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  • Welcome (Slide Show has already been running)
    As we get started let’s get a brief video picture by viewing a 2 minute portion of the “Obligations of Investigators” video and a dialog between an experienced and new investigator
  • CMEs for each part ot the series
    Everyone needs to fill out the orange cards, as the training must be documented in official UM database, in addition to the sign in sheet
    Use this slide when the intro slide show has not been run to publicly state CMEs
  • I would like to address these questions at this session
  • Ask for a show of hands from audience for those who have directly been involved in an FDA inspection
  • FDA Inspections of investigators since 1977
    Last known inspections on July 9, 2002 (Oncology) and 3 in 2003, Dr. Kaminsky [Yes, Kaminski was audited for Corixa's NDA, May 19-June 4] , Dr Locke and Dr Brewer
    21 different UMHS investigators such that a couple have been inspected >1time
    Limited list since this only covers drug trials with oversight by CDER (Center for Drug Evaluation and Research)
  • Information supplied by IRBMED
    Usually IRBs are targeted separately by FDA, but common for investigators at locations where the IRB resides for them to make a visit. Example: Dermatology experience where the FDA visited the IRB first to obtain a master list of studies done by a specific investigator
  • Comment briefy on 3 part motto
    Science/Medicine (The data)
    Protection (The subject)
    Compliance (The rules)
  • UM (all locations) sits in the Central Region and typically has inspectors from the downtown Detroit office (but possible from other regional offices, eg, Grand Repids), but for cause inspections can send someone from headquarters.
  • To assure adherence to regulations
    To assure adherence to guidelines
    To validate the study (data)
    To protect the subjects
    Interested in really examining the paper record
  • GLP (animal laboratories)
    GMP (manufacturing facilities)
    Are also inspected with regards to research and new products
  • Main target is the investigator, then IRBs, then sponsor /CRO (very small numbers)
    US and International based
    Other groups listed on overhead usually are ancillary dependent on the questions and needs posed by FDA investigators
  • Other: IND
    Drugs, Biologics, Devices, combinations
    Bioequivalence (I.e., pharmacokinetics)
    For cause changes the whole mix, then any study is fair inspection game
  • Although slides, I have created a flow chart and a table for posting and file retention
  • Inspectors manual cites these metrics….
  • Will cover some case studies in the last of the series
    However, do not want the NIH folks to get to comfortable. Just this year, a patient complained about an NIH study to FDA and they visited for 3 weeks.
  • Be in a state of readiness at all times. Eg: files organized and accessible
    No notice = “for cause” inspection. Example: One UM investigator (and study coordinator) arrived after FDA who already visited the IRB, then stayed 6 weeks.
    Be ready to validate patient existence. One study coordinator had this question posed….and had to generate lists of the screened patients, too (who did not get on study)
  • 1 day to 6 weeks is the known range
    Data inspection: 1 study
    For Cause: all studies are possible
  • OGC Rachel Nosowsky
    IRBMED: Send email to general mailbox (June Insco and/or Pat Ward)
    Want to start tracking centrally what is happening. Have not been so good about this to date
    In case problems, need to address together.
    Do not have the sponsor present at the inspection
  • Normal business hours, although recent example, was arrival at 7 am.
    Usual data inspection, one inspector, common for 2 or more during for cause inspections
  • Copy or keep very detailed list of documents, and make the copies for them, perhaps gather through the day and do all at once (ready for the next day, if multi-day inspection)
    Pull all the requested patient charts (it takes a while to gather them because of the complexity of UMHS system)
    Examples: Could locate all, but one. Placed the chart of the complaining patient on top of pile, upfront, shrewd and set a good tone for the inspection
  • Data needs to be directly related to the study generated data
  • Target the expert, and the level headed and the knowledgeable ones
  • Clinical Investigator CPGM Headers:
    Authority and Administration
    Subjects’ Records
    Other Study Records
    Consent of Human Subjects
    Institutional Review Board
    Investigational Product Accountability
    Records Retention
    Electronic Records and Signatures
    Animal Clinical Studies (if applicable)
    Device Studies (if applicable)
    Report Format
    Sample Collection (if applicable)
  • Be cool, calm, collected and concise!
