Perspectives from a Primary InvestigatorPerry S. Brown, Jr., MD

February 9, 2021

Disclosures / Conflicts of InterestNone

(Other than being a life-long, die-hard New Orleans Saints fan)

ObjectivesFrom a primary investigator’s perspective: •Learn about FDA inspections and inspectors •Review observations and fixes identified during a FDA audit

•Plan how to respond to an FDA 483 letter •Appreciate lessons learned from prior FDA inspections / audits

FDA inspection targets• New Drug Application (NDA) filings

– High enrollers– Data outliers, unusually beneficial results compared with

other sites or previous research• For cause: report of quality issue from sponsor, IRB, employee

Big problem: Trying to correct things after the fact.Best solution: Preventative care

• Avoid needing to correct things• Correct things that need to be corrected contemporaneously!!

Possible FDA inspection outcomes• Letter of basic compliance (~30%)

– No significant deviations • Form FDA 483 Letter (~64%)

– Deviations from statutes and regulations that do not meet warning letter severity

– Usually (always…) requires a written response from the investigator • Warning Letter (~5%) [after 483 Letter]

– Serious deviations from statutes and regulations – Violations of regulatory significance that would lead to enforcement

action if not corrected – Requests correction and written response

• Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) (~1%)

• All of these are public record

Why were we chosen?First study (literally my first study as PI; study done in 2009, audit 2012): We made 2 "big mistakes..."1. We participated in research for a drug that actually worked and application for FDA approval of the

drug was submitted2. We were one of the top enrollers for Pharmaxis’ inhaled mannitol Study, and when the study was

done, we were the top enroller/retainerOutcome: 483 (violation warning) letter

Second study (study done in 2011, audit 2018):1. We participated in research for a drug that worked and application for FDA approval of the drug was

submitted2. We were “randomly selected” for pre-review audit by the FDA (probably not random—probably due

to our prior 483 letter)Outcome: no 483 letter, just observations (suggestions)

•When we asked this question of the FDA auditor, we did not get a straight answer at all from our first auditor, and were told that it was a “routine pre-market audit” by the second auditor•The FDA denies that it specifically targets high-enrolling sites, but its actions contradict this

FDA:Concerned about:•Patient Safety

• Informed consent process and documentation is critical! (correct form and version of form [IRB approved and date stamped], correctly and contemporaneously signed, by subject, RC, and PI [even if no space for PI to sign!], completed BEFORE any research happens)

• Staff Training and Delegation• Adverse Event management and reporting (promptness for SAE’s)• Protocol Deviation reporting to IRB• IRB Compliance

•Data Integrity• Protocol followed to an extremely literal degree• Data is real and reliable and valid• eCRF data is supported by source documentation and has been entered correctly

Our first FDA inspector focused primarily on the protocol and data integrity; our second inspector covered all of this

Both inspections lasted more than 5 business days—very detailed

If you don’t think you can follow and perform the study protocol, don’t agree to do the studyDon’t put yourself and your research team at risk

The role of the FDA•In regards to new drug development:

• Increase benefit to patients• Reduce risk of bad outcomes• Prevent problems before they happen• Enforcement • Integrity and Transparency

Inspector Styles•Naïve-acting•Friendly, Gregarious•Strict, serious, and very upfront•Some may want you around all the time•Some may want to be left alone

Be prepared to deal with whomever your inspector may be!

Be prepared to think like and speak like a defendant on trial--only answer the question that was asked, and only with factual

responses or "I don't know"

Form 1572• The PI agrees to:

–Personally conduct or supervise the investigation –Follow the protocol –Ensure all persons assisting the protocol are informed of

obligations –Inform subjects that investigational drugs are being used –Ensure informed consent, IRB review, approval and

reporting –Report to sponsor all adverse events –Assume TOTAL responsibility for the study and its

conduct at your site

The role of the PI• The PI of the research project is the sole target for an FDA inspection, not the

sponsor, not the research coordinator, and not the CRO• Best question of our first inspection (to my RC without me present): "I see your

signature all over these records, but not as many from Dr. Brown. Did he really do much of anything during this study?"

• Follow-up question to me, without RC present: "How involved were you with this study? What specifically did you do?”

