U.S. FDA Survival - Norton Audits to Supervise Data Integrity: Repeated Failure to Comply with the Regulations 30 Failure to Supervise Paul Kornak Bruce Diamond James Holland Richard

Norton Audits, Inc. U.S. FDA Survival

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U.S. FDA SurvivalU.S. FDA Survival

Tamera Norton SmithTamera Norton SmithPresident and Senior President and Senior

ConsultantConsultantNorton Audits, Inc.Norton Audits, Inc.

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ObjectivesObjectives

Increase knowledge of the FDA Inspectional and Audit Process

Increase skills for conducting and interacting with FDA Investigators, Monitors and Auditors

Increase Good Clinical Practice skills to prevent noncompliance in clinical trial conduct

Improve inspection and audit outcomes through successful study conduct

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Training OverviewTraining Overview

Part One – Direct Knowledge of the FDA’s Purpose and Inspectional Process-You and the United States Government

Part Two – Understanding How Regulations Are Interpreted and Applied during Clinical Investigator Inspections, Monitoring Assessments and Audits-Regulatory Application


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You and the United States GovernmentYou and the United States Government

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Summary of Federal LawSummary of Federal Law

Debarment;Disqualification;Restitution;Reimbursement;Supervision;Certification

Agency by agency

Preponderance of evidence (usual)

Admin. hearing

Research misconduct, abuse of human/animal subjects; agency entitlements (grants/IND); Medicare/Medicaid fraud

Code of Federal Regulations

Administrative

Restitution;Penalties;Fine

FREClear and convincing (usual)

Trial by jury or judge

Suits for private or government rights; civil rights; False Claims; Antitrust Act; Medicare/Medicaid

U.S. Civil Code

Civil

Capital punishment;Prison;Probation; Fine

Federal Rules of Evidence (FRE)

Beyond reasonable doubt

Entitled to trial by jury

Title 18:1001 false statements; 1002 false, altered, or forged writing or documents; 1030 unauthorized access to computers; 1341 mail fraud; 1343 wire fraud; Title 31: 641 theft of public money, property, or records; Medicare/Medicaid fraud

U.S Criminal Code

Criminal

SanctionsStandard of Evidence

Std of Proof

ProcessExample ViolationsPublishedType


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Specific Federal Regulations for Specific Federal Regulations for Sponsor and InvestigatorsSponsor and Investigators

U.S.C. Criminal CodeU.S.C. Criminal CodeTitle 18Title 18

Protection of Human SubjectsProtection of Human Subjects45 CFR45 CFR

Investigational Device Exemption (IDE)Investigational Device Exemption (IDE)21 CFR 81221 CFR 812

Investigational New Drugs (IND)Investigational New Drugs (IND)21 CFR 31221 CFR 312

Institutional Review Boards (IRB)Institutional Review Boards (IRB)21 CFR 5621 CFR 56

Financial Disclosure by Clinical InvestigatorsFinancial Disclosure by Clinical Investigators21 CFR 5421 CFR 54

Protection of Human SubjectsProtection of Human Subjects21 CFR 50 21 CFR 50

Official Title NameOfficial Title NameCode of Federal Code of Federal RegulationsRegulations

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BIMO Program ObjectivesBIMO Program Objectives

Protect the rights, safety, and welfare of human research subjects

Assure the quality and integrity of data collected


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7348.811 CHAPTER 48 - Bioresearch Monitoring

– Clinical Investigators:

– Compliance Programs (CPGM) were developed to provide uniform guidance and specific instruction for inspections:

• Clinical investigators (CP 7348.811)• Sponsors (CP 7348.810)• In Vivo Bioequivalence (CP 7348.001) • Institutional review boards (CP 7348.809)• Nonclinical laboratories (CP 7348.808)

Compliance Policy Guidance Compliance Policy Guidance Manual 7348.811Manual 7348.811

New Study, A New RelationshipNew Study, A New Relationship


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Differences in NoncomplianceDifferences in NoncomplianceSeveritySeverity

Minor negligence– sloppy recordkeeping– disorganized data can be corrected

Negligence– only some data are compromised and must be removed

from the database– potential human subject concerns

Scientific misconduct– reckless failure to exercise adequate control; all subject

data is compromised and efficacy data must be removed– potential or proven human subject concerns

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FDA Inspection ClassificationsFDA Inspection Classifications

