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FDA Audit Prep


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FDA Audit Prep

  1. 1. “The Facility’s Perspective” (FDA) Inspections
  2. 2. The Speaker Patrick R. Ayd RN, MBA 2
  3. 3. The Facility‘s Perspective How to prepare for an FDA Inspection Understanding the Goal of the Auditor 3
  4. 4. Why Does the FDA Conduct Inspections? • • Assess adherence to federal laws and regulations • • Confirm validity of data supporting INDs and NDAs Determine that the safety, rights and welfare of subjects were protected through consent and IRB/EC procedures Determine whether the trial was well controlled and conducted according to the trial protocol/SOPs/ contracts/regulatory guidelines/CFRs 4
  5. 5. Major Federal Regulations Governing Clinical Research Title 21, Code of Federal Regulations Electronic Records; Electronic Signatures: Part 11 Protection of Human Subjects: Part 50 Financial Disclosure by Clinical Investigators: Part 54 Institutional Review Boards: Part 56 Investigational New Drug Applications: Part 312 (Subpart D), Responsibilities of Clinical Investigators and Sponsor New Drug Applications: Part 314 5
  6. 6. Inspection of Clinical Investigators • Does the principal investigator retain control of the trial and has any authority been delegated? • If authority has been delegated, has the principal investigator retained control of the trial or has he/she given full or partial control to someone else who FDA may not be aware of until they initiate their inspection? • FDA inspectors will conduct interviews and review documentation in effort to identify all other physicians, assistants, and any other personnel who are, or were, associated with the trial; and to assess compliance to protocol/SOPs/regulations 6
  7. 7. Three Types of Inspections of Clinical Investigators Trial Oriented Inspection • Primary focus is on verification of reported trial data related to an NDA submission (pivotal trials) Investigator Oriented Inspection • Investigator Oriented: an inspection in which the focus is related to suspicious behavior by the clinical investigator Bioequivalence/Bioavailability Inspection • Focus is mainly related to the conduct of the trial and collection of data 7
  8. 8. Routine Inspections Advance Notice Usually Inspect trials That Were Completed and Reported in NDA Inspections Usually Last 3-4 Days 8
  9. 9. Why is “My” Site Being Audited  Investigator is conducting a significant # of clinical trials  Investigator is conducting clinical trials outside his/her field of specialization  The investigator reports efficacy for a drug that appears to be too good compared with the results of other investigators conducting the same trial  The investigator reports few adverse drug reactions as compared with other investigators conducting the same trial  Luck 9
  10. 10. “For Cause” Inspections No Advance Notice (1 day if lucky) More Stressful Than Routine Inspections Can Last for Weeks or Months with Intermittent Visits May Involve FDA HQ Personnel 10
  11. 11. What Could Prompt a “For Cause” Audit  Complaint Related To Safety, Informed Consent, Coercion  The Investigator Is Conducting Clinical Trials Outside His/Her Field Of Specialization  The FDA has received complaints from a patient or the sponsor that the investigator is in alleged violation of the regulations, protocol, or human rights  The Investigator Reports Few Adverse Drug Reactions As Compared With Other Investigators Conducting The Same Trial 11
  12. 12. Four Major Segments of an FDA Inspection Announcement of an Inspection Conduct of the Inspection Exit Interview Post Inspection 12
  13. 13. They’re Here! Now what????? 13
  14. 14. Upon Arrival of the Auditor  Contact Appropriate Personnel  Confirm Credentials  Receive FDA Form 482  Determine Purpose  Request Guidelines/expectations (Schedule, Debriefing, Etc.)  Assign an Appropriate Room  FDA Inspection SOP 14
  15. 15. Upon Announcement of an Inspection,  Notify sponsor cont.  Retrieve CRFs for each subject  Establish roles • primary/secondary contacts  Gather source documents • documentation • making copies  Retrieve & review trial file & trial protocol  Alert & prepare support staff  Visit/alert ancillary facilities ( pharmacy, clinical laboratory, etc.) 15
  16. 16. Conduct of Inspection  Tour/Facility Inspection  Accompany At All Times • Allow Inspector Quiet Time To Work • Set Expectations • Check Periodically To Answer Questions  Staff Interviews  Data Reviews  Daily Debriefing 16
  17. 17. Investigator Interview and Facility Inspection People-Related Issues  Who assisted in performing the trial?  What were each person’s specific duties?  How were the trial subjects recruited?  Describe the monitoring (quality control) procedures & your interaction with the monitor • frequency of visits • frequency of telephone calls • information provided by monitor 17
  18. 18. Investigator Interview and Facility Inspection, cont. Facility-Related Issues  Where was the trial conducted?  What protocol specific equipment was used? Where is it located?  How and where were data recorded and stored?  Where was investigational drug stored?  What records provide documentation of drug accountability to and from the sponsor? 18
  19. 19. Review of Investigator Trial File • • • • Protocol Investigators Brochure 1572 with CV(s) IRB/EC approval letter(s) & correspondence • Sample IRB/IEC approved informed consent form • Randomization schedule • • • • • Monitoring documentation • Signed consent form for each subject • Copies of completed CRFs IND Safety Reports Drug Accountability records Lab Certification/CV(s) Notification of trial end to IRB/IEC & sponsor 19
