fda inspections_jasonsoltismbaccrc_acrppresentation2012

Jason Soltis, MBA, CCRC

Preparing for Your Educational Experience


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.


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


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.


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


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.


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


Who could be inspected?

Investigators and Study Coordinators

Sponsor

Contract Research Organization

Central Laboratories and Readers

Pharmacy (i.e., Investigational Drug Services)

IRB


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


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.


Where do the inspectors come from?

Local – Likely through Cincinnati


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


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.


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


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


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


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


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


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


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


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


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


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.


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


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


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”


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


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


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


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


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


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


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


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


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.


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


http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133773.pdf



http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126555.pdf

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126555.pdf

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm