FDA Inspections – Best and Worst Practices

Bioresearch Monitoring Inspections

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FDA Inspections

• Intro

• Before FDA arrives

• While FDA is on-site

• As the inspection closes

• Common observations

• Following the inspection

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Before FDA Arrives… • Be in compliance!

– Have the appropriate staff

– Provide training to staff on regulatory requirements, specific protocol requirements, any processes or procedures

– Facilitate open communications

– Not just the what, but the why compliance matters

– Assume all studies conducted will be inspected

• Be prepared for an inspection

– Have procedures for how to handle an inspection

– Mock inspection with staff; use sponsor audits as a tool

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While FDA is on-site

• Opening meeting

– Scope of inspection

– Schedule

– Explain roles and responsibilities, study conduct

– Explain records, organization, access

• Objective is to ensure investigator and site staff have clear communication and expectations

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While FDA is on-site

• During the inspection

– Be accessible to answer questions, provide copies

– Don’t delay unnecessarily, if time is needed to retrieve records/answer, explain why

• Daily wrap up

– Questions?

– Concerns?

– Progress?

– Plan for following day

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As the inspection closes

• Schedule close out meeting, ensure responsible/knowledgeable parties available

• Is there an FDA 483?

– Observations clear?

– Do you have additional documentation not reviewed during inspection?

– Verbal response? Will be included in Establishment Inspection Report

– Plan to respond in writing?

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After the Inspection has Ended

• If there was an FDA 483 – should respond in writing

– Recap observation

– Provide explanation if appropriate

– Describe corrective actions considered and when they will be implemented including any SOP revisions, staff training

– Consider impact on any other on-going or future studies

• No FDA 483, but discussion items?

– Consider any impacts and corrective actions you may need to do

– Consider a written response, the items will be reported in the Establishment Inspection Report and reviewed

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Written Responses

• Will be reviewed by investigator and center

• Will be considered if any regulatory/administrative action is contemplated

• Thorough responses help!

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Common Observations Warning Letters and FDA 483s

21 CFR 312.60 – General Responsibilities

• Failure to Follow the Investigational Plan

• Failure to Personally Conduct or Supervise

• Failure to Protect Rights, Safety & Welfare of Human Subjects

• Failure to Obtain Consent

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Common Observations Warning Letters and FDA 483s

21 CFR 312.62 - RECORDKEEPING

AND RECORD RETENTION

• Inadequate Case Histories

• Record Retention

• Drug Disposition

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How do these Drug findings compare to Medical Device Research?

• Failure to ensure that an investigation was conducted in accordance with the investigational plan [21 CFR 812.100 & 21 CFR 812.110(b)] was cited in 3 of 3 Warning Letters to Medical Device CIs.

• Failure to maintain accurate, complete, and current records of each subject’s case history and exposure to the device [21 CFR 812.140(a)(3)] was included in 2 of 3 Warning Letters issued in 2014 & 2015.

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Failure to follow the Investigational Plan – WLs specifically identified

• Eligibility Violations - including unacceptable ECG results, a subject previously enrolled in a study and received a treatment that was disqualifying, out of range clinical labs (e.g., liver function, kidney function, hematology), disqualifying medical history, prohibited prior/ConMeds, (+) pregnancy test

• Randomization prior to receipt/evaluation of Eligibility Data

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Failure to follow the Investigational Plan – WLs identified

• Dosing Errors – including overdosing, under-dosing, dispensing wrong drug, wrong sequence of dosing, & failing to follow titration or stopping rules

• Missed Efficacy and/or Safety Assessments

- blood, urine, and/or stool specimens, ECGs, scans

• Out of Window Tests/Assessments

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Violations Can Be Avoided

• As I mentioned previously, ensuring staff understand the protocol and regulatory requirements will aid in conducting research in compliance with the regulations

• Training

– make it effective for your staff

– Most sites provide training and yet there are still violations

– Not just standard GCP training, but training tailored to the study requirements

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Investigator Interaction

• Most investigators are well trained professionals…

• Each site and study are different, help the investigator understand how your site works and any specific study requirements that may be unique

• What to do when there are disagreements between investigator and study staff

• Should I fear retaliation?

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Contacts

• FDA 482 will list the geographical district office and phone number

• District/Program Division Director, HQ – Deputy Program Director, Program Director

• Ombudsman

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Contacts

• Program Director

– Chrissy Cochran – Chrissy Cochran@fda.hhs.gov (301) 796-5663

• Deputy Program Director

– David Glasgow – David.Glasgow@fda.hhs.gov (301) 796-5403

• BIMO East Director

– Anne Johnson – Anne.Johnson@fda.hhs.gov (215) 717-3003

• BIMO West Director

– Eric Pittman – Eric.Pittman@fda.hhs.gov (312) 596-4259

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ORA Ombudsman • Jessica Zeller ORAOmbudsman@fda.hhs.gov 240-535-6021

• The ORA Ombudsman is dedicated to two primary objectives:

– Informally address concerns, complaints, and other issues that arise between ORA and stakeholders outside of the Agency, including industry, governmental organizations (federal, state, territorial, and tribal), and other members of the public; and

– Engage in outreach and education for these stakeholders and employees of ORA to enhance communication and transparency with stakeholders.

