Clinical Trials of Medicines
in Ukraine
Public Enterprise “The State Expert Center
of the Ministry of Health of Ukraine”
Valentina Nikolaieva
PhD, Director of the Board of Preclinical and
Clinical Trials
Ukraine
• Gained its independence in 1991
• Situated in the central part of
Eastern Europe
• Capital – Kyiv (about 4 million)
• 27 regions
• Population – about 45 million
• State language - Ukrainian
• Precise legislation: Constitution,
Laws, Regulations, Orders
• More then 1 500 Trial Sites with
experience in CT
The rules governing clinical trials
(CTs) in Ukraine
• Law of Ukraine “On Medicines”
– Adopted in 1996
– Articles 7 and 8 regulate conducting of clinical trials
Art. 7 « Clinical trial of medicinal products»
Clinical trials (CT) are conducted out:
- at health care settings (HCSs);
- if the positive results of the expert evaluation and assessment of the
Ethics Committees at HCS are available;
- MoH establishes procedure for conducting expert evaluation;
- Ethics Committee (EC) are created and operate at HCSs;
- decision to approve a CT protocol is accepted by central executive
body for health or its authorized body
The rules governing clinical trials
(CTs) in Ukraine
• Orders of Ministry of Health of Ukraine which take
into account requirements of:
– Council Directives 2001/20/EC, 2005/28 EC
– ICH GCP
– Declaration of Helsinki
– WHO recommendations
Regulations of CTs
Order of MoH Ukraine # 690 from 23.09.2009 in the wording
of Order of MoH Ukraine # 523 from 12.07.2012
(Registered at the Ministry of Justice of Ukraine on
20.07.2012 under № 1235/21547 and № 1236/21548)
Procedure for Conducting Clinical Trials of Medicinal
Products and Expert Evaluation of Materials Pertinent to
Clinical Trials
and Model Regulations of the Ethics Committees
Regulations of CTs
CPMP/ICH/135/95 (E 6) “Note for Guidance on Good
Clinical Practice”
Order of MoH Ukraine # 95 from 16.02.2009:
Guidance “Medicinal Products. Good Clinical Practice
ССТ-Н МОЗУ 42-7.0:2008”
Regulations of CTs
CPMP/EWP/QWP/1401/98 “Guideline on the Investigation of
Bioequivalence”
Order of MoH Ukraine # 191 from 25.04.2005: Clinical Trials
Guidance 42-7.1:2005 “Medicinal Products. Investigations
of Bioavailability and Bioequivalence”
Directive 2004/10/ЕС
Order of MoH Ukraine # 95 from 16.02.2009 Guidance
“Medicinal Products. Good Laboratory practice”
Regulations of CTs
•«Guideline on similar biological medicinal products» (CHMP/437/04/),
•«Guideline on similar biological medicinal products containing biotechnology-derived proteins
as active substance: non-clinical and clinical issues» (EMEA/CHMP/BMWP/42832/2005),
«Guideline on non-clinical and clinical development of similar biological medicinal products
containing:
• low-molecular-weight-heparins EMEA/CHMP/BMWP/118264/2007)
• recombinant erythropoietins (Revision) (EMEA/CHMP/BMWP/301636/2008)
•recombinant human soluble insulin (EMEA/CHMP/BMWP/32775/2005)
•somatropin (EMEA/CHMP/BMWP/94528/2005)
•containing recombinant interferon alfa (EMEA/CHMP/BMWP/102046/2006)
•containing recombinant granulocyte-colony stimulating factor
(EMEA/CHMP/BMWP/31329/2005)».