• The PI is solely responsible for the conduct of a research project at their site.• The PI acknowledges that this is their responsibility by signing the FDA 1572 form. • If the PFT lab or micro lab or RC screw up, the FDA sees this as the PI having

screwed up• If the research coordinator enters wrong data into the eCRF, then that is as good as

the PI having done so from the FDA perspective• PI's: TAKE YOUR JOBS OF OVERSIGHT, DELEGATION, AND INVOLVEMENT,

AND CLEAR AND FREQUENT DOCUMENTATION OF ALL OF THIS SERIOUSLY!!!

Our 483 letter observations (first audit):

• Caveat: In 2009, research was new in our CF Center, and minimally supported in our health system…

Observation #1• An investigation was not conducted in accordance with the signed

statement of investigator and investigational plan• Details (and context):

• Protocol section 3.3.7.3 Reporting of Spirometry states “Flow volume curves should be provided for data verification”

• At the time, PFT lab used for Mannitol Tolerance Test. PFT lab was not able to provide flow volume loops for source documentation, and only reported numerical data from the best test.

• Protocol states “for any subject who is withdrawn before completing all study visits, the Investigator will perform a termination visit, including all assessments scheduled for Visit 4. These assessments will be performed no later than 14 days after withdrawal/discontinuation”

Observation #1 (cont’d)• Protocol states “if subject is formally admitted to

the hospital this is considered to constitute a serious adverse event and a SAE is completed” and “serious adverse events must be reported to Pharmaxis within 24 hours of the occurrence.

• Protocol states “predicted values for all spirometry will be based on the Wang and Hankinson predicted tables.”

• Protocol section 3.3.7.2 states “results of spirometry testing should meet ATS criteria for number of trials, acceptability, and repeatability.”

Observation #2• Protocol section 11.2 Study Record/Progress Notes

states “during each study visit, a physician participating in the study will maintain progress notes, in ink, in the subject’s medical records to document all significant observations.”

Observation #3• An unanticipated event was not reported promptly to

the IRB.

Our fixes:• During the study itself, we worked diligently to get the

appropriate documentation from the PFT lab, but were unable to satisfy all of the requirements of the protocol. •Failing this, we asked our clinic respiratory therapists to do CITI training so they could perform the testing in the future•PFT lab got new equipment after the study was done

• SOP addressing PI direct communication with department head when outside departments relied upon for research study•Importance of SOP’s—we all now use the St Luke’s Health System RPM (Research Procedure Manual)

• Patient withdrew consent at visit 5. Coordinator performed visit 6 (final visit) assessments at early termination visit instead of visit 4 (so no questionnaires were done, and pregnancy test not done)• SOP 100: Management of Study Visits created after

the audit. This SOP dictates protocol review for every study visit with special attention for early termination visits. Again, this is now covered in our RPM

•SAE not reported within 24 hours• Checklist created for keeping track of our SAE’s as well

as the SUSAR reports that arrive• SOP 106: Serious Adverse Events was revised to

reinforce reporting• Back up coordinator trained and in place

•Wrong spirometer used for study visit. new SOP required documentation of spirometer number to help keep track of which unit is used. Protocol defined predicted equation is always to be used.•Reproducibility in PFT sometimes isn’t always possible

for our population.

• Progress notes not done per protocol on four patients.• When the study monitor pointed this out in March, a

progress note template was promptly created and put into use.

• SOP 100: Management of study visits also requires progress notes to be maintained for every study visit

• IRB not notified promptly of internal SAE that was judged “possibly related” to research • Uncertain how this was overlooked, but SAE tracker

helped us going forward

483 response letter “Do’s”• Take FDA Form 483 very, very seriously • Respond within 15 business days• Collaborate with sponsor on response• Response comes from the PI, and only the PI• Send by certified mail and call to confirm receipt (believe it or not,

our 483 response was lost by the USPS...)• Include all supporting documents (SOPs, logs, etc.)• Response letter should state: the observations listed

• The observations listed• Summary of corrective action• Detailed discussion of corrective action for each point• Time line for completing corrective action • Thank the FDA for their time

483 Response Letter “Don’ts”• Do not:• Use emotional language• Rationalize• Throw your hands up and ignore the 483 completely

Guidance and Lessons Learned•Get help from the sponsor and from the institution—“pre-audit the audit”

•Schedule only one contact person (the RC) for the inspector to deal with aside from the PI.•One additional person should be available to help with copying documents and being available 100% of the time that the inspector is on site•The fewer people the inspector has access to, the less chance someone will say the wrong thing.•The person who is with the inspector 100% of the time should ideally know nothing about the study being audited, and should take notes of all questions asked and responses to the questions, and record all issues brought up

•Would not have made it through without research department and research compliance department support!

