The Good, Bad and Ugly of Site Visits: A CRA s Perspective

1. The Good, Bad and Ugly of Site Visits: A CRA�s Perspective Ray Policare, MPH, CCRA

2. Types of Site Visits The most common types of site visits for industry-sponsored studies: Site Evaluation/Qualification Visit Site Initiation Visit Site Monitoring Visit Site Close-Out Visit

3. Site Visits Site visit activities are based on the following: ICH Guideline for Good Clinical Practice FDA Regulations Title 21 CFR 11, 50, 56 and 312 Sponsor�s Standard Operating Procedures

4. Site Evaluation Visit The Purpose of the Site Evaluation visit: ICH GCP 4.1.1-�An Investigator should be qualified by education, training and experience to assume the responsibilities for the proper conduct of the trial� ICH GCP 4.2.3-�The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely�

5. Site Evaluation Visit ICH Guidelines nor FDA regulations specifically require a Site Evaluation Visit. ICH does require a pre-trial monitoring report as part of the �Essential Documents� and states that there is a need for on-site monitoring �before, during and after� a trial. FDA �Guidelines for the Monitoring of Clinical Investigations� does recommend that a monitor visit the site of the clinical investigation prior to the initiation of the trial.

6. Site Evaluation Visit It would be difficult to assess ICH 4.1 and 4.2 without a site visit. FDA Guidelines state that an Evaluation Visit can be waived if a sponsor has recently worked with a site and there are no questions regarding its capabilities.

7. Site Evaluation Visit Assess Physician qualifications: Current CV and medical license for the principal investigator What is the physician�s specialty/subspecialty? What is the PI�s experience in conducting clinical trials? Has the PI been audited by regulatory authorities or sponsors previously?

8. Site Evaluation Visit Protocol review/discussion Study objectives Inclusion/exclusion criteria Are there barriers to enrollment at your site? Study population Retrospective review of enrollment in past studies? Chart audit or database search of current patients that have the disease being studied-HIPAA? Will advertising or referrals be required?

9. Site Evaluation Visit Protocol review/discussion (continued) Study Procedures/Tests Can you perform all the procedures/tests required for the study? Schedule of Assessments Special considerations such as weekend/24 hour coverage, etc. Are there any competing trials?

10. Site Evaluation Visit Adequate Staff to properly conduct the trial Define who will do what for the study Study coordinator Sub-investigators Data Managers How much time do you have for the study? How many trials are you currently working on? How much experience do you have in conducting clinical trials?

11. Site Evaluation Visit Adequate Facilities Exam rooms Pharmacy/Study drug storage area Laboratory or specimen processing area Special testing areas ( x-rays, CT scans, endoscopy, etc.) Record keeping facilities

12. Site Evaluation Visit Overall Site Assessment Type of IRB and meeting frequency Contract execution requirements Source documents (paper vs. computerized) Monitoring facilities (desk, phone, copier, etc.)

13. Site Evaluation Visit Site Preparation for an Evaluation Visit Review the protocol and Investigator Brochure and ensure the study is feasible for your site. Have information on available subjects at your site or how you will recruit subjects for the study. Notify all required staff of the visit. Have IRB submission and meeting dates available. Have current CV of the PI available.

14. Site Initiation Visit The purpose of the SIV is to assists the site in its preparation to enroll its first subject. The SIV is not specifically required by FDA or ICH guidelines and can be conducted at an Investigator Meeting or via teleconference/videoconference. ICH GCP does require a Trial Initiation Monitoring report as part of the �Essential Documents� and the report should be in both the sponsor and site file.

15. Site Initiation Visit The SIV should take place after all required supplies are at the site and just before subject recruitment begins. FDA Guidelines recommend that a monitoring visit should take place �shortly� after the site has enrolled its first few subjects if an SIV was not conducted.

16. Site Initiation Visit Components of an SIV Detailed protocol review Review of the study drug and the common adverse events Review of the Investigator�s Responsibilities CRF review Study drug receipt verification and storage conditions

17. Site Initiation Visit Components of an SIV (continued) Study drug dispensing, preparation and return Regulatory document review Inventory of supplies required for the study Lab kits CRFs PROs or QOL IVRS supplies

18. Site Initiation Visit Site Preparation for an SIV Ensure all supplies have been received prior to the visit. Schedule a room for the meeting, if required Block adequate time for the visit (can be up to 4-5 hours to complete). Ensure the PI is available for the visit (typically about 1 hour).

19. Site Initiation Visit Site Preparation for an SIV (continued) Notify all appropriate staff of the visit including the pharmacist, if applicable. Have the regulatory binder up to date and ready for review. Prepare the Delegation of Authority form in advance of the visit, if possible.

