FDA Sponsor Inspections: How to Prepare and Survive

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FDA Sponsor Inspections How to Prepare and
Survive

• 17 February, 2005
• Authored by Susan Petersen-Stejskal, Clinical
  Research Director
• Presented by Lynn Ford, Clinical Research
  Manager
• Christine Boes, Senior Manager, Clinical Quality
• Cardiac Rhythm Management
• Medtronic, Inc.

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Topics for Today

• How does the FDA inspector prepare to inspect a
  sponsor?
• How does a sponsor prepare?
• How should the sponsor act during the inspection?
• How should a sponsor respond post-inspection?

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Background

• Summary
• Investigative site inspections commonplace with
  original PMA and NDA
• Although sponsor on site inspections are rare,
  they have far reaching implications for device
  under review and future submissions

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Our example for Today Original PMA

• The very first bi-ventricular pacing system
  designed to provide symptomatic improvement for
  patients with heart failure as determined by
  improvement in the following functional status
  parameters
• NYHA functional classification
• Six minute hall walk
• Quality of Life Questionnaire
• These patients did NOT have a standard indication
  for a pacemaker

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One example what was new ?Original PMA for a
CRT system

• InSync Model 8040
• One Atrial Channel, Two Ventricular Channels
• Simultaneous Biventricular Pacing
• Programmer 9790, Model 9980 Software

• Attain LV Model 2187
• Transvenous
• Stylet/catheter Delivered
• Unipolar

• Attain CS Model 2188
• Transvenous
• Stylet Delivered
• Bipolar

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Follow up and FDA Approval Timelines the big
picture
1st implant Attempt October 28, 98
Submit PMA March 1, 01
1st successful Implant Nov 1, 98
FDA Approval Aug 28 01
September, 1998......August 28,
2001 35 months from IDE submission to FDA approval
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Follow up and FDA Approval Timelinesthe details
1st implant Attempt October 28, 98
Submit PMA Update May 24, 01
FDA Panel July 10, 01
Submit PMA March 1, 01
1st successful Implant Nov 1, 98
FDA Approval Aug 28 01
Restart 6 month Study (Amendment 1.0) July 99
300 Implants (6 mo study) July 00
Achieve 224 6 month follow-ups Dec 7, 00
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Follow up and FDA Approval Timelines
Site inspections and sponsor inspection occurred
during this period
1st implant Attempt October 28, 98
Submit PMA Update May 24, 01
FDA Panel July 10, 01
Submit PMA March 1, 01
1st successful Implant Nov 1, 98
FDA Approval Aug 28 01
Restart 6 month Study (Amendment 1.0) July 99
300 Implants (6 mo study) July 00
Achieve 224 6 month follow-ups Dec 7, 00
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Post PMA Submission Activities

• PMA submitted March 1, 2001
• Update to PMA Clinical Report
• Data cutoff March 19, 2001 Submitted May 24,
  2001
• May 24, 2001 submission also included
• Labeling (generator, leads, patient manual)
• Summary of Safety and Effectiveness
• Panel Pack
• Supplied all pre and post monitoring letters to
  investigators to FDA
• FDA Circulatory System Devices Panel meeting on
  July 10, 2001
• Mock panel prep meetings x 2 (June 18 and June
  25) prior to actual panel

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FDA Post Panel Activities

• FDA Inspection of 3 Investigational Sites
• FDA inspection of Medtronic Clinical
• August 8, 2001 - August 28, 3001
• Ongoing labeling conference calls with FDA
• Labeling Updates to FDA
• Continued until August 27, 2001!

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InSync approval success

• The InSync CRT system was approved within 179
  days of PMA submission

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Sponsor Audit nuts and bolts

• Preparation
• Inspection
• Response (Survival and Recovery!)

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Sponsor Key Items for Preparation

• Inspection Materials and ongoing preparation of
  Sites
• Bimo Inspection Checklist
• Study Files self-audit checklists
• Case Report Form (CRF) and site document
  self-audit checklist
• Corporate Audit
• Study Master File document checklist
• Discussion with other colleagues who were
  recently audited
• Knowing what to expect..
• Ideally a well run study is the best preparation

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In the end it was good for us but did hurt a bit
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FDA Sponsor Inspection Scope

• 3 day notice from FDA (20 days before 180 day
  clock!)
• 3 weeks in duration
• 4 inspectors, 10 total days
• Focus
• 21 CFR Parts 50 Informed Consent,
  56-Institutional Review Boards (IRB)
• 812-Investigational Device Exemptions (IDE) and
  814-Pre-Approval Application (PMA) (10 days)
• 21 CFR Part 11-Electronic Records (6 days)
• Manufacturing (3 days)
• Site and data focus suspended sites,
  compassionate use, high enrollment, then randomly
  selected

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Information Supplied to FDA Inspector by
Washington D.C.

