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Jason Soltis, MBA, CCRC
Preparing for Your Educational Experience
Jason Soltis, MBA, CCRC
Program/Presentation Objectives
1. Identify why Regulatory Agencies inspect Clinical Investigators? What are inspectors like? Who could be inspected? How long will the inspection take?
2. Outline the process needed to prepare for an FDA Inspection – Starting from Pre-inspection to Post-inspection and everything in between.
3. Incorporate examples of a successful inspection to streamline your inspection visit and to keep yourself “relatively” stress-free.
Jason Soltis, MBA, CCRC
Why do Regulatory Agencies inspect Clinical Investigators?
“To ensure the safety, quality and efficacy of medical products/devices, Regulatory Agencies may perform GCP inspections either during or after a study is completed.”
Common goal – to ensure safety, quality, efficacy of marketed product
Jason Soltis, MBA, CCRC
Why was my site selected?
The Agency will not usually inform you or the sponsor of the type of inspection to be performed.
Take all inspections seriously and be prepared!
Inspectors must comply with their SOPs for inspection. They will inspect against GCP and local regulations.
Jason Soltis, MBA, CCRC
Why was my site selected?
Regulatory Agencies typically select a few sites for inspection. The inspections may be classified as either routine or for-cause.
You were/are a high enroller (usually in the top 3)
You had/have data that significantly differs from other sites
You were selected as a representative random sample
Agency’s prior experience with the investigator
Study outside area of investigator expertise
Approximately 3 sites per pivotal study
Within 1-6 months of any regulatory submission
Jason Soltis, MBA, CCRC
Why was my site selected? cont’d
For-cause Inspections
There may be issues with the quality and/or integrity of the data;
There may be issues where the rights of subjects may have infringed
A Regulatory Agency may have received a “complaint” from someone.
Jason Soltis, MBA, CCRC
Who will notify me of the inspection? Sometimes the agency will inform the sponsor of
selected sites and the sponsor will alert you.
If you are first notified by the agency or if an agency inspector arrives unannounced, please immediately inform your monitor. Typically short advance notice – 1-2 weeks
In some cases, somewhat compassionate inspectors will call you in advance and send you a list of materials to have prepared Best to have all of the items on the list ready upon their
visit if that is the case
Jason Soltis, MBA, CCRC
Who could be inspected?
Investigators and Study Coordinators
Sponsor
Contract Research Organization
Central Laboratories and Readers
Pharmacy (i.e., Investigational Drug Services)
IRB
Jason Soltis, MBA, CCRC
How long will the inspection take?
Typical – about 1 week
Depends on the amount of data to be reviewed at your site
Clear your schedule
How many agency inspectors will conduct the inspection?
Normally – one or two
Jason Soltis, MBA, CCRC
What are inspectors like? They are all different
They are individuals with their own personalities
The approach they take to the inspection will depend on their personalities and experience
Difficult to predict unless you have had a past experience with that inspector
They are professionals. They will be serious about accomplishing their mission. They will be very data-driven.
They will not offer perspective or aid so you must be prepared to “read between the lines”
They may pose questions in such a way that gets you to offer more information than was actually asked.
Jason Soltis, MBA, CCRC
Where do the inspectors come from?
Local – Likely through Cincinnati
Jason Soltis, MBA, CCRC
When you are contacted
Notify all staff involved in AND/OR knowledgeable about the study
Notify applicable Sponsors/IRBs/CRO
Get your study materials out of storage/archives
If an agenda is presented before an inspection
Great – get working on the list
Assign a site escort/facilitator
Assign subject experts
Review institutional procedures
Site SOPs – should be updated approximately every 2 years
Jason Soltis, MBA, CCRC
When you are contacted – cont’d Assemble all study documents in one place Review staff responsibilities & training
Request all patient charts – ensure 21CFRpart11 compliance and access to electronic medical records
Prepare a list of: Investigator’s studies
Any SAEs
Numbers of enrolled/screen failures/Lost to Follow-up
Any pregnancies/deaths
Percent of total enrollments consented and/or enrolled by the PI
Protocol violations – be knowledgeable/aware of these
Etc.
Jason Soltis, MBA, CCRC
When you are contacted – cont’d
Timelines – be prepared to answer questions in this area
When was the first subject enrolled?
When data entry was completed?
How often did the site review electronic diary data for safety – when first able to access the site?
When was the first subject enrolled under the subsequent amendment? Etc.
