September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 1 GCP QA for Russia and the Ukraine

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 2 Attractive Features Attractive Features FDA Inspections Overview in Russia and Ukraine FDA Inspections Overview in Russia and Ukraine Review of Personal Data from the Audits Review of Personal Data from the Audits Compliance Issues in Russia and Ukraine and Possible Resolutions Compliance Issues in Russia and Ukraine and Possible Resolutions Recommendations Recommendations GCP QA for Russia and the Ukraine

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 3 Comparative Characteristics Area (1000 km 2 ) Inhabitants (Million) Major Cities (more 1.0 Mill) Physicians per 1000 Inhabit. Hospital Beds per 1000 Inhabit. Russia 17, Ukraine USA 9,

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 4 Attractive Features (Russia and the Ukraine) Population: Prevalence of Different Diseases, Including Rare ones Treatment-naïve Patients Low Residential Movements Patients’ Compliance

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 5 Attractive Features (Russia and the Ukraine) Healthcare System Features: Centralized and Vertical Healthcare Well-maintained Patient Databases Large In-patient Facilities Long Hospital Stays

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 6 Example of Enrollment Rate - 1

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 7 Example of Enrollment Rate - 2

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 8 Attractive Features (Russia and the Ukraine) Clinical Investigators: Highly Motivated to Participate in Trials Level of Medical Training and Education Good Cooperation with Monitors Study Coordinators – Qualified Physicians Trust-based Relationships between Patients and Investigators

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 9 Example of Drop-out Rate

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 10 Attractive Features (Russia and the Ukraine) Regulations Compatible with ICH GCP National Ethics Committee Data Quality: There have been Many Reports from Different Sources of the High Quality of Data Obtained in Russia and Ukraine

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 11 Example of Query Rate

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 12 Clinical Trails Performed by Sponsors 2008 – about trials in USA

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 13 FDA Inspections in Russia

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 14 Results of FDA Inspections RussiaUkraine NAI285 VAI212 OAI10 Total507

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 15 FDA Inspections in Russia and the Ukraine Most Frequent Deficiencies Found During FDA Inspections: Inadequate and Incorrect Records – 14 (25%) Failure to Adhere to Protocol – 10 (18%) Failure to Report Adverse Reactions – 3 (5%) Inadequate Drug Accountability – 3 (5%)

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 16 “Equivalent” Results of Personal Data RussiaUkraine NAI184 VAI634 OAI20 Total838

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 17 Audits in Russia and the Ukraine (Personal Data) Most Frequent “Equivalent” Deficiencies Found During the Audits (Personal Data): Inadequate and Incorrect Records – 35 (38%) Failure to Adhere to Protocol – 24 (26%) Failure to Report Adverse Reactions – 15 (16%) Inadequate Drug Accountability – 15 (16%)

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 18 Compliance Issues in Russia and the Ukraine Experience Level of Investigators: Quite a few Investigators are Still Inexperienced in Conducting Clinical Trials Studies (mainly Phase IV) Conducted by Local Pharmaceutical Companies are Still far from ICH GCP Standards National Authorities have only Started Continuous Inspections of Clinical Sites

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 19 Compliance Issues in Russia and the Ukraine Resolutions for Experience Level of Investigators: Monitors Experienced in Local and ICH GCP Requirements Intensive Investigators’ Training Sufficient Time for Site Management Audits of New Investigators

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 20 Compliance Issues in Russia and the Ukraine High Patient’s Recruitment Rate: High Ratio Patient per Site Higher Ratio active/ non-active Sites than in the West High Number of Patients are Enrolled within a Very Short Period of TimeResolutions: Increased Number of Monitors More Intense Monitoring Frequency

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 21 Compliance Issues in Russia and the Ukraine Cultural Features: Cultural Differences in Perception of Health, Symptoms, and PainResolution: Special Attention to the Registration of Adverse Events during Site Monitoring and Site Audits

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 22 Compliance Issues in Russia and the Ukraine Source Data: Very Detailed after Patient’s Enrollment Less Detailed with Regard to Patient’s Previous Medical HistoryResolutions: Intensive Site Monitoring Agreement on Source Documents Medical Background of Monitors/ Auditors

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 23 Compliance Issues in Russia and the Ukraine Language: English Skills of Investigators Translation of Study Documents MiscommunicationResolution: Monitors and Auditors with Knowledge of Local Language and English

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 24 Compliance Issues in Russia and the Ukraine Other Issues that can Influence Compliance: Less Efficient Logistics/ Transportation Limited Communication Infrastructure Lack of Standards in Local Laboratories Complicated Regulatory Process

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 25 Compliance Issues in Russia and the Ukraine Resolution - Other Issues: Local Drug Depot Experienced Courier Service Provision of Study Equipment to Sites Establishment of High-Speed Internet for Efficient Communication and EDC Continuous Monitoring on Regulatory Process

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 26 Recommendations Use Professionals with Local Expertise Conduct Intensive Site Monitoring and Site Management Monitors and Auditors – Medically Qualified and Trained to International Standards with Knowledge of Local Language

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 27 GCP QA for Russia and the Ukraine Thank you!

September 18, 2009 Prepared for DIA GCP QA SIAC teleconference 28 Contact Information Dmitry V. Vorobiev, MD, PhD, MRQA Tel : Fax: Mob: