medical device regulatory update -...

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Medical Device Medical Device Regulatory UpdateRegulatory Update

Matthew Matthew TaroskyTaroskyDivision of Bioresearch MonitoringDivision of Bioresearch MonitoringOffice of ComplianceOffice of ComplianceCenter for Devices and Radiological HealthCenter for Devices and Radiological HealthUS Food and Drug AdministrationUS Food and Drug Administration

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Presentation TopicsPresentation Topics

IntroductionIntroductionPrioritiesPrioritiesInitiativesInitiativesGuidance DocumentsGuidance DocumentsNonNon--clinical (GLP) Program Updateclinical (GLP) Program UpdateInspection MetricsInspection MetricsBIMO Inspection PreparationBIMO Inspection Preparation

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CDRHCDRH’’s mission iss mission is……

Getting safe and Getting safe and effective devices effective devices to market as to market as quickly as quickly as possiblepossible……

…… while ensuring while ensuring that devices and that devices and

radiological products radiological products currently on the currently on the

market remain safe market remain safe and effective.and effective.

Helping the public get scienceHelping the public get science--based accurate based accurate information about medical devices and radiological information about medical devices and radiological

products needed to improve healthproducts needed to improve health

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CDRHCDRH’’ss vision is...vision is...

Total Product Life CycleTotal Product Life Cycle

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Who We AreWho We Are……

CDRH is a team of over 1,000 dedicated, highly CDRH is a team of over 1,000 dedicated, highly skilled, and internationally respected public skilled, and internationally respected public health employeeshealth employees

Our employees are drawn from a wealth of Our employees are drawn from a wealth of science and public health professionsscience and public health professions

Biologists, chemists, physicists, engineers, microbiologists, Biologists, chemists, physicists, engineers, microbiologists, statisticians, epidemiologists, physicians, nurses, statisticians, epidemiologists, physicians, nurses, pharmacologists, veterinarians, toxicologists, and specialists ipharmacologists, veterinarians, toxicologists, and specialists in n public health education and communicationpublic health education and communication

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CDRHCDRH’’s Organizational Charts Organizational Chart

CDRH CDRH OmbudsmanOmbudsmanLes WeinsteinLes Weinstein

Office of the Center DirectorOffice of the Center DirectorDaniel G. Schultz, M.D., DirectorDaniel G. Schultz, M.D., Director

Linda Kahan, Deputy DirectorLinda Kahan, Deputy DirectorLillian Gill, D.P.A., Senior Associate Lillian Gill, D.P.A., Senior Associate

DirectorDirectorPostmarket Transformation Postmarket Transformation Management GroupManagement GroupDon St. PierreDon St. PierreDiane Mitchell, M.D.Diane Mitchell, M.D.Susan MeadowsSusan Meadows

Office of In Vitro Office of In Vitro Diagnostic DeviceDiagnostic DeviceEvaluation Evaluation & Safety & Safety Steven I. Gutman, M.D.Steven I. Gutman, M.D.

Office ofOffice ofComplianceComplianceTimothy A. UlatowskiTimothy A. Ulatowski

Office of DeviceOffice of DeviceEvaluationEvaluationDonnaDonna--Bea Tillman, Ph.D.Bea Tillman, Ph.D.

Office of Office of Science & Science & Engineering Engineering LaboratoriesLaboratoriesLarry Kessler, Sc.D.Larry Kessler, Sc.D.

Office of Office of Communication, Communication, Education, &Education, &Radiation Radiation ProgramsProgramsLynne L. RiceLynne L. Rice

Office of Office of Surveillance & Surveillance & BiometricsBiometricsSusan N. Gardner, Ph.D.Susan N. Gardner, Ph.D.

Office of Office of ManagementManagementOperationsOperationsRuth E. McKeeRuth E. McKee

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CDRHCDRH’’s Compliance Offices Compliance Office

Office of ComplianceOffice of ComplianceTim Tim UlatowskiUlatowski, Director, Director

Larry Spears, Deputy Director RegulatoryLarry Spears, Deputy Director RegulatoryKimberKimber Richter, M.D., Deputy Director MedicalRichter, M.D., Deputy Director Medical

Division of Enforcement ADivision of Enforcement ABetty Collins, DirectorBetty Collins, Director

Division of Enforcement BDivision of Enforcement BGladys Rodriguez, DirectorGladys Rodriguez, Director

Division of Risk Management Division of Risk Management OperationsOperationsKaren Moss, DirectorKaren Moss, Director

Division of Bioresearch Division of Bioresearch MonitoringMonitoringMichael Michael MarcarelliMarcarelli, Director, Director

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What does the domestic medical What does the domestic medical device industry look like? device industry look like?

