The FDA Inspection ProcessThe FDA Inspection Process

February 17, 2010February 17, 2010

TopicsTopics

Discuss the FDA inspection processDiscuss the FDA inspection process

Describe the type of outcomesDescribe the type of outcomes

Review material that is reviewed during an Review material that is reviewed during an inspectioninspection

Who Performs the Inspections?Who Performs the Inspections?

Office of the Commissioner

Office of Regulatory Affairs

Bioresearch Monitoring

Program (BIMO)

CDER

CDRH

CBER

6 Region Offices

20 District Offices

130 Resident Posts

FDA Inspections in Clinical ResearchFDA Inspections in Clinical Research

BIMO INSPECTION PROGRAM (CDER)BIMO INSPECTION PROGRAM (CDER)

Good Laboratory Practice (GLP)Good Laboratory Practice (GLP)

* In vivo Bioequivalence* In vivo Bioequivalence

Good Clinical Practice (GCP)Good Clinical Practice (GCP)

* Institutional Review Boards* Institutional Review Boards

* Clinical Investigators* Clinical Investigators

* Sponsor-Monitors, CROs* Sponsor-Monitors, CROs

Essential PiecesEssential Pieces

Project CohesivenessProject Cohesiveness

Complete ApplicationComplete Application

BIMO InspectionsBIMO Inspections

Inspections can be performed during any Inspections can be performed during any phase of the development processphase of the development process

““Directed” inspections are typically Directed” inspections are typically assigned during the IND phaseassigned during the IND phase

Inspections conducted during the NDA Inspections conducted during the NDA phase can be “Routine”, “For Cause”, or phase can be “Routine”, “For Cause”, or “Directed” “Directed”

Regulatory Authority to Conduct Regulatory Authority to Conduct Inspections/AuditsInspections/Audits

21 CFR 312.68 21 CFR 312.68

““An investigator shall upon request from any An investigator shall upon request from any properly authorized officer or employee of properly authorized officer or employee of FDA, at reasonable times, permit such FDA, at reasonable times, permit such officer or employee to have access to, and officer or employee to have access to, and copy and verify any records or reports made copy and verify any records or reports made by the investigator pursuant to 312.62.”by the investigator pursuant to 312.62.”

General Goals of Inspection: Clinical Investigator General Goals of Inspection: Clinical Investigator ProgramProgram

Adherence to applicable regulations with Adherence to applicable regulations with respect to Good Clinical Practicerespect to Good Clinical Practice

Validity of studies in support of marketing Validity of studies in support of marketing applicationsapplications

Ensuring that rights, safety and welfare of Ensuring that rights, safety and welfare of study subjects have been protectedstudy subjects have been protected

Inspection PreparationInspection Preparation

Preparing Ahead For anPreparing Ahead For anFDA InspectionFDA Inspection

General TipsGeneral Tips The time to start The time to start preparingpreparing for an FDA for an FDA

inspection is at the inspection is at the beginningbeginning of a study! of a study! Keep all records and documents current and Keep all records and documents current and

appropriately filed (easily accessible)appropriately filed (easily accessible) Keep all communications from different Keep all communications from different

studies separate from each otherstudies separate from each other

Preparing Ahead For an FDA InspectionPreparing Ahead For an FDA Inspection

General Tips (continued)General Tips (continued)

Document and file all pertinent communication with Document and file all pertinent communication with key sponsor personnel and with other external key sponsor personnel and with other external personnel (vendors, project partners, etc.)personnel (vendors, project partners, etc.)

Conduct periodic QC reviews to ensure data integrity Conduct periodic QC reviews to ensure data integrity

Identify/know team/personnel who will Identify/know team/personnel who will interact/respond to FDA during an inspectioninteract/respond to FDA during an inspection

Ensure all staff are educated on proper conduct Ensure all staff are educated on proper conduct during an FDA inspectionduring an FDA inspection

Know GCPs, regulations/guidelines, SOPs and study Know GCPs, regulations/guidelines, SOPs and study specific information (or at least know how to access specific information (or at least know how to access resources to get the information)resources to get the information)

Preparing Ahead for an FDA InspectionPreparing Ahead for an FDA Inspection

General Tips (continued)General Tips (continued)

-Use an “adequate” NTF system to explain -Use an “adequate” NTF system to explain situations or provide information that situations or provide information that doesn’t fit nicely into other categories.doesn’t fit nicely into other categories.