• Investigational Protocol excerpts
• IRB Status List (from Clinical Report)
• Original PMA Report (not update)
• First draft of Summary of Safety and
  Effectiveness
• Death narratives from PMA
• Adverse events section from PMA

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Documents Reviewed on Site

• 35 patient Case Report Form files from 7 sites
• Site training records
• Site correspondence
• Proof of randomization
• statistical run (original)
• envelopes to/from sites
• database comparison to originally generated
  schedule

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Documents Reviewed on Site Cont.

• Investigator nomination process and documentation
  (why or why not selected)
• Investigator files/binders
• CVs
• IRB approvals/renewals
• Study agreements
• Monitoring reports

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Documents Reviewed on Site Cont.

• Standard Operating Procedures (SOPs) covering
  entire duration of trial
• Returned Product Lists
• Manufacturing Lists
• Design Change History
• Full IDE and IDE-S submission(s) and all
  correspondence to the FDA
• Record retention and storage SOPs

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Documents Reviewed on Site Cont.

• Database system
• Data process overview
• Data entry training/access
• OC login and screens
• Core lab contracts and data process
• Corporate Audit report
• Statisticians data handling process

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Practical Considerations

• Notification who should you inform?
• Corporate Compliance Officer, relevant functional
  areas, reception desk, etc.
• Is there a Corporate Procedure for on-site
  inspections?
• Organize and prepare (and calm down)
• MUST to be able to reflect history of entire
  project!
• Gather and organize all study and personnel
  training records

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Practical Considerations Cont.

• Reserve large conference rooms
• Copy machine access (and lots of paper and toner)
• Phone access in the conference room
• Consider location within corp
• Escort FDA inspectors
• Provide overview of study before inspection
  begins
• FDA panel presentation excerpts
• Product demos
• Heart models

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Practical Considerations Cont.

• Limit staff that interface with inspectors,
  select your most experienced person with clear,
  calm communication skills
• Be on time, respond quickly
• Be organized and thorough
• Always tell the truth, if you arent sure about
  something it is ok to excuse yourself and get
  help!

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Profile of an Inspector

• They are auditing experts! And are instructed to
  immediately notify Washington should they become
  aware of any significant adverse inspectional,
  analytical or other information which may affect
  the agencys new product approval decisions
• They may not be experts in
• Your area of study
• Your studys disease state
• Your company
• Your therapy/device/drug/test

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You must have documentation of all adjudication
processes and training
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Preparation Tips(its never too early or too late
to start!)

• Know your Regulations (812, 814, 11, 50, 54, 56)
  and Information Sheets
• Refer to FDA Compliance Program and Guidance
  Manual, Chapter 48 Bioresearch Monitoring
  February 21, 2001 parts I, II, III
• Checklist created from Compliance Program
  Guidance Manual

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Bioresearch Monitoring Sponsors, Contract
Research Organizations and Monitors

• Program 7348.810

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Part I Specific Sponsor Obligations

• Purpose of Inspection
• Obtaining FDA approval prior to study start
• Manufacturing and labeling investigational
  products appropriately
• Initiate, withhold or discontinue clinical trials
  as required
• Refrain from commercialization of investigational
  products
• Control distribution and return of
  investigational products
• Select qualified investigators to conduct studies

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Part I Specific Sponsor Obligations Cont.

