1. Youve been WARNED…. Everyday occurrences that landed your colleagues with a Warning Letter from the FDA Laura B. Cummins, J.D. Manager, Contract Administration Office of Clinical Research UT Medical Group, Inc. This presentation does not constitute legal advice. The views expressed are the presenters own and do not necessarily express the views of UT Medical Group, Inc. 1

2. FDA Warning Letter: What is a FDA Warning Letter? What is a FDA Warning Letter? What are the common violations cited by the FDA? What are the common violations cited by the FDA? How can you avoid and correct these violations? How can you avoid and correct these violations? 2

3. What is a FDA Warning Letter? A Warning Letter is an informal advisory, to a firm or clinical investigator, communicating the Agency's position on a matter but does not commit FDA to taking enforcement action. A Warning Letter is issued for significant regulatory violations that require prompt and adequate corrective actions. A Warning Letter is an informal advisory, to a firm or clinical investigator, communicating the Agency's position on a matter but does not commit FDA to taking enforcement action. A Warning Letter is issued for significant regulatory violations that require prompt and adequate corrective actions. http://www.fda.gov/cder/Offices/DSI/enforcement.htm 3

4. FDA Warning Letter 4

5. What are the common violations cited by the FDA? Informed consent Informed consent Investigator responsibilities Investigator responsibilities Protocol deviations Protocol deviations Study records Study records IRB approval IRB approval 5

6. Informed Consent 6

7. Informed Consent You failed to obtain the informed consent of each human subject in accordance with 21 CFR part 50 [21 CFR 312.60]. FDA Citation: we were unable to determine from your site records if subjects gave informed consent prior to participation in the study and/or if subjects were given sufficient opportunity to consider whether or not to participate in the study. we were unable to determine from your site records if subjects gave informed consent prior to participation in the study and/or if subjects were given sufficient opportunity to consider whether or not to participate in the study. 7

8. Informed Consent You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60] Informed Consent You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60] FDA Citation: Informed consent documents were dated by study personnel rather than the legally authorized representative Informed consent documents were dated by study personnel rather than the legally authorized representative 8

9. Informed Consent You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60] FDA Citation: pharmacokinetic samples were collected from subjects without obtaining informed consent for blood sampling. pharmacokinetic samples were collected from subjects without obtaining informed consent for blood sampling. 9

10. Informed Consent You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60] FDA Citation: According to study records, representatives for subjects 114302 and 114504 were non-English speaking. The subjects representatives signed informed consent documents written in English rather than a language understandable to the representative. According to study records, representatives for subjects 114302 and 114504 were non-English speaking. The subjects representatives signed informed consent documents written in English rather than a language understandable to the representative. 10

11. Informed Consent You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60] FDA Citation: Subject signed the consent form on [redacted]; however, the witness signed the consent on [redacted]. Subject signed the consent form on [redacted]; however, the witness signed the consent on [redacted]. 11

12. Informed Consent You failed to provide a copy of the signed and dated written Informed Consent document, which had been approved by the IRB to the subject or subjects legally authorized representative [21 CFR 50.2(a)] FDA Citation: There was no documentation that subjects who were enrolled in this study received informed consent. There was no documentation that subjects who were enrolled in this study received informed consent. 12

13. Informed Consent Failed to obtain proper assent as determined to be appropriate by the IRB [21 CFR § 50.55] FDA Citation: the IRB requires that subjects who are 7- 13 years old sign a Research Assent form. Subject 124501 was seven years old at the time of consent, but did not sign a Research Assent form prior to being enrolled in the study. the IRB requires that subjects who are 7- 13 years old sign a Research Assent form. Subject 124501 was seven years old at the time of consent, but did not sign a Research Assent form prior to being enrolled in the study. 13

14. How to avoid and correct: Do not date for subjects Do not date for subjects If someone forgets to date the consent form, write a signed and dated note-to-file explaining how and when the subject was consented, report to IRB If someone forgets to date the consent form, write a signed and dated note-to-file explaining how and when the subject was consented, report to IRB Write a signed and dated note-to-file explaining why dates are different Write a signed and dated note-to-file explaining why dates are different Always give subject a copy of the signed and dated consent form Always give subject a copy of the signed and dated consent form Document the informed consent process Document the informed consent process Always maintain the original signed and dated consent form in the research file Always maintain the original signed and dated consent form in the research file 14