The NTF should have the following elementsThe NTF should have the following elements::

1)1) Identify and correct the problemIdentify and correct the problem

2)2) Record changes in procedure to prevent Record changes in procedure to prevent future occurrencesfuture occurrences

3)3) Follow through – document that a new Follow through – document that a new process/procedure is in placeprocess/procedure is in place

FDA Inspection OutcomesFDA Inspection Outcomes No inspectional findingsNo inspectional findings

FDA 483 ObservationsFDA 483 Observations Documents non-compliance with regulations Documents non-compliance with regulations

only (can not cite for non-compliance with only (can not cite for non-compliance with guidelines)guidelines)

May be left at the site at the end of the May be left at the site at the end of the inspection or sent laterinspection or sent later

• EIR (Establishment Inspection Report) EIR (Establishment Inspection Report) • Will list findings: non-compliance with both Will list findings: non-compliance with both

regulations and guidelinesregulations and guidelines• Site/Organization may or may not receive a Site/Organization may or may not receive a

copycopy

FDA Compliance Program Guidance FDA Compliance Program Guidance 7348.1117348.111Bioresearch Monitoring Clinical Bioresearch Monitoring Clinical Investigators Investigators

Determining facts surrounding studyDetermining facts surrounding study Who performed specific tasksWho performed specific tasks Degree of delegation of authorityDegree of delegation of authority Where study procedures were performedWhere study procedures were performed How and where data was recordedHow and where data was recorded How test article accountability was maintainedHow test article accountability was maintained How monitor communicated with investigatorHow monitor communicated with investigator How monitor evaluated the study’s progressHow monitor evaluated the study’s progress

What will FDA Inspect?What will FDA Inspect?

What will FDA Inspect?What will FDA Inspect? Study dataStudy data

Subjects exist and have diseaseSubjects exist and have disease Subjects meet Subjects meet

inclusion/exclusion criteriainclusion/exclusion criteria Protocol followedProtocol followed AEs reported and all reports AEs reported and all reports

adequateadequate Consent obtainedConsent obtained IRB approval obtainedIRB approval obtained CRFs accurateCRFs accurate Dropout subject documentationDropout subject documentation Retention of study blindRetention of study blind

Authority and AdministrationAuthority and Administration How investigator was notified of study specificsHow investigator was notified of study specifics Was delegation appropriate?Was delegation appropriate? What laboratory was used. If local, was laboratory What laboratory was used. If local, was laboratory

facility adequatefacility adequate Determine if and why investigator discontinued Determine if and why investigator discontinued

study before completionstudy before completion

Protocol ComplianceProtocol Compliance

Test Article AccountabilityTest Article Accountability

Electronic Records and SignaturesElectronic Records and Signatures

Consent of Human SubjectsConsent of Human Subjects

IRB InteractionsIRB Interactions

What will FDA Inspect?What will FDA Inspect?The InvestigatorThe Investigator

Subject RecordsSubject Records

AE Documentation and Reporting AE Documentation and Reporting Records RetentionRecords Retention

SponsorSponsor Was copy of ICF provided to sponsor?Was copy of ICF provided to sponsor? Were periodic reports submitted?Were periodic reports submitted? Determine if and how AEs were reported to sponsorDetermine if and how AEs were reported to sponsor Timeliness of CRF submission to sponsorTimeliness of CRF submission to sponsor Were all intercurrent illnesses/concomitant therapies reported to Were all intercurrent illnesses/concomitant therapies reported to

sponsorsponsor How was study monitored; method and frequencyHow was study monitored; method and frequency Review all 1572’s Review all 1572’s

What will FDA Inspect?What will FDA Inspect?