Methodological recommendations (99.12/190.12.):
The general principles of non-clinical and clinical issues on similar
biological medicinal products containing biotechnology-derived
proteins as active substance
Regulations of CTs
State Expert Centre of the Ministry of Health
of Ukraine (SEC) has been authorized to
regulate CTs
Main tasks of SEC:
– Expertise of materials of CTs
– Approval CTs
– Control of CTs (Clinical audit / inspections)
– Monitoring SUSAR
– Control of compliance of scientific research to the
principles of biological and medical ethics
PROCEDURE for Conducting CT of MP
and Expert Evaluation of Materials of CT
14 chapters:
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General
Definition of terms
General principles of conducting clinical trials
Main requirements to protection of subjects
Requirements to investigators and HCS/clinical trial site
The main requirements to labeling of investigational medicinal
product
Obtaining conclusion about expert evaluation of materials
concerning a clinical trial of medicinal product (-s)
Assessment of ethical, moral, and legal aspects of the clinical trial
Conducting a clinical trial
Changes and additions during clinical trial
Termination of clinical trial
Notification of adverse events and reactions
Clinical audit of clinical trials of medicinal products
Suspension or full stoppage of a clinical trial
PROCEDURE for Conducting CT of MP
and Expert Evaluation of Materials of CT
15 annexes:
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LIST OF MAIN DOCUMENTS PERTINENT TO CT
COVER LETTER (CT)
APPLICATION FORM (CT)
COMPLETE DOSSIER OF INVESTIGATIONAL MEDICINAL PRODUCT
APPLICATION OF PRINCIPAL INVESTIGATOR
INFORMATION ABOUT HEALTH CARE SETTING AND CLINICAL TRIAL SITE
NOTIFICATION ABOUT THE START OF CLINICAL TRIAL IN UKRAINE
LIST OF ASPECTS OF CLINICAL TRIAL WHICH MAY BE AMENDED
SIGNIFICANTLY BY SPONSOR (LIST OF SIGNIFICANT AMENDMENTS)
COVER LETTER (amendment)
APPLICATION FORM (amendment)
NOTIFICATION ABOUT COMPLETION OF CT
PERIODICAL REPORT ON STATUS OF CT
FORMAT OF FINAL CLINICAL TRIAL REPORT
REQUIREMENTS TO NOTIFICATION ABOUT SUSPECTED UNEXPECTED
SERIOUS ADVERSE REACTION
REQUIREMENTS TO STRUCTURE OF UPDATE REPORT ABOUT SAFETY (DSUR)
PROCEDURE for Conducting CT of MP
and Expert Evaluation of Materials of CT
General principles of clinical trial
• CT are conducted according to the ethical principles of the
Declaration of Helsinki
• CT are conducted at HCS determined by MoH based on the State
Expert Center (SEC) positive conclusion
• Persons attracted to the performance of clinical trial should have
appropriate education, proficiency and experience to perform
their functions in CT
• Sponsor is entrusted with a choice of investigators
• The sponsor may delegate his powers to CRO, but is responsible
for initiating CT and the data obtained
• Clinical trials shall be commenced when the Center’s positive
conclusion approved by MoH, and positive assessment (minutes of
the meeting) of the Ethics Committees at HCS are available
PROCEDURE for Conducting CT of MP
and Expert Evaluation of Materials of CT
General principles of clinical trial
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Ensuring confidentiality
CT are planned and conducted in compliance with GCP
If IMP is a narcotic one - compliance with relevant legislation
System of procedures is used to ensure CT quality
Collection, processing and presentation of reliable data
Data storage in HCS at least 15 years
IMPs are produced according to GMP
SEC may conduct clinical audit of CT
Main requirements to conducting CTs
– Investigators and the applicant shall be
governed by ICH GCP standards
– Freely given informed consent should be
obtained from every patient or his legal
representative prior to participation in a
clinical trial
Approval of CTs by SEC
Approval of amendments by SEC
Order of MoH Ukraine # 523 from 12.07.2012
For conducting CT
applicant submit documents are
subject to an expert evaluation at the
SEC:
–
–
–
–
Application (set form)
CT protocol
Investigator’s brochure
Information for patients and
informed consent form
– Main pages of CRF
– Insurance contract
– Certificate of analysis for batch of
the IMP ...
• Approvals based on results of
an expert evaluation of CT
protocol / amendments
The main stages of CT approval
Applicant
Application
CT materials
Expert evaluation
?
