Lessons Learned from FDA Warning Letters

1. Lessons Learned from FDA Warning Letters Partners Human Research Quality Improvement Program QUICK BITE Series September 2, 2004

2. Lessons Learned from FDA Warning Letters • What is a warning letter? • Why should you care if you are not conducting FDA-regulated research? • What are the common violations cited by the FDA? • How can you avoid/correct these violations?

3. What is an FDA Warning Letter? Letter issued by the FDA, citing violations identified during its routine or for-cause audit of investigators/study sites. It usually requires immediate response that includes corrective actions from the investigator.

4. Sample Warning Letter

5. Sample Warning Letter

6. Why should you care if you are not conducting FDA-regulated research? • Similar requirements • FDA requirements vs. Partners requirements • Similar violations • FDA warning letter citation vs. QI Program onsite review common findings • You may be audited by the FDA even though you are not conducting an FDA-regulated study

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

8. Informed ConsentDating the consent form FDA Citations… “You did not ensure that subjects dated their signature on the consent form. Your study coordinator recorded the date of signature on the consent form for subjects.” “Subjects signing the informed consent in most cases did not complete dates. It appears that the study coordinator…completed the date.” “You did not ensure that the subject’s brother dated his signature to indicate when he provided written consent for the subject’s study participation.” “Subject signed the consent form on [redacted]; however, the witness signed the consent on [redacted].” “You did not ensure that the witness dated the signature.”

9. Informed ConsentDating the Consent Form How to avoid and correct… • Do not date for subjects • All individuals MUST sign AND date the consent form for themselves • If someone forgets to date the consent form, write a signed and dated note to file explaining how and when the subject was consented • Write a signed and dated note to file explaining why dates are different

10. Informed ConsentCopies of the Consent Form FDA Citations… “The original consent forms could not be located for 18…subjects enrolled in the study. Copies were available in study binders and subject charts.” “You failed to provide study subjects with a copy of their signed informed consent document.” “There was no documentation that subjects who were enrolled in this study received informed consent.”

11. Informed ConsentCopies of the Consent Form How to avoid and correct… • Always give subjects a copy of the signed and dated consent form • Document that this was done! • Always maintain the original signed and dated consent form in the subject file

12. Investigator Responsibilities FDA Citations… “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.” “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.” “Staff who were delegated the authority to perform certain functions were not adequately credentialed, trained, or monitored.” “You did not personally conduct or supervise this study.”

13. Investigator Responsibilities How to avoid and correct… • Stay involved • Give yourself credit – document your involvement • Only delegate responsibilities to appropriate individuals who are qualified and trained • Maintain documentation of training for all staff • ALL study staff must be approved by the IRB!

14. Protocol Deviations FDA Citations… “An ultrasound was not done at six months for subject.” “You did not conduct certain follow up visits or document efforts to locate missing subjects.” “Numerous assessments were not completed as required by the protocol.” “Physical exam at six months was not done for subject.” “The cholesterol profile testing was not done for subject.”

15. Protocol Deviations How to avoid and correct… • Report ALL protocol deviations to the IRB according to the reporting guidelines, which can be found at http://healthcare.partners.org/phsirb/prodevex.htm • Develop and implement an adequate corrective action plan to avoid future deviations • Amend the protocol if necessary

16. Study RecordsIncomplete/Inaccurate Records FDA Citations… “Number of discrepancies were noted between source documents and data recorded on the CRFs…[CRF] indicates that a pericardial effusion was present, but echocardiogram report…states that no pericardial effusion was present.” “There was no supporting data…to confirm information contained in their case histories to demonstrate their eligibility…” “There is no record of who administered the study drug…Without a record of who administered the study drug, you cannot assure that these injections were performed by a member of the blinded study team.” “Source data for various assessments could not be located.” “The CRF contained blank fields.”

17. Study RecordsIncomplete/Inaccurate Records How to avoid and correct… • 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: • How information was obtained • Who obtained information • Any discrepancies • Missing or incomplete data

18. Study RecordsPoor Quality FDA Citations… “All medical records/case reports audited had numerous write-over corrections which lacked dates and initials.” “There is no documentation of the name or initials of the person making entries in the records.” “Records…were written in pencil, and many entries are illegible.” “Entries were obscured by correction fluid.”

19. Study RecordsPoor Quality How to avoid and correct… • Never obscure the initial entry • Use a single line to cross-out the incorrect information; enter the correct information next to it, and initial and date the change • Always use ink to enter data • Sign/initial and date ALL entries

20. IRB Requirements/Approval FDA Citations… “Your IRB requires that a written report of the death of any research subject be made within 5 business days…five or more subject deaths have not been reported to the IRB.” “You failed to ensure IRB approval…for the duration of the clinical study. Study records document that [you performed study procedures] after the IRB withdrew its approval and informed you that your appeal for continued approval was denied.” “Revised case report forms identifying additional data to be collected…, for which IRB approval was not documented, were used after initiation of the study.” “You failed to obtain IRB approval for the media advertisements used to recruit an enroll subjects for the protocol.”

21. IRB Requirements/Approval How to avoid and correct… • Obtain IRB approval prior to initiating study • Obtain IRB approval for any changes made during the course of the study • Do not allow study to lapse. Submit continuing review at least 45 days prior to expiration • Report all adverse events to the IRB according to Partners guidelines: http://healthcare.partners.org/phsirb/adverse.htm

22. Regulatory Documentation FDA Citations… “The sponsor provided a log sheet, on which all study personnel are required to provide their signature, initials, title, responsibility for the study, and start and stop dates. The log is incomplete in that the start and stop dates were not recorded for several of the study personnel.” “The Form FDA-1571, dated August 22, 1996, lists Dr. [redacted] the principal investigator for the study, as the monitor. No record was available during the inspection to document any monitoring by Dr. [redacted].”

23. Regulatory Documentation How to avoid and correct… • Maintain all essential documents as required by section 8 of the ICH GCP Guidelines • Use the QI Program Self-Assessment checklist to ensure compliance

24. How can you avoid/correct these violations? • Stay involved • Educate Staff • Delegate responsibility appropriately • Document…Document…Document • Report… Report … Report • Utilized the QI Program services

25. Services Provided by the QI Program • Conduct on-site review of your study files to ensure regulatory compliance and good clinical practice • Provide on-site consultation as you set up new studies or monitor on-going studies Delegate responsibility appropriately • Provide an annotated study binder to facilitate proper documentation • Assist study sites as they prepare for upcoming audits by FDA, NIH, or other external agencies • Assist study sites in conducting self-assessment