•Schedule a conference room•Quiet, comfortable, away from all document storage•Put up a sign that says “Do Not Disturb—Federal Audit”

•Do NOT give the protocol deviation log to the FDA auditor—this is not required (unless directly asked for by the auditor), and provides a “roadmap” to the auditor

•If it isn’t documented, it didn’t happen•If you are asked about something, answer truthfully•Even if the answer is “I don’t know”

•Don’t blame co-workers (even the PI)—very tempting…

More lessons learned•Ask for clarification if needed•Take your time formulating your thoughts or questions, before speaking•Answer only the question asked •Do NOT explain, tell story, offer more information

•Don’t teach!

•The FDA inspectors are geniuses at the long pause•Our first inspector often made loaded comments aimed at getting an emotional reaction

Yet more lessons learned•Double-check EVERY DECISION MADE during the study in the protocol, prohibited meds list, etc. to ensure compliance•If you’re not 100% sure of the right decision, email the study monitor and/or sponsor and ask for guidance, then print and keep the email in the subject’s source documents

•Complete progress notes (dated and timed and signed) for every study visit•Single line cross out, initialed and dated, for each written mistake•If you later change something of substance in the source documents (i.e., a date, time, etc.), ALWAYS provide written documentation of why that change was made, either as a progress note or a NTF (note to file), and date and time this.•Know what makes an AE an SAE!

7 Deadly Mistakes• Delaying the audit

• For both audits, I had plans to be out of town…• Lack of preparation• Denying access• Lack of protocol knowledge

• Review the entire protocol of the study prior to the first day of the audit. Twice!

• Not asking for feedback• Defensive response• Assuming the auditor is perfect

Last few lessons learned•Chocolate fixes almost everything• Bourbon is even better.

• Try to approach an FDA Inspection as an opportunity to learn

Going forward• Document investigator oversight at all pivotal

points • Consent process • Inclusion/exclusion • Rollover • Termination • Progress notes • Emails • AE interpretation • SAE reporting • IRB communication • Monitor/sponsor communication • eCRF sign off

THANK YOU!!

Katelyn Penney, Research Compliance Supervisor

FDA Audit – Compliance Perspective

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Triggers for FDA Audit

What the FDA Looks for in an Audit

How to Proactively Prepare for an FDA Audit

Metrics and Common Findings

Overview

Triggers for an FDA Audit

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New Drug Application (Data Validation) 70% of audits are associated with applications May be linked with a sponsor/CRO audit

Complaints (“For cause” inspection) 30% of audits follow a complaint Complaints are from any source

Surveillance inspections IRB GLP Facilities

What Triggers a GCP Audit?

What the FDA Looks for During an Audit

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What the FDA Looks for During

an AuditFDA

Reviews

Clinical Investigator Obligations

Source Documents

Electronic Records

Test Article Control

Study Records

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Obligations of Clinical Investigator

Investigator maintains control of the study by appropriate delegation of study tasks to research staff that are qualified by experience and training

Investigator follows protocol as approved by the IRB

Amendments to protocol approved by IRB prior to implementation except when necessary to eliminate apparent immediate hazard to subjects

What the FDA Looks for During an Audit

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Obligations of Clinical Investigator (Cont.)