Reserve adequate work space – away from traffic/water cooler talk
Keep chatter/gossip exposure to a minimum
Jason Soltis, MBA, CCRC
Upon Inspector Arrival
Ask for them to display:
Their credentials/badge, expiration date
Form FDA 482 – Notice of Inspection
These do not contain information for the cause of the inspection. Serves as an official, form notice of inspection.
Take notes throughout inspection process
Inspection normally during business hours
Inspectors should be aware of your operating hours but be prepared to accommodate some as you do not want to hinder the inspector’s ability to complete their work
Jason Soltis, MBA, CCRC
Opening Meeting Allow time for the inspector to get settled
Promptly review the agenda and inform the inspector of the landscape of study materials available
Indicate the available office equipment
Identify an individual as the FDA contact person
Do show the inspector the location of the restroom
Must otherwise have an escort when navigating the building.
Determine purpose and scope of the inspection
Discuss agenda, logistics, phone, photocopier requirements, etc
Jason Soltis, MBA, CCRC
The Inspection
Personnel interviews
Have subject experts predetermined
Redirect questions you cannot answer to appropriate staff – (i.e., if you were the study phlebotomist – don’t try answering site delegation log/regulatory questions unless that was also your role. Have the person best equipped handle those types of questions.)
The inspector may request to interview any staff member directly involved in the study conduct
Fair game – PI (should make themselves available regardless) and Sub-Is, Study Coordinator, Pharmacists, Laboratory Personnel, Regulatory Staff
Jason Soltis, MBA, CCRC
The Inspection
Personnel interviews – cont’d
An interview covers:
Study training – was there an investigator’s meeting, etc
Staff involvement and qualifications
Study conduct
Drug storage and dispensing
Facility (i.e., lab, IP storage, sera storage)
Communications with the IRB
Jason Soltis, MBA, CCRC
Examples of study related documents to be reviewed ICFs/Assents IRB Approvals, correspondences, etc Signed protocol/amendments Local regulatory approvals CV’s – should be updated annually Documentation of study personnel qualifications FDA Form 1572’s Investigator Brochures CRFs Source Documents Drug inventory, shipping, and dispensing records,
temperature log
Jason Soltis, MBA, CCRC
Examples of study related documents to be reviewed – cont’d Financial disclosures
Monitoring log
Adverse event handling information
Study reports
Enrollment log
Pharmacy binder
eCRF disk
CRF health disk
End of study immunogenicity disk
Jason Soltis, MBA, CCRC
Sample question – Electronic Records
What is the source of the hardware and software and do you have a document for 21CFRpart11 compliance?
Be prepared to answer what was viewable to the monitor and how access was restricted/limited.
Sample question – Delegation of Duties
Please identify any individuals involved with the conduct of this study and summarize their responsibilities with regard to study conduct
Jason Soltis, MBA, CCRC
Other interview topics Facility Subject recruitment Study conduct PI oversight – How did you assure adequate PI oversight for the study? Staff involvement (blinded/unblinded) Training ICF process Evaluation of labs/test results Communications and interactions with Sponsor, IRB, Investigators, CRO,
Lab, Data management, etc Data transcription from source to eCRFs Drug storage and dispensing Monitoring activities Computer systems eCRF data system entry eDiary review
Jason Soltis, MBA, CCRC
The Do’s Do assume a friendly, open, honest, professional, polite,
cooperative attitude But…don’t over do it
Do project an attitude of confidence and professionalism Do make sure you understand all questions and their contexts
before you answer Ask for clarification, if needed Repeat questions back to the inspector to be clear Answer succintly
Do make extra copies for site records of inspection Do take notes of your discussions
Note what was asked, what was answered Record any items requested by or promised to FDA
Do take the inspection as a learning experience! Don’t be intimidated.
