SHEDDING LIGHT ON AN FDA VISIT - PowerPoint Presentation

Slide1

SHEDDING LIGHT ON ANFDA VISIT

Joyce Nancarrow Tull, MSN, RN, CCRP

University of Southern California

USC Norris Comprehensive Cancer Center

Clinical Investigations Support Office

Slide2

DISCLOSURESI have no financial disclosures

I have been through four (4) FDA visits and met three different FDA Inspectors for IND approval; this does not make me an expert, just somewhat of a survivor. I am willing to talk with you about what I learned and encourage for you to join me in sharing experiences.

I am not speaking on behalf of any institution or their audit preparation.

Slide3

OBJECTIVES FOR TODAY

Begin to understand the legal authority and objectives of the FDA Inspection/Inspector (no substitute for legal advise).

Develop an understanding of basic inspection procedures

Develop awareness of the “BIMO” Regulations

Identify key strategies for success during an FDA Audit:

Develop an understanding of how to answer questions during an inspection

“Homework” needed for a successful audit

Develop an understanding of how to host the FDA and manage the Inspection

Understand the key FDA Terms

Slide4

KEEPING THE FDA IN PERSPECTIVE

It’s amazing what you see on FACEBOOK…..

Be mindful of what you post online…..

Slide5

OTHER CAVEATSBefore any visit is announced explore the topic with your QA and Leadership – what is your risk and what do you need to be prepared

?

When was the last time you or your Investigator were audited by the FDA? By another agency?

Get to know an expert and consider having someone outside your institution “look over” your processes and procedures.

Acquaint yourself to people

who have been through this; sharing knowledge and experience helps.

Trust your instincts and “keep your wits about you

”.

Slide6

PREPARATION IS KEY

If you receive notification you’ll be visited by an FDA Inspector keep the following in mind:

Time is of the essence; they want to come within days (3-10), not weeks or

months (at the direction of the FDA)

The visit is often scheduled around the PI

The company has an idea if you may be a site for inspection

H

igh accrual [driving the trial results]

site

with issues affecting trial

outcome [safety]

Imbalance or outlier [“too many” or “too few”]

Clinical Investigator History (483s are public knowledge/searchable)

Regional or county diversity

There is usually a pre-FDA visit from the Sponsor’s internal QA group; they will look to determine your “readiness” for the FDA

Slide7

…AND MORE PREPARATION

Get to know the Bioresearch Monitoring Program (BIMO) of the FDA

http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm255614.htm

Keep notes of the lessons learned; that’s where the BIMO checklist came from!

They work as long

as

they

want each day;

they have certain objectives they have to achieve in the visit so plan ahead and have adequate support for potential long (and tiring) days.

Slide8

…AND MORE PREPARATION

It’s a “team sport” so try to have more than just one person who will be working with the Inspector: roles can include host, scribe, runners, and “base-camp” staff

The Host is the main speaker who knows the trial participants, conduct of the trial, and important events which occurred including SAEs, deaths on study, etc. (It is NOT necessarily the RN or CRC who cared for the patients.)

The Scribe writes everything down that is said in the Inspection room.

The Runners bring requested document copies to the Inspection room.

The Base Camp Team makes copies, keeps logs of documents copied, and helps in any way needed.

Slide9

KEY REMINDERS

It’s important to remember:

The company’s reputation and IND success depends on the site visits – both at the company and at the accruing sites

. They will stay in close contact with you if you are under FDA audit

The Principal Investigator’s reputation and future in research is linked to the success of the IND application

. A 483 is a matter of public record and can be

searched

by Investigator name

https

://fdazilla.com/store/483s

/ and

http://

www.fda.gov/ICECI/Inspections/default.htm

Slide10

GCP, Guidance, & RegulationsGCP: a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting on clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of the trial participants are protected.

http://fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf

Slide11

KEY CONCEPTSClinical Investigationany experiment in which a drug is administered to human subjects. An

experiment

is any use of a drug except for the use of a marketed drug in the course of medical

practice [21CFR312.3

]

Clinical Investigator

Individual who actually conducts the clinical investigation [21CFR312.3, 21CFR812.3(i)]

Slide12

KEY RESPONSIBILITIESClinical Investigator:Responsible for the overall conduct of the study at the study site [21CFR312.60]

Directing administration or dispensing of test article

Ensuring that data are collected and maintained in accordance with the protocol and regulatory requirements

Following the approved investigational plan

Obtaining Informed Consent prior to conducting any study-related procedures

Maintaining adequate and accurate records [21CFR312.62]

Administer test article only to subjects under control of the Investigator

Ensure Adverse Events are appropriately reported

Ensure adequate IRB review

Investigator Agreement, Statement of Investigator (1572), Financial Disclosure [21CFR54]

Slide13

DID I EMPHASIZE PREPARING?

It’s tremendously important to have good records (be audit ready every day):

clear policies/standards of practice,

Clear training records,

Complete charts and regulatory binders

Quality documentation

Job descriptions

Drug accountability records

Plan

for an opening meeting and a

debrief

at the end of the day

Help everyone prepare, including the PI (scripting helps)

Slide14

MORE ABOUT THE FDA

Their authority:

Extends to what is reasonably necessary to achieve the objective of the inspection

Is held under federal statutes (Section 704 of the FDCA-Federal Food Drug and Cosmetic Act)

Concept of “reasonableness”

Focuses on the trial being conducted in a manner which ensures the rights and safety/welfare of the trial participants, the accurate capture and reliability of the trial data, and assess compliance with the FDA’s regulations for clinical trials

Slide15

IT’S VISIT TIME…Letter or phone call to PI – FDA scheduling visit.

Don’t forget to prepare them too!

Encourage communication with the Clinical Trials Office at all stages (IND application, sponsor updates, accrual position, fast track status)

The Arrival: Issuing the Form 482: Generally must meet with PI to obtain signature

Questions PI must know during initial interview and possible preparation (scripting).

Slide16

THE FDA’S OBJECTIVESExamine the conduct of the trial through the available study documents and ensure this documentation supports the trial being conducted in

compliance

with FDA regulations

Assess the

safety

of the participants and ensure they were treated in accordance with clinical practice which would assess and support their safety.

Verify the data

from the company and sites to ensure it supports both of these objectives in the use of the experimental agent.

Slide17

THE FDA’S OBJECTIVES

Source

CRF

Data

Submitted

to FDA

Slide18

CLINICAL TRIALS OFFICE

Escorting the Inspector to the visit room:

Segregate the Inspector

Inform staff and caution on behavior (no hallway conversations this week…

)

Professionalism and conduct – friendly and professional

Inspection techniques

Inspector makes observations of conditions, equipment, facilities, products, etc.

Behavior; statements and note taking

Document review: Inspector will compare information, ask questions, and confirm through interviewing

Questions, question, questions…..

Declarative statements which SEEM like questions…

Slide19

QUESTIONS AND ANSWERSInterviewing: non-accusatory, conversational in Q&A; fact finding.

Check and confirm with multiple sources – do not be offended if they ask multiple people the same question

Direct, leading, hypothetical and open ended questions and statements– how much will you talk?

FDA may ask questions for which they already have or know the answers. They are validating your knowledge and the information provided by the company. This can happen to multiple people.

The Inspectors are very intuitive and will look for indicators of possible deception (verbal and nonverbal)

“Interrogation” vs. “interview”

Slide20

RECORDS THEY CAN REQUEST

…..and copy:

Study protocol

Procedures/SOPs

Informed consent documents

IRB documents

Test article preparation, dispensing, and storage records (DARF –accountability)

Clinical records and raw data

Concomitant Meds

Records of Adverse Reactions, Deaths

Records of instances of emergency code breaking

Qualifications and Job Descriptions of Any Staff

Training Records (including SIV, etc.)

Slide21

RECORDS THEY CAN’T REQUEST

Sales and financial data

Personnel records (employee file)

R&D data for articles not yet the subject of a marketing submission (Example: an IND or NDA not yet filed)

Other non-study related data

**It

may

help to

have a relationship with a law firm familiar with the FDA and their “jurisdiction

”. The firm must be admitted to the bar in your state and consults with you on issues if they arise.

