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
Greatest cities are Kiev, Kharkov, Dnepropetrovsk Donetsk Odessa, Lvov

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 Trial Sites with experience in CT
Greatest cities are Kiev, Kharkov, Dnepropetrovsk Donetsk Odessa, Lvov

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. and Model Regulations of the Ethics Committees
Regulations of CTs
Order of MoH Ukraine # 690 from in the wording of Order of MoH Ukraine # 523 from
(Registered at the Ministry of Justice of Ukraine on 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. CPMP/ICH/135/95 (E 6) “Note for Guidance on Good Clinical Practice”
Regulations of CTs
CPMP/ICH/135/95 (E 6) “Note for Guidance on Good Clinical Practice”
Order of MoH Ukraine # 95 from :
Guidance “Medicinal Products. Good Clinical Practice ССТ-Н МОЗУ :2008”

7. Regulations of CTs
CPMP/EWP/QWP/1401/98 “Guideline on the Investigation of Bioequivalence”
Order of MoH Ukraine # 191 from : Clinical Trials Guidance :2005 “Medicinal Products. Investigations of Bioavailability and Bioequivalence”
Directive 2004/10/ЕС
Order of MoH Ukraine # 95 from Guidance “Medicinal Products. Good Laboratory practice”

8. Regulations of CTs Methodological recommendations (99.12/190.12.):
«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/ ):
The 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 MP and 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 MP and 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 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

13. PROCEDURE for Conducting CT of MP and 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 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

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 – 2012 Specialities (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 investigator’s 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. Notifications to be made by the responsible investigator/ investigator
Order of MoH Ukraine # 523 from
Notification of adverse events and reactions (section XII to Procedure)
Notifications to be made by the responsible investigator/ investigator
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 (‘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 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.

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 subject’s death the responsible investigator/investigator shall provide to the sponsor, the Center and the ethics committee any additional information requested by them.

27. 2. Notifications to be made by the sponsor:
Order of MoH Ukraine # 523 from
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.

28. Notifications to be made by the sponsor:
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.

29. «Development Safety Update Report», September 2010
Order of MoH Ukraine # 523 from
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)

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. 8.1.Completed clinical trials. 8.2.Ongoing clinical trials.
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.Overall safety assessment:
18.1.Evaluation of the risks.
18.2.Benefit/risk considerations.
19.Summary 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
Section XIII to Procedure
Main stages of inspection check-ups
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
Order of the Ministry of Health of Ukraine of №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.

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