No Action Indicated (NAI)– No objectionable conditions or practices– No Form FDA 483 issued

Voluntary Action Indicated (VAI)– Objectionable conditions or practices– Form FDA 483 issued (not extensive)– But not at threshold to take or recommend

administrative or regulatory action– Untitled letters

Official Action Indicated (OAI)– Form FDA 483 issued– Serious objectionable conditions found– Regulatory action recommended


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FDAFDA’’s Three Distinct s Three Distinct InspectionsInspections

Clinical Investigator Inspection Program

FDA carries out three distinct types of clinical investigator inspections:

1. Study-Oriented Inspections

2. Investigator-Oriented Inspections

3. Bioequivalence Study Inspections

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Sponsor

InvestigatorInvestigator

SponsorSponsor

UMBRELLA OF PROTECTIONUMBRELLA OF PROTECTION

FDAFDA

IRBIRB


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HQ Assignment

Form FDA 482 Notice of Inspection

Form FDA 483Inspectional Observations

Establishment InspectionalReport (EIR)

ClassificationNAIVAI OAI

District Office

District Office District Office

Regulatory Review and Action

U.S. FDAU.S. FDA’’s Inspectional Processs Inspectional Process

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#5 Report to IRB and approving #5 Report to IRB and approving Regulatory AuthorityRegulatory Authority

#3 Stop shipment of additional #3 Stop shipment of additional and Secure New Drugsand Secure New Drugs

21 CFR 312.56(b) and 312.7021 CFR 312.56(b) and 312.70 Regulatory Regulatory Requirements for Securing ComplianceRequirements for Securing Compliance

#4 Investigator#4 Investigator’’s participations participationis terminatedis terminated

#2#2 ****Promptly secure compliance**Promptly secure compliance**

#1 Monitor investigators#1 Monitor investigators21 CFR 312.50; 312.53; 312.5621 CFR 312.50; 312.53; 312.56

Stopping the ProcessStopping the ProcessPREVENT

Major Parts:21 CFR 312.5021 CFR 312.6021 CFR 312.70


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Preventing Persistent Preventing Persistent NoncomplianceNoncompliance

Action taken at first occurrence of noncompliance

Purpose of addressing noncompliance:

– Occurrences are investigated to determine the impact of the noncompliance and to determine the best actions to take to provide correction and prevention of further occurrences of a similar type

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You can have Data without having You can have Data without having Data IntegrityData Integrity

SymptomsSymptomsMonitoring or IRB SelfMonitoring or IRB Self--

Reports Paper TrailReports Paper TrailDependencyDependency

Underneath the Underneath the SurfaceSurface

SurfaceSurface

DATADATA


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Understanding Symptoms and Root Understanding Symptoms and Root CausesCauses

Systemic Systemic IssuesIssues

OrganizationallyOrganizationally

Causation:Lack of clear expectationsLack of oversightPoor research trainingLack of FDA regulated trialexperienceLack of resourcesLimited systems andprocedures

Intent:Deliberate or Repeated

Underneath the Underneath the SurfaceSurface

SurfaceSurface

IntegrityIntegrity

Where Data Comes FromWhere Data Comes From

Leading Indicators– Qualified Investigator (Input)– Involved – Leader / Supervisor– Quality Research Systems

Lagging Indicators– Clinical data (Output) – From established systems and

qualifications


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Current Sponsor Warning Current Sponsor Warning LettersLetters

11 Dec 2009 21

CitationCitation RegulationsRegulations SanofiSanofi--AventisAventis

(23Oct07)(23Oct07)

Johnson & Johnson & JohnsonJohnson

(10Aug09)(10Aug09)Failure to ensure proper monitoring of the Failure to ensure proper monitoring of the clinical investigationsclinical investigations

21 CFR 312.50; 21 CFR 312.50; 312.56(a)312.56(a)

√√ √√

Failure to ensure that an investigation was conducted in accordance with the general investigational plan and protocols as specified in the IND

21 CFR 312.50 √ √

Failure to secure investigator compliance with Failure to secure investigator compliance with the investigational plan and applicable FDA the investigational plan and applicable FDA regulationsregulations

21 CFR 312.56(b)21 CFR 312.56(b) √√ √√

Failure to ensure that only investigators who were qualified by training and experience were selected as appropriate experts to investigate a drug

