Recent Evolution of Regulatory Framework in Europe Clinical trials of medicinal products in Ukraine Conference 19 November 2015, Kiev, Ukraine Magdalena Matusiak, MPharm Manager, Clinical Development Pharmacovigilance Team Lead, KCR

1. Recent Evolution of Regulatory
Framework in Europe
Clinical trials of medicinal products in Ukraine Conference
19 NOVEMBER 2015,
KIEV
Magdalena Matusiak MPharm
Manager, Clinical Development
Pharmacovigilance Team Lead KCR S.A.

2. topics
Evolution of Member States legislation and EU Directives
implementation
Authorization of clinical trials - knowledge transfer from Member
States
Ethical review and infrastructure of ethical boards - review of
Member States approach and correlations with timelines
Upcoming changes in the EU regulatory framework (Clinical Trial
Regulation and Voluntary Harmonization Procedure)
EudraVigilance concept and implications for non-Member States
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3. European union laws - GENERAL information*
I. Primary legislation – EU treaties - every action taken by the EU is
based on treaties which have been approved voluntarily and
democratically by all EU member countries.
A treaty is a binding agreement between EU member countries. It sets out:
EU objectives
Rules for EU institutions
How decisions are made and
The relationship between the EU and its member countries
II. Secondary legislation – the aims set out in the EU treaties are
achieved by several types of legal act:
EU Regulations
Directives
Decisions
Recommendations, Opinions
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* source: www.europa.eu

4. European union laws - GENERAL information*
Regulations - binding legislative acts for the whole EU – directly
applicable
Directives - legislative acts that set out a goal that all EU countries
must achieve and specific deadline – require implementation to
local laws
Decisions - binding on those to whom it is addressed
(e.g. an EU country or an individual company) - directly applicable
Recommendations, Opinions – not binding, no legal
consequences
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* source: www.europa.eu

5. European union directives related to
clinical trials of medicinal products
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE
COUNCIL
of 4 April 2001on 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
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
The new regulation will apply NOT EARLIER THAN from 28 May 2016:
REGULATION (EU) NO 536/2014 OF THE EUROPEAN PARLIAMENT
AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal
products for human use, and repealing Directive 2001/20/EC Text with EEA
relevance
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6. Poland – adjustment of local laws to eu
standards
Basic acts in scope of pharmaceutical law & clinical trials were
adopted in year 2001 (before Poland became a member of EU)
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September 6, 2001
Pharmaceutical Law
November 29, 2002
Order of the Minister of
Health on central register of
clinical trials
December 10, 2002
Order of the Minister
of Health on the detailed requirements of
Good Clinical Practice
December 10, 2002
Order of the Minister of Health on the manner and
scope of conducting clinical trials inspections
on the compliance of these studies with the
requirements of Good Clinical Practice
Start: 2001

7. directives implementation in Poland
DIRECTIVE 2001/20/EC
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April 20, 2004
Amendment to
Pharmaceutical Law,
Medical Profession
Act
April 30, 2004
Order of the Minister
of Health on reporting
suspected unexpected
serious adverse reactions
April 30, 2004
Order of the Minister of
Health on clinical trials
on minors
April 30, 2004
Order of the Minister
of Finance concerning the mandatory
civil liability insurance of investigator and
sponsor
STAGE I - 2004

8. DIRECTIVE 2001/20/EC
directives implementation in Poland
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March 11, 2005
Order of the Minister
of Health on the detailed
requirements of Good
Clinical Practice
April 7, 2005
Order of the Minister
of Health on the manner and
scope of conducting clinical
trials inspections
March 3, 2006
Order of the Minister
of Health on the amount and method of
payment for the commencement of the
clinical trial
STAGE II –
2005-2006

9. DIRECTIVE 2005/28/EC - official EU deadline for implementation
was 29 January 2006
directives implementation in Poland
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March 30, 2007
Amendment to Pharmaceutical
Law
+ further amendments in years 2007-2011 to
Pharmaceutical Law and Orders of Minister of
Health and Finance
STAGE II –
2007-2011

10. directives implementation
General problems identified:
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DELAYS IN
IMPLEMENTATION TO
LoCAL LAW
DISCREPANCIES IN
LOCAL LAW BETWEEN
MEMBERS STATES
In order to avoid it in the future, new EU law regarding clinical trials
has a form of regulation which is a binding legislative act for the
whole EU and is directly applicable (no implementation needed).