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Questions?

• Post Conference Follow-up

David K. Glasgow

Deputy Program Director

David.Glasgow@fda.hhs.gov

301-796-5403

Confidential

Copyright © 2016 Covance. All Rights Reserved

FDA INSPECTIONS

SPONSOR/MONITOR/CRO

PERSPECTIVE

Cassandra Kennedy

Global Head, Regulatory Compliance & Quality

Assurance

Confidential

Best Approaches to Inspections Inspection Preparation begins at the time of study start

Posted company policies on photography, internet, guests

Creation of Tried and True Inspection Management Procedures

Official Management/Sponsor Notifications

Clear Roles and Responsibilities

• Inspection Lead

• Dedicated Scribe

• Document Assembly/Reviewers

• Runner

• Administrative Assistance

Log of all Document Requested and Provided – Reviewed at least daily

Live display of scribe notes to the Prep Room

Maintenance of Duplicate Set of Documents Taken

Official Daily Updates

Final Report

Response Process including internal/external reviewers

Resolution and completion of findings (both written and verbal)

Confidential

Inspection Lessons Learned

Inspection Training – will need to be refreshed often!

Receptionist

Security Guards

Inspection Roles

Inspection Participation

Senior Leaders – Not always a good idea

Affiliated representatives (sponsor, CRO, vendor, etc) – Good idea or more to manage??

Training opportunity as an observer

Don’t lose an inspector within your facility..

“Typically”, “Usually”, “I think” – if this is the beginning of your inspection response – STOP

The inspection isn’t over until the inspector is gone!

FDA Inspections

• Philip T. Leese MD

• Board Certified in Internal Medicine (1980); I year ER Fellowship.

• Investigator for Phase I/II Clinical Research studies (1979-2016)

• VP Ph. I for Quintiles’ Phase I CRU in KC (1996-2013)

• Retired from Quintiles in Spring of 2016

• IRB Board Member for Midlands IRB (MLIRB)- 2016 to present

• Consultant for Private Practice Research Initiatives 2016-2018

• Presently consulting with Dept. of Psychiatry Kansas University Medical Center

• No Conflicts of Interest to disclose.

1572 Investigator Commitments

• I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.

• I agree to personally conduct or supervise the described investigation(s).

• I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.

1572 Investigator Commitments

• I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.

• I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.

• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

• I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.

1572Investigator Commitments

• I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

• I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.

The FDA Inspector wants to ascertain • who performed various aspects of the protocol for the study (e.g., who

verified inclusion and exclusion criteria, who obtained informed consent, who collected adverse event data);

• whether the IRB approved the protocol, informed consent form, and any amendments to the protocol prior to implementation;

• whether the clinical investigator and study staff adhered to the sponsor’s protocol and investigational plan and whether protocol deviations were documented and reported appropriately;

• whether informed consent documents were signed by the subject or the subjects’ legally authorized representative prior to entry in the study (i.e., performance of any study related procedures);

• whether authority to conduct aspects of the study was delegated, and if so, how the conduct of the study was supervised by the clinical investigator2 ;

• where specific aspects of the investigation were performed;

The FDA Inspector wants to ascertain

• how the study data were obtained and where the study data were recorded;

• accountability for the investigational product, including shipping records and disposition of unused investigational product;

• whether the clinical investigator disclosed information regarding his financial interests to the sponsor and/or interests of any sub-investigator(s), spouse(s) and dependent children3 ;

• the monitor’s communications with the clinical investigator;

• the monitor’s evaluations of the progress of the investigation; and

• corrective actions in response to previous FDA inspections, if any, regulatory, sponsor and/or monitor correspondence.

Common Clinical Investigator Deficiencies*

• Failure to follow the investigational plan/agreement &/or regulations.

• Protocol deviations.

• Inadequate recordkeeping.

• Inadequate subject protection – informed consent issues, failure to report Aes.

• Inadequate accountability for the investigational product.

• Inadequate communication with the IRB.

• Investigational product represented as safe/effective.

* Clinical Investigator (CP 7348.811) deficiencies identified in FDA Form 483 issued at close of inspections. 2017 BIMO Data

Pre-study Preparation • Review past Audits/Inspections: Recommendations and lessons

learned?

• Identify Study Specific tasks which are potential problem areas.

• Are there nuances to the I/E criteria, screening, admission, dosing, safety monitoring procedures which could deep six your study?

• Review Training files and update for study specific purposes.

• Apply Failure Mode Effect Analysis (FMEA) tool to your study.

• Use the SIV to clarify questions/issues which surfaced during the above steps.

• Implement Checkoff sheets. Have verifiers for critical steps.

• Communicate “knowledge” to your study team- not just by e-mail.

During Study preparation • Evaluate FMEA risk mitigation action steps.

• Document what is working, what is not working.

• Make certain your CAPAs are clearly written.

• Make certain you document follow-up on your CAPA action steps.

• Document if your action steps worked, needed modifications.

