Notes from a Former Regulator

Transcription

1 Notes from a Former Regulator Blake Jensen Senior Director, Quality Assurance INC Research, Inc.

2 Objectives Describe audit / inspection techniques and practices Review common findings and potential outcomes Discuss how to respond and follow-up on issues identified Case studies

3 Audits and Inspections Differences in audits vs. inspections Why conducted By whom Timing Aftermath Different reasons, same motivation Time spent; sample size (different) Records reviewed; focus (same)

4 Inspections

5 Audits

6 Audit / Inspection Techniques Understanding the study and/or processes Interrogations Review/discussion regarding qualifications Looking for clues to identify potential issues Overall view of site or Sponsor / CRO

7 Audit Techniques Auditor has limited amount of time on-site Must focus attention on critical items Data integrity and subject safety Audit Sample Audits should not to be confused with ongoing QC of documentation Interviews/discussions vs. documentation Not the auditor s job to identify ALL issues or to correct issues

8 Audit Techniques Auditors not part of operational / project team Don t know informal instructions/rules; only what is documented Independent perspective while reviewing documentation Auditing the monitors as well

9 Audit Findings Classification of findings Critical: data integrity or subject safety Major: major non-compliance with regulations and/or systemic issues Minor: no apparent indication of systemic issues Categorization of findings Assists with tracking & trending

10 Audit / Inspection Findings Inappropriate delegation of authority Source data inadequate to confirm eligibility Failure to re-consent subjects with updated Informed Consent Form Non-compliance with protocol requirements Not reported to IRB/EC Source data vs. CRF discrepancies Missing essential regulatory documents

11 Audit / Inspection Findings Trends and systemic issues Seemingly minor findings can lead to serious problems Dr. Thomas Gazda Warning Letter (24-NOV-2009) Insufficient qualifications/training of staff to perform delegated tasks Missed or late assessments, including ECGs, phone contacts, PK samples, etc. Source / CRF data discrepancies

12 Audit / Inspection Findings Issues identified at Investigator Sites Issues with Sponsor / CRO

13 After the Audit / Inspection

14 After the Audit / Inspection Observations vs. Findings Audits are not pass vs. fail Audit Report Narrative section List of findings Recommendations? Distribution (Hint: site won t get a copy!) Available to Regulatory Authorities?

15 After the Audit / Inspection What to do with the findings What follow-up is needed When/how to respond Responsibility for response What a response should include CAPA Not only the audit sample

16 After the Audit / Inspection Your audit response can make or break you Take it seriously!

17 After the Audit / Inspection Elements of CAPA Correction: Actions taken to repair and/or eliminate identified nonconformity Corrective Action: Actions taken or planned to eliminate the cause of identified nonconformity or other undesirable situation Preventive Action: Actions taken or planned to eliminate the cause of potential / future nonconformity or other undesirable potential / future situation

18 After the Audit / Inspection Who is involved in responding? Where does the response go? Who evaluates the response? How are responses/actions confirmed? Will there be a re-audit? Where are the report and response ultimately filed?

19 After the Audit / Inspection Potential Outcomes Audit Additional time/money spent on follow-up and corrections Loss of future business Reporting to Authorities Breach of contract Inspection Warning Letter (or other Admin Action) Disqualification (PI or data) Restrictions/Assurance Criminal or civil charges

20 Case Study # 1 For-cause investigator site audit (issues first identified during routine monitoring) Suspicious consent signatures Apparent late entries, not identified as such Confirmation of issues during audit and new ones PI didn t take audit seriously; not available for discussions; no explanations for discrepancies Staff reported issues with PI Financial trouble; skipping town Reported to FDA (and new employer)

21 Case Study # 2 Multiple sites with same types of issues Changing source data after the fact and/or only when identified by monitors Some changes made correctly while others had no indication of late entry Investigation into issues, including site audit (not all sites audited) Close sites and report to FDA? With new proposed rule? Use of data at site?

22 Case Study # 3 Several sites in Mexico Study was already over (different Sponsor) Missed exams; pregnancy tests, labs, ECGs Why not performed? (frightening!!) Couldn t confirm eligibility from source data AEs in diary not recorded/reported Affected submission because data couldn t be used Audit reports sent to FDA!

23 Case Study # 4 Contracted Investigator Site Audit Routine audit; site selected based on high enrollment Lack of PI oversight; overworked (and overdelegated) Study Coordinators PI signatures on dates he was known to be out of office Uncertified and unqualified raters PI was being used by Sponsor on several other studies (not anymore!)

24 Case Study # 5 Dr. Kioschos Warning Letter Ineligible subjects Inadequate documentation (BMI method not documented, not done according to protocol) Followed unapproved protocol version Missed follow-up visits Device accountability tracking/documentation Informed consent issues (re-consenting and procedures before consent) Threw 483 in my face (not smart!)

25 Questions?

26 Thank you