Impact of legislative changes
on conducting clinical trials
in Ireland
Dr. Agnieszka Przybyszewska, Medical Officer, HPRA
Changes in regulatory environment
for clinical trials
23/11/2015 2
Clinical Trials
Regulation No
536/2014
Clinical Trials Directive
(2001/20/EC)
Control of Clinical
Trials Acts, 1987 and
1990
Situation of clinical trials in Europe before the
Clinical Trials Directive
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Clinical Trials Directive 2001/20/EC
Established to:
– provide greater protection to subjects participating
in clinical trials
– ensure quality of conduct
– harmonise regulation and conduct of clinical trials
throughout Europe
Number of clinical trials applied for in the EU
Situation after the implementation of the
Clinical Trials Directive
Situation of clinical trials after the
implementation of the Clinical Trials
Directive in 2004
Assessment of the functioning of the Clinical
Trials Directive – public consultation
23/11/2015 6
multiple and
divergent
assessment of the
same clinical trials
application
different
requests for
information
from NCAsdifferent ‘national
versions’ of the same
protocol
costs created
by the present
system
delay of the
‘first patient
in’
Implementation of the Clinical Trials Directive-
harmonization has not been achieved
• Clinical Trials are assessed by several
National Competent Authorities (CA)
independently
• Independent assessment ethics
committees
Fragmentation
of the
authorisation
regime
• National laws
• Different interpretation of the CT
directive/guidelines
• Different approach to assessment
Lack of
harmonization
Divergent
decisions
for the same
clinical trial !
Improving clinical trials legislation in the EU
• On April 2, 2014, the European Parliament approved
the Clinical Trials Regulation
• On 27 May 2014, the Clinical Trials Regulation was
published in the Official Journal of the EU (OJEU).
• Implementation –December 2017?
823/11/2015
Implementation date of Clinical Trials Regulation
depends on the development of the EU portal
Improving clinical trials legislation in the EU
23/11/2015 9
Regulation
The Clinical Trials Directive 2001/20/EC is replaced by
the Clinical Trials Regulation 536/2014
Directive National law
Implementation
Implementation of Directive
Implementation of Regulation
Implementation
Clinical Trials Regulation No536/2014
Main changes:
• Single submission portal
• Coordinated assessment process with reporting
Member State/new timelines
• Single decision per Member State and involvement
of ethics committees in assessment
Single submission portal and clinical trials database
Sponsor
Portal and EU database
National systems
CA Ethics committees
All submissions and communications
(with the sponsor and between MSs)
must be made through the EU portal
or database.
All documents will be stored in the EU
database.
The European Medicines Agency is
responsible for the development of the
portal and database
Single submission portal
There are 4,000-5,000 applications per year in the EU.
In Ireland there about 90-115 new applications per year
and 250-300 substantial amendments per year.
The Portal will be used not only for new applications and
amendments but also for other communications.
EU portal and
database
Notifications:
- Withdrawal
- Start of trial
- First Visit first
subject
- End of
recruitment
- End of trial (in
each MS, All MS,
Global)
- Temporary Halt
- Restart of the
trial
- Early termination
- Serious Breaches
- Unexpected
Events which
affect Risk/Ben
- Result summary
Public
Ethics committeesAssessment report
Decisions
NCAAssessment report
Decisions, Inspections
Commission
Union Control Reports
Search and view all CT related
information saved in the EU database
Sponsor
New applications and amendments
Portal and database to be developed by
the EMA
23/11/2015 14
Portal and database-
Impact on conducting clinical trials in Ireland
Potential
benefits
Potential
difficulties
23/11/2015 15
Clinical Trials Regulation
23/11/2015 16
Increased transparency
and availability of
information on
clinical trials
and their results
What type of information is currently
publicly available?
• General information about a clinical trial
• Study results
Nov-15 17
EU
Application
Form
EU Clinical
Trials
Register
Public data!Not all fields
https://www.clinicaltrialsregister.eu
Clinical Trials Regulation- Transparency-
Article 81
The EU database shall be publicly accessible unless ......
• protecting personal data,
• protecting commercially confidential information,
• protecting confidential communication between Member States in
relation to the preparation of the assessment report,
• ensuring effective supervision of the conduct of a clinical trial by
Member States.