• Disseminate appropriate information to
  investigators
• Select qualified persons to monitor the conduct
  of studies
• Adequately monitor clinical investigations
• Evaluate and report adverse experiences
• Maintain adequate records of studies
• Submit progress report and the final results of
  studies

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Part II Implementation

• Purpose of inspection
• How sponsors assure data validity submitted by
  clinical investigators
• Adherence of sponsors, CROs and monitors to
  applicable regulations
• If any or all of the sponsor responsibilities are
  contracted to a CRO, the Center is notified (the
  CRO may also be inspected)

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Part III Inspection of Sponsor

• Generally, inspections are to be conducted
  without prior notification
• Compare practices and procedures of sponsor, CROs
  and monitors to commitment made in the IDE
• Determine humanitarian use involvement,
  compliance to 21 CFR Part 814 subpart H
• If significant violative practices are
  encountered, inspector is to contact the Center
  (Washington DC)
• Issue a 483 at conclusion, if deviations from
  regulations are found Guidance documents should
  NOT be listed on the 483. But should be
  documented in the EIR

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Part III Inspection of Sponsor

• Organization, Personnel, Management of Study
• Selection of Investigators
• Monitors/Monitoring Activities
• Adverse Event Reporting
• Tabulation Data Collection and Handling
• Electronic Records/ Clinical Database
• Test Article / Investigational Products

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Organization, Personnel, and Management of Study

• Organizational Charts
• Identify personnel responsible for review and
  approval
• Protocol development
• Investigator selection
• Statistics
• Clinical Supplies
• Monitoring
• Report writing and approval
• Adverse event review and decisions
• CRO and IRB activities and sponsor transfers

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Organization, Personnel, and Management of Study
Cont.

• Your applicable SOP must support these
  responsibilities (throughout the duration of the
  study)
• Your documentation must support the
  qualifications of each of these individuals (CVs)
• Your documentation must support the activities of
  these personnel (job descriptions)
• You will be cited if transfer of responsibility
  was not documented
• Focus on monitors

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Clinical Personnel Training Records

• Inspector focused on
• Attendance at investigator meetings (and proof)
• Specific monitoring training

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Use of External Services/Contractors

• CROs
• Core labs
• Clin/reg consultants
• Contract study personnel

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Use of External Services/Contractors

• Provide the following documentation and
  rationale
• Duration of relationship
• Contracts
• Specific responsibilities
• must be documented
• Be prepared with real examples of their work
• Which SOPs did they follow?
• Were they reported in IDE?
• Certification/accreditation

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Selection and Monitoring of Investigators

• Investigator List
• Investigator Agreements, confirm all signed
• How selected, what criteria used?
• Which materials provided to sites?
• Protocol
• Report of Prior Investigations (RPI)/Investigator
  s Brochure
• Labeling
• Training
• All versions and updates

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Selection of Investigators continued

• Investigator Compliance including
• Any deviations from FDA regulations?
• Any serious deviations form protocol?
• Any investigators terminated?
• Who signs the CRFs?
• For each of the above
• What do you do about it?
• Was it reported to FDA?
• Was investigator corrected, terminated, other?

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Monitors/Monitoring Activities continued

• List all monitors for study duration
• Selection criteria for monitors
• Job descriptions/responsibilities
• Qualifications
• Training Records and CVs
• Reporting structure

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Monitors/Monitoring Activities continued

• Monitoring SOP
• Frequency, scope and process
• Monitoring Plan
• Monitoring Reports

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Monitors/Monitoring Activities Cont

• Monitoring Reports
• Content
• How was compliance to protocol verified?
• How were Investigator responsibilities verified?
• IRB approvals, updates, communication
• Consents obtained, approved, adequate
• Which CRFs were compared to source docs?
• Data correction handling
• Compliance to Monitoring Plan
• Frequency
• Follow up

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Quality Assurance

• Organization of group
• Frequency
• Who performs them
• Audits versus Monitoring
• Applicable SOPs

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Adverse Event Reporting

• Lists of adverse events
• AE information provided to investigators
• CRF used and review
• Tracking systems

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Adverse Event Reporting Cont

• Unanticipated Adverse Device Events
• Notification to FDA
• Notification to investigators

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Adverse Events Discussion

• Adverse Events
• 1st by center, then alphabetical, then with
  outcome and treatment
• Numerous discussions about
• Medical relevance and treatment of events related
  to implanted system
• Classification of events
• Qualifications of all involved staff and sites
• Management of transferred patients
• Event Date vs Event Notification date

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Data Collection and Handling

• Study Tabulations List of all studies in PMA
• Investigator Tabulations List of all
  investigators part if IND/IDE, review
  1572/agreements, identify if part of PMA
• Data Tabulations List of subjects, verify if
  number in IND/IDE is same as NDA/PMA (compare to
  CRFs submitted)
• Review SOPs and verify compliance to SOPs
• Foreign data receipt and handling

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Other Examples of Requests for Data

• Deviations
• 1st by center, then alphabetical
• Primary endpoints
• By patient and visit

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Electronic Records/Clinical Database

• Includes hardware and software
• Provide all relevant manuals
• Training documentation
• SOPs

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Electronic Records/Clinical Database Cont.

