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The following are general actions to be taken during an FDA inspection from the time the FDA inspector is greeted to the time the exit interview is conducted and a response to the FDA’s observations are made.
Investigators are required to permit the FDA to inspect and copy any records pertaining to the investigation including, in certain situations, those which identify subjects.
Designate a person to serve as escort who will oversee the inspection (usually the research coordinator for the study). The FDA investigator must not be permitted free access to areas where files are kept, and the escort serves as an institutional monitor as well as guide and general study contact person.
1.
Before the Site Inspection, Identify Records FDA are Likely to Audit (See Appendix I) a.
Identify all subjects, enrollment/screening log, and ALL Informed Consents. b.
Selected Case Report Forms and all supportive source documentation including: i.
AE Reports ii.
Clinic or hospital chart iii.
Consultation reports iv.
All informed consents v.
Laboratory, radiology reports, EKGs, etc. vi.
Patient diaries c.
Write a summary (enrollment, AEs, SAEs, deviations, violations) d.
Identify all IRB correspondence (approvals, continuing reviews) e.
Device /Drug Accountability Logs f.
Notify others that may be involved, e.g. sponsor, pharmacy, IRB g.
Locate and organize records, review for: i.
Comprehensiveness, accuracy and compliance ii.
Identify weakness/gaps iii.
Correct those that can be corrected iv.
Understand scope of remaining issues v.
Read and understand your obligations under Form 1571 and Form 1572 (See
Appendix II)
Always wait for a specific request to provide information.
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2.
Arrival of Inspector a.
There may be times that persons/department directors should be notified that the FDA is conducting an inspection in the building. b.
Where a sign in log is used: if the inspector will not sign in, make a note in the sign in log of the name, date/time, purpose and escort name. c.
The escort will walk the inspector to an appropriate meeting room. The inspector will present his/ her credentials to verify that they are in order; do not expect the investigator to permit a copy to be made of his/her badge/credentials. d.
The inspector will then present a Notice of Inspection (482) to the Principal
Investigator, this notice authorizes the inspection and its presentation officially begins the inspection. e.
The inspector will explain the intended purpose and scope of the inspection, then ask the PI to summarize the study (See Appendix III).
3.
The Inspection a.
The escort should have made arrangements for a comfortable work area for the FDA inspector(s) for the duration of the inspection. The room must contain no confidential records, including clinical or research related. The inspector should be accompanied by the escort or designee at all times while in the presence of study related documents, samples, or other confidential information. If the inspector needs to make a phone call and requires some privacy, they should have access to a “sterile” room
(no study related information is present) or public area where they can conduct their business. In general, while an inspector is here in an official capacity, they should not be left alone. b.
The inspector must never have access to any site records not specifically provided by the host. Standard procedure is for the inspector to request files for review, starting with the “general” study materials including the regulatory documents binders, then all signed informed consent forms, followed by a sampling of specific patient records. Study finances and personnel records are not included in the standard inspection. c.
The Principal Investigator should set aside time each day to talk with the inspector, as well as being available for questions that may arise. d.
The escort’s role is to coordinate all FDA requests and see that the inspector’s questions are answered honestly and completely. Listen to the question; answer the question that was asked. Defer to others if you don't know; when possible use documents already provided for support of answers. Stop when the question is fully answered. There is nothing wrong with silence: when you have answered, wait for the next questions. e.
How to answer FDA Questions: i.
Be concise; answer only the question that is asked. ii.
Always be clear with the answers to questions. iii.
Be positive and confident. iv.
Take corrective actions if possible, commit only to what you can deliver. v.
DO NOT volunteer information. DO NOT guess or speculate.
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vi.
DO NOT lie. DO NOT argue. vii.
DO NOT panic. viii.
DO NOT sign affidavits.
4.
Inspection of Documents a.
Escort the inspector to an information sterile room away from sources of casual conversation to review requested documents. Always sequester the reviewer in an isolated room and bring the requested documents to them. b.
Only documents specifically requested by the inspector shall be provided for review.
The escort may need to obtain patient records from the hospital or clinic records to supplement or corroborate the research records. c.
Gather the documents requested for review. When documents are copied for inspectors, either a copy is also made to retain or identify each copied document by maintaining an inspection record log. All copies provided should be stamped
“Confidential”. Usually copies are provided without charge to the FDA; however, if the inspector requests an inordinate number of copies, notify the inspector that an invoice will be provided. d.
Documents that the inspector is not entitled to review or copy: financial, personnel
(except for training/qualification records), and internal audits (section 704(a) FDC
Act). e.
Photographs- If the FDA insists on taking photographs, take duplicates at the same time f.
Samples- If the FDA requests a reasonable quantity of samples, fill the request but pull identical samples to retain. Ask the FDA to issue a receipt for the samples (form
484). Depending on the nature of the samples requested, advise the FDA that an invoice will be presented.
5.
Exit Interview a.