15. Investigator Responsibilities 15

16. Investigator Responsibilities You failed to conduct the studies according to the signed investigator statement [21 CFR 312.60] FDA Citation: You failed to adequately supervise individuals to whom you delegated study tasks. You failed to adequately supervise individuals to whom you delegated study tasks. 16

17. Investigator Responsibilities You failed to conduct the studies according to the signed investigator statement [21 CFR 312.60] FDA Citation: you did not list the names of all subinvestigators who would be assisting in the conduct of the investigation, as required by the Statement of Investigator, Form FDA 1572. you did not list the names of all subinvestigators who would be assisting in the conduct of the investigation, as required by the Statement of Investigator, Form FDA 1572. 17

18. Investigator Responsibilities You failed to personally conduct or to supervise the clinical investigation [21 CRF 312.60] FDA Citation: You did not personally conduct or supervise this study. You did not personally conduct or supervise this study. 18

19. Investigator Responsibilities You failed to personally conduct or to supervise the clinical investigation [21 CRF 312.60] FDA Citation: We also note that during the inspection you admitted that you are conducting many studies that you are not able to remember all of them. This suggests that you are not as involved as we would expect of a Principal Investigator. We also note that during the inspection you admitted that you are conducting many studies that you are not able to remember all of them. This suggests that you are not as involved as we would expect of a Principal Investigator. 19

20. Investigator Responsibilities You failed to maintain adequate case histories that record all observations and other data pertinent to the investigation on each individual [21CFR 312.62(b)] FDA Citation: You misrepresented your presence at the Institution by signing and dating source documents and consent forms on days you were, in fact, absent from the Institution. You misrepresented your presence at the Institution by signing and dating source documents and consent forms on days you were, in fact, absent from the Institution. 20

21. How to avoid and correct: Stay involved Stay involved Document your involvement Document your involvement Only delegate responsibilities to appropriate individuals who are qualified, trained and supervised Only delegate responsibilities to appropriate individuals who are qualified, trained and supervised Maintain documentation of training for all staff Maintain documentation of training for all staff 21

22. Read the small print of the 1572 Supervise Supervise Maintain Records Maintain Records Adhere to Protocol Adhere to Protocol Learn Investigator Learn Investigator Brochure Brochure Let FDA inspect Let FDA inspect RePort Adverse Events RePort Adverse Events Retain Records Retain Records Inform Subjects Inform Subjects Notify IRB Notify IRB Train Staff Train Staff 22

23. Protocol Deviations 23

24. Protocol Deviations You failed to conduct the studies or to ensure they were conducted according to the investigational plans [21 CFR 312.60] FDA citation: The protocol specified that women of childbearing potential were to be excluded from the study. The protocol further specified that pregnancy tests were to be taken at the Visits P1 and T1. Protocol-specified pregnancy tests were not performed for subjects [(b)(6)] and [(b)(6)] on one and/or both of these visits. The protocol specified that women of childbearing potential were to be excluded from the study. The protocol further specified that pregnancy tests were to be taken at the Visits P1 and T1. Protocol-specified pregnancy tests were not performed for subjects [(b)(6)] and [(b)(6)] on one and/or both of these visits. 24

25. Protocol Deviations You failed to conduct the studies or to ensure they were conducted according to the investigational plans [21 CFR 312.60] FDA citation: Subject [(b)(6)] did not meet the protocol specified blood pressure inclusion criterion at either Visit P2, Visit P3, or Visit P4, but was randomized into that study. That the study sponsor ultimately permitted this subject to remain in the trial does not mitigate this initial failure to follow the protocol. Subject [(b)(6)] did not meet the protocol specified blood pressure inclusion criterion at either Visit P2, Visit P3, or Visit P4, but was randomized into that study. That the study sponsor ultimately permitted this subject to remain in the trial does not mitigate this initial failure to follow the protocol. 25

26. How to avoid and correct: Report all protocol deviations to the IRB according to the reporting guidelines Report all protocol deviations to the IRB according to the reporting guidelines Develop and implement an adequate corrective plan to avoid future deviations Develop and implement an adequate corrective plan to avoid future deviations Retrain study team Retrain study team Create checklist of procedures to be performed at each visit Create checklist of procedures to be performed at each visit 26

27. Study Records 27

28. Study Records You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation of each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)] FDA citation: on the source document for the administration of (infusion) maintenance dose was recorded as 1:1 or 0.5:1. Based on this documentation, the actual drug concentration is uncertain. on the source document for the administration of (infusion) maintenance dose was recorded as 1:1 or 0.5:1. Based on this documentation, the actual drug concentration is uncertain. 28

