Good Clinical Practice and Audit Preparedness

1. Good Clinical Practice and Audit Preparedness IUPU Symposium - October 2010 Michael R. Hamrell, Ph.D. MORIAH Consultants

2. What is Clinical Research? • The essential piece to demonstrate that a new product is safe and effective • The most costly part of development • 60% of cost spent on clinical • The most time-consuming part of product development

3. Quality Concepts in Clinical Trials • Sponsor Responsibilities: • Ensure proper monitoring of investigations (21 CFR 312.50) • Monitor the progress of all clinical investigations being conducted under its IND (21 CFR 312.56(a)) • Correct and/or report serious non-compliance to the FDA (812.46(a))

4. Quality Concepts in Clinical Trials • Clinical Investigator Responsibilities • Conduct study according to the protocol (21 CFR 312.60 & 812.100) • Maintain adequate and accurate case histories (21 CFR 312.62(b) & 812.140)

5. Role of the Coordinator Clinical Research Coordinator (CRC) • Works under the direction of the Principal Investigator • Expected to perform many of the tasks in the clinical study • need to be qualified (and trained) to perform the task • PI still responsible for all patients

6. Role of the Coordinator • Often is the key person for the successful conduct of a trial • Typically has the most patient contact and direct role in many key tasks • Usually the person who fills out the CRFs, lab slips, etc. • Tasks will depend on professional qualifications and training

7. Safety Reports • Investigator is required to report all adverse events to Sponsor • timing depends on nature and severity • has major impact on subject safety 21 CFR §312.64(b) & 812.150

8. Quality Concepts in Clinical Trials • IRB Responsibilities • Organization and Personnel through review of IRB membership list (21 CFR 56.107) • Functions and Operations through evidence of written SOPs (21 CFR 56.108) • Review of Research through sufficient details of IRB meeting minutes (21 CFR 56.109)

9. Product Accountability • Focus on complete picture • Shipping • Receipt • Use • Returns • Reconciliation

10. 1 Sponsor Test Article Received By Investigator 2 3 Test Articles Dispensed To Patient Test Articles Returned To Investigator Product Accountability 4 Test Articles Reconciled By Sponsor Investigator Timepoint A Investigator Timepoint B Patient

11. Test Article – FDA Comment • “Although the site’s personnel have been delegated the responsibility for test article accountability, it is the Principal Investigator who is ultimately responsible for the this task…. • Even when a research pharmacist is involved in a study at a site, the clinical investigator retains responsibility for ensuring that the test article was appropriately prepared, dispensed and administered.”

12. FDA Viewpoint on Auditing • FDA takes no official position on whether companies should conduct clinical audits • FDA viewpoint on sponsor responsibilities: “Sponsors are responsible for selecting qualified investigators… ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND…” 21 CFR 312.50 & 812.40

13. According to the Inspector General’s Report: on ‘The FDA Oversight of Clinical Trials’ (Sept 2007) FDA only inspects less than 1% of all clinical trial sites 75% of inspections overall were routine (surveillance) What’s the Chance of an Audit http://oig.hhhs.gov/oei/reports/oei-01-06-00160.pdf

14. How would you characterize your site? • How would you characterize the staff • What is the commitment/focus to research relative to medical practice • How is their research performance perceived?

15. Some fun examples

16. Reality Check • How many of you do multiple clinical trials each year? • Investigator initiated vs. sponsor • How many of your sites/groups have SOPs? • How many of your sites use electronic medical records? • How many of you have experience with eCRFs? • How do you communicate with your IRB (paper or electronic)?

17. Should a Site have SOPs? • Reiterates role of PI in all studies; including delegation of responsibilities to study staff and supervision • Defines role of PI and staff in study oversight • Suggests the need for site SOPs

18. From Guidance Document ‘The investigator should develop a plan for the supervision and oversight of the clinical trial at the site. Supervision and oversight should be provided even for individuals who are highly qualified and experienced. A plan might include the following elements, to the extent they apply to a particular trial:’

19. ICH GCP Viewpoint • “The auditing of clinical trials is conducted in accordance with the Sponsor’s written procedures of what to audit, how to audit, the frequency of audits and the form and content of audit reports.” Section 5.19.3

20. FDA Role in GCP Compliance • Determine compliance with regulations • Verify integrity of data

21. FDA GCP Inspections • FDA will routinely inspect some or all of the data for pivotal studies in support of an application • FDA choice of sites are based on a variety of factors • number of sites • Number of studies at site • importance of data • type of study • Geographic location

22. Role of FDA Inspection • Essential part of PMA/510K/NDA/BLA review process • Know your rights • Use sponsor/CRO/consultants help to prepare • Build quality into your work

23. FDA Role in Clinical Investigations • Bioresearch Monitoring Program • An on-going audit program managed by the Division of BIMO in each Center • To determine the adherence of sponsors, CROs, monitors, IRBs and clinical investigators to current regulations and official guidelines • To assess through audit procedures whether data submitted to FDA are substantiated by records

