Warning! Warning! Warning! Letters

1. Warning! Warning! Warning! Letters Learning Tools (for Investigators and others)

2. “Public” Learning Tools • Warning Letters • By Erich Jensen • Project Manager • Center for the Advancement of Clinical Research [CACR] • Determination Letters • By Judy Nowack • Associate Vice President • Office of the Vice President of Research [OVPR]

3. Presentation Outline • FDA Warning Letters • Process • Location • Case Studies • OHRP Determination Letters • Process • Location • Case Studies

4. FDA Warning Letters Process Location Cases

5. “Read the SMALL PRINTof the 1572” [Investigator Commitments: Box 9] I agree…to make those records available for inspection

6. The Essential GCP Document “Read the SMALL PRINTof the 1572” [Investigator Commitments: Box 9] upervise • S _______ • M ______ ______ • A _____ to _______ • L ____ __________ ________ • L etFDA Inspect • __P__ _______ _______ • R etainRecords • I _____ _______ • N ____ _ _ _ • T ____ ______ aintain Records dhere Protocol earn Investigator’s Brochure Re ort Adverse Events nform Subjects otify I R B rain Staff

7. Select Site • Contact Site • Schedule Site 4. Arrive (482) 5. Review Records 6. Interview Staff 7. Present Findings 8. Depart (483) 9. Write Report (EIR) 10. Classify Inspection “FDA Inspector Cometh” Process FDA Office Site Location

8. Step 10. FDA classifies Inspection • When evaluation is completed, FDA classifies inspection and sends a letter to site

9. FDA Warning Letters (WL) • A post FDA inspection document • An informal advisory to a firm communicating FDA's position on a matter but does not commit FDA to taking enforcement action • http://www.fda.gov/oc/gcp/clinenforce.html

10. Warning Letter Case: “1572” Academic Investigator: Dr. Yu [U of C, San Diego]

11. WL (17 Apr 02): Yu, MD, PhD • “You failed to obtain a signed investigator statement, Form FDA 1572.” • from all investigators prior to permitting them to begin participation in the investigation.” • “You failed to provide a complete list of the sub-investigators.” • who assisted you in the conduct of the investigation.”

12. Warning Letter Case: “S upervise” and “T rain Staff” Academic Investigator: Dr. Bear [Virginia Commonwealth University]

13. PeopleIssues 1572 Commitments: Box 9 upervise • S _______ • M ______ ______ • A _____ to _______ • L ____ __________ ________ • L etFDA Inspect • __P__ _______ _______ • R etainRecords • I _____ _______ • N ____ _ _ _ • T ____ ______ aintain Records dhere Protocol earn Investigator’s Brochure Re ort Adverse Events nform Subjects otify I R B rain Staff

14. WL (27 Sep 02): Bear, MD, PhD • How many times are the following “people issues” mentioned? • “Not qualified,” “inexperienced,” “unauthorized” • Need to “retrain,” “monitor,” “supervise” • http://www.fda.gov/foi/warning_letters/g3537d.htm

15. S upervise “It is your responsibility to monitor all personnel…” “There are several examples of…reports that were not signed or dated by you or a subinvestigator responsible to you.” “…please explain how you will supervise study staff to ensure…” “Your response is therefore inadequate to explain how a different person was granted the authority to…” T rain staff “…individuals who have prepared study drugs have not been registered pharmacists qualified by training and experience…” “…visits were conducted by personnel not medically qualified to evaluate the subject’ disease status,…” “…attributes these errors to the “initial inexperience” of the person who…” WL (27 Sep 02): Bear, MD, PhD

16. WL (27 Sep 02): Bear, MD, PhD • “These errors reflect a pattern of insufficient training and experience that may impact the safety and welfareof subjects, and the ability to determine the safety and efficacy of the study drug.”

17. Good Clinical Practice (GCP) • A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that • the Data and Reported Results are Credible, and Accurate, • and that • the Rights, Integrity, and Confidentiality of Trial Subjects are Protected. =the safety and efficacy of the study drug =the safety and welfare of subjects

18. Warning Letter Cases:SMALL PRINT Issues Academic Investigators Dr Mitchell Creinin Dr Michael Gruber Dr Alkis Togias

19. Academic Investigator Cases

20. The Essential GCP Document What are the 1572 issues in each case? • S upervise • M aintain Records • A dhere to Protocol • L earn Investigator’s Brochure • L et FDA Inspect • Re P ort Adverse Events • R etain Records • I nform Subjects • N otify IRB • T rain Staff

21. Mitchell Creinin: Pittsburgh [Device] • Inform Subject • “…informed consent document…does not identify foreseeable risks…” • Notify IRB • “…failed to submit the sponsor’s model consent form … to the Magee-Womens Hospital IRB…” • Adhere to Protocol • “…log forms were not completed…in specific dates.” • Report Adverse Events • “irritation or discomfort…was not recorded on …case report forms.” • Maintain Records • “You did not maintain complete records related to each…case history.”