66%

16%

7%3%

5% 3%< 10

10 .. 29

30 .. 59

60 .. 99

100 .. 499

500 or more

1%

90%

1%6%

1%

1%

Total Manufacturers*

N = 14,937Total 2004 Sales

$320 Billion

Smallest Smallest FirmsFirms

Largest Largest FirmsFirms

Employees

Per Firm*

* Dun & Bradstreet 2004 Medical Device Firm Data* Dun & Bradstreet 2004 Medical Device Firm Data

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PrioritiesPriorities

Medical Device User Fee & Modernization ActMedical Device User Fee & Modernization ActPostmarketPostmarket TransformationTransformationInformation TechnologyInformation TechnologyStaff DevelopmentStaff DevelopmentDevice Critical PathDevice Critical PathWhite Oak CampusWhite Oak Campus

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Medical Device User Fee and Medical Device User Fee and Modernization Act of 2002Modernization Act of 2002

MDUFMA IMDUFMA ISunsets 9/30/07Sunsets 9/30/07Annual public stakeholder meetingsAnnual public stakeholder meetings

MDUFMA IIMDUFMA IINegotiations with industry over last 18 monthsNegotiations with industry over last 18 months

Stronger performance goalsStronger performance goals

More predictable user fee structureMore predictable user fee structureRegistration, annual reportsRegistration, annual reports

Sent to Congress for review/approvalSent to Congress for review/approval

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Postmarket TransformationPostmarket TransformationConnecting the dotsConnecting the dots……

Public Health Partners

Information Education

Adverse EventReporting

Additional Signals

PostmarketProblem

Assessment

Laboratory Research &

Analysis

Problem Assessment

Groups

Post Approval Studies

External DataAnalysis

Internal DataAnalysis

PostmarketTools Public Health

Response

Enforcement

Information Dissemination

Premarket Approval Process

PostmarketProblem

Identification Tools

Inspections

Postmarket PublicHealth Response

Postmarket ProblemIdentification

Postmarket ProblemAssessment

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Postmarket TransformationPostmarket TransformationPrioritiesPriorities

1.1. Create a matrix organization to optimize medical device regulatiCreate a matrix organization to optimize medical device regulation on across the Total Product Lifecycleacross the Total Product Lifecycle

2.2. Develop metrics and methods for tracking postmarket issues Develop metrics and methods for tracking postmarket issues

3.3. Pursue the development of unique identification (UDI) Pursue the development of unique identification (UDI)

4.4. Propose mandatory electronic MDR reporting Propose mandatory electronic MDR reporting

5.5. Revise and update the MAUDE system, and expand the premarket Revise and update the MAUDE system, and expand the premarket datadata--warehousingwarehousing

6.6. Increase the quality and quantity of Center/ORA/OCC interactionsIncrease the quality and quantity of Center/ORA/OCC interactions

7.7. Develop and implement a riskDevelop and implement a risk--communication strategy communication strategy

8.8. Design a pilot project to test the usefulness of quantitative deDesign a pilot project to test the usefulness of quantitative decisioncision--making methods making methods

9.9. Enhance utility of MedSun programs Enhance utility of MedSun programs

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Matrix OrganizationMatrix Organization

Establish crossEstablish cross--cutting productcutting product--related related groups over the current functionallygroups over the current functionally--based organization to:based organization to:

Foster information sharing and more effective PH Foster information sharing and more effective PH promotion and protectionpromotion and protectionCollaboration as a part of dayCollaboration as a part of day--toto--day operations, day operations, not just in crisis situationsnot just in crisis situations

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Information TechnologyInformation Technology