21 CFR 312.53(a) √

Failure to select qualified investigators and Failure to select qualified investigators and provide investigators with the information provide investigators with the information needed to conduct the study properlyneeded to conduct the study properly

21 CFR 312.5021 CFR 312.50 √√

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Together We SucceedTogether We Succeed

InvestigatorsStudy Team

In-houseStudy Team

MonitorsIRBFDA

Sponsor/CROManagement


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Questions, Discussion and a Questions, Discussion and a BreakBreak

Regulation Regulation ApplicationApplication


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Suggestions to Avoid Suggestions to Avoid Integrity ProblemsIntegrity Problems

Follow investigational plan

Ensure accurate and complete reports

Maintain accurate and complete records

Standardize your research processes and follow standard operating procedures

Supervise, train and empower your staff

Be proactive in assessing your operation– Aim for being ‘in front of the process’ and ‘not

behind the process’

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Behaviors Behaviors NotNot RecommendedRecommended

Make off-the-record remarks

Speculate

Respond to questions that are improper or outside your area or expertise

Attempt to answer “What if...” or other hypothetical questions

Delay providing records

Get nervous, anxious or defensive


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FDA and Sponsor Inspection or FDA and Sponsor Inspection or Audit SelectionAudit Selection

Audits are selected based on the identification and evaluation of significant risk exposures as defined under Risk Based Inspections/Audits Approaches.

Inspections and Audits are planed under certain conditions and criteria:– Criticality of the study or processes– Risk level of drug and/or indications being investigated– Clinical Data Metrics (done more by the FDA)– Monitoring feedback or other evidence that there may be

compliance issues with a study, particular site/investigator or specific clinical study process

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FDA and Sponsor Inspection or FDA and Sponsor Inspection or Audit SelectionAudit Selection

Inspections and Audits are planed under certain conditions and criteria:– Involvement of a particular site/ investigator (conducts multiple IND,

high to medium enroller; regulatory or sponsor audit status– Number of anticipated sites to be activated/subjects to be enrolled in

study– Need to assure quality prior to marketing approval– Geographic location– Training needs of FDA or Sponsor– Lack of prior inspections or audits


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Failure to SuperviseFailure to SuperviseData Integrity: Repeated Failure Data Integrity: Repeated Failure to Comply with the Regulationsto Comply with the Regulations

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Failure to SuperviseFailure to Supervise

Bruce DiamondPaul Kornak

Richard BorisonJames Holland


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Failure to Report Serious or Failure to Report Serious or LifeLife--Threatening Adverse Threatening Adverse

EventsEvents

Inadequate Human Subject ProtectionInadequate Human Subject Protection

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Inadequate SupervisionInadequate SupervisionData Integrity: Submission of Data Integrity: Submission of

False Information to FDA False Information to FDA or the Sponsoror the Sponsor


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Protocol DeviationsProtocol DeviationsInadequate Human Subject Inadequate Human Subject

ProtectionsProtections

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Deviation from the Deviation from the Investigational Plan, Investigator Investigational Plan, Investigator

Statement and RegulationsStatement and Regulations


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False InformationFalse Information

Scott Reuben

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Data Integrity: Submission of Data Integrity: Submission of False Information to FDA or the False Information to FDA or the

SponsorSponsor


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Inadequate and Inaccurate Inadequate and Inaccurate Case HistoriesCase Histories

Data Integrity: Repeated or Deliberate Failure to Comply with the Regulations

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Ketek Case

http://archives.energycommerce.house.gov/cmte_mtgs/021208.KetekHhttp://archives.energycommerce.house.gov/cmte_mtgs/021208.KetekHearing.ExhibitBinder.shtmlearing.ExhibitBinder.shtml


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39Weight Loss Clinic, AL 06/02/2008 Maria Anne Kirkman Campbell, M.D.

Urologist, Urology Associates of North Texas, TX

05/15/2008 James C. Vestal, M.D.

Pediatrics, Sandy, UT 05/06/2008 David N. Lofgren, M.D.

Family Medicine, Seagrove, NC 04/28/2008 Manjeet Kaur Achreja, M.D.

Pediatrician, Tulsa, OK 03/21/2008 Patrick J. Daley

Dermatologist, University of Florida, Miami, FL

03/05/2008 Mary Sawaya

Pediatric Allergist, Central California Research Institute, CA

03/05/2008 William H. Ziering, M.D.