22. Michael Gruber: NYU [Biologics] • Maintain Records • “…failed to prepare and maintain…accurate case histories…” AND “…lack of source data…” • Retain Records • “…failed to retain investigational records.” • Adhere to Protocol • “…there were many deviations from the protocol requirements…” • Supervise • “…nurse practitioner was not listed on the Form FDA-1572 as subinvestigator,…”

23. Alkis Togias: John Hopkins [Drug] • Significant Issues • “… an investigation into the death of a healthy volunteer…” • “You failed to submit an IND…”

24. Alkis Togias: John Hopkins [Drug] • Learn Investigator’s Brochure • “…you also failed to submit supporting data…” • Notify IRB • “You failed to notify and obtain IRB approval…” • Report Adverse Events • “…you failed to promptly report…unanticipated problems…” • Adhere to Protocol • “You changed the dosing conditions set forth in the protocol…” • Inform Subjects • “…the following essential elements…were not included…” • Maintain AND Retain Records • “You failed to systematically record..” “No records were available…”

25. FDA Restricted List[http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm]

26. More info: Dr Togias: John Hopkins • John Hopkins University: www.jhu.edu • JH Medicine Press Releases • http://www.hopkinsmedicine.org/Press_releases/archive.html • The Gazette On-Line • http://www.jhu.edu/~gazette/ • Hopkins Medical News • http://www.hopkinsmedicine.org/hmn/ • JH Public Health Magazine • http://www.jhsph.edu/Magazine/toc.html • Keyword search: “Ellen Roche” “OHRP”

27. More info: Dr Togias: John Hopkins • Office of Human Research Protection • Compliance Oversight • OHRP Compliance Activities: Determination Letters • Jul 19, 2001 (Suspends Multiple Project Assurance) • Jul 23, 2001 (Reinstates Multiple Project Assurance) • Oct 03, 2001 (First Monthly Report) • Aug 23, 2002 (Follow-up Site Inspection and Restriction Removal)

28. OHRP Determination Letters Process Location Cases

29. Office for Human Research Protections (OHRP) • Administratively located in the Office of the Assistant Secretary of HHS • Implements 45 CFR 46 (Subparts A, B, C, D) • Interprets the Common Rule

30. Relationship of OHRP to UM • Federal Wide Assurance (FWA) • UM would be subject to Federal regulation even without FWA • FWA allows multiple submissions under one University certification • FWA grants OHRP special compliance authority

31. OHRP looks at the Institution • OHRP holds the institution responsible for the conduct of its agents, but does not take direct action against those individual investigators who are conducting research under the university’s auspices • In this regard, it differs from FDA

32. OHRP Compliance Procedures • OHRP evaluates all written allegations or indications of noncompliance with HHS regulations from any source. • OHRP initiates a compliance oversight evaluation by writing to the “Institutional Official” • At UM, the Institutional Official is Fawwaz Ulaby, the Vice President for Research

33. Contents of a letter from OHRP initiating a compliance action • Description of the apparent or alleged noncompliance with reference to 45 CFR 46. • Except in rare instances in which there is a need to act immediately, OHRP allows the institution to conduct an investigation and report the results. • Request for ALL institutional documents associated with a protocol. • Request for an institutional response within 30 or 60 days. • Request for a “corrective action plan” if the institutional finds noncompliance anywhere in the study.

34. After Receiving a University Response OHRP evaluates report • May ask for more information • May conduct site visit • May make non-compliance determinations • May require specific actions or institutional development of a “corrective action plan”

35. OHRP compliance close-out letters • Are posted to the web, whether non-compliance found or not. (http://ohrp.osophs.dhhs.gov/compovr.htm) • Communications TO OHPR are available under FedFOIA, but only the communications FROM OHRP are posted • Letters may include “reminders” to institutions of interpretations OHRP has previously made

36. Case 1: JHU (Dr. Rolley E. Johnson) • Clean bill of health - but still damaging because the posting of a letter implies wrongdoing • Notice that complaint is not specified • (Notice the list of cc’s - almost as long as the letter itself)

37. Case 2: TJU and Willis Eye Hospital • Ultimate determination after several communications • No federal funding source • Non-compliance not itemized in this one • Letter emphasizes corrective action for this research and for the entire research compliance program • Contacting all subjects of this research • Campus-wide audit of research that might not have undergone review • Education plan • Policies and Procedures, more support for IRB • Suspension and re-review of 268 protocols

38. Case 3: Mass General Hospital • Non-compliance issues specified in particular research study AND on the part of the IRB • Funded by HHS • Acknowledgment of Corrective Action already taken regarding • “Additional guidance” provided

39. Case 4: JHU (Lead paint abatement) • Findings of IRB non-compliance • Improper use of expedited review • Improper approval of informed consent document • Inadequate expertise on the IRB OHRP acknowledges corrective actions.

40. Reminder: Dr Togias: John Hopkins • Office of Human Research Protection • Compliance Oversight • OHRP Compliance Activities: Determination Letters • Jul 19, 2001 (Suspends Multiple Project Assurance) • Jul 23, 2001 (Reinstates Multiple Project Assurance) • Oct 03, 2001 (First Monthly Report) • Aug 23, 2002 (Follow-up Site Inspection and Restriction Removal)

41. Summary: Determination Letters Not always determinations of non-compliance. Of interest in terms of current OHRP interpretations -- recognizing that you are getting only one side of the story Actions/corrective actions taken by the institutions; although the institution may require actions by the investigator.