The FDA will usually hold an exit interview at the conclusion of the inspection. The escort, Principal Investigator, a representative from Institutional Compliance, and other individuals as appropriate should be notified of the time and place and expect to attend. During this exchange, if serious deficiencies have been found during the inspection, an Inspectional Observations form 483 will follow from the regional office, listing the deficiencies. If no deficiencies are found, or the inspector has comments that she or he believes are not serious enough to warrant a 483, no form will be issued. b.
During the exit interview:
The Principal Investigator will seek to correct any errors in the findings ( See
Appendix IV ).
1.
Both the FDA and Principal Investigator will make sure everything is clear and understood.
2.
Observations, comments, and commitments will be noted in the escort inspection notes.
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6.
Response to FDA 483 a.
The PI or a designate shall draft a response to an FDA 483. The PI is responsible for sending the draft of the response to the UT Southwestern Institutional Review Board
(IRB). The PI is also responsible for sending the written response to the FDA. b.
The written response should include specifics: i.
Determine if a finding was an oversight/one-time occurrence; or systemic, where a change of procedure is indicated. ii.
Delineate corrective actions: including justification of why the proposed response will remediate the issue; and a realistic timeline for correction. iii.
If the PI disagrees with an observation: respond factually, providing clear and verifiable evidence. iv.
Address each particular observation or finding, point by point. v.
The reply should be sent within two weeks. Keep a copy of the final signed response in your office.
7.
Request an Establishment Inspection Report (EIR)
The FDA inspector will file an EIR within approximately 30 days. This report is subsequently available through FOI. It may be requested from:
Freedom of Information
Division of Dockets Management
5630 Fishers Lane, Room 1061, Mail Stop HFA-305
Rockville, MD 20852.
8.
Institutional Follow-Up
Please provide a copy of the final establishment inspection report (EIR) and/or the
Inspectional Observation Form 483 upon receipt to the UT Southwestern IRB office.
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UT  Southwestern  IRB
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Appendix I
FDA AUDIT CHECKLIST
At least one week before the scheduled FDA visit, study team should complete the following activities:
Check Title
Step 1 Gather and review study documents – detailed list follows
Note any problems (e.g. missing or incorrect documents)
Step 2 Secure/reserve work space for FDA representative away from other study/clinical records and research staff
Optional: Contact the Office of Research to reserve audit work space
Step 3 Coordinate with appropriate affiliate institutions to confirm plans for site visit support
Step 4 Prepare the following documents:
A. Study overview
A general overview of the study
List of all personnel and delegated responsibilities
B. Subjects list
List of all subjects enrolled, including name, study number, date enrolled and completed, medical record number
List of all subjects screened
Comments
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C. Current Active Studies
List of Principal Investigator’s current active studies
Step 5 Gather and organize the following documents:
A. Organize all Regulatory Files by general heading arranged in chronological order (or reverse chronological order)
Protocol, include all versions: recent version, previous versions, ability to identify each version and date of the protocol
Investigator’s Brochure, all versions
Informed Consent Form, all versions
Protocol Modifications/ Amendments
Form FDA 1571
Form FDA 1572, all versions
CVs for PI and Sub-investigators listed on all versions of Form FDA 1572
B. Communications
Sponsor Correspondence
CRO Correspondence
Monitoring Log
C. IRB Files note: pay attention to date of IRB notification and date of IRB acknowledgment &/or approval
Approval Letter (initial) for initial protocol with original informed consent
Modification approval(s) with the approved informed
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consent
If there is a data safety monitoring board (DSMB) or data safety monitoring plan (DSMP) for the study, have all reports been submitted and acknowledged by the IRB?
Approvals for:
Continuing Review (s) (CR)
Renewal Documents (protocol, consent,
HIPAA Authorization, etc.)
Notification of:
Adverse Events (reported all, timely, unsubmitted, pending follow-up, reposted to the sponsor or regulatory agencies)
Acknowledgement of:
IND Safety Reports
Study Termination
Final Summary
D. Laboratory
Protocol Violations
Protocol Deviations (during CRs)
Laboratory Certification and normal ranges
CV of laboratory director
E. Drug Accountability - drug log to include:
Receipt of Drug
Dispensing
Return
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Drug/Device Accountability Overview
Who is responsible for shipping/receiving?
Who is the person authorized to dispense and/or administer the drug/device to the subject?
* Investigator * Study Staff
* Investigational Drug Pharmacy
* Other: __________________________
* Investigator * Research Nurse
* Coordinator * Other:
* IDS Pharmacy:
____________________________
If IDS Pharmacy is selected above, STOP
Is the drug/device stored in a secure location?
Is there documentation of drug/device use for each subject?
Is there a shipping receipt?
Is there appropriate documentation for the return or destruction of the drug/device?
YES NO N/A
Is a dispensing and accountability log being maintained?
F. Subject Documents
Informed Consents for screened/enrolled subjects
Is there a subject enrollment log?
If yes, is the subject enrollment log up to date?
Consents obtained prior to any study procedures?
Source documents for each subject enrolled
(including labs, x-rays, scans, etc.)