    FDA inspector from Detroit nicknamed “Columbo” Self effacing, same question for numerous people, tenacious until satisfied with the answer (oh yes, also wore a rumpled lab coat that he brought along)
  • Daily summaries for next day preparation and information gathering
    Exit interview: Management/Investigator and key person, study coordinator
    Important piece of discussion especially if a written response is needed in the future
  • Goal: Try not to get one
  • Does not discriminate between minor and major (misspelled words in a consent versus many missing consents)
  • Informed consents typically reviewed post inspection
    EIRs sent to site of inspection, uncensored, but anyone can request under Freedom of Information (FOIA requests)
  • Describe classifications, can view on line, that the problem situations and warning letters are subject of future date in this series
  • Included in packet
    Green = FDA office activities
    Purple = Site activities
    Remind about CME cards
    Remind about feedback
    Remind about next class: Oct 20, 2003
    Q and A
    Remind about speaking into microphone
  • CRE_Talk_1.ppt

    1. 1. “The FDA Inspector Cometh” Inspection Process for Clinical Trials
    2. 2. FDA “Good Clinical Practice” Inspections  What has happened at UMHS?  Who conducts the inspections?  Who and what are inspected?  What is the inspection process?  How can the process go better?
    3. 3. What has happened at UMHS? Some Metrics
    4. 4. FDA Inspection History at UMHS  Hematology/Oncology  Endocrinology/Metabolism  Neurosurgery  Rheumatology  Human Genetics  Gastroenterology  Dermatology  Opthamology  Pharmacology  Urology  Cardiology  Radiology  Anaesthesiology  Pulmonary  >24 investigators and/or drug trials since 1981
    5. 5. FDA Inspection History at UMHS  FDA has inspected IRBs since 1980  Per IRBMED: – Inspections occur about every 5 years – Known inspections  1992  1997  Latest in Oct, 2001
    6. 6. Who conducts inspections? Hint: Motto: Compliance, Science, Protection
    7. 7. Office of Regulatory Affairs (ORA) Headquarters: Rockville, MD Regional Office: Philadelphia, PA District Office: Detroit, MI
    8. 8. FDA Field Investigators  Conduct inspections to enforce the Food, Drug and Cosmetic Act  Train themselves in “evidence collection” – “If it’s not documented, it didn’t happen.”
    9. 9. Who and What are Inspected? Today’s Focus: GCP-Related People and Places
    10. 10. Who?  Investigators (Doctors) and Study Coordinators  IRB (IRBMED)  Sponsor, if applicable (Industry)  Contract Research Organization, if involved  Laboratories (e.g., Mlabs)  Pharmacy (e.g., Investigational Drug Services)  Devices (e.g., Biomedical Engineering)
    11. 11. What studies?  Usual Emphasis: Phase 3 – Adequate and well controlled  Blinded  Safety and Efficacy – Multi-site  High patient enrolling sites – Recent marketing application (e.g. New Drug Application) filed to an Investigational New Drug (IND)
    12. 12. What is the inspection process? 10 Steps for Investigators
    13. 13. 1. FDA selects Site(s) • FDA selects site for inspection: • Usually within 6 months of marketing application [NDA] (Data Audit) • Selects 3 sites (average) per study, if multi-site • May concurrently inspect the associated IRB: • If no previous inspection; or • Last inspection >5 years OR • May conduct a “For Cause” Audit
    14. 14. Reasons: “For Cause” Inspections  Study of “singular importance” in product approval  Study has major impact on medical practice  Sponsor reports concerns about investigator  Patient complaint  Investigator conducts too many studies  Investigator works outside of specialty area  Safety or efficacy findings are inconsistent with other investigators  Lab results are outside range of biological expectations
    15. 15. 2. FDA Investigator contacts Site • FDA investigator from local District Office contacts responsible person at site: • Gives short advance notice or no notice of visit • Becomes suspicious on attempts to delay visit (e.g., >10 days without valid reason) • Previews internally following subject related data: • Number of total subjects, dropouts and evaluable subjects • List of AEs and deaths (with description and cause)
