Контроль качества проведения международных клинических исследований ( I-IV phases)

1. Контроль качества проведениямеждународных клинических исследований (I-IV phases)

2. Quintiles C&EE 1996-2004: Studies by Therapeutic Area Enrolled Patients:71765 Initiated Sites:6388

3. Studies in Russia by Therapeutic Area (Historical Data – 2nd Quarter 2004) Enrolled Patients:9136 Initiated Sites:1026

4. Количество проведенных инспекций, аудитов в регионе за 2002-2004 г (первое полугодие)

5. Среднее количество замечаний, ошибокза 2004 (Average Number of Major/Critical Findings byCountry) Above EuropeanAverage Below EuropeanAverage EuropeanAverage = 0.9

6. Наиболее важные аспекты принимаемые во внимание во время проведения Инспекций и Аудитов. • Информированное согласие пациента • Исследуемый препарат (все параметры) • Данные пациента в сравнении с документированными в “CRF” • Этический комитет • Процесс мониторирования, проверки данных • Конфиденциальность • Обязанности исследователя • Процедуры по безопасности (SAE, AE….)

8. FDA: 1 Bulgaria 1 Czech 3 Russia 1 Poland 1 Israel 2 Greece Inspections in Q C&EE since 2002 • French RA: • 2 Russia • EMEA: • 1 Hungary • 2 Poland • 3 Russia • 1 Bulgaria • 1 Estonia • Audits & National Regulatory Inspections since 2002 • 130 audits and inspections were performed without critical findings: • 10% of them regulatory inspections • 30% customer audits

9. Query rate and pages processed by country Queries /100 pages 2000 4000 6000 8000 10000 12000 14000 16000 18000 Nber of pages

10. Non-Small Cell Lung Cancer (NSCLC) (US-IND) 155 152 150 Sites total: 185 Patients total:1173 54,1 % 45,9 % 47,1 % 52,9 % 100 99 100 88 80 53 51 51 40 50 36 32 32 29 24 24 20 17 16 16 13 11 10 10 9 3 2 0 ITALY SPAIN BRAZIL ISRAEL MEXICO RUSSIA TAIWAN TURKEY POLAND FRANCE CANADA GREECE UKRAINE BELGIUM HOLLAND SWEDEN MALAISIA HUNGARY BULGARIA SLOVAKIA GERMANY AUSTRALIA CZECH REP HONG KONG NEW ZELAND SWITZERLAND GREAT BRITAIN

11. NSCLC (US-IND): Query Rate 120 95 80 72 68 67 67 67 66 65 65 61 59 58 55 55 53 53 52 49 49 46 44 43 39 38 38 37 40 30 0 ITALY SPAIN BRAZIL ISRAEL TAIWAN RUSSIA MEXICO TURKEY POLAND FRANCE UKRAINE MALAISIA BELGIUM GREECE CANADA SWEDEN HUNGARY HOLLAND GERMANY SLOVAKIA BULGARIA AUSTRALIA CZECH REP HONG KONG NEW ZELAND SWITZERLAND GREAT BRITAIN

12. FDA • EMEA( The European Medicines Evaluation Agency) • Европейское Агентство Экспертизы • Лекарственных Средств • GCP inspections

13. FDA • Более 500 инспекций в течении 20 лет • 57%- в Европе • 7%- в Восточной Европе • Ожидается усиление внимания ! • Основные 5 категорий : • 1- протокол 45% • 2- Мед.документация 54% • 3- Информиров.согласие пациента 27% • 4- Безопасность • 5 – Процедуры связанные с препаратом

14. Difference between FDA and EMEA Inspections & Findings

15. Pivotal studies in Regulatory submission Inspections are done at the early stages of the regulatory submissions Pivotal studies in Regulatory submission Inspections are done during the regulatory review process (round about 120 days) Difference between FDA and EMEA Inspections & Findings Studies Targeted for the inspections F D A E M E A Duration of the inspections • 3-5 days for European sites • 3 days at the investigational site Version 1, dated 27 Jul 2004

16. 1 inspector for US sites 1-2 inspectors for non-US sites 3-4 inspectors, accompanied by the medical reviewer Difference between FDA and EMEA Inspections & Findings Number of inspectors Inspection’s process at the site • Focusing on comparing the Source data with CRF copies at the site and the copies available at Data Base • The Target is to review all patients enrolled at the site • EMEA inspectors are divided into 2 groups. • The 1st one is reviewing all CRFs against the Source Data for at least 6-7 CRFs • Detailed review of all submissions and approvals • SOP and protocol compliance • Monitoring process • The 2nd team is focused on • The procedures used to generate the source data at the site, • Drug accountability • Activity of the Third Parties F D A E M E A Version 1, dated 27 Jul 2004

17. Inspectors request copies of all study and site specific documents prior the inspection Copies are required as supportive evidence of what was found during the inspection Inspectors request copies of all study and site specific documents prior the inspection Copies are required in part to continue the inspection after the site was seen. Some extra documents can be requested after the inspection at the site is finished Difference between FDA and EMEA Inspections & Findings Inspection’s requirements F D A E M E A Findings reporting process • Key findings are reported during the final interview with the site and CRO representative • FDA483 form is to be responded by the investigators – inspectors will determine whether the responses are acceptable or not • Key findings are reported in the draft report. • Investigators are required to respond within 2 weeks since the report is issued • Final report is released and does not necessarily include all responses received from the investigators Version 1, dated 27 Jul 2004