Cardiology Associates of Central Connecticut, CT

02/25/2008 Stephen D. Rossner, M.D.

Rheumatologist at New York University, NY

02/15/2008 Bertrand Agus, M.D.

Urologist, Scottsdale, AZ01/31/2008 Jamie Kapner, M.D.

Locations2008 Debarred Investigators

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Inadequate AccountabilityInadequate Accountability


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Promotion or CommercializationPromotion or Commercialization

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Common Reasons for Common Reasons for Unsuccessful InspectionsUnsuccessful Inspections

Expounding on answers instead of answering just what is asked

Signing affidavits that are not a legal requirement

Not controlling the inspection environment by being ‘inspection ready’

Not actively engaging the FDA investigator on progress and observations

Not demonstrating ‘voluntary compliance’


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Common Reasons for Common Reasons for Unsuccessful InspectionsUnsuccessful Inspections

Not implementing corrective actions while the FDA is present

Operating a noncompliant organization without knowing the ‘status of the organization’

Dependency on external sources to indicate how well the investigator is doing

‘Trying to prepare’ for an inspection instead of being inspection ready

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Assisting the FDA Assisting the FDA InvestigatorInvestigator

Provide requested records in a timely manner – any delays should be explained to the FDA InvestigatorAssist in assuring that each question is answered by person knowledgeable about the issue

Accompany FDA Investigator during tours and interviews

FDA Investigators are escorted throughout the facility including the restroom.

Assist the FDA Investigator as needed

Arrange for follow-up, if required, to any unanswered questions or unfulfilled document reports


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Do Not Attempt to Befriend Do Not Attempt to Befriend the FDAthe FDA

Employees should not have discussions with the FDA Investigator in casual areas to

discuss clinical operations or personnel. All conversations should occur in front of the

primary escort.

Do not offer the FDA Investigator anything of monetary value including lunch or dinner.

Investigators will accept coffee (not Starbuck’s® though).

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Recording Request for Records Recording Request for Records and Line of Questioningand Line of Questioning

During the inspection, a designated escort will take notes concerning the progress of the inspection

Communicate requests to a document person who will obtain requested records and make photocopies for the FDA and clinical investigator/sponsor

The escort will forward requests from the FDA Investigator, for interviews of study team members

The escort will document any line of questioning pursued by the FDA Investigator and should summarized


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Request Daily Discussions Request Daily Discussions of Observationsof Observations

Clinical investigator and those he or she designates should request an end of day session with the FDA to review any observations.

Details to prevent observations should be provided.

The escort will document any questions whose answer could not be provided, along with appropriate follow-up to obtain the requested information.

This is usually the only opportunity you will have to ensure incorrect and misunderstood items will not appear on the Form FDA 483.

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Discussing Inspection Discussing Inspection ResultsResults

The clinical investigator will meet with the FDA Investigator at the conclusion of the inspection to discuss any questions or observations.

If the clinical investigator receives a Form FDA 483, Inspectional Observations, after the inspection, he/she should consult the sponsor and/or legal on how to respond.

The clinical investigator should state, he/she will voluntarily comply with all observations and research the issues further and provide a written response to the FDA District Office.

Clinical investigator or study team designee should send a copy of the Form FDA 483 to the sponsor’s contact that includes their response.


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When to ask for helpWhen to ask for help……

If statements are made indicating a compliant has been filed regarding reports of misconduct

If the inspection is extended beyond one week

If you receive an extensive Form FDA 483

If you have received a prior Warning Letter and you are receiving another Form FDA 483

If you receive unreasonable treatment or requests

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Expressing Voluntary Expressing Voluntary ComplianceCompliance

If a Form FDA 483 is issued, respond verbally ‘that you will immediately review the issues and respond to the District Office during the final discussion

Your comments will be included in the FDA’s investigator EIR – Establishment Inspection Report

Send a written response to District Office and Center contact within 10 days


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MISSED OPPORTUNITYMISSED OPPORTUNITY

DO NOTDO NOTBLAME THE COORDINATORBLAME THE COORDINATOR


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Contact InformationContact Information

• Tamera Norton Smith• P:803.233.4809• F:803.233.4819• E: [email protected]• W: www.nortonaudits.com

Documents

U.S. FDA Survival - Norton Audits to Supervise Data Integrity: Repeated Failure to Comply with the Regulations 30 Failure to Supervise Paul Kornak Bruce Diamond James Holland Richard