FDA Inspection Preparation Guide · 7. Request an Establishment Inspection Report (EIR) ......

FDA Inspection Preparation Guide

UT Southwestern IRB Page 1 V1.0_11-‐2012

Table of Contents General Overview

1. Before the Site Inspection 2

2. Arrival of Inspector 2

3. The Inspection 3

4. Inspection of Documents 4

5. Exit Interview 4

6. Response of FDA 483 5

7. Established Inspection Report (EIR) 5

8. Institutional Follow-Up 5

Appendix I _6 Appendix II 12 Appendix III 13 Appendix IV 14


FDA Inspection Preparation Guide

Please alert the IRB upon receiving the call or letter from the FDA to schedule the inspection.

_________________________________________________________________

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.


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.


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.


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.


Appendix I

FDA AUDIT CHECKLIST

At least one week before the scheduled FDA visit, study team should complete the following activities:

Check Title Comments

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


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


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, un-submitted, pending follow-up, reposted to the sponsor or regulatory agencies)

Acknowledgement of:

IND Safety Reports

Study Termination

Final Summary

Protocol Violations

Protocol Deviations (during CRs)

D. Laboratory

Laboratory Certification and normal ranges

CV of laboratory director

E. Drug Accountability - drug log to include:

Receipt of Drug

Dispensing

Return


Drug/Device Accountability Overview

Who is responsible for shipping/receiving?

* Investigator * Study Staff

* Investigational Drug Pharmacy

* Other: __________________________

Who is the person authorized to dispense and/or administer the drug/device to the subject?

* Investigator * Research Nurse

* Coordinator * Other:

* IDS Pharmacy: ____________________________

If IDS Pharmacy is selected above, STOP YES NO N/A

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?

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


How many consent forms are currently in use?

Yes No

Are non-English speaking subjects being enrolled?

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:

YES NO

Are all-prior IRB-approved versions of the IRB approved consent being retained?

HIPAA Authorization YES NO

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?

HIPAA Waiver YES NO

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?


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


Appendix II

Form FDA 1571 (PI is the Sponsor-Investigator (IND holder)):

• Not begin study until 30 days after FDA’s receipt of IND • Not to begin or continue studies that are placed on hold • 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


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


Appendix IV

Common Audit Findings at Clinical Sites:

• Protocol non-adherence- Study processes inadequately followed

• Failure to report concomitant therapy

• Inadequate and inaccurate records

• 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

FDA Inspection Preparation Guide · 7. Request an Establishment Inspection Report (EIR) ......

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