Commercially confidential information
- transparency rules for Clinical Trials
Regulation
Nov-15 19
Sponsor’s economic
interest
(commercial and non-
commercial sponsors)
Over-riding public
interest
Information which will be publicly
available – examples
• Application form
• Protocol
• Investigator’s brochure
• Names of investigators
• Clinical trial sites
• Results
• Inspection reports
23/11/2015 20
Increased transparency - Impact on
conducting clinical trials in Ireland
Potential
benefits
Potential
difficulties
23/11/2015 21
Other significant changes:
• Coordinated assessment process with reporting
Member State/new timelines
• Single decision per Member State and
involvement of ethics committees in assessment
23/11/2015 22
Assessment of multinational clinical trials
as per Clinical Trials Directive 2001/20/EC
Time
30
120
90
60
150
Competent authorities Ethics committees
positive
negative
positive
positive
positive
IE
UKIE
UK
DE
DE
HPRA
Ethics committee
Authorisation
Single positive
opinion
SponsorStart of
CT
National assessment as per Clinical Trials Directive 2001/20/EC
Independent assessment
Assessment-changes as per Clinical Trials
Regulation
National
assessment of
multinational
trials
Coordinated
assessment
process
RMS or CMS
role
NCA and Ethics
committees
independent
assessment
Coordinated
assessment and
one decision per
MSs
Communications
with ethics
committees
60 days
90 days (ATMPs)
New
timelines
New timelines
Many steps
during procedure
.
Format of the clinical trials application –
changes as per Regulation
Part I and Part II
Part I - scientific part,
common for all Member
States - coordinated review
Part II – national/local part –
ethical review – independent
national review
Examples:
• Protocol
• Investigator’s brochure
• Investigational Medicinal Product Dossier
Article 6 – Aspects covered by Part I
Part I - scientific part,
common for all MSs
Examples:
• Informed consent
• Suitability of investigators and trial sites
• Damage compensation
• Collection, storage and future use of biological samples of the subject.
Article 7– Aspects covered by Part II
Part II – national/local part –
ethical review
Assessment process as per the Clinical
Trials Regulation - example
23/11/2015 29
Part II
Part II
Part II
Part I - scientific part,
common for all MSs,
coordinated review
Clinical trial application
Part I of application – assessment at the
EU level
• Assessment of Part I is lead by the Reporting
Member State (RMS)
• The RMS circulates the assessment report
• Communication is done through the portal
23/11/2015 30
Reporting
Member StateConcerned
Member
State
Concerned
Member
State
Sponsor
Part I of application – assessment at the
national level
• How work is shared/divided within the member state is to be
decided by the member state
• Co-operation between a National competent authority and
Ethics committees is possible
• The relevant national procedures
need to be devloped
23/11/2015 31
National
competent
authority
Ethics
committees
Currently - approval process 60 days
Regulation - new longer timelines
Part I:
Validation
25 days10+10+5
Max. time – questions to the sponor
Validation
10 days
Final decision
5 days
Min. Time – no questions to the sponsor
45 days
Assessment
76 days
45+12+12+7
Assessment
5 days
Final decision
Assessment of Part I
• New timelines, multiple steps during assessment
• No longer additional national requirements possible
• Collaboration between the HPRA and ethics committees in
an assessment of Part I?
Final assessment report publically available
Tacit approval – if no decision provided within
timeline
Assessment
Validation
10 days
Final decision
5 days
Min. Time – no questions to the sponsor
45 days
Assessment
Assessment of Part II –independent in each Member State
Questions to
sponsor
+31days
Article 8 - Decision on the clinical trial
• Each Member State concerned shall notify the sponsor through the
EU portal as to whether the clinical trial is authorised/refused……
• Notification shall be done by way of one single decision within
five days from the reporting date
• Any disagreement together with a detailed justification, needs to
be communicated through the EU portal, to the Commission, to all
Member States, and to the sponsor.
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23/11/2015 36
Opinion
on Part IOpinion
on Part II
One final decision per Member state
(HPRA + ethics committees) is submitted
through the portal
Final decision
New assessment process- Impact on conducting
clinical trials in Ireland
Potential
benefits
Potential
difficulties
23/11/2015 37
Impact of legislative changes on
conducting clinical trials in Ireland??
23/11/2015 38
Questions?
Health Products Regulatory Authority, Kevin O'Malley House, Earlsfort Centre, Earlsfort Terrace
23/11/2015 39
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