29. Study Records You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation of each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)] FDA citation: The CRFs contained blank fields. The CRFs contained blank fields. 29

30. Study Records You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation of each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)] FDA citation: All medical records/case reports audited had numerous write-over corrections which lacked dates and initials. All medical records/case reports audited had numerous write-over corrections which lacked dates and initials. 30

31. How to avoid and correct: All information entered on a CRF or data collection sheet must be supported by source documents All information entered on a CRF or data collection sheet must be supported by source documents A signed and dated note-to-file can be used to explain: A signed and dated note-to-file can be used to explain: How information was obtained How information was obtained Who obtained information Who obtained information Any discrepancies Any discrepancies Missing or incomplete data Missing or incomplete data Use a single line to cross-out the incorrect information; enter the correct information next to it, and initial and date (time) the change Use a single line to cross-out the incorrect information; enter the correct information next to it, and initial and date (time) the change Never obscure the initial entry Never obscure the initial entry Sign/initial and date all entries Sign/initial and date all entries Always use ink to enter data Always use ink to enter data 31

32. IRB Requirements/Approval 32

33. IRB Requirements/Approval You failed to promptly report to the IRB all unanticipated problems involving risk to human subjects or others [21 CFR 312.66] FDA citation: You failed to notify the IRB per IRB requirements within three business days of becoming aware of this serious adverse event, and you reported this event to the IRB as a protocol deviation rather than an adverse event. You failed to notify the IRB per IRB requirements within three business days of becoming aware of this serious adverse event, and you reported this event to the IRB as a protocol deviation rather than an adverse event. 33

34. IRB Requirements/Approval You failed to assure that an Institutional Review Board (IRB) complying with applicable regulatory requirements was responsible for the continuing review and approval of the clinical study [121 CFR 312.66]. FDA citation: Specifically, our investigation revealed that IRB approval for the above-referenced study expired on October 7, 2005, and was not renewed until October 19, 2006. During this time period, when IRB approval was lapsed you screened, enrolled, or randomized 16 subjects and continued to perform research activities (study visits and phone contacts). Specifically, our investigation revealed that IRB approval for the above-referenced study expired on October 7, 2005, and was not renewed until October 19, 2006. During this time period, when IRB approval was lapsed you screened, enrolled, or randomized 16 subjects and continued to perform research activities (study visits and phone contacts). 34

35. FDA citation: You failed to obtain IRB approval for the media advertisements used to recruit and enroll Subjects for the protocol. You failed to obtain IRB approval for the media advertisements used to recruit and enroll Subjects for the protocol. 35

36. FDA citation: Revised case report forms identifying additional data to be collected.., for which IRB approval was not documented, were used after initiation of the study. Revised case report forms identifying additional data to be collected.., for which IRB approval was not documented, were used after initiation of the study. 36

37. How to avoid and correct: Obtain IRB approval prior to initiating study Obtain IRB approval prior to initiating study Report all adverse events to the IRB according to the IRBs guidelines Report all adverse events to the IRB according to the IRBs guidelines Do not allow study to lapse. Submit continuing review prior to expiration Do not allow study to lapse. Submit continuing review prior to expiration Obtain prior IRB approval for any changes made during the course of the study Obtain prior IRB approval for any changes made during the course of the study 37

38. Clinical Researchers and Criminal Liability Clinical Researchers and Criminal Liability 38

39. FDA Definition of Fraud: Falsification of data in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research results Falsification of data in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research results Falsification includes both acts of omission (consciously not revealing all data) and commission (consciously altering or fabricating data) Falsification includes both acts of omission (consciously not revealing all data) and commission (consciously altering or fabricating data) Fraud does not include honest errors or honest differences in opinion Fraud does not include honest errors or honest differences in opinion Deliberate or repeated noncompliance with the protocol and GCPs can be considered fraud, but is considered secondary to falsification of data Deliberate or repeated noncompliance with the protocol and GCPs can be considered fraud, but is considered secondary to falsification of data 39

40. Investigators Investigators 40

41. Ronald C. Smith, M.D. Barry D. Garfinkel, M.D. Maria C. Palazzo, M.D. 41

42. Richard Borison, M.D. Bruce Diamond, Ph.D Drug Money, 48 hours, July 31, 2000 42

43. Robert Fiddes, M.D. Of Mice and Men, 60 Minutes, April 1, 2001 43

44. Study Coordinators Study Coordinators 44

45. Anne Butkovitz 45

46. Paul H. Kornak Paul H. Kornak Abuses Endangered Veterans in Cancer Drug Experiments, New York Times, February 6, 2005 46