Jason Soltis, MBA, CCRC
The Don’ts
Don’t guess, lie, deny the obvious, or make misleading statements, be evasive
Don’t engage in unconstructive arguments with the inspector
Don’t volunteer information
Don’t volunteer tours of the facility
If they do not ask, do not offer to show them
Don’t offer special favors
Jason Soltis, MBA, CCRC
The Don’ts – cont’d
Don’t respond to questions outside your area of expertise or responsibility
Do not rely on memory, refer to the protocol, SOPs, etc
If you do not know the answer, say so
Do not give false, misleading information
Don’t attempt to answer “what if” questions – always refer to facts
Do not answer leading questions
Don’t delay in providing requested records or copies
Delays may be perceived as suspicious to an inspector
Jason Soltis, MBA, CCRC
The Don’ts – cont’d Don’t contradict something being said by a colleague
Confirm the correct answer in private
Follow-up with the correct information
Don’t offer audit reports/findings from internal or sponsor audits
Don’t give copies of patient names/personal identifiers Patient names and other personal identifiers on the inspector’s
copies should be redacted and replaced with study subject number and initials only
Post-it notes work well for photocopying
Ideally, copies supplied to the inspector should be stamped “confidential”
Jason Soltis, MBA, CCRC
The exit meeting Take notes You could get offered “read between the lines” tips for
your response
Have the PI available - is responsible for the conduct of the study at the site
The inspector may present a FDA Form 483 This is a list of observations the inspector found
objectionable
Should be nonconformities with FDA regulations May be any deviations to the protocol, lack of proper
documentation of study procedures, may be violations of temporary exclusion/study delay criteria
Jason Soltis, MBA, CCRC
The exit meeting
The inspector may present a FDA Form 483 – cont’d
Does not represent a final Agency determination of your compliance.
If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative during the inspection or submit this information to the address provided in the 483.
The inspector may not present you a FDA Form 483
Good job
Jason Soltis, MBA, CCRC
Responding to a FDA Form 483
Prepare and submit a response to the Agency within 2 weeks (recommended)
State how and when you intend to correct findings
Be descriptive, provide examples/exhibits
“Preventative” vs “Corrective” actions
It is better to indicate step implemented to prevent the same mistake from ever occurring again.
Acknowledge the findings if they are accurate
If you disagree, give reasons, referencing regulations
Jason Soltis, MBA, CCRC
What happens after you submit a response to the FDA?
The post-inspection activities inspector composes an Establishment Inspection Report (EIR)
Composes a Warning Letter (if applicable)
Issues EIR with supporting documentation to FDA HQ
FDA HQ reviews documents and gives a rating
FDA provides EIR to the site
This is the government – may take several months for a response
Jason Soltis, MBA, CCRC
Establishment Inspection Report Classifications NAI – No Action Indicated
No objectionable conditions or practices No regulatory action Good
VAI – Voluntary Action Indicated Objectionable conditions or practices Not at threshold to take or recommend administrative or
regulatory action Notso Good
OAI – Official Action Indicated Serious objectionable conditions found Regulatory action recommended Bad
Jason Soltis, MBA, CCRC
Approximately 30% are NAI’s Notify the Sponsor of any VAI’s/OAI’s immediately Common Investigator Deficiencies
Failure to follow study protocol – 30% 21CFR312.60
Failure to keep adequate & accurate study records – 20% 21CFR312.62(b)
Problems with informed consent documentation/process - >50% 21CFR312.62 (b) & 812.40
Failure to keep IRB informed – 10% Failure to account for study drug – 25%
21CFR312.62(a)
Failure to report AEs – 5% 21CFR312.60 and Part 50
Jason Soltis, MBA, CCRC
Recent Inspection Findings: General Study oversight Lack of involvement of Principal Investigator
Subject existence No confirmation of identity of volunteers
Subject confidentiality Subject details sent into Sponsor company
Ineligible subjects enrolled
SAEs not reported to Sponsor and/or IRB
Records/CRF with numerous write-over corrections Lacked dates and initials
Jason Soltis, MBA, CCRC
Recent Inspection Findings: Informed Consent
Missing elements
Not updated with protocol amendments
Incorrect form used
Version control
Language
Unclear process
Provide some documentation of any questions asked in your source and be sure to indicate the time the ICF process was conducted
Jason Soltis, MBA, CCRC
You’re not in this alone – Sponsors are just as interested in inspection success as you are. They will help you answer questions and possibly provide additional information. They will provide you counsel.
Become familiar with your inspection resources References attached
A clinical research motto to live by is “Be inspection ready at all times” Finish each study out as though it will be inspected
Have all documents organized – i.e., subject visit tabs, communication filing (an ongoing process)
Facilitate the flow of work for the inspector If the study has been closed – do not alter materials in any way. (i.e.,
too late for corrections) Yes – the world does stop for an inspection, in a sense (i.e., cancel
vacations/trips/out of office time…) BUT the research departments do not have to shut down. Just make sure you
have the appropriate personnel available to work alongside the inspector. Schedule staff accordingly.
Jason Soltis, MBA, CCRC
FDA BIMO - Compliance Program Guidance Manual (CPMG 7348.811) http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133773.pdf
FDA – Information Sheet Guidance http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126555.pdf
FDA - Warning Letters http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm
Jason Soltis, MBA, CCRC