CLINICAL RESEARCHES ASSOCIATION AUDIT AND FOLLOW-UP IN CLINICAL STUDIES

1. AUDIT FROM THE VIEWPOINTS OF THE INVESTIGATOR AND THE CRO CLINICAL RESEARCHES ASSOCIATIONAUDIT AND FOLLOW-UP IN CLINICAL STUDIES FDA AUDIT EXPERIENCE By Ulus Salih Akarca Ege University Faculty of Medicine Department of Gastroenterology

2. FDA Audit Experience • In this lecture, we will be sharing our experience about the FDA audit conducted on our center on 24-28 January 2005 for studies no. BMS 463AI-026 and 463AI-027.

3. FDA Audit Experience • For a FDA audit, conformity to the rules is more significant than a special preparation.

4. FDA Audit Experience • During the above-mentioned audit, some of the deficiencies of our center came to our attention. • In fact, our most important deficiency stems from our lack of experience and our failure to be well-organized for clinical studies. • The clinic underwent reorganization in the aftermath of the said audit, and three members of the staff were put on salary by the “Aegean Liver Association” to follow up clinical studies.

5. Time • The most important deficiency in clinical studies is the failure of the investigators to devote sufficient time to the study. • Failure to read the protocol thoroughly • Failure to spend time to collect the necessary patient documentation • Failure to make the necessary announcements to the Ethics Committee on time • Failure to report side effects on time • Failure to fill in the CRF’s (Case Report Forms) on time

6. Insufficient Number of Centers • To overcome this problem, the Central Ethics Committee decided not to overburden investigators with too many studies. • However, due to the insufficient number of centers willing to take part in studies, and • To the scantiness of centers organized for studies, pharmaceutics companies are presenting their offers only to particular centers.

7. The most important part of any clinical study, which comprises of interviewing and examining the patient and taking notes on source documentation, actually takes the least amount of time. • Activities that can be conducted by auxiliary personnel such as the following tend to take a lot more time: • Monitoring correspondences and fax messages related to the study • Monitoring correspondences with the Ethics Committee • Drug counts • Collecting and sending patient samples • Monitoring results.

8. Click to Add Heading • For this reason, our center opted to employ personnel only for use in clinical studies. • Thanks to this, our center has conducted or is in the course of conducting a total of 25 international Phase II-III studies since 2000. • Out of the said studies, the first two had been entecavir studies subjected to the FDA audit.

9. Deficiencies towards the audit • In spite of having attended good clinical practices trainings, it has been the first time that we have encountered many practices which are considered daily routine today. • Training in action! • The Investigator in charge of a clinical study should have taken part in other clinical studies led by other investigators beforehand.

10. Most Common Principal Errors • To consider the exclusion and inclusion criteria within the framework of our own logic; • Inclusion criteria: Chronic B hepatitis should be established by means of liver biopsy within the 52 weeks prior to randomization. • Error: There is no doubt that the patient has chronic B hepatitis as he/she has previously gone through biopsy and interpheron treatment. For this reason, the patient is randomized without conducting a biopsy and waiting for results.

11. Most Common Principal Errors • The idea that deviation from the protocol may be overlooked in case of a valid excuse. • The patient is not suffering from hepatocellular cancer. • This indicates lack of US and BT. • The hospital’s laboratory is incapable of conducting AFP. • The patient may be included in the study without an AFP. • In all of the current studies, laboratory analyses are conducted in central laboratories

12. Most Common Principal Errors • Correcting the retained copies after sending the CRF’s. • Knowledge, knowledge, knowledge • Filling in the CRF’s after the pre-determined period of time has elapsed. • Time, time, time • Returning any laboratory results obtained prior to the study to the patients. • Documentation, documentation, documentation

13. Most Common Principal Errors • Putting any protocol changes approved by the local ethics committee into practice without waiting for the approval of the central ethics committee • Lack of knowledge again

14. Excitement towards the audit • Success overrules all excuses. • We were excited like students about to sit an exam as we were well aware of our deficiencies. • The sponsor company was even more excited than us.

15. What we have been through during the audit • Various rumors about how to treat the auditor. Childish • Show – do not show interest • Invite – do not invite to lunch/dinner • Interpret – do not interpret • The investigator in charge problem • Language problem • Distress caused by errors and mistakes

16. What we have learned out of the audit • Documentation is everything. • Even telephone conversations should be documented. • The investigators should never deviate from the protocol for no reason whatsoever. • The exclusion and inclusion criteria should not be pressed insistently in order to enroll more students.

17. What we have earned out of the audit • Always take the inclusion – exclusion criteria into account • Be very exacting about documentation • Make good use of the auxiliary personnel • But make sure that they are under constant inspection

18. RESULT • Clinical studies are labor-intensive works requiring discipline, knowledge and time. • What is more important than the FDA audit is the self-audit. • The investigator should always and at all times be available during every step of the way and closely inspect any tasks performed by others. • The investigator should be extremely fastidious in each and every study as if a FDA audit is imminent.