24. FDA Inspection of Clinical Research FDA Conducts Two Types of Inspections • Routine data audits (study oriented) • Audit of key pivotal data from NDAs, BLAs, 510(k)s, PMAs, etc. to verify data and procedures • 'For-cause' audits (investigator oriented) • Targeted audit of data or investigators as a result of prior knowledge or suspicion or alleged violations of the regulations

25. The Facts About Source Documents • FDA Requirements Related to source documents in clinical trials • 312.62(b) An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigations on each individual administered the investigational drug or employed as a control • Similar requirement in 812.140 for devices

26. Preparing for the Inspection Before you start, make sure you are prepared • (re)Familiarize with protocol, CRFs, other study documents • Review Study archives • Check FOI for other inspection results

27. Plan for FDA Inspection FDA Arrival • Who is to be called • Check FDA inspector credentials • Accept Notice of Inspection (Form 482) • Confirm purpose of FDA inspection

28. FDA Form 482

29. Site Policy Main Contact • Identify who is to be notified at the time inspection commences and how • Identify who is authorized to receive and accompany FDA inspector • Plan how oral inquiries and requests for documents are processed

30. General Do’s and Don’ts DO ! • Greet FDA and ask for identification and FDA Form 482 • Provide work area that affords privacy • Make available phone/internet/power • Offer coffee, tea, water, bathroom • Provide visitor pass or parking pass • Keep conversation polite and professional • Extend common courtesy

31. General Do’s and Don’ts Don’t even think about: ! • Pay for meals • Offer any monetary compensation • Offer gifts (even at holiday time) • Photograph, record or tape things • Socialize with FDA after work hours • Ask personal questions • Look over the inspector’s shoulder • Complain about government, taxes, FDA

32. Company/Site Policy • Document Production

33. Company/Site Policy Document Marking and Duplication • Do not permit marking of documents by FDA Inspector • Make copies for FDA and retain a copy of each document provided to FDA • Mark documents containing trade secret or confidential information before providing • If confidential information is conveyed orally, establish these facts to FDA; use witness

34. Company/Site Policy Affidavits • Establish policy on whether to review FDA prepared affidavits • Circumstances under which an affidavit could be signed • Do not sign affidavit or volunteer any information unless such disclosure is consistent with company policy

35. Plan for FDA Inspection During Inspection • Company/site representative should accompany FDA Inspector at all times, to ensure access only to information and those parts of the premises under the FD&C Act

36. Plan for FDA Inspection Keep an accurate written record of: • Areas of the site visited and to whom he/she spoke • Accurate and complete record of all comments and suggestions made by inspector, unanswered questions and site commitments • Any commitments made to FDA should have concurrence of top management

37. Plan for FDA Inspection • A daily summation with FDA, and separately with site staff is helpful • If additional inspection days are required, prepare an agenda for next day with FDA • Prepare daily report to management

38. Company/Site Policy Corrections during Inspection • If a change is made during the inspection, decide whether the change/correction will be conveyed to the FDA inspector and, if so, in what manner

39. Correction to 483

40. The Inspection Process

41. “What will the Inspectors ask me to produce for the audit” Source Documentation • All of the source documents should cover the entire period of the study and be present at the time of the audit to allow the auditor(s) to properly conduct the audit • A ‘standard’ GCP site inspection will include a tour of the facility and a thorough review of the documentation

42. “What will the Inspectors ask me to produce for the audit” • Documents in the project notebook filed during the course of the trial • List of the study subjects and their corresponding study numbers • Should the FDA investigator ask for the identities and demographics of your study subjects because of some concern, you are required to comply with the request

43. Warning Letter 07-HFD-45-0601

44. “What will the Inspectors ask me to produce for the audit” • Two-way correspondence with the IRB, sponsor/monitor • Original signed consent forms for all the patients • Case Report Forms (CRFs) for all the patients • Source Documentation (Patient medical records, clinic and hospital charts)

45. “What will the Inspectors ask me to produce for the audit” • Records of patients who were study drop outs • Product storage facilities and accountability records • Serious Adverse Event Reports and documentation • Monitor visit log

46. Data Inspection Process Subject Records • Did the Investigator maintain records that are supportive of each entry in CRFs for each subject • Were all CRFs completed in a timely fashion Could you recreate CRF from source?

47. Data Inspection Process For eCRF situations • Were all regulations and requirements followed relative to 21 CFR §11 • Do source documents support any changes/corrections to the e-CRF

48. Data Inspection Process Reporting of Study Progress • Did investigator terminate or discontinue the study before completion • Incidence and reports of SAEs to Sponsor and IRB handled properly • Did Investigator maintain copies of all reports submitted to sponsor and IRB

49. Data Inspection Process Records Retention • Who maintains custody of required records • Data storage media • Record storage conditions • Investigator aware of FDA record retention regulations

50. Data Inspection Process Data Audit Procedures • Subject study data • Number and type of subjects • Existence and availability of subjects • Documentation of prior conditions • Subject inclusion/exclusion criteria • Screen log/failures