Clinical Trials of Medicines in Ukraine

1
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

2
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

3
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
4
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

5
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

6
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 Guidanc
e Medicinal Products. Good Clinical Practice
???-? ???? 42-7.02008
7
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 42-7.12005 Medicinal
Products. Investigations of Bioavailability and
Bioequivalence
Directive 2004/10/??
Order of MoH Ukraine 95 from 16.02.2009
Guidance Medicinal Products. Good Laboratory
practice
8
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/1182
  64/2007)
• 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.) Th
e general principles of non-clinical and clinical
issues on similar biological medicinal products
containing biotechnology-derived proteins as
active substance
9
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

10
PROCEDURE for Conducting CT of MPand Expert
Evaluation of Materials of CT

• 14 chapters
• 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

11
PROCEDURE for Conducting CT of MPand Expert
Evaluation of Materials of CT

• 15 annexes
• 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)

12
PROCEDURE for Conducting CT of MPand 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
  Centers positive conclusion approved by MoH, and
  positive assessment (minutes of the meeting) of
  the Ethics Committees at HCS are available

13
PROCEDURE for Conducting CT of MPand Expert
Evaluation of Materials of CT General principles
of clinical trial

• 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

14
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

15
Approval of CTs by SECApproval 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
• Investigators 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

16
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
17
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

18
Quantity of approved CTs per year
19
International MCTs ( 2008 2012)
20
International MCTs 2008 2012Specialities
(main)
21
Monitoring of Adverse Reactions during CTs
Local Ethic Committee
System of Immediate Reporting
SAE immediately According to the Protocol
Investigator
Sponsor
No later 15 days SUSAR (7days if death)
Revealing of serious adverse events (SAEs)
SEC
Additional information
22
Monitoring of Adverse Reactions during CTs
Periodic Safety Reporting
Periodic reports on safety, at least once a year
SEC
Sponsor
Updates of investigators brochure
23
Monitoring of Adverse Reactions during CTs
Taking of results into consideration during
registration of medicines

• Recording of Reports
• Collecting of Information
• Analyzing of Information

SEC
Taking appropriate measures regarding CTs
3 CT were stopped due to serious ADRs
24
Notification of adverse events and reactions
(section XII to Procedure)
Order of MoH Ukraine 523 from 12.07.2012

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)

25
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
investigators 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.
26
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 life-threatening, 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 subjects death the responsible
investigator/investigator shall provide to the
sponsor, the Center and the ethics committee any
additional information requested by them.
27
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 Centers 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.
28
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 Ukraines
participation which are associated with this
report. In this case the term of annual reporting
begins from the date of receipt of the Centers
conclusion on the conduct of the first listed
clinical trial.
29
REQUIREMENTS TO DEVELOPMENT SAFETY UPDATE REPORT
ABOUT INVESTIGATIONAL MEDICINAL PRODUCT
(Hereinafter-DSUR) (Annex 15 to Procedure)
Order of MoH Ukraine 523 from 12.07.2012
ICH guideline E2F Development Safety Update
Report, September 2010 (EMA/CHMP/ICH/309348/2008
Committee for medicinal products for human use
(CHMP)
30
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.

31
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 non-interventional
  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.Over
all safety assessment 18.1.Evaluation of the
risks. 18.2.Benefit/risk considerations. 19.Summar
y of important risks. 20.Conclusions.
32
SUSAR reports originating worldwide in clinical
trials according to protocols approved or not
approved in Ukraine and obtained by the Center
33
SUSAR reports originating in Ukraine and received
by the Center
34
Inspections of Clinical trials(Clinical audit)

• Standard Operating Procedures
• Inspections cover all CTs including domestic
  and international CTs
• Inspectors specialists of SEC

35
Main stages of inspection check-ups
Order of MoH Ukraine 523 from 12.07.2012
Section XIII to Procedure

• Preparing the plan
• Notification of sponsor and investigators
• Conducting inspection

2001/20/EC 2005/28/EC

• Investigator
• Sponsor

Positive conclusion
Final inspection report (Act)
Detailed inspection report
Negative conclusion
Critical remarks Essential remarks
Non-essential remarks
CT Stopped
SEC data bank
36
Inspections of Clinical Trials

• Performance
• Routing check-up during CT conducting
• Retrospective check-up after fulfillment CT
  based on archive data
• Targeted check-up review of specific issues

• 8 CT were stopped due to
• serious ADRs
• Critical Violation

37
Import of registered and unregistered medicines,
samples of placebo, related materials/export of
biological samples

• 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.

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
38
Quantity of confirmation letters per year
39
Quantity of confirmation letters per year
40
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
41
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)

42
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