Specialized assessment of CT materials
Scientific and expert council
Protocols – 60 days
Amendments – 35 days
Approval of CT
Ethical approval of CTs
A favorable opinion by Local Ethics Committee
is necessary
– Obligatory requirement to Ethics Committees to act according to ICH GCP and Declaration of
Helsinki
Quantity of approved CTs per
year
265
280
250
260
240
227
Total
220
213
201
220
184
200
International
MCT
Domestic CT
177
177
180
142
160
140
120
100
80
50
60
42
49
43
52
40
20
12
20
11
20
10
20
09
20
20
08
0
International MCTs ( 2008 –2012)
220
200
213
201
177
Total
I phase
177
180
II phase
160
142
140
140
122
IV phase
109
120
89
100
80
60
III phase
138
75
56
49
53
49
40
20
3
3
0
4
6
6
4
6
7
20
12
20
11
20
10
20
09
20
08
0
9
International MCTs 2008 – 2012
Specialities (main)
Gastroenterology
21 4 5 6
Psychiatry and
neurology
Cardiology
35
21
Pulmonology 15
Oncology
2008
17
35
13 12
16 10
17
41
2009
36
39
44
24
18
30
25
39
2010
45
31
2011
2012
Monitoring of Adverse Reactions
during CTs
System of Immediate Reporting
Investigator
Local Ethic
Committee
SAE immediately
According to the
Protocol
Sponsor
No later 15 days
SUSAR
Revealing of
serious adverse
events (SAEs)
(7days – if death)
SEC
Additional
information
Monitoring of Adverse Reactions
during CTs
Periodic Safety Reporting
Periodic reports on
safety, at least once a
year
Sponsor
SEC
Updates of investigator’s
brochure
Monitoring of Adverse Reactions
during CTs
•Recording of
Reports
SEC
•Collecting of
Information
•Analyzing of
Information
Taking of results
into consideration
during registration
of medicines
Taking appropriate
measures regarding
CTs
3 CT were stopped due
to serious ADRs
Order of MoH Ukraine # 523 from 12.07.2012
Notification of adverse events and
reactions (section XII to Procedure)
1. Notifications to be made by the responsible
investigator/ investigator
2. Notifications to be made by the sponsor
• ICH Topic E2A «Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting», June 1995 (CPMP/ICH/377/95)
• ICH Topic E 6 (R1) Guideline for Good Clinical Practice, July 2002
CPMP/ICH/135/95
• Guidance EC «Communication from the Commission - Detailed guidance on the
collection, verification and presentation of adverse event/reaction reports arising
from clinical trials on medicinal products for human use, 11 June 2011 (‘CT-3’)
(2011/C 172/01)
Order of MoH Ukraine # 523 from 12.07.2012
1. Notifications to be made by the responsible
investigator / investigator:
1.1.
While
conducting
clinical
trial
the
responsible
investigator/investigator shall report all serious adverse events
to the sponsor except for those that the protocol or
investigator’s brochure identifies as such not requiring
immediate reporting. The initial and follow-up reports shall
identify subjects by unique code numbers assigned to them for
the study.
1.2. The responsible investigator/investigator shall also report the
sponsor any adverse events and/or laboratory abnormalities
identified in the clinical trial protocol as critical to safety
evaluations according to the requirements and within the time
periods specified by the sponsor in the protocol.
continuance
Notifications to be made by the responsible
investigator / investigator:
1.3. The responsible investigator/investigator shall record immediately
and within 7 calendar days after learning about this case all
suspected unexpected serious adverse reactions associated with the
investigational medicinal product which resulted in death or were lifethreatening, to the ethics committee. The follow-up information on
this case shall be given to the ethics committee within subsequent 8
calendar days. Requirements to the notification on a suspected
unexpected serious adverse reaction are listed in Annex 14 to this
Procedure.
1.4. The responsible investigator/investigator shall inform the ethics
committee about all other suspected unexpected serious adverse
reactions associated with the investigational medicinal product
which become known to him within 15 calendar days.