Slide22

PREPARING THE TRIAL

Immediate Action List: who needs to know the FDA is coming at your institution?

Preparation Checklist and the BIMO Regulations point to all documents they may request; have these prepared and held for review (can use staging area)

Prepare the PI with the information they should know (scripting).

Talk with staff and “demystify” this audit; it is often worrisome for many and like all audits represents an opportunity for improvement!

Two copies of every document; one for you to keep, one to give to the Inspector. You can prepare ahead!

Close communication with the Sponsor/QA Team

Slide23

PROCESS OF INSPECTION

INTRODUCTION

Credentials & Notice reading

Focus of Inspection: “For cause” or routine inspection

ENTRY & OBSERVATION

Ground rules

Location

Access to documents

Daily breaks & scheduling

DAILY ACTIVITIES

Interviews

One time meetings (can repeat!

Records

Document copying

CLOSE-OUT

Scheduled

PI may or may not be physically present (can call

in)

Notes, review

with Company

- WHEW!!!

Slide24

OBSERVATIONS VS. FINDINGS

Daily Debrief with the Inspector and team and potentially with the Sponsor

The “Official” Exit Meeting – A Critical Part of the Inspection (usually “the worst comes first”)

Observations

List of factual

observations

– if opinions or conclusions are present, must be backed up with factual examples

The Form 483

Findings

“Significant” items only

Discussion and Follow-up – ask for help. The response is due within 15 calendar days and requires careful preparation and composition.

Slide25

KEY GUIDANCEDo not offer anything of monetary value (food, beverages, etc.).

Know your rights (and FDA’s).

Listen to the question.

Ensure you understand the questions;

Ask for clarification if necessary.

Review pertinent documentation, if

possible-it’s OK!

Answer the question that is asked.

Answer ONLY the question that is asked. (Don’t volunteer information.)

STOP when the question is fully answered.

Slide26

KEY GUIDANCE, CON’T.Answer questions you know, otherwise:

I don’t know, I’ll / (name) will follow up

Be polite, non-defensive, non-argumentative

Correct any erroneous information provided

Follow company policy regarding FDA affidavits

Always respond to questions with a witness (scribe) present; this avoids statements which require future clarification.

Do not allow FDA free access to files; obtain records for them

Answer truthfully and completely, within the scope of the question. ALWAYS TELL THE TRUTH!

Slide27

GUIDES & DOCUMENTS, con’t.

BIMO (Bioresearch Monitoring) Regulations

PI Questions and Answers

Notification List

Inspection Preparation Questions

Documentation Log

Phone Contact Log

Key Date Information

Your consent and protocol opening processes (develop yourself)

Slide28

IN REVIEW…INSPECTOR CHARACTERISTICSCharacteristics depend on the Inspector and their tenure with the AgencyCan be friendly/casual or confronting/aggressive: “old style vs. new style”

Questioning, questioning, questioning

Multi-checking of key information

Unassuming

Open-ended statements that lead you into answering a question which is not really a question

Varying backgrounds with varying experience in inspections

Slide29

IN REVIEW…KEY STRATEGIESKey Strategies for success

Be audit ready every day; preparation is key.

Notify the “important people” of the FDA visit.

Communicate

Team Support

Have a clear knowledge of the FDA BIMO Regulations

Determine if you’re being asked a question or hearing a declarative statement; one requires an answer, one does not.

Limit your responses to just what is being asked. If you’re uncertain, clarify; if you don’t know indicate you will find the answer.

Know your inspector and their background

Help your PI prepare for their part

Limit the number of people involved

Debrief at the end of every day

Share learning experiences – we learn by helping each other!

Slide30

IN REVIEW…FDA TERMSKey TermsInspectorBIMO

Host, Scribe, Runner

482

483

Jurisdiction

Reasonableness

Findings

Slide31

QUESTIONS?Thank you!

joyce.tull@med.usc.edu