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7/27/2019 How to Prepare for a FDA Inspections
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FDA Inspections
How to Prepare for a FDAInspection
Sreeraj
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Table of Contents
1. Overview of Bioresearch Monitoring (BIMO)Program
2. Preparing for the Inspection
3. The FDA Inspection
4. Post-Inspection
5. Most Common Findings
6. TIPS
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Bioresearch Monitoring (BIMO)Program
FDA developed BIMO to ensure:
The protection of the rights, safety, and welfare ofhuman research subjects
The quality and integrity of data submitted to theAgency
BIMO Program involves site visits to clinicalinvestigators, IRBs, and nonclinical (animal)
laboratories.
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Types of BIMO Inspections
FDA conducts inspections of clinicalinvestigators: Routinely to verify data that has been submitted to
the Agency
As a result of a complaint to the Agency about theconduct of the study at the site
In response to sponsor concerns or termination of theclinical site
Related to certain classes of investigational productsthat FDA has identified as products of special interestin its current work plan
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Types of BIMO Inspections
Routine Inspection
VS
For-Cause Inspection
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Types of BIMO Inspections
Routine inspection:
Routine inspections account for over 80% of theinspections performed each year
Clinical Investigators who enroll the most subjects inthe trial are the most likely to be inspected.
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Types of BIMO Inspections
For Cause Inspection:
Conducting a large volume of clinical trials
Conducting clinical studies outside of onesfield of specialization
Reporting significantly better efficacy, feweradverse effects, or different laboratory results
than other investigators studying the samedrug
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Types of BIMO Inspections
For-Cause Inspections (contd)
Complaints from a patient or sponsor of analleged violation of the regulations, protocol,or human rights
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Preparing for the Inspection
When FDA calls to schedule an inspection,obtain the following information:
The name of the PI being inspected
What studies are being inspected The reason for the inspection
Does the FDA want specific personnel available
Does the FDA want specific documents available
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Preparing for the Inspection
Document any telephone conversation(s) thatoccurs between the FDA inspector and the studystaff
Notify study team, Sponsor (is the only way thesponsor will know the site is being audited),Ethics Committee
The FDA inspector will usually request theinspection take place within 10 days
Collect the medical records for all subjectsenrolled in the study
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Preparing for the Inspection
Reserve a room in a private area for theinspection
The room should contain no other files or records
A copy machine should be located next to the room Prepare a general overview of the study for the
PI and study staff
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Preparing for the Inspection
Update the Principal Investigators CV. Thisshould include a list of all current studies.
Review study documentation for:
Accuracy, and compliance Weakness/gaps; correct those that can be corrected
(i.e. notes-to-file, locate missing documents, etc.)
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During the Inspection
The PI or his/her representatives should meetthe inspector and receive and sign the FDA form482 Notice of Inspection.
Write down the inspectors identificationinformationyou cannot make a copy of theinspectors badge!!
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During the Inspection
FDA inspector may request a tour of thefacility where research took place.
Escort should accompany the inspector atall times.
Upon request, provide the inspector onlythe files that have been requested.
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During the Inspection
If the inspector requests copies of documents:
Remove subject identifiers from the copies given tothe inspector
Make a copy for yourself The inspectors copies should be stampedConfidential and your copies should be stampedCopy.
The PI should set aside time each day to talkwith the inspector
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During the Inspection
How to answer questions from the inspector:
Be concise; answer only the question that is asked
Always be clear with answers to questions
Answer honestly and openly DO NOT volunteer information
DO NOT guess
DO NOT argue
If you dont know the answer, write down thequestion and refer it to the appropriate person
Keep a log of questions asked by the inspector
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During the Inspection
FDA Inspector will verify: Who performed various aspects of the protocol
(eligibility, consenting, etc.)
The degree of delegation of authority
Where specific aspects of the investigation wereperformed
How and where data were recorded
How were study staff oriented/trained on the protocol
and investigational product That the PI followed the study protocol approved by
the IRB
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During the Inspection
In addition, the inspector will record thefollowing information:
Dates of IRB approvals (original, continuing
review, etc.)
When the first subject was screened
When the first subject was consented
First administration of the investigationalproduct
Last follow-up for any study subject
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Inspected Documents
The following items are routinely examined:
Adequacy of communication with the IRB, includingthe initial submission, continuing reviews, adverseevent reporting, progress reports, etc.
Completeness of accountability documentation for thereceipt, storage, administration and return of theinvestigational product
Compliance with the study protocol anddocumentation that each deviation notified to IRB andsponsor approval
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Inspected Documents
Inspected documents (cont)
Appropriateness of the informed consent process
Prompt and complete reporting of adverse events to
the IRB and sponsor Compliance with record retention requirements
Adequate monitoring of the site and communicationof the sponsor (monitoring reports)
Consent Forms (including the consent process)
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Inspected Documents The inspector will review subject data to verify that:
Data entered on the CRF is has been accurately andcompletely recorded (matches source documents)
Subjects meet inclusion/exclusion criteria
Clinical laboratory testing was documented by laboratoryrecords
All adverse events were documented and appropriatelyreported
The PI assessed the severity of the adverse event and
documented the relationship of the event to theinvestigational product
All concomitant therapies and/or inter-current illnesseswere documented and reported
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After the Inspection
The FDA inspector will hold an exit interview atthe conclusion of the audit to discuss findingsand deficiencies
Study staff should document the interview,specifically noting observations, comments, andcommitments
Any deficiencies will be noted on the FDA form483 and given to the PI
PI can respond to the 483 verbally during the exitinterview and/or in writing
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FDA Form 483
Written response should:
Address each specific finding, point by point
Describe corrective action plan The response should be sent to the FDA within 30
days
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Post-Inspection
After the inspection, the inspector will write anEstablishment Inspection Report (EIR) andsubmit it to FDA headquarters
After the report has been evaluated you willreceive one of three letters:
No action indicated (NAI): No objectionableconditions or practices were found during the
inspection, or the conditions does not justify furtherFDA action
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Post-Inspection
Post-inspection letters (cont)
Voluntary Action Indicated (VAI): Objectionableconditions were found and documented, but the FDAis not prepared to take or recommend furtherregulatory action because the objectionableconditions are few and do not seriously impactsubject safety or data integrity
Official Action Indicated (OAI): Regulatory violations
uncovered during the inspection are repeated ordeliberate and/or involve submission of falseinformation to FDA or to the sponsor
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Post-Inspection
OAI may result in:
Warning letter (WL)
Violations can be corrected through specific action(s) by theinvestigator and adherence to the corrective action plan has
a high probability of preventing similar or other violations inthe future
Notice of Initiation of Disqualification Proceedings andOpportunity to Explain (NIDPOE)
Repeatedly or deliberately failed to comply with therequirements for conducting clinical trials
Repeatedly or deliberately submitted false information toFDA or to the sponsor
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Most Common Findings
Failure to ensure that informed consent wasobtained
Failure to maintain accurate, complete, and
current records Inadequate device/drug accountability
Failure to obtain IRB approval
Different handwriting in subject diary
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TIPS
Train all the staff before the inspection
SOPs: Standard Operating Procedures to achieve
consistency Source Documentation: Maintain all the applicable
original documents, data, and records thatcorrespond with the CRFs
Checklists/Logs: A way to verify completion of study-related procedures
Note-to-file
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