1.5. In case of subject’s death the responsible investigator/investigator
shall provide to the sponsor, the Center and the ethics committee
any additional information requested by them.
Order of MoH Ukraine # 523 from 12.07.2012
2. Notifications to be made by the
sponsor:
2.1.Reporting the suspected unexpected serious adverse reactions to the
Center (reporting period) begins from the date of approval by CEBHC of
the Center’s conclusion on clinical trial and terminates with the end of
clinical trial in Ukraine.
2.2. The sponsor shall record immediately and within 7 calendar days after
learning about such case report all suspected unexpected serious
adverse reactions associated with the investigational medicinal product
which resulted in death or were life-threatening to the Center. Relevant
follow-up information on this case shall be given to the Center within
subsequent 8 calendar days. Requirements to the notification on a
suspected unexpected serious adverse reaction are listed in Annex 14 to
this Procedure.
2.3. The sponsor shall report to the Center all other serious unexpected
adverse reactions associated with the investigational medicinal product
which become known to him within 15 calendar days.
2.4. The sponsor shall inform all responsible investigators/investigators
who take part in the clinical trial of this investigational medicinal product
concerned on all detected events capable of affecting subjects' safety.
continuance
Notifications to be made by the sponsor:
2.5. The sponsor shall keep documentation related to all adverse events
the responsible investigators/investigators report to him.
2.6. During long-term clinical trials the sponsor shall provide the Center a
written report on the safety of the investigational medicinal product
under development in paper and electronic format at least once a year,
within 60 calendar days after preparation of the report according to the
requirements stated in Annex 15 to this Procedure.
In case of the substantiated suspicion on the increased risk for the
subjects the Center may oblige the sponsor to submit safety report on
the investigational medicinal product under development more
frequently.
2.7. In case of conducting several clinical trials of the same investigational
medicinal product, the sponsor shall provide to the Center a single
generalized report on the safety of investigational medicinal product. In
a cover letter attached to the report the sponsor shall provide a listing
of all clinical trials conducted in Ukraine or with Ukraine’s participation
which are associated with this report. In this case the term of annual
reporting begins from the date of receipt of the Center’s conclusion on
the conduct of the first listed clinical trial.
Order of MoH Ukraine # 523 from 12.07.2012
REQUIREMENTS TO DEVELOPMENT SAFETY UPDATE
REPORT ABOUT INVESTIGATIONAL MEDICINAL PRODUCT
(Hereinafter-DSUR)
(Annex 15 to Procedure)
ICH guideline E2F
«Development Safety Update Report», September 2010
(EMA/CHMP/ICH/309348/2008 Committee for medicinal products for
human use (CHMP)
Order of MoH Ukraine # 523 from 12.07.2012
DSUR shall consist of 20 sections:
1.Introduction.
2.Worldwide authorization/registration status.
3.Actions taken in the reporting period for safety reasons.
4.Changes to reference safety information.
5.Inventory of clinical trials ongoing and completed during the
reporting period.
6.Estimated cumulative exposure (overall effect):
6.1.Cumulative exposure in the development program.
6.2.Patient exposure (patient effect) from marketing
experience.
7.Data in line listings and summary tabulations:
7.1.Reference information.
7.2.Line listings of serious adverse reactions during the
reporting period.
7.3.Cumulative/summary tabulations of serious adverse
events.
continuance of Annex 15
8.Significant findings from clinical trials
during the reporting period:
8.1.Completed clinical trials.
8.2.Ongoing clinical trials.
8.3.Long-term control (follow-up).
8.4.Other therapeutic use of
investigational medicinal product.
8.5.New safety data related to the
combination therapies.
9.Safety findings from noninterventional studies.
10.Other clinical trial safety
information.
11.Safety findings from marketing
experience.
12.Non-clinical data.
13.Literature.
14.Other DSURs.
15.Lack of efficacy.
16.Region-specific information.
17.Late-breaking information.
