Clinical and Regulatory Environment in Russia and

Eastern Europe

Aleksandar Skuban, M.D.

August 2012| Philadelphia

disclosure

All images used with permission: www.istockphoto.com or as noted

2

I took a speed-reading course and read War and Peace in twenty

minutes. It involves Russia.

Woody Allen

Pharmaceutical R&D and Global CROsEmerging Markets DevelopmentClinical Drug Development in Psychiatry

Background Eastern Europe and United States

Phase II-III global studies including: Russia, Serbia, Croatia, Hungary, Romania, Bulgaria, Ukraine, Czech Republic, Slovakia, Poland, Estonia, Slovenia

Your Experience in CEE

Expectations

5

Presentation Overview

+ 20 years in global clinical trials Eastern Europe and Russia relatively unknown

6

Countries with Similar

Background and Great Regional

Diversity

Transition from Emerging to Established

Markets

Dynamically changing

regulatory and market

environment

Overview of Central and Eastern Europe*

Baltic States

Estonia

Lithuania

Latvia

Commonwealth of Independent States (CIS)

Russian Federation

Ukraine

BelarusGeorgia

Kazakhstan

(…)

Moldova

7

Central Europe

Czech Republic

Poland

SlovakiaHungary

Slovenia

Croatia

Balkans

Serbia

Montenegro

FYR MacedoniaRomania

Bulgaria

Bosnia and Herzegovina

*not all countries in region listed

Ongoing Phase 2&3 Studies (n=4832)

US Russia Germany Ukraine Serbia Hungary

2611

390*

840

17371

354

Number of Trials

Open industry-sponsored studies at www.clinicaltrials.gov as of 5 August 2012 8

* 63 ongoing pediatric trials

Active Phase 1 Trials (n=2043)

US Germany Russian Federation

Ukraine Serbia Hungary

1230

159

25 5 2 16

Number of Trials

Open studies at www.clinicaltrials.gov as of 5 August 2012 9

Regional Considerations for Global Development Access to Population with Target Disease

Diagnostic Reliability

Compatible Treatment Paradigms

Competent Sites & Data Quality

Regulatory and Ethics Framework

Recruitment Speed, Cost, Infrastructure 10

Eastern Europe in Clinical Research: The first 10 years

11

Clinical Investigators Working Under IND Regulations in

Selected Countries. Fiscal Year 1991 to 1999

91-93 94-96 97-99

Hungary 9 35 161

Poland 4 100 190

Russia 0 5 170

Dept. HHS OIG: The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects (September 2001 OEI-01-00-00190) pp.10 Table 2

New Global Trials Initiated in CEE*

Hungary Poland Russia Romania Ukraine

146213 196

62 47

204

573

725

212

375

2002 2007

Center Watch Data August 2008 (*selected countries)

Growth Rate of New Global Trials Initiated in CEE*

Center Watch Data August 2008 (*selected countries)

Approved marketing applications FY2008 (FDA):

Source of SubjectsDrugs Biologics

Foreign and domestic subjects 92,859 206,842

Percentage of foreign subjects 56.9% 86.9%

Foreign and domestic trial sites

11,227 717

Percentage of foreign trial sites 54.6% 49.7%

14

Source: "Challenges to FDA's Ability to Monitor and Inspect Foreign Clinical Trials," Dept. of Health and Human Services Office of Inspector General, June (oig.hhs.gov/oei/reports/oei-01-08-00510.pdf)

Approved marketing applications FY2008 (FDA): Source of Foreign

SubjectsDrugs Biologics

Number of foreign subjects 52820 179712

WE, AU, Japan,NZ, CAN 32761 (62%) 109706 (61%)

New EU members 5474 (10%) 1062(0.5%)

Emerging Countries (BRICM) 4789 (9%) 19888 (11%)*

Number of Countries 68 38

15

Data from : "Challenges to FDA's Ability to Monitor and Inspect Foreign Clinical Trials," Dept. of Health and Human Services Office of Inspector General, June (oig.hhs.gov/oei/reports/oei-01-08-00510.pdf) *No subjects from China or India

Leading physicians and InstitutionsEarly adoption of GCP guidelines Excellent Data QualityHigh Patient recruitmentEnthusiasm for international R&D collaboration“Rescue Studies”

Evolving regulatory institutionsInfrastructure challengesSkilled clinical research professionalsLower study costs

Cautious Wave: 1990s Eastern Europe

Russia In Global Clinical Research

17

CEE, CIS, BRIC, Asia, Emerging Country,Key Pharmaceutical

Market

Russia: Key Facts

Large, diverse, decreasing population: 143 mGeography across nine time zonesEthnically and culturally diverse countryCentralized health care systemAccessible patient populationResearch concentrated in Moscow, St. Petersburg 73% population in urban areas

18

Health Care in Russia

Government remains major provider,

payer in the system and owner of 99%

institutions

Primary Care >22000 out-patient

clinics GPs and Specialists

Secondary Care1.5 mil beds in

>10000 hospitals (Municipal, University,

Specialized)

