Joan A. Kavuru, J.D. Director of Compliance July 20, 2006

1. The Brody School of MedicineClinical Trial Coordinators Lunch and Learn SeriesRecent FDA Warning Letters: What we can learn from others’ mishaps Joan A. Kavuru, J.D. Director of Compliance July 20, 2006

2. Welcome to everyone!Overview of Today’s Presentation • Introduction to BSOM Office of Compliance • Background on FDA Warning Letters • 2006 FDA Warning Letters: Major Issues

3. Introduction • BSOM Office of Compliance • Who are we? • Responsibility includes research compliance • Education is critical to our mission • Operation of Clinical Trials is Complex • Highly regulated • Patient subject safety is paramount • We are here as a resource to you • Questions, concerns: Office of Compliance General Number 744-5200 • New website soon • BSOM Compliance Hotline: (866) 515-4587 • You may remain anonymous

4. Background on FDA Warning Letters FDA Routine Audits and Possible Outcomes • FDA may conduct routine audits of drug or device trials to ensure data and information contained in the IDE and PMA applications or the 510(k) are scientifically valid and accurate. • FDA also audits to ensure human subject protections are in place and there is no undue hazard or risk during the investigation. • At close of inspection, FDA issues a form FDA 483 with audit findings: • NAI – No action indicated • VAI – Voluntary action indicated • OAI – Official action indicated

5. Background on FDA Warning Letters • Consequence of failure to properly respond to audit findings. • Failure to properly respond to warning letter and take appropriate corrective action may result in disqualification proceedings or prohibition on use of data obtained in trial. • Per the FDA, who does the PI fault for deficiencies? • 9% - Self • 39% - Study coordinator • 17% - Nurse • 9% - Sponsor • 9% - Office staff • 9% - Hospital • 4% - Sub investigator • 4% - Monitor

6. 2006 FDA Warning Letters • Seven (7) warning letters issued to PIs thus far in 2006 • http://www.fda.gov/foi/warning.htm • All appear to be related to medical device trials • Major issues identified

7. Failure to Obtain Proper Informed Consent • Performance of study-related procedures prior to obtaining signed informed consent • Use of ICF that has not been approved by the IRB • Failure to use ICF with IRB-required language

8. Failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50. [21 CRF 812.100 and 21 CFR 50.27] An investigator is responsible for ensuring that the IRB-approved version of the informed consent document is obtained from each subject participating in the investigation prior to performance of any study related procedures. You failed to adhere to the above stated regulations. Examples of this failure include but are not limited to the following: • The IRB notified you on February 15, 2001, “The consent form is also approved pending inclusion of the LMC cost and payment language…. The study may not begin until the corrected informed consent is received.” You began the study without revising the language in the consent form and obtaining the IRB approval of the consent. You obtained consent with the unapproved consent document for all 241 subjects enrolled at Lexington Hospital. In your response, you state you have contacted the IRB to discuss this issue. In a letter dated July 26, 2005, the IRB states this language was no longer needed as part of the consent; however this is 4 years after you began the study, at which time the LMC cost and payment language was required. This response is inadequate, as you did not provide a corrective action plan to ensure informed consent is obtained prior to enrolling any subjects on an investigational study. Please provide copies of policies, procedures, and training with expected completion dates that are being developed and implemented to ensure proper approval of informed consent documents is obtained prior to enrolling any subjects on a study. In addition, please provide dated documentation of when the informed consent document was approved by the IRB. FDA Warning Letter to Thomas P. Gross, M.D. (2/24/2006), Page 3

9. Failure to Obtain Proper Informed Consent (Cont’d) • For children, lack of assent for older children • Use of expired ICF • Use of ICFs with missing elements • Lack of completeness: Blanks left where name of PI, city, state, etc. supposed to be completed; no PI signature; no witness signature

10. Failure to Obtain Proper Informed Consent (Cont’d) Use of White-Out Consent form documents signed by study subjects contained revisions that raise questions about accuracy of the records pertaining to each subject’s case history and exposure to the device. Specifically: • At least two consent forms signed by study subjects had the investigator’s signature covered over with “white-out” and another signature over-written in the space. • At lease two consent forms signed by study subjects had the date of the investigator’s signature covered over with “white-out” and another date over-written in the space. • At least three consent forms signed by study subjects used an investigator signature stamp, instead of the actual investigator signature. FDA Warning Letter to Scott Spiro, M.D. (6/28/2006) page 4

11. Failure to Follow Protocol • Failure to meet inclusion criteria but enrolled anyway • Failure to report adverse events to the sponsor and IRB within the time period required by the protocol or applicable law • Failure to forward CRFs to sponsor within the time set forth in the protocol • Unapproved deviations from protocol (no approval from either IRB or sponsor) • Failure to adhere to follow-up exam schedule per protocol

12. Failure to Maintain Accurate, Complete and Current Case Histories • Discrepancies between source documents and CRFs • No CRFs completed at all • Incomplete or incorrect information on CRFs • Failure to specifically evaluate a condition because you “know” whether patient will meet criteria

13. You failed to maintain accurate, complete, and current records of each subject’s case history and exposure to the device, as required by 21 CFR 812.140(a)(3) and the study protocol. Examples of this failure include, but are not limited to the following: Harris Hip Scores (HHS) were not documented in any of the 38 subjects’ charts inspected. In your response, you state you have not performed a total hip replacement on a patient who does not have a HHS of 70 or less, and that, while you do not formally calculate the HHS for the patients, you know the symptoms well enough to determine whether or not the score is less than 70. While this may be acceptable in you standard practice, clinical investigations often require additional testing and documentation to evaluate a subject’s eligibility status and the safety and effectiveness of the investigational device. Documentation of case histories is an essential component of conducting a clinical investigation; if it is not documented, it is considered as not occurring (emphasis added). The investigational plan requires specific exams and diagnostic tests to be performed and the results documented at specific intervals throughout the study.(FDA Warning Letter to Thomas P. Gross, M.D. (2/24/2006) pp. 3-4)

14. Failure to Supervise Device Use and Failure to Control Devices • Unapproved study physician implanted investigational device in study subjects • Device accountability logs not maintained by the investigator • Devices stored in an unsecured area where employees not part of the study had access to them • Devices observed by FDA at study site did not match serial numbers of the devices listed as being on-site in the Device Inventory Records received from the sponsor

15. Avoiding FDA Warning Letters • Begins at Study initiation • Be sure to understand informed consent process and Study protocol • Work out protocol issues with Sponsor as soon as they arise • Good documentation and recordkeeping essential • Prepare for audit; enlist help of Sponsor and Institution

16. Thank You • Feedback please and ideas or volunteers for speakers for future sessions • 744-5200 • kavuruj@ecu.edu