Appropriate consent process and documentation

What the FDA Looks for During an Audit

• Consent in language understandable to subjects or LAR• Method of consent (in person, telephone, translator used)• Consent prior to enrollment or any study-related procedures• Each subject or LAR given a signed and dated copy of

consent• Appropriate version of consent document used

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Source Documentation

Study documents organized and complete

Case Report Forms

What the FDA Looks for During an Audit

• Compared with source documents• Verify eligibility of enrolled subjects• Protocol-specific labs• AEs documented and reported

– Investigator assessed severity and relationship to protocol

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Electronic RecordsAccurate and complete

Suitable for review and copying

Meets requirements for paper records

What the FDA Looks for During an Audit

AAttributable L

Legible CContempor-aneous

OOriginal A

Accurate

ALCOA = Data Integrity

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Test Article ControlWho is authorized to administer and dispense

Supplied only to those authorized to receive

Compare amount shipped, received, used, returned or destroyed

Proper Storage• How is it secured• Who has access

Proper labeling of article

What the FDA Looks for During an Audit

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Study Records

Retained according to protocol and regulatory requirements

Reports required by sponsor

Study monitor reports

Follow-up to deficiencies found by monitor

Monitoring for sponsor-investigator studies

What the FDA Looks for During an Audit

Metrics and Common Findings

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FDA Office of ComplianceDeficiencies Found in FDA Audits

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Who Investigators Believe is Responsible for Compliance Failures

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• Will give you a timeframe for audit Can request a delay

• Gather source documentation• Alert study staff• Assign and define inspection roles Host Interviewee Scribe Runner Escort

FDA Called – Now What?

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FDA Called – Now What? (cont.)

Discuss ground rules with study staff on answering questions, be honest and truthful, etc.

1Find a workspace for the auditor• Out of earshot• Comfortable• Provide a desk

2Document what you provide to the auditor

3

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• Check what the auditor returns• OK to ask Questions An explanation of the regulatory basis

• Recommended actions Take responsibility (don’t blame others) Be careful about offering unrequested

information

FDA Called – Now What? (cont.)

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Protecting the Rights, Safety, and Welfare of Study Subjects

• In assessing the adequacy of supervision by an investigator, FDA focuses on four major areas: Whether individuals who are delegated tasks were qualified to perform

such tasks Whether study staff received adequate training on how to conduct the

delegated tasks Whether there was adequate supervision and involvement in the ongoing

conduct of the study, and Whether there was adequate supervision or oversight of any third parties

involved in the conduct of a study.

FDA Guidance Investigator Responsibilities

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Screening evaluations, including obtaining medical histories and assessment of inclusion/exclusion criteria, conducted by individuals with adequate training.

Evaluation of adverse events by individuals having appropriate training, knowledge of the clinical protocol, and knowledge of the investigational product.

Assessments of primary study endpoints by individuals having appropriate training and knowledge of the protocol.

Informed consent obtained by individuals with adequate training, knowledge of the clinical protocol, familiarity of the investigational product, and ability to discuss the

risks and benefits of a clinical trial with prospective subjects.

Appropriate Delegation

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• Routine meetings with staff to review trial progress and update staff on any changes to the protocol or other procedures.

• Written materials to ensure appropriate supervision and conduct.

Adequate Supervision

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Job descriptions, training plans, on-the-

job training documentation, training records, licenses, CV

and resume

PI supervision, oversight, delegation, staff qualifications for study responsibilities

Procedural documents (SOPs, forms, etc.)• Make sure you follow your

SOPs

Written Materials to Ensure Appropriate Supervision and Conduct

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• Ensure that staff: Have a general familiarity with the study and the protocol. Have a specific understanding of the details of the protocol and the

investigational product, relevant to the tasks they will be performing. Are aware of regulatory requirements and acceptable standards for the

conduct of clinical trials, both in respect to conduct of the clinical trial and human subject protection.

Are competent to perform the tasks that they are delegated. Are informed of any pertinent changes during the conduct of the trial and

educated or given additional training as appropriate.

Adequate Training

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Build quality into the conduct of the study• Create systems that limit opportunity for errors.• Simplify protocol and outcomes assessments.• Standardize systems and formats when possible, use validated

instruments/definitions.• Keep protocol amendments to a minimum and check CRFs and consent forms

against each change.• Insist on training and then test it, do beta tests/dry runs.• Have a disaster plan, e.g. back ups if key study staff leave or site experiences

flood or disaster.

Ensure High Quality Data and Subject Safety

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Questions?