20. Site Monitoring Visit Purpose: ICH GCP 5.1.8 Verify that the rights and well-being of human subjects are protected. Verify that reported trial data are accurate, complete and verifiable from source documents. Verify that the conduct of the trial is in compliance with the currently approved protocol/amendments, with GCP regulations and with the applicable regulatory requirements.

21. Site Monitoring Visit Frequency of monitoring visits is not defined by ICH or FDA regulations ICH states that �the sponsor should ensure trials are adequately monitored before, during and after the study�. The frequency of monitoring depends on The complexity of the study Rate of enrollment GCP compliance issues

22. Site Monitoring Visit Monitoring visits are typically every 4-8 weeks during a trial. Monitoring practices are based on the SOPs of the sponsor in addition to ICH and FDA regulations. Sponsor SOPs may be more detailed than ICH guidelines and will vary from sponsor to sponsor.

23. Site Monitoring Visit ICH 5.1.8.4, Monitor�s Responsibilities Acting as the main line of communication between the sponsor and the investigator. Verifying that the investigator has adequate qualifications and resources throughout the study. Verifying that the investigational product is stored, dispensed and returned properly and that only eligible subjects receive it at the protocol specified dose. Verifying that the investigator follows the approved protocol/amendments.

24. Site Monitoring Visit Verifying that written informed consent was obtained before each subject�s participation in the trial. Ensuring that the investigator receives the current Investigator�s Brochure and safety updates. Ensuring that the investigator and the investigator�s staff are adequately informed about the trial. Verifying that the investigator is enrolling only eligible subjects.

25. Site Monitoring Visit Verifying that the investigator and the investigator�s trial staff are performing the specified trial functions, in accordance with the protocol, and have not delegated these functions to unauthorized staff. Reporting the subject recruitment rate. Verifying that source documents and other trial records are accurate, complete and up-to-date.

26. Site Monitoring Visit Verifying that the investigator provides all the required reports, notifications, applications, and submissions and that these documents are accurate, complete, timely, legible, dated and identify the trial. Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other.

27. Site Monitoring Visit Informing the investigator of any CRF entry error, omission or illegibility. The monitor should ensure that appropriate corrections, additions or deletions are made, dated, explained (if necessary) and initialed by the investigator or a trial staff member that has been authorized to make CRF changes for the investigator. This authorization should be documented. Determining whether the investigator is maintaining the essential documents.

28. Site Monitoring Visit Determining whether all adverse events are appropriately reported within the time periods required by GCP, the protocol, the IRB, the sponsor and the applicable regulatory authorities. Communicating deviations from the protocol, SOPs and GCP to the investigator and taking appropriate action designed to prevent recurrence of the deviations.

29. Site Monitoring Visit Site Preparation for a Monitoring Visit Have CRFs up to date for completed visits Have source documents available for review (request patient charts in advance, if applicable) Schedule a room for the visit, if applicable Notify appropriate site personnel about the visit Have the Regulatory Binder up to date and available

30. Site Monitoring Visit Ensure study drug accountability forms are up to date Arrange time for the Pharmacist to meet with the Monitor, if applicable Arrange time for the Study Coordinator or Data Manager to meet with the Monitor for CRF corrections/issue resolution Arrange time for the PI to meet with the Monitor for study discussion

31. Site Close-Out Visit There are no clear ICH or FDA regulations regarding the close-out visit. ICH GCP requires a close-out monitoring report as an Essential Document.

32. Site Close-Out Visit In general, three activities are required to �officially� close-out a site. The sponsor conducts a close-out visit and signs the monitoring log. The investigator submits a final report to the IRB stating that the site is closed. The sponsor sends the investigator a letter stating that the site is closed.

33. Site Close-Out Visit Close-Out Visit Activities Final data review/collection of all outstanding data Return or destruction of all study drug Final review of Regulatory Binder Verification that all biological samples have been submitted

34. Site Close-Out Visit Return or destruction of all unused study forms/CRFs Review and collection of Delegation of Authority forms Collection of IRB closure report/letter

35. Site Close-Out Visit Site Preparation for a Close-Out Visit Have all CRFs available for the visit. Have all unused study forms available for return/destruction. Have the Regulatory File up to date and available for the visit. Is Delegation of Authority up to date? Is IRB Close-out report available?

36. Site Close-Out Visit Site Preparation for a Close-Out Visit (cont.) Have all used and unused study drug available for return/destruction, if not previously completed. Notify appropriate site personnel of the visit. Prepare for the storage of all study documents, either on-site or at an off-site facility.