Fair game for the inspection?Fair game for the inspection? ECGsECGs

Videos (i.e. 2Videos (i.e. 2nd.nd. Look laparoscopic procedures) Look laparoscopic procedures)

DiariesDiaries

Electronic recordsElectronic records

X-raysX-rays

Flyers/Radio AdsFlyers/Radio Ads

Post-it-notesPost-it-notes

Audit ReportsAudit Reports

Key Areas to controlKey Areas to control

PI InvolvementPI Involvement

Adequate Staffing/timeAdequate Staffing/time

Well documented screeningWell documented screening

Processes to assure protocol complianceProcesses to assure protocol compliance

Documentation, Documentation, Documentation, Documentation, DocumentationDocumentation

AEs taken seriouslyAEs taken seriously

Title 21 CFR Part 11Title 21 CFR Part 11 ValidationValidation

Record generation and copyingRecord generation and copying

Record protectionRecord protection

AccessAccess

Audit TrailsAudit Trails

Operational system checksOperational system checks

Authority checksAuthority checks

Device/Terminal ChecksDevice/Terminal Checks

Training/User accountabilityTraining/User accountability

System document controlSystem document control

Controls for open systemsControls for open systems

Electronic SignaturesElectronic Signatures

GCP TipsGCP Tips

VERY POPULAR ACRONYMVERY POPULAR ACRONYM

((ALCOAALCOA))

AA – Attributable – Attributable

LL – Legible – Legible

CC – Contemporaneous – Contemporaneous

OO – Organized – Organized

AA – Accurate – Accurate

GCP Tips cont.GCP Tips cont.

(RARE)(RARE)

RR – reproducible – reproducible

AA – accurate – accurate

RR – reliable – reliable

EE – (able to be) evaluated – (able to be) evaluated

Compliance ClassificationsCompliance Classifications

NAI – NAI – No Action IndicatedNo Action Indicated

Inspected firm is in complianceInspected firm is in compliance

VAI - VAI - Voluntary Action IndicatedVoluntary Action Indicated

Deviation(s) from the regulationsDeviation(s) from the regulations

Voluntary correction is requestedVoluntary correction is requested

OAI - OAI - Official Action IndicatedOfficial Action IndicatedBecause of serious non-compliance Because of serious non-compliance

requiring requiring regulatory or regulatory or administrative action by FDAadministrative action by FDA

Violative ActionsViolative Actions Revision to the protocol without obtaining the sponsor’s written Revision to the protocol without obtaining the sponsor’s written

concurrenceconcurrence

Failure to submit revised protocol to IRB for approvalFailure to submit revised protocol to IRB for approval

Failure to obtain written informed consent and provide oral explanation Failure to obtain written informed consent and provide oral explanation of the studyof the study

Failure to update consent forms to reflect changes in the protocolFailure to update consent forms to reflect changes in the protocol

Over-delegation to non-physicians (e.g., diagnosis that Over-delegation to non-physicians (e.g., diagnosis that qualifies/determines eligibility for entry into the study)qualifies/determines eligibility for entry into the study)

Improper corrections to essential documents - Erasures, white-out or Improper corrections to essential documents - Erasures, white-out or obliteration of original data entered on either CRFs or medical chartsobliteration of original data entered on either CRFs or medical charts

Changes made to study data without checking the source documents or Changes made to study data without checking the source documents or without justification for change without justification for change

Back dating consent forms and signaturesBack dating consent forms and signatures

Failure to obtain IRB approval of consent form revisionsFailure to obtain IRB approval of consent form revisions

Changes to study data without the investigator’s concurrence, especially Changes to study data without the investigator’s concurrence, especially after the investigator has “signed-off” the completed CRFafter the investigator has “signed-off” the completed CRF

Violative ActionsViolative Actions

Creation of fake records or patients by using Creation of fake records or patients by using demographic data or using blood, urine and tissue demographic data or using blood, urine and tissue samples from other subjectssamples from other subjects

Patients’ diaries altered to reflect a positive outcomePatients’ diaries altered to reflect a positive outcome

Using site personnel as subjects to which they did Using site personnel as subjects to which they did not meet inclusion criteria for study article under not meet inclusion criteria for study article under investigationinvestigation

Destruction of study recordsDestruction of study records

Consequences of non-compliance (not all Consequences of non-compliance (not all inclusive)inclusive)

Warning LettersWarning Letters

NIDPOE LettersNIDPOE Letters

DisqualificationDisqualification

Untitled LettersUntitled Letters

Clinical Investigator DeficienciesClinical Investigator DeficienciesCDER Inspections (all) – FY 2006CDER Inspections (all) – FY 2006

35% of the deviations related to protocol 35% of the deviations related to protocol deviationsdeviations

23% related to records maintenance23% related to records maintenance

9% related to drug accountability 9% related to drug accountability documentationdocumentation

