u.s. fda survival - norton audits to supervise data integrity: repeated failure to comply with the...
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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