    16. 16. 3. FDA and Site agree on Visit Date • FDA investigator and site person agree on appointment for site visit: • Averages 3-5 days for appointment • Targets typically one study, but may review other studies performed by same investigator
    17. 17. Preparation Tips for Site  Notify all staff involved in AND/OR knowledgeable about the study: – Key staff, “information providers” are on standby – Office of General Counsel – Industry sponsor, if any  Review UMHS procedures – for unannounced inspections – for IRBMED notification
    18. 18. Preparation Tips for Site  Assign a site escort/facilitator  Assemble all study documents in 1 place – Include list of staff responsibilities and training – Request all patient charts  Prepare a list of investigator’s studies  Reserve adequate work space for field investigator for entire inspection  Assure accessible photocopier
    19. 19. 4. FDA presents Notice of Inspection • Upon arrival FDA displays credentials (eg., photo ID) and FDA Form 482, Notice of Inspection • Conducts inspection during routine business hours • May “meet and greet” 1-3 FDA investigators
    20. 20. FDA Form 482
    21. 21. 5. FDA requests data and documents • FDA investigator requests related trial data and documents during site visit • May need copies of documents • Make 2 copies: • Give 1 copy to FDA • Keep 1 copy at site to facilitate future communications
    22. 22. Tips on Document Requests  Do not provide or copy these information for FDA: – Financial data (salary information, budgets)  (except financial disclosure of clinical investigators) – Personnel data (performance appraisals)  (except qualifications [job descriptions] and training records)
    23. 23. 6. FDA interviews Site Staff • FDA investigator interviews site staff directly involved in trial activities and processes • May question any staff member during inspection • May use Compliance Program Guidance Manual as interview guide
    24. 24. Tips for Anticipating FDA Questions  Compliance Program Guidance Manuals (CPGMs) In Vivo Bioequivalence 7348.001 IRBs 7348.809 Sponsors, CROs and Monitors 7348.810 Clinical Investigators 7348.811
    25. 25. Tips for Handling FDA Questions  Answer – Politely, cooperatively, understanding them (ask for clarification), factually, briefly, within one’s expertise (seek expert), directly (remain within scope), without speculation or guesswork  Avoid – Unsolicited questions, hypothetical questions, long delays to requests, affidavits
    26. 26. 7. FDA conducts “Exit Interview” • [Review findings with FDA investigator at end of each inspection day] • At site visit completion, FDA investigator conducts “exit interview” with responsible site personnel to: • Review findings • Clarify misunderstandings • Describe any deviations from current regulations • Suggest corrective action, if appropriate
    27. 27. 8. FDA presents Notice of Observations • If deviations, FDA investigator leaves a FDA Form 483, Notice of Observations • Submits findings to local District Office for any additional needed actions
    28. 28. FDA Form 483
    29. 29. Most Common Observations (for Investigators)  Protocol non-adherence  Inadequate and inaccurate records  Failure to report adverse events  Failure to report concomitant therapy  Inadequate drug accountability  IRB/IEC problems  Informed consent issues
    30. 30. 9. FDA writes Inspection Report • Upon return to local District Office, FDA investigator: • Writes an Establishment Inspection Report (EIR); and • Forwards to headquarters for evaluation
    31. 31. 10. FDA classifies Inspection • When evaluation is completed, FDA classifies inspection and sends a letter to site Classification Type of Letter NAI (No Action Indicated) Notice of no significant deviations VAI (Voluntary Action Indicated) Informational OAI (Official Action Indicated) Warning
    32. 32. 1. Select Site 2. Contact Site 3. 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 Office Site Location FDA Inspection Process