Clinical Trials of Medicines in Ukraine

Clinical Trials of Medicines in Ukraine

Public Enterprise “The State Expert Center of the Ministry of Health of Ukraine”

Valentina NikolaievaPhD, 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

Directive 2004/10/ЕС

Order of MoH Ukraine # 95 from 16.02.2009 Guidance “Medicinal Products. Good Laboratory practice”

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”

Regulations of CTs

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

•«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)».

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 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


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)


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


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

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 SECApproval of amendments by SEC Order of MoH Ukraine # 523 from 12.07.2012

• Approvals based on results of an expert evaluation of CT protocol / amendments

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 ...

The main stages of CT approval

Applicant

Application CT materials

Expert evaluationSpecialized assessment of CT materials

Scientific and expert council

Approval of CT

?

Protocols – 60 days Amendments – 35 days

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

227

177

50

184

142

42

220

177

43

250

201

49

265

213

52

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

Total

InternationalMCTDomestic CT

International MCTs ( 2008 –2012)

177

3

49

140

3

142

0

49

89

4

177

6

56

109

6

201

4

53

138

6

213

7

75

122

9

0

20

40

60

80

100

120

140

160

180

200

220

2008

2009

2010

2011

2012

TotalI phase II phaseIII phaseIV phase

International MCTs 2008 – 2012Specialities (main)

41 18 39 31 45

15 17 24 25 30

21 16 10 13 12

35 35 44 39 36

21 4 56 17

Oncology

Pulmonology

Cardiology

Psychiatry andneurology

Gastroenterology

2008 2009 2010 2011 2012

Monitoring of Adverse Reactions during CTs

System of Immediate Reporting

Investigator

Revealing of serious adverse events (SAEs)

SAE immediatelyAccording to the

Protocol

Sponsor

SEC

No later 15 days SUSAR

(7days – if death)

Additional

information

Local Ethic Committee

Periodic Safety Reporting

Sponsor SEC

Periodic reports on safety, at least once a

year

Updates of investigator’s brochure


SEC

•Recording of Reports

•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


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

Order of MoH Ukraine # 523 from 12.07.2012

• 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)

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 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.

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. Notifications to be made by the sponsor:

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.

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)

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 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.

SUSAR reports originating worldwide in clinical trials according to protocols approved or not approved in

Ukraine and obtained by the Center

12305

15943 16708 16494

22766

2008 2009 2010 2011 2012

SUSAR reports originating in Ukraine and received by the Center

331

176

257

133

221

143

180

87

240

134

0

50

100

150

200

250

300

350

2008 2009 2010 2011 2012

Reports (initial+follow up)

SUSAR cases

Inspections of Clinical trials(Clinical audit)

– Standard Operating Procedures

Inspections cover all CTs including domestic and international CTs

Inspectors – specialists of SEC

Main stages of inspection check-upsPreparing the planNotification of sponsor and investigatorsConducting inspection

Detailed inspection

report

SEC data bank

Final inspection

report (Act)

•Investigator•Sponsor

Positive conclusion

Negative conclusion

CT Stopped


2001/20/EC 2005/28/EC

Section XIII to Procedure

Critical remarks Essential remarks

Non-essential remarks

Inspections of Clinical Trials

3448 48 49 52

65

010203040506070

2007

2008

2009

2010

2011

2012

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

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”

Quantity of confirmation letters per year

11351282 1428

0

500

1000

1500

2010 year 2011 year 2012 year

Quantity of confirmation letters per year

1428

456

671

301

0

100

200

300

400

500

600

700

2012 year

All confirmationletters - 100%

Import ofmedicines - 32%

Import of relatedmaterials - 47%

Export of biologicalsamples - 21%

Issues in clinical trials

The problem of taxToday, 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

Clinical Trials of Medicines in Ukraine

Documents

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