union.
 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
concerned.
 The Management Board of the Agency shall, on the basis of an independent
audit report, inform the Commission when it has verified that the EU portal
and the EU database have achieved full functionality
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18.  The subject shall be informed that the summary of the results of the
clinical trial and a summary presented in terms understandable to a
layperson will be made available in the EU database.
Informed consent
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19.  A clinical trial on minors may be conducted only where, all of the following
conditions are met:
a) The informed consent of their legally designated representative has been
obtained;
b) the minors have received the information referred in a way adapted to their
age and mental maturity and from investigators or members of the
investigating team who are trained or experienced in working with children;
Clinical trials on minors
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20. c) the explicit wish of a minor who is capable of forming an opinion and
assessing the information to refuse participation in, or to withdraw from, the
clinical trial at any time, is respected by the investigator;
d) no incentives or financial inducements are given to the subject or his or her
legally designated representative except for compensation for expenses and
loss of earnings directly related to the participation in the clinical trial;
e) the clinical trial is intended to investigate treatments for a medical condition
that only occurs in minors or the clinical trial is essential with respect to
minors to validate data obtained in clinical trials on persons able to give
informed consent or by other research methods; 20

21.  The minor shall take part in the informed consent procedure in a way
adapted to his or her age and mental maturity.
 If during a clinical trial the minor reaches the age of legal
competence to give informed consent as defined in the law of the
Member State concerned, his or her express informed consent shall
be obtained before that subject can continue to participate in the
clinical trial.
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22. (a) Clinical trial has the potential to produce a direct benefit for the pregnant or
breastfeeding woman concerned, or her embryo, fetus, or child after birth,
outweighing the risks and burdens involved; or
(b) if such clinical trial has no direct benefit for the pregnant or breastfeeding
woman concerned or her embryo, fetus, or child after birth, it can be
conducted only if:
(i) a clinical trial of comparable effectiveness cannot be carried out on
women who are not pregnant or breastfeeding;
Clinical trials on pregnant or breastfeeding women
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23. (ii) the clinical trial contributes to the attainment of results capable of benefitting
pregnant or breastfeeding women or other women about reproduction or other
embryos, fetuses, or children; and
(iii) the clinical trial poses minimal risk to, and imposes a minimal burden on, the
pregnant or breastfeeding woman concerned, her embryo, fetus, or child after
birth;
(c) where research is undertaken on breastfeeding women, particular care is
taken to avoid any adverse impact on the health of the child; and
(d) no incentives or financial inducements are given to the subject except for
compensation for expenses and loss of earnings directly related to participation
in the clinical trial.
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24.  The European Commission confirmed 31 January 2022 as the date of entry
into application of the Clinical Trials Regulation and the go-live of CTIS, by
publishing a notice in the Official Journal of the European Union on 31 July
2021.
 When the Regulation becomes applicable on 31 January 2022, it will
repeal the existing EU Clinical Trials Directive (EC) No. 2001/20/EC and
national legislation that was put in place to implement the Directive. It will also
apply to trials authorized under the previous legislation if they are still ongoing
three years after the Regulation has come into operation.
 Current Scenario:-
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25.  How the CTIS will work:-
 The way clinical trials are conducted in the European Union (EU) will
undergo a major change when the Clinical Trials Regulation
(Regulation (EU) No 536/2014) comes into application on 31 January 2022.
 The Regulation harmonizes the assessment and supervision processes
for clinical trials throughout the EU, via a Clinical Trials Information System
(CTIS).
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26.  CTIS will contain the centralized EU portal and database for clinical
trials foreseen by the Regulation. The European Medicines Agency (EMA)
sets up and maintains CTIS, in collaboration with the Member States and the
European Commission.
 CTIS will be the single entry point for submitting clinical trial information in
the EU, which will be stored in the system. EMA will make information stored
in CTIS publicly available subject to transparency rules.
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27.  The clinical trial application form and supporting dossier will cover all
regulatory and ethics assessments from the Member States concerned. It will
also include the public registration of the clinical trial and any subsequent
updates.
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28.  CTIS is due to go live on 31 January 2022.
 EMA's Management Board endorsed a delivery timeframe in December
2015. However, the system's go-live date was postponed due to technical
difficulties with the development of the IT system.
 The IT supplier submitted to EMA a revised project plan with improved
project management, development and testing processes, resources, and
increased contingency. EMA also subsequently revised the CTIS project
methodology and delivery plan.
 Clinical Trial Information System Development:-
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29.  Since June 2019, the development of CTIS followed an agile and iterative
delivery model, with functionalities delivered in short development cycles. This
is based on a revised project plan from the IT supplier, with improved project
management, development and testing processes, resources, and increased
contingency.
 The Member States and stakeholders are directly engaged in the development
of CTIS through nominated ‘product owners’ to ensure their expectations are
taken into account. This means that nominated business experts representing
user groups from the national competent authorities and ethics committees
and sponsors have an enhanced and continuous opportunity to test, review,
select and verify functionalities.
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30. In 2021 EMA is focusing on:
• the findings of a system audit;
• improving usability, quality, and stability of the CTIS;
• knowledge transfer to prepare users and their organizations for CTIS.
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31.  Progress Update:-
 Progress updates are available below on the development of CTIS and its
functionalities, rollout of training, and user support.
 These include the CTIS Highlights newsletter. Editions start from June
2020.
 To subscribe to the newsletter, write to ct.communication@ema.europa.eu.
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32.  Clinical Trials conducted in countries outside the EU:-
 Clinical trials conducted outside the EU but submitted in an application
for marketing authorization in the EU have to follow the principles which are
equivalent to the provisions of the Directive 2001/20/EC.
 This paper aims to strengthen existing processes to provide assurance
that clinical trials meet the required ethical and GCP standards, no matter
where in the world they have been conducted.
 The number of clinical trials and clinical trial subjects outside Western
Europe and North America has been increasing for several years 32

33.  References:-
• https://www.ema.europa.eu/en/human-regulatory/research-
development/clinical-trials/clinical-trials-regulation
• https://www.ema.europa.eu/en/human-regulatory/research-
development/clinical-trials-human-medicines
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34. Thank You!
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