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

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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

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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

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Portal and database-

Impact on conducting clinical trials in Ireland

Potential

benefits

Potential

difficulties

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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

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Increased transparency - Impact on

conducting clinical trials in Ireland

Potential

benefits

Potential

difficulties

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Other significant changes:

• Coordinated assessment process with reporting

Member State/new timelines

• Single decision per Member State and

involvement of ethics committees in assessment

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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

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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

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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

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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

clinicaltrials@hpra.ie

23/11/2015 39