Turbo 510(k) ProgramTurbo 510(k) Programhttp://www.fda.gov/cdrh/oivd/turbo510kcesub1.htmlhttp://www.fda.gov/cdrh/oivd/turbo510kcesub1.html

eCopyeCopy Initiative Initiative http://http://www.fda.gov/cdrh/elecsub.htmlwww.fda.gov/cdrh/elecsub.htmlMay be submitted for any premarket submissionMay be submitted for any premarket submissionImmediately available for CDRH staffImmediately available for CDRH staff

eRevieweReviewStreamline and facilitate review processStreamline and facilitate review process

Electronic Medical Device ReportingElectronic Medical Device ReportingElectronic adverse device effects as HL7 standardElectronic adverse device effects as HL7 standard

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Staff DevelopmentStaff Development

New HiresNew HiresShared HiresShared Hires

ODEODE--OCOCODEODE--OSBOSB

Medical Device Fellowship Program (MDFP)Medical Device Fellowship Program (MDFP)

Special Government Employees (Special Government Employees (SGEsSGEs) as members and ) as members and consultants to our 18 Advisory Panelsconsultants to our 18 Advisory Panels

Over 700 Over 700 SGEsSGEs

ContractorsContractors

Collaborations with the clinical community and professional Collaborations with the clinical community and professional groupsgroups

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Device Critical PathDevice Critical Path

A serious commitment to make product A serious commitment to make product development more predictable and less costlydevelopment more predictable and less costly

Work together with industry, academia, and Work together with industry, academia, and patient care advocates to modernize, develop and patient care advocates to modernize, develop and disseminate solutions (tools) to address scientific disseminate solutions (tools) to address scientific hurdles in product developmenthurdles in product development

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BasicResearch

PrototypeDesign or Discovery

Clinical Development

FDA Filing/Approval &

LaunchPreparation

PreclinicalDevelopment

Critical PathCritical Path

ApprovalApprovalMarketMarket

ApplicationApplication

The journey from medical product candidate to full-scale production and marketing

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DrugsDrugs DevicesDevices

Pure moleculesPure molecules Complex componentsComplex components

ToxicologyToxicology BiocompatibilityBiocompatibility

Short halfShort half--lifelife Durable EquipmentDurable Equipment

Long market lifeLong market life Rapid product cyclesRapid product cycles

Drug interactionsDrug interactions Device MalfunctionDevice Malfunction

Wrong Drug / DoseWrong Drug / Dose User ErrorUser Error

Clinical studiesClinical studies Bench and Clinical studiesBench and Clinical studies

Good Manufacturing Practices Good Manufacturing Practices (cGMP)(cGMP)

Quality Systems Quality Systems (ISO 9000)(ISO 9000)

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Device Critical Path Projects Device Critical Path Projects

Working with a West Coast University on Working with a West Coast University on combination productscombination products

Analyze the development of biomarkers and diagnostics and Analyze the development of biomarkers and diagnostics and their application to their application to pharmacogenomicspharmacogenomicsIdentify barriers to drug/diagnostic device coIdentify barriers to drug/diagnostic device co--developmentdevelopment

Working with the Juvenile Diabetes Research Working with the Juvenile Diabetes Research Foundation Foundation

Accelerate development of a closedAccelerate development of a closed--loop system using loop system using continuous glucose sensors and insulin pumps linked by a continuous glucose sensors and insulin pumps linked by a controlcontrol--algorithmalgorithm

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Device Critical Path ProjectsDevice Critical Path Projects

Working with academia on peripheral vascular Working with academia on peripheral vascular stent developmentstent development

Computer models of human physiology to test and predict failure Computer models of human physiology to test and predict failure (before animal and human studies)(before animal and human studies)

Validating surrogate markers especially in the Validating surrogate markers especially in the area of cardiovascular devicesarea of cardiovascular devices

““Late lossLate loss”” via imagingvia imaging

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White Oak CampusWhite Oak Campus

Office of Science & Engineering Laboratories move completeOffice of Science & Engineering Laboratories move completeRemaining CDRH staff move anticipated in March 2009Remaining CDRH staff move anticipated in March 2009

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InitiativesInitiatives

International HarmonizationInternational HarmonizationOffice of Regulatory Affairs (ORA) TransformationOffice of Regulatory Affairs (ORA) TransformationRiskRisk--Based Work PlanBased Work PlanBioresearch Monitoring (BIMO) ModernizationBioresearch Monitoring (BIMO) ModernizationProbability Sampling Probability Sampling