  20. 20. Review of the Subjects’ Consent Forms • Review of the Signed Original And/or Revised Consent Forms for Selected trial Subjects • Verify Who Obtained or Witnessed Consent Process • Verify Date of Consent to Ensure the Process Was Before the Date of the First Trial Procedure • Verify That Subjects Were Consented With the IRBApproved Form • Verify That Each Subject Received a Copy of the Original Signed Consent Form 20
  21. 21. Audit of Subjects’ Records • Review of Organization, Completeness, Condition, and Location of Subjects’ Records • Review of Documentation to Assure That the Trial Subjects Did Exist and Were Alive and Available for Trial Participation • Review and Cross-comparison of Selected Case Report Forms With Corresponding Source Documentation 21
  22. 22. Audit of Subjects’ Records, cont. • Review and evaluation of Serious Adverse Events, and how and when they were reported to the IRB/IEC and Sponsor • Review for subject Drop-Outs • Are they being reported to the sponsor? • What are the reported reasons for Drop-Outs? • Did patient move, experience some type of adverse event, or decide to voluntarily withdraw? 22
  23. 23. Examples of Areas Reviewed • Compare adherence to practices & procedures to Contract/SOPs/ protocol/guidelines • Identify departments/functions/ key personnel • Authority delegated • Authority to review & approve reports & data tables, evaluations , AE’s • Review contractual agreement • Organization charts • Names/titles of responsible persons • Job descriptions, CV’s, training records • Facility • Subject records • Drug accountability 23
  24. 24. Be Prepared to Discuss • Responsibilities • SOPs • Organization Chart • Roles/Functions • Training • general • trial specific • Transfer of obligations • Tracking of activities • • • • • • • • • Central Files Source Documents Trial Documentation Problem Resolution Subject Screening/Decisions AE Reporting Validation Equipment Quality Assurance 24
  25. 25. Be Prepared to Discuss Essentially, anything related to your job, internal processes and the project 25
  26. 26. During the Interview…...  be able to clearly & succinctly explain your job responsibilities, processes (know your job description, SOPs, contracts, protocol, etc.)  think before you speak  make sure you understand the question • DON’T ASSUME • clarify if necessary 26
  27. 27. During the Interview…… cont.  answer ONLY questions asked • don’t volunteer • get comfortable with ‘pregnant pause’  answer ONLY questions related to your position  answer ONLY questions you know, otherwise • I don’t know • I will/someone else will follow up  answer truthfully 27
  28. 28. During the Interview…… cont.  Correct Erroneous Information Provided  Know & Refer Back to Processes  Refer Back to Protocol, Reports, and Other Documents  Know Contract & Protocol Expectations  Be Positive  Be Polite  Be Prepared  Be Alert to Hallway Talk 28
  29. 29. During the Interview…… cont.  Do Not Argue  Do Not Deny the Obvious  Do Not Get Hooked on ‘Fishing Expeditions’  Do Not Comment on Quality  Do Not Respond to Casual Comments 29
  30. 30. During the Interview…… cont.  Do Not Express Frustrations or Editorialize  Do Not Respond to Questions Unless QA/Management Is Present  Do Not Read or Sign Affidavits or Statements  Do Not Provide Copies of Any Documents (QA/Management) 30
  31. 31. FDA is trained in interviewing & interrogation techniques 31
  32. 32. Conclusion  Know & Follow SOPs, Protocol, Contract, Plans, etc.  Ensure Your CV, Training Records Are Current  Document & Follow up With Problems  Be Aware of Quality Trends  Ensure Documentation Is Adequate & Accurately Reflects Activities 32
  33. 33. Most Common Reasons for FDA to Reject a Trial • Source Documentation Not Available • Failed to Follow the Protocol • Unreported Concomitant Medications That Might Interfere With Evaluation of the Drug • Unreported Adverse Experiences That Could Be Associated With the Investigational Drug 33
  34. 34. Investigator-Oriented Inspections Results (FDA) Inadequate and inaccurate records 52% failure to adhere to protocol 52% Inadequate subject consent form 44% inadequate record of drug accountability 28% Failure to inform IRB/IEC of changes / progress 14% 34
  35. 35. Investigator-Oriented Inspections Results (FDA), Deficiency cont. 451 Inspections Unapproved Concomitant Therapy 11% Submission of False Data 11% Problems With Records Availability 9% Inappropriate Follow-up of Adverse Reactions 7% Inappropriate Delegation of Authority 5% Failure to Obtain IRB Approval 3% Sub-investigators Not Listed 4% June, 2008 to October, 2009 35
  36. 36. Trial Oriented Inspections Results (FDA) Deficiency 483 Inspections Inadequate Consent Form 49% Failure to Adhere to Protocol 31% Inadequate and Inaccurate Records 26% Inadequate Drug Accountability 20% Failure to Inform IRB of Changes / Progress 7% Inappropriate Follow-up of Adverse Reactions 3% Unapproved Concomitant Therapy 3% Failure to Obtain IRB Approval 3% Problems With Record Availability 3% Sub-investigators Not Listed 2% Failure to Obtain Informed Consent 1% June, 2008 to October, 2009 36
  37. 37. Possible Adverse Consequences of FDA’s Observation of Deficient Clinical Research Investigator Sponsor • Restrictive Sanctions • Rejection of Invalid Data • Disqualification • Delay of NDA Review and Approval • Criminal Prosecution • Unapproved NDA 37
  38. 38. Contact ClinPharm Network at