18.Overall safety assessment:
18.1.Evaluation of the risks.
18.2.Benefit/risk considerations.
19.Summary of important risks.
20.Conclusions.
SUSAR reports originating worldwide in clinical trials
according to protocols approved or not approved in
Ukraine and obtained by the Center
22766
15943
16708
16494
2009
2010
2011
12305
2008
2012
SUSAR reports originating in Ukraine
and received by the Center
350
331
300
257
250
200
240
Reports (initial
+follow up)
221
176
150
180
133
SUSAR cases
143
134
87
100
50
0
2008
2009
2010
2011
2012
Inspections of Clinical trials
(Clinical audit)
– Standard Operating Procedures
 Inspections cover all CTs including domestic
and international CTs
 Inspectors – specialists of SEC
Order of MoH Ukraine # 523 from 12.07.2012
Section XIII to Procedure
Main stages of inspection check-ups
Preparing the plan
Notification of sponsor
and investigators
Conducting inspection
•Investigator
•Sponsor
Detailed
inspection
report
Final
inspection
report
(Act)
SEC
data bank
Critical remarks
Essential remarks
Non-essential remarks
2001/20/EC
2005/28/EC
Positive
conclusion
Negative
conclusion
CT Stopped
Inspections of Clinical Trials
Performance
12
20
11
20
10
20
09
20
08
20
• Targeted check-up
review of specific issues
07
• Retrospective check-up
after fulfillment CT
based on archive data
20
• Routing check-up
during CT conducting
65
70
60
48 48 49 52
50
40 34
30
20
10
0
8 CT were stopped due to
- serious ADRs
- Critical Violation
Import of registered and unregistered
medicines, samples of placebo, related
materials/export of biological samples
Order of the Ministry of
Health of Ukraine of
26.04.2011 №237 “On
Approval of the
Procedure for the
Import of Unregistered
Medicinal Products,
Certified Reference
Materials, and Reagents
to the territory of
Ukraine”
— samples of substances for researches for
conducting pre-clinical study;
— investigational medicines, reference
preparations, samples of placebo for clinical
trials and research;
— samples of medicines in pharmaceutical forms
for registration;
— finished medicines for exhibits at exhibitions,
conferences, etc. without the right to sell;
— finished medicines for individual use by citizens;
— in cases of natural disasters, accidents, etc.;
— import to the territory of Ukraine of reference
medicines and/or substances, contaminants,
biological standard preparations (substances
comparison), the reference spectra and reagents
for laboratory studies of drug quality.
Quantity of confirmation letters per
year
1500
1135
1282
1428
1000
500
0
2010 year
2011 year
2012 year
Quantity of confirmation letters per
year
700
1428
671
All confirmation
letters - 100%
600
500
456
400
301
Import of
medicines - 32%
Import of related
materials - 47%
300
200
Export of biological
samples - 21%
100
0
2012 year
Issues in clinical trials
The problem of tax
Today, according to the
Tax Code of Ukraine
medicines imported
for the purpose of
clinical trials are
subject to tax at 20%
- This approach is contrary to the European
regulatory practice and recommendations
of the International Convention on the
Simplification and Harmonization of
Customs Procedures, which joined
Ukraine in 2006
- Factor taxation prevents the development of
clinical trials and reduces investment
attractiveness of Ukraine
The exemption will increase the level of foreign investment of 1
billion UAH per year to 3 billion UAH per year over the next 2
years to 8 billion UAH a year over the next 4 years
The present stage of CTs in
Ukraine
• Adopted CTs regulations
• Training programs
• Publications:
– Periodical medical journals and other
publications
– Guides on clinical trials
– Guidelines on specific issues (organization
CTs, statistic considerations, certain patient
population: oncology, pulmonology,
cardiology etc)
Future of CTs in Ukraine
Subsequent development of
CTs regulations according to
international requirements
• Training of investigators and
specialists in the field of
clinical trials organization
• Spreading knowledge of GCP
through seminars,
conferences, publications