47. Now that you have been WARNED Always: Stay involved Stay involved Delegate responsibility appropriately Delegate responsibility appropriately Document Document Report Report Seek out more education in GCPs Seek out more education in GCPs Develop strong partnership between investigator and study coordinator Develop strong partnership between investigator and study coordinator 47

48. References: Warning Letters: Christopher Chappel, M.D. Ref #: 09-HFD-45-01-02 Charles J. Cote, M.D. Ref: 09-HFD-45-02-04 http://www.fda.gov/oc/ohrt/IRBS/faqs.htmlhttp://www.fda.gov/oc/ohrt/IRBS/faqs.html (#41,47,51) http://www.fda.gov/oc/ohrt/IRBS/faqs.html http://www.hhs.gov/ohrp/investigatefaq.html http://www.fda.gov/ora/ftparea/compliance/48_811.pdfhttp://www.fda.gov/ora/ftparea/compliance/48_811.pdf (page 15) http://www.fda.gov/ora/ftparea/compliance/48_811.pdf Risa TAKAYANAGI, Kaori WATANABE, Ayako NAKAHARA, Hitoshi NAKAMURA, Yasuhiko YAMADA, Hiroshi SUZUKI, Yoshihiro ARAKAWA, Masao OMATA and Tatsuji ISA, Items of Concern Associated with Source Document Verification of clinical Trials for New Drugs, YAKUGAKU ZASSHI, Vol. 124, 89-92 (2004). F. Well, Reuters Health, January 2002 U.S. v. Smith 740 F.2d 734 (9 th Cir. 1984) U.S. v. Garfinkel 29 F.3d 451 (8 th Cir. 1994) U.S. v. Palazzo 2007 WL 3124697, 7n.7 (E.D. La. 2007) The Wall Street Journal Europe, test Case: Drug Makers Relied on Two Researchers Who Now Await Trial. The Americans Are Accused of Endangering Patients and Stealing $10 million checks and Balances Failed By Steve Stecklow and Laura Johannes, August 18, 1997 48

49. References: Ex-Profs Charged in Psych Department Research Scam by Michael Jonathan Grinfeld, Psychiatric Times, April 1997, Vol. XIV Issue 4 A doctors Drug Trials Turn Into Fraud, New York Times, By KURT EICHENWALD and GINA KOLATA, Published: Monday, May 17, 1999 United States v. Butkovitz, Case No. 05-CR-10128-DPW (D. Ma.) Meredith Wadman, One in Three Scientists Confesses to Having Sinned, 435 Nature 718 (2005) http://www.nytimes.com/2005/02/06/nyregion/06vets.html http://ori.dhhs.gov/misconduct/cases/Kornak.shtml http://www.circare.org/lex/03cr436.pdf

50. References: Partners Human Research, Quality Improvement Program, Quick Bite Series September 2, 2004, Lessons Learned from FDA Warning Letters Warning! Warning! Warning! Letters, Lecture by Erich Jensen and Judy Nowack University of Michigan - Center for the Advancement of Clinical Research, and Office of Vice President for Research, 17 November 2003 http://www.wlap.org/browser.php?ID=20031117-annarbor-01-jensen Read the SMALL PRINT of the 1572, The Essential GCP Document http://www.wlap.org/file-archive/cacr/CACR_CRE_2.ppt#256,1,Read the SMALL PRINT of the 1572 The Good, The Bad and The Ugly of Clinical Research Sites http://www.wlap.org/wl-repository/umich/cacr/cre/20031215-annarbor-01- jensen/realaudio/sld001.htm http://www.wlap.org/wl-repository/umich/cacr/cre/20031215-annarbor-01- jensen/realaudio/sld001.htm Fraud & Misconduct at Investigator Sites, Paul Below, Clinical Research Consultant P. Below Consulting, Inc., Chicagoland Chapter ACRP Clinical Research Conference & Career Fair, Schaumburg, IL, November 10, 2006 http://www.pbelow-consulting.com/power_point/fraud_chicago_10-2006.ppt#259,1,Fraud & Misconduct at Investigator Sites

51. Contact Information: Phone: (901) 448.2406 Email: laura.cummins@utmg.org