6% related to consent process6% related to consent process

5% were related to reporting of AEs5% were related to reporting of AEs

Adequate FDA 483 ResponseAdequate FDA 483 Response

Submit a prompt written responseSubmit a prompt written response

-assess the root cause of the problem-assess the root cause of the problem

-Explain actions to correct the problem-Explain actions to correct the problem

-Evaluate the extent of the problem-Evaluate the extent of the problem

-Implement preventative actions to avoid recurrence-Implement preventative actions to avoid recurrence

-include supporting documentation-include supporting documentation

-provide REALISTIC timelines for implementation and correction-provide REALISTIC timelines for implementation and correction

Questionable ResearchQuestionable Research

Scientific MisconductScientific MisconductPercentage in survey of US based scientists who Percentage in survey of US based scientists who engaged in questionable research practicesengaged in questionable research practices

15.5% - Changed a study's results to satisfy a funding source15.5% - Changed a study's results to satisfy a funding source

15.3% - Dropped data from analysis based upon a "gut feeling"15.3% - Dropped data from analysis based upon a "gut feeling"

12.5% - Overlooked other's use of flawed/questionable data12.5% - Overlooked other's use of flawed/questionable data

10.8% - Withheld research results10.8% - Withheld research results

7.6% - Circumvented minor rules protecting humans subjects7.6% - Circumvented minor rules protecting humans subjects

Source: Nature June 2005Source: Nature June 2005

n = 3247n = 3247

Warning LetterWarning Letter

Failure to personally conduct or supervise the clinical Failure to personally conduct or supervise the clinical investigation [21 CFR 312.60].investigation [21 CFR 312.60].

““Specifically, during the FDA inspection you informed the FDA Specifically, during the FDA inspection you informed the FDA investigators that you did not personally meet with at least two investigators that you did not personally meet with at least two sub-investigators … who conducted the study, nor reviewed sub-investigators … who conducted the study, nor reviewed their research or clinic records regarding the subjects they their research or clinic records regarding the subjects they enrolled. enrolled.

You also informed FDA investigators that you were not aware You also informed FDA investigators that you were not aware that all the screening x-rays obtained by the two sub-that all the screening x-rays obtained by the two sub-investigators were re-interpreted by a second radiologist at the investigators were re-interpreted by a second radiologist at the end of the study and that you were also not aware that only the end of the study and that you were also not aware that only the results from the second radiologist were reported to the results from the second radiologist were reported to the sponsor.”sponsor.”

Warning Letter CitationsWarning Letter Citations

Failure to secure investigator compliance with the Failure to secure investigator compliance with the investigational plan and applicable FDA regulations investigational plan and applicable FDA regulations [21 CFR 312.56(b)][21 CFR 312.56(b)]

-”…despite several clinical monitoring visits from …-”…despite several clinical monitoring visits from …monitors, …and [your] own audits documenting monitors, …and [your] own audits documenting serious protocol violations and regulatory serious protocol violations and regulatory noncompliance by multiple clinical investigators, noncompliance by multiple clinical investigators, these violations persisted.these violations persisted.

-”there were overwrites on several subjects’ signature -”there were overwrites on several subjects’ signature dates; thus, the actual date the subject signed the dates; thus, the actual date the subject signed the consent document was not clear”consent document was not clear”

Warning Letter CitationsWarning Letter Citations

Failure to secure investigator compliance with the Failure to secure investigator compliance with the investigational plan and applicable FDA investigational plan and applicable FDA regulations [21 CFR 312.56(b)]regulations [21 CFR 312.56(b)]

““We note that generation of numerous memos to We note that generation of numerous memos to file after all subjects have completed the study file after all subjects have completed the study does not adequately secure compliance of an does not adequately secure compliance of an investigator.”investigator.”

“… “… method for securing compliance (i.e., the method for securing compliance (i.e., the generation of more than 125 memos to file for generation of more than 125 memos to file for protocol and informed consent deviations noted protocol and informed consent deviations noted at the site) was not adequate.”at the site) was not adequate.”

Contact InformationContact Information

Al ChesterAl Chester

Quality Assurance & Regulatory ComplianceQuality Assurance & Regulatory Compliance

919-668-8690919-668-8690

Alfred.chester@duke.eduAlfred.chester@duke.edu