• Scrutinize amendments for important changes to I/E criteria, dose instructions or procedures, safety monitoring, stopping thresholds.

• Communicate, Communicate, Communicate. (esp. Staff turnover).

• Study specific sign off sheets for important delegation: PI and partner/s each sign off on a study specific delegation form.

Post study Preparation

• Have an internal post study “lessons learned session” and do the same with the CRO/Sponsor.

• Use a checklist (e.g. UT Southwestern IRB FDA Inspection Preparation Guide) to scrutinize your study TMF and documents for FDA Inspection preparedness.

• Go back to your study specific worksheets, your CAPA documents, your CRA memos, etc. to make certain you have documented follow-up on your action items.

• Make your corrections and notes to file now, not months or years later when your are preparing for an audit.

• Review page 4 of Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical Investigators

FDA Inspections • If you have SOPs- periodically review, revise, and update them and then

read them and sign off that you have read them. • Have a “sign off” sheet for critical research documents: IB, Protocol, ICF,

amendments, revised consents. Use a master checklist to track that Sub Investigators and other team members are updating their knowledge of the investigation. (Keep good team meeting minutes).

• Use I/E exclusion checklists. • Dose escalation, Dose titration checklists- use them. • Subject is lost to follow-up- go the extra mile and find out why? • Train, Train, Train. • Communicate, Communicate, Communicate • Problem anticipate and expect errors. Promptly implement plan to address

errors or omissions. • Document, Document, Document.

FDA Inspection: “Do” • Have a Procedure for handling Audits/Inspections.

a. Audit room, War room, scribes, document request process, etc.

• Follow that procedure with the help of your team.

• Concisely answer only the question asked.

• It’s OK to say- I will get back to you.

• Be prompt, accurate, honest, and courteous with your responses.

• Ask questions to seek clarity around the Inspector’s observations or concerns.

• Update your team daily as to the flow of the “Inspection”.

• Ask for recommendations on how to improve: “What have you seen at other sites that you would recommend for us”.

FDA Inspection: “Do Not”

• Don’t state you will do something and then fail to follow through.

• Don’t try to recreate source documents.

• Don’t Back date. Use Note to File.

• Avoid saying “We usually do this procedure this way or most of the time”.

• Don’t blame others for errors, omissions, protocol deviations.

• Don’t fail to implement recommendations from an earlier inspection-esp. from the same inspector

• Don’t treat the Inspector as an Adversary

Some Relevant References • Howard Lee, Heechan Lee. Failure mode and effects analysis drastically

reduced potential risks in clinical trial conduct. Drug Design, Development and Therapy 2017:11 3035-3043.

• Robert J. Cody, M.D., M.B.A. Anticipating Risk for Human Subjects Participating in Clinical Research: Application of Failure Mode and Effects Analysis. Cancer Investigation, 24:209–214, 2006

• www.utsouthwestern.edu/research/research-administration/irb/ • 1 U.S. FDA, Inspections, Compliance, Enforcement, and Criminal

Investigations,http://www.fda.gov/ICECI/EnforcementActions/Warningletters/defauIt.htm

• Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors FDA Inspections of Clinical Investigators

• http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf

FDA Inspections

• Questions?

Reasons for Routine PI Federal Inspections

• Top Recruiter

• PI Reputation (Good or Bad)

• Data are inconsistent with data from other sites

• Importance of a particular study

• Impact of site’s data

• Just a chance occurrence

• Scheduled pre-planned inspection

Reasons for Directed (for cause) Inspection

• Suspect false or fraudulent data; outlier data

• PI appears to be “outside” his/her specialty

• Sponsor appears to have rejected data from the site

• Appearance of delay in reporting/submitting safety data (SAE and SUSAR reports are delayed)

• Questionable sponsor or PI-sponsor monitoring

• Questionable informed consent procedures

• Questionable IRB approvals

• Study carries significant influence on IP approval

• Questionable compliance from the site’s IRB

Reasons for Direct (for cause) Inspection • Complaint filed by

• a subject/patient/family member,

• Research team staff, Institution, or

• Sponsor

• IRB

• Concern for conflict of interest (COI) among the research team at the site

FDA Inspections from the IRB Perspective

David Borasky

Vice President, IRB Compliance

Scope of IRB Inspections

FDA Regs

21 CFR 11, 50, and 56

Published guidance (not typically held to it)

Documentation

IRB records Roster and related membership information

Written procedures i.e., SOPs and controlled documents

Protocol-level documents, correspondence, etc.

Inspection guided by BIMO manual

Manual should guide the inspections

Covers all areas of IRB work that fall under FDA regulation

Can also be used to self-inspect an IRB or to audit vendors

Typical IRB Experience with BIMO Inspection

Announced 1 to 3 business days in advance

21 CFR 50 and 56

21 CFR 11 has not been part of audits even when IRB is on Part 11 system

Follow the manual

Rosters, SOPs, etc

1 FDA person on site for 2 – 3 days

2 – 3 studies and a sample of approved sites

Site level records including ICFs, approval documentation, correspondence

Questions for the Panel