Informed Consent
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How many consent forms are currently in use?
Are non-English speaking subjects being enrolled?
Yes No
Are fully translated Consent Forms being used?
Please identify all consent documents currently in use by the date approved by the IRB.
NOTE: Date of IRB stamp on a current consent document should NOT exceed 365 days.
Consent Description and Version ID : Valid/IRB Approval Date:
Are all-prior IRB-approved versions of the IRB approved consent being retained?
YES NO
HIPAA Authorization
Is a HIPAA Authorization Form necessary?
Is a translated HIPAA Authorization Form necessary?
Is a translated HIPAA Authorization available?
Does the information listed on the authorization match the information collected in the subject file and outlined on the consent form?
Is the authorization available in the subject’s preferred language?
YES NO
HIPAA Waiver
Is a HIPAA Waiver Form necessary?
Does the information listed on the waiver match the information collected in the subject file and outlined on the consent form?
YES NO
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Step 6 Complete the following review and note any issues to discuss with PI, CTO, ORC
A. Review for each subject enrolled
Review Inclusion/Exclusion Criteria
Document reason for excluded subjects
CRFs completed for each enrolled subject
Source documentation for all CRF entries
Data Clarification issues satisfied
Consent obtained for all subjects screened/enrolled
Verify correct version of informed consent signed
Confirm ‘Notes to File’ present as appropriate
B. Medical Records and/or Study Files
Condition of subject at time of entry into the study
(i.e. all inclusion/exclusion criteria met)
Exposure to Study Drugs
Concomitant medications
Laboratory reports
Diagnostic tests
Dose Modifications
Adverse Events/Deaths
Protocol Exceptions
Early Termination
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Appendix II
Form FDA 1571 (PI is the Sponsor-Investigator (IND holder)) :
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Not begin study until 30 days after FDA’s receipt of IND
• Not to begin or continue studies that are placed on hold
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An IRB that complies with 21 CFR Part 56 is responsible for the initial and continuing review of the study
•
An agreement to follow all other applicable requirements
• Name of individuals who are responsible for monitoring the conduct and progress of the study
•
Name of individuals who are responsible for the review and evaluation of safety information
Form FDA 1572 (FDA Regulated Study):
• Will assure that the study will not start prior to review and approval by the IRB
• Will conduct and personally supervise the study according to the relevant protocol
• Will only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change
•
Will seek a properly constituted IRB and obtain initial and on-going review
• Will obtain informed consent of subjects and submit progress reports to the IRB at intervals not to exceed 1 year
•
Will prepare and maintain adequate and accurate case histories designed to record all pertinent observations for each subject
•
Will prepare and maintain adequate and accurate drug accountability records
•
Will collect and report the data in a way to accurately and completely reflect the observations noted during the study
• Will report immediately and promptly if adverse events are alarming
•
Will assure that the study will not start prior to review and approval by the IRB
• Will conduct and personally supervise the study according to the relevant protocol
• Will only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change
• Will communicate to sub-investigators information on scientific matters of importance related to the investigation
• Will ensure that the drug is administered according to the stated dosing regimen, including dose, route, rate, and duration, and maintains records documenting such facts
• Will certify that the drugs are being tested for investigational purposes and will obtain informed consent of subjects or their representative prior to enrollment
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Appendix III
PI Responsibilities:
The responsibilities of the Principal Investigator prior to arrival of the FDA inspector(s) include:
— Notify the Sponsor of the Inspection as soon as it is scheduled
— Notify all relevant site personnel of inspection responsibilities and schedule and ensure they are trained on interacting with FDA
— Ensure the availability/preparation of room for the FDA investigator
— Ensure all regulatory authority approval documents are on file
— Ensure IRB approvals/correspondence are on file
— Ensure all original study files are readily available (e.g. Investigator Site File, original subject charts, and consultation reports, such as x-rays and lab reports, etc.)
— Current CVs are on file and readily available
— If any external procedures are required and have taken place, i.e., the use of ECG machine, lab draws; ensure that the site personnel are knowledgeable regarding procedures, including calibration, certification of machines and personnel as appropriate
— Documentation of investigational product reconciliation is present
— Documented roles and responsibilities for site personnel is present
— Ensure study documents are organized and accessible
— Review SAEs for the study, if applicable
— Ensure that implementation of corrective actions for all issues identified during the study has occurred
— Ensure an Informed Consent Form is available and signed for each screened study subject
— Site personnel training documentation, including the investigator meeting and any training received after study initiation are available
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Appendix IV
Common Audit Findings at Clinical Sites:
• Protocol non-adherence- Study processes inadequately followed
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Failure to report concomitant therapy
• Inadequate and inaccurate records
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Failure to report adverse events- Safety reporting violation
• Inadequate drug accountability
•
IRB problems
• Informed consent- Improper informed consent process
•
Documentation issues- Source document and CRF mismatch
• Inadequate training records
• Protocol violations
• Procedural violation
• Source document and CRF mismatch
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