Tertiary CareOver 300

Universities and Research Institutions

19

Health care expenditure

United Kingdom*

Hungary

Switzerland

Russian Federation

8.1

7.9

11.5

6

2560

1308

4011

583

US$ PPP2 % of GDP

Source: WHO EU Atlas of Health 2008

Among Highest in Europe: Hospitals Beds and Physicians

Hungary

Switzerland

Russian Federation

304

397

431

896

833

806

792

568

966

Hospital beds Nurses Physicians

Per 100000 population Source: WHO Atlas of Health 2008 in Europe

Russia Health Statistics (WHO)1st Deaths All Causes, CV, IHD, Pulmonary, Injury & Poisoning

2nd Deaths Cancer, Cerebrovascular, Suicide

3rd HIV New Cases

Source: WHO Europe 2008

Russia Health Statistics (WHO)

2nd Highest % male smokers and spirits consumption

Lowest life expectancy at birth for men (59 years)

(Source: WHO Europe 2008)

Deaths from diseases of circulatory system

Russian Federation

Hungary

France

301.2

175.3

28.6

157.1

47.8

4.9

Females Males

Per 100 000 population (25-64 years) Source: WHO Atlas of Health 2008 in Europe

24

Deaths from cancer

Russian Federation

Hungary

Sweden

224.5

301.2

86.8

123.3

157.1

102.5

Females Males

Per 100 000 population (25-64 years) Source: WHO Atlas of Health 2008 in Europe

25

Regional Health Statistics

*Per 100000 male population Source: WHO Atlas of Health 2008 in Europe 26

HungaryRussian Federation

Ukraine

Population(million)

10 142 46

Deaths All causes*

13th Highest (782.2*) 4th

Circulatory System

12th Highest (762.2) 4th

Ischemic HD 5th Highest (406.3) 2nd

Cancer Highest (301.2)

2nd (224.5)

Lung Cancer Highest (99.7)

5th 10th

Suicide 5th (40) 2nd (56.1) 8th

AIDS new cases

Low (0.2) Low (0.6) Highest (9.7)

HIV infection new cases

Low (0.8) 3rd highest (27.5) 2nd highest (28.4)

Regulatory Framework

New Federal Drug Law “On Drugs Circulation” 1 Sep 2010

Local study required if no Russian patients in global Phase 3 program

Need for local study may delay registration in Russia for 2-3 years

27http://www.efgcp.eu/Downloads/EFGCPReportFiles/Russia%20definitive.pdf

Local Clinical Trial Requirements

Local Patient Data Needed for New Products, Line Extensions, New Indications

No specific guidance on design, type of study or required number of patients

Guidance based on Expert feedback, Company expertize, informal discussions, industry benchmarks 28

Impact on Product RegistrationFor timely product registration consider including Russian sites in Phase II-III trials

Requirements for Local Regulatory Studies may further evolve

Strategy for product launch in Russia

29

Local Ethics Committees (LECs)

LEC at each investigative siteSubmission after Russian Ministry of Health approvalProtocol & documents in Russian2-4 weeks review cycle Some with executed clinical trial agreement Most LECs review without a fee

30

Clinical Investigative Sites

700000 physicians1% involved in clinical studies900 institutions accredited by Ministry of Health

31

Global Share of Sites and Patients

Country Density* WW site share %

United States 120.2 48.7

Germany 51.2 5.7

Japan 15.7 2.7

Russia 7.7 1.5

Hungary 62.5 0.8

Poland 30.9 1.6

32*number of recruiting sites/country population (m) Data selection from Thiers at al: “Trends in the globalization of clinical trials” Nature Vol.7, Jan 2008 (*as of April 12th 2007)

0.03% population in Russia participated in clinical studies in 2006

Russia in Global Clinical Trials

CV outcome studies from 1990s:Patient Population and Expertize

Notable Proof of Concept studies: Alzheimer’s Disease and Schizophrenia

Current Phase II-III landscape:Oncology, CV, Diabetes, Respiratory, CNS

In 2011 MoH issued 567 approvals- 370 for global studies

33

Opportunities and Challenges

EnrollmentStudy CostExecution QualitySite QualificationDiverse patient populationMulti-specialty large medical centersNew legislation

Changing reg. environment

Saturation of Good Sites

Customs proceduresLogistics

Language BarrierInfrastructure

POC Phase II Studies New Legislation

34

In SumCountries with Unique Advantages – Continue to

Attract Clinical Research Opportunities

Evolving regulations and Health Authorities: Local Clinical Trials for Product Registrations

Experienced and well-qualified investigators:

Increasing local and global competition for quality sites

Build Own Expertise andCritically Evaluate ExpectationsOn Regular Basis

35

Clinical and Regulatory Environment in Russia and Eastern Europe

Aleksandar Skuban, M.D.

August 15, 2012| Philadelphia

Thank you