11. Clinical Trial Authorisation
– MEMBER STATES GENERAL VIEW
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REGULATORY AUTHORITY
Submission to REGULATORY AUTHORITY
possible at any time (no fixed dates)
APPROVAL EXPECTED
after 60 days if no questions raised
ETHICS COMMITTEE
Submission to CENTRAL ETHICS
COMMITTEE
for particular EC session date
OPINION EXPECTED
after 60 days if no questions raised
Process based on EU Directive 2001/20/EC implemented into local law – assessment by
one central Ethics Committee

12. SUBMISSION & review PROCESS in POLAND–
AS EXAMPLE OF PROCESS facilitation
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BEFORE MARCH 2011:
AFTER MARCH 2011:
URPL review and assessment
DRAFT of DECISION prepared by
URPL
Transfer of DECISION to MOH
for execution of the approval
URPL review and assessment of Clinical trial FINAL DECISION signed and executed by URPL
 After changes in Polish legislation 2-step process of DECISION on CLINICAL TRIAL
(with Involvement of Ministry of Health) has become shortened to 1 step process.
 Head of Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
(URPL) is issuing final decision on Clinical trial. Delays in obtaining of final decision are
eliminated.
DELAYS IN APPROVAL OBTAINING
DELAYS ELIMINATED

13. SUBMISSION & review PROCESS in POLAND–
AS EXAMPLE OF PROCESS facilitation
In case NO QUESTIONS have been raised by Regulatory Authority
and
60 DAYS of assessment HAVE ELAPSED and no written decision
has not been issued by RA
and
EC opinion is FAVOURABLE
CLINICAL TRIAL CAN BE COMMENCED
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14. SUBMISSION & review PROCESS in Poland
– regulatory authority
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Submission
Formal validation
within 2-3 weeks
Scientific review
ApprovaL
No comments
Comments
Deficiencies
Completion
of package
within 30 days
Answers
within 90 days
Submission &
validation phase
Review phase
within 60 days
from „Start of process”
Approval phase
Start of process
= date when complete package
was submitted

15. SUBMISSION & review PROCESS in Poland
– ethics committee
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Submission
Expert review
OPINION
No comments
Comments
ANSWERS
Submission &
review phase
60 days per law
approx. 30 days in practice
Approval phase
EC session

16. SUBMISSION & review PROCESS in Poland
– ethics committee
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Submission
CENTRAL ETHICS
COMMITTEE (CEC)
CEC OPINION
No comments
Opinion
on SITES
from LECs
Submission &
review phase
60 days per law
approx. 30 days
in practice
Approval phase
LOCAL ETHICS
COMMITTEES (LECs)

17. documentATION REQUIREMENTS SPECIFICS
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IMPD
Certificates of
analysis
Manufacturing
Authorisation
and GMP
certificate
Required only for Investigational Medicinal Products which are not authorised
in EEA and US.
For Authorised products Summary of Product Characteristics is sufficient
Required:
• In exceptional cases, when unexpected impurities are detected
• Only for representative batches of the Investigational Medicinal Products
Required for the Manufacturer which is responsible for batch release on the
EU territory (not all manufacturers involved in manufacturing process)

18. Assessment step I
(32 calendar days)
Responses
preparation
(10 calendar
days)
Assessment step II
(24-28 calendar days)
Phase 1
Request
for VHP
5 days
Phase 2
Assessment Phase
60 days
Phase 3
National
Member Stage
step
10 days
Core docs in EN:
Protocol, IB,
IMPD, MA , GMPs
20 DAYS to submit
to P-NCAS**
Can be shortened
VHP submission process- Voluntary
EU CENTRALISED ASSESSMENT
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*GNA – Grounds for Non-acceptance
RFI – Request for Information
**P-NCAS – participating national Competent Authorities

19. EudraVigilance system
Electronic exchange of suspected adverse drug reaction reports
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Individual
Case
Safety
Reports
EMA
NCAs
MAHs
Clinical
trial
Sponsors

20. EudraVigilance system
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•Strict reporting timelines
•Acceleration of the communication for safety reporting
•Standarisation of secure data transmission
Early
detection
•Clear legal obligations
•Public access to reports of suspected side effects
•Extended Medicinal Product Dictionary (XEVMPD)
Transparency
•Continual monitoring of the benefits and risks of medicines
•Risk management facilitation
•Safety monitoring across the EU
Safety
assessment

21. Eu database for Susar reports
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* source: www.adrreports.eu/en/index.html

22. Eu database for Susar reports
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* source: www.adrreports.eu/en/index.html

23. Enhancement of the EudraVigilance
system (2017)
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simplified reporting, better quality data and improved
searching, analysis and tracking functionalities
change from a national to a centralised system for reporting
ICSRs in the EU
the reporting of non-serious cases of suspected adverse
drug reactions to EudraVigilance
enhanced collaboration between EMA and the World Health
Organization (WHO)

24. Magdalena Matusiak MPharm
Manager, Clinical Development
Pharmacovigilance Team Lead KCR S.A.
THANK YOU