• Database System responsibilities for
• design
• validation
• loading
• entry
• database changes
• error logs
• corrections

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Electronic Records/Clinical Database Cont.

• Database Security
• Sign on
• Passwords
• Access
• Change in staff management
• Audit trail
• Can data be altered after entered?
• Tracking changes
• Backup and Disaster planning

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Electronic Records/Clinical Database Cont.

• Remote Data Entry
• Core lab database
• Transferred data from core lab to sponsor

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Test Article / Investigational Products

• Provide labeling (all versions)
• Patient Recruitment Materials
• Fees charged
• Any modifications, repair or replacement during
  trial?
• Any recalls, withdrawals, returns?

54
Test Article / Investigational Products

• Provide original manufacturing testing data
  (during and post)
• Shipment records
• Receipt records
• Tracking records
• Returned product

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Test Article / Investigational Products continued

• Unused/reusable product records
• Account for return of all product

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Conclusion

• Sample collection
• May receive a FDA Form 483
• Establishment Inspection Report
• Information in EIR may be used to support or
  denial of a pre-marketing application
• The Center classifies the EIR
• NAI No objectionale conditions or practices
• VAI Objectionable conditions or practices were
  found agency not prepared to take/recommend
  admin action
• OAI Regulatory and/or administrative actions
  will be recommended

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FDA Findings The 483

• Two Main categories
• Clinical study conduct
• Database validation

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Clinical Study Conduct

• IRB temporary suspension not reported promptly to
  FDA (was reported when site termination not
  during temporary suspension period occurred)
• Investigationally labeled lead used in non study
  pt (lead was also labeled for market release use)
• Incorrect dates on 5 pre-study visit forms
• Adverse events timing of reporting to FDA
• Inconsistent documentation of annual report being
  sent to the IRBs

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Clinical Study Conduct Continued

• Non compliance to specific SOP requirements
• Inclusion/exclusion criteria not verified by
  field staff (was done by investigator and
  monitors)
• No separate clinical project plan (was part of
  protocol)
• Monitoring Plan did not specify which specific
  data we would monitor (said we monitor all and we
  could not prove we did this)

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Database Validation Findings

• Incomplete documentation of
• Database validation plan
• Data transfer plan and documentation of data from
  one database to another
• Plan for data transfer plan to statistical
  programs
• Storage of PMA dataset

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Findings

• There were no findings that were considered to
  impact the scientific validity or integrity of
  the data

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Response

• Change SOPs
• Comply with SOPs
• Re-educate and re-train
• SOPs
• GCPs
• 21 CFR Parts 11, 50, 54, 56, 812, 814
• Written response to FDA within 15 days

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Response

• Modified SOPs
• Investigational Protocol (confirm receipt of
  annual reports by IRB or send directly to IRB)
• Clinical Study Suspension and Closure (notify FDA
  within 5 working days)
• Database Development and Validation (to document
  plan, process and results and all updates)
• Creating Datasets for analysis and reporting (to
  document plan, process and results and all
  updates)

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What paid off

• Ongoing documented Center training for inspection
  readiness
• Well organized master binder of Center
  correspondence
• Thorough Data review and reporting to FDA
• Monitoring and associated documentation
• Corporate audit
• Compliance tracking and redirecting
• Physician review of data

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The most important attribute

• The InSync team
• teamwork is the ability to work together toward
  a common vision. The ability to direct
  individual accomplishment toward organization
  objectives. It is the fuel that allows the
  realization of objectives of amazing goals that
  no one person could ever achieve alone

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FDA Information

• FDA Home Web Page
• http//www.fda.gov
• FDA Compliance Web Page
• http//www.fda.gov/ora/compliance_ref/default.htm
• Compliance Program Guidance Manuals
• Disqualified List
• Debarment List
• Warning Letters

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Questions?

• Thank you!
• I encourage you to share your experiences with
  inspections so that we can learn from each other,
  avoid 483 findings and ensure better FDA/sponsor
  relationships!