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International HarmonizationInternational Harmonization

Educating Foreign Government Officials on the Educating Foreign Government Officials on the U.S. Regulatory ProcessU.S. Regulatory ProcessSupporting Global Harmonization, Mutual Supporting Global Harmonization, Mutual Recognition Agreements (Recognition Agreements (MRAsMRAs) and other ) and other International AgreementsInternational AgreementsManaging US/EC Mutual Recognition Agreement Managing US/EC Mutual Recognition Agreement www.fda.gov/cdrh/mrawww.fda.gov/cdrh/mra1111thth Conference of Global Harmonization Task Conference of Global Harmonization Task Force, October 3Force, October 3--4, 2007, Washington, DC4, 2007, Washington, DC

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ORA ReorganizationORA Reorganization

Strategic Plan FrameworkStrategic Plan FrameworkLeveragingLeveragingWorkforce CapabilityWorkforce CapabilityQuality Management SystemsQuality Management SystemsRisk ManagementRisk ManagementInformation TechnologyInformation TechnologyLaboratoriesLaboratoriesImportsImports

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ORA ReorganizationORA Reorganization

Proposed Organization ChartProposed Organization ChartConsolidate 13 labs and align under Science Consolidate 13 labs and align under Science DirectorateDirectorateConsolidate 19 district offices under Inspection Consolidate 19 district offices under Inspection Compliance DirectorateCompliance DirectorateEliminate Regional OfficesEliminate Regional OfficesHire 100 new consumer safety officersHire 100 new consumer safety officers

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RiskRisk--Based BIMO InspectionsBased BIMO Inspections

Allegations of Research MisconductAllegations of Research MisconductFor Cause AssignmentsFor Cause Assignments

PMA and Panel Track SupplementsPMA and Panel Track SupplementsDirected InspectionsDirected Inspections

IDE Early Intervention InspectionsIDE Early Intervention InspectionsNovel technologiesNovel technologiesVulnerable populationsVulnerable populations

NonNon--compliant historycompliant historyPreviously violative (OAI) inspectionPreviously violative (OAI) inspection

Routine surveillanceRoutine surveillanceInstitutional Review BoardsInstitutional Review Boards

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BIMO ModernizationBIMO Modernization

HSP/BIMO CouncilHSP/BIMO CouncilMandate to systematically and comprehensively Mandate to systematically and comprehensively reexamine FDAreexamine FDA’’s approach to human subject s approach to human subject protection and bioresearch monitoringprotection and bioresearch monitoring5 Year Charter 5 Year Charter Oversight and central coordination of all Oversight and central coordination of all modernization activities related to BIMO and HSPmodernization activities related to BIMO and HSP

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Clinical Research LandscapeClinical Research Landscape

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Regulatory Research LandscapeRegulatory Research Landscape

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Evolution of Clinical Trial Evolution of Clinical Trial PracticesPractices

New trial methods and designsNew trial methods and designsNew methods of data collection and processingNew methods of data collection and processing

Electronic data captureElectronic data capture

GlobalizationGlobalizationNew arrangements New arrangements

Sponsors and various contractors, among investigators, among Sponsors and various contractors, among investigators, among institutions, among IRBs, and rise of freeinstitutions, among IRBs, and rise of free--standing forstanding for--profit profit study centersstudy centers

Greater number of studies in children and other Greater number of studies in children and other vulnerable populationsvulnerable populationsCombination productsCombination products

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FDAFDA’’s Oversight Must s Oversight Must Evolve TooEvolve Too……

How should FDA regulate this new clinical trial How should FDA regulate this new clinical trial paradigm?paradigm?

Responsibilities of investigatorsResponsibilities of investigatorsData qualityData quality

How should FDA facilitate reasonable & effective How should FDA facilitate reasonable & effective IRB oversight of clinical trials?IRB oversight of clinical trials?

IRB oversight of human subject protection IRB oversight of human subject protection FDA oversight of IRB functionFDA oversight of IRB function

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FDAFDA’’s Oversight s Oversight Must Evolve TooMust Evolve Too……

Common standards and regulatory requirements Common standards and regulatory requirements for electronic data handlingfor electronic data handlingAccommodate globalization of clinical trialsAccommodate globalization of clinical trialsComprehensive approach to protection of Comprehensive approach to protection of vulnerable populationsvulnerable populations

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Internal ChallengesInternal Challenges

BIMO highly decentralized function BIMO highly decentralized function Units of varying size in review centersUnits of varying size in review centersField force; only a few experts in any given districtField force; only a few experts in any given districtVery small centralized group in OCVery small centralized group in OC

Relative lack of guidance and standardsRelative lack of guidance and standardsNonNon--automated environmentautomated environmentMultiplicity of stakeholdersMultiplicity of stakeholders

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Areas of InterestAreas of Interest……

Risk ManagementRisk ManagementQuality SystemsQuality SystemsTransparencyTransparencyCritical PathCritical Path

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Current HSP/BIMO IssuesCurrent HSP/BIMO Issues

Subject SafetySubject SafetyCI training/supervisionCI training/supervisionOversight of subOversight of sub-- and coand co--investigatorsinvestigators

A Strong IRB SystemA Strong IRB SystemRegistrationRegistrationModernize AE reportingModernize AE reportingGuidanceGuidance

Protection of Vulnerable PopulationsProtection of Vulnerable PopulationsPediatricPediatricDecisionDecision--impairedimpairedEmergency ResearchEmergency Research

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Data Quality and IntegrityData Quality and IntegrityCommon definition(s) of Common definition(s) of ““highhigh--qualityquality”” datadataMethods to assessMethods to assessQuality systems (buildQuality systems (build--in vs. inspectin vs. inspect--in)in)Evaluating the role and performance of monitoring, Evaluating the role and performance of monitoring, auditing, and inspectingauditing, and inspectingPursuing falsification and highPursuing falsification and high--risk challengesrisk challenges

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Advancing TechnologyAdvancing TechnologyCCT (computerized systems used in clinical trials)CCT (computerized systems used in clinical trials)ee--PRO (Patient Reported Outcomes)PRO (Patient Reported Outcomes)EHR (Electronic Health Records)EHR (Electronic Health Records)

Research EnterpriseResearch EnterpriseRegulatory expectations (e.g., site management organizations, Regulatory expectations (e.g., site management organizations, AE Adjudication)AE Adjudication)International Harmonization and StandardizationInternational Harmonization and Standardization

GCP Information from/to FDAGCP Information from/to FDAFor Consumers and for ProfessionalsFor Consumers and for ProfessionalsReporting of and responsiveness to Reporting of and responsiveness to ““complaintscomplaints””

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Initial AccomplishmentsInitial Accomplishments

Part 15 Hearing: AE Reporting to Part 15 Hearing: AE Reporting to IRBsIRBs (3/05)(3/05)http://www.fda.gov/OHRMS/DOCKETS/98fr/05http://www.fda.gov/OHRMS/DOCKETS/98fr/05--2300.pdf2300.pdf

Final Guidance: Exploratory IND Studies (1/06)Final Guidance: Exploratory IND Studies (1/06)http://www.fda.gov/cder/guidance/7086fnl.pdfhttp://www.fda.gov/cder/guidance/7086fnl.pdf

Direct Final Rule and Draft Guidance Direct Final Rule and Draft Guidance –– INDs: INDs: Approaches to Complying with CGMP (1/06) Approaches to Complying with CGMP (1/06)

http://www.fda.gov/cder/guidance/6164dft.pdfhttp://www.fda.gov/cder/guidance/6164dft.pdf

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Updated: Five Information Sheet Guidances for Updated: Five Information Sheet Guidances for Sponsors, Clinical Investigators, and IRBs 2/06 Sponsors, Clinical Investigators, and IRBs 2/06

http://http://www.fda.gov/oc/ohrt/irbs/default.htmwww.fda.gov/oc/ohrt/irbs/default.htm

Final Guidance: Using a Centralized IRB Review Final Guidance: Using a Centralized IRB Review Process in Multicenter Trials (3/06) Process in Multicenter Trials (3/06)

http://www.fda.gov/cder/guidance/OC2005201fnl.pdfhttp://www.fda.gov/cder/guidance/OC2005201fnl.pdf

Final Guidance: Establishment and Operation of Final Guidance: Establishment and Operation of Clinical Trial Data Monitoring Committees (3/06) Clinical Trial Data Monitoring Committees (3/06)

http://http://www.fda.gov/cber/gdlns/clintrialdmc.pdfwww.fda.gov/cber/gdlns/clintrialdmc.pdf

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Critical Path Opportunities Report and List (3/06)Critical Path Opportunities Report and List (3/06)http://www.fda.gov/oc/initiatives/criticalpath/http://www.fda.gov/oc/initiatives/criticalpath/

Final Guidance: Informed Consent for IVD device Final Guidance: Informed Consent for IVD device studies using leftover specimens that are not studies using leftover specimens that are not individually identifiable (4/06) individually identifiable (4/06)

http://www.fda.gov/cdrh/oivd/guidance/1588.pdfhttp://www.fda.gov/cdrh/oivd/guidance/1588.pdf

Draft Guidance: Adverse Event Reporting Draft Guidance: Adverse Event Reporting ––Improving Human Subject Protection (4/07)Improving Human Subject Protection (4/07)

http://http://www.fda.gov/cber/gdlns/advreport.pdfwww.fda.gov/cber/gdlns/advreport.pdf

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Data Quality InitiativeData Quality Initiative

Joint DIA and FDA Workshop, May 10Joint DIA and FDA Workshop, May 10--11, 200711, 2007Defining and Implementing Quality in Clinical Investigations froDefining and Implementing Quality in Clinical Investigations from m Design to CompletionDesign to Completion

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Probability SamplingProbability Sampling

What?What?Random sampling of Random sampling of clinical investigator clinical investigator population population Results of the sample Results of the sample generalized to the generalized to the entire populationentire population

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Why?Why?Develop a scienceDevelop a science--based based report cardreport card of the device of the device research communityresearch communityLarge device researcher Large device researcher population; scarce agency population; scarce agency resourcesresources

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How?How?Random sample of active IDEsRandom sample of active IDEsStratified by device type & geographyStratified by device type & geographyCompleted 199 CI inspections Completed 199 CI inspections Focus on protocol adherence and human Focus on protocol adherence and human subject protection issues, subject protection issues, notnot data verificationdata verificationUse CI Compliance Program (83811)Use CI Compliance Program (83811)Analysis, assessment, and interventionsAnalysis, assessment, and interventions

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StatusStatusSampling plan completeSampling plan completeFDA field investigators to conduct FDA field investigators to conduct inspectionsinspections202 assignments issued (FY04, 05, & 06) 202 assignments issued (FY04, 05, & 06) 198 inspections classified to date198 inspections classified to date

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Probability SamplingProbability SamplingInterim ResultsInterim Results

NAI

VAI

OAI

7%

37%

56%

PS CI Inspections All CI Inspections

37%

15%

48%

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NAI

VAI

OAI

7%

37%

56%

PS CI Inspections All CI Inspections*

39%

9%

52%

*Excluding For Cause Inspections

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72 hrs per operation 72 hrs per operation (79 hrs planned)(79 hrs planned)53% (105/198) issued 483s 53% (105/198) issued 483s (51% for all CIs)(51% for all CIs)7% (13/198) OAI Rate 7% (13/198) OAI Rate (15% for all CIs)(15% for all CIs)Inspection findings similarInspection findings similarPossible explanations for OAI disparityPossible explanations for OAI disparity

Studies involve smaller number of subjectsStudies involve smaller number of subjectsOutreach having impact (i.e., active studies)Outreach having impact (i.e., active studies)Higher rate for directed / for causeHigher rate for directed / for cause

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Guidance and StandardsGuidance and Standards

Guidance DevelopmentGuidance DevelopmentCDRH has instituted guidance prioritizationCDRH has instituted guidance prioritizationCDRH frequently reaches out to industry for drafts of guidance tCDRH frequently reaches out to industry for drafts of guidance that hat would be usefulwould be usefulCDRH added guidance development to its performance scorecardCDRH added guidance development to its performance scorecard

FY 06 goal was 32 guidances out of CDRHFY 06 goal was 32 guidances out of CDRHResults Results -- 46 guidances out of CDRH46 guidances out of CDRH

Standards Development Standards Development Standards ParticipationStandards Participation

38 Development Organizations38 Development Organizations238 Liaison Reps: 220 National Committees and 128 International 238 Liaison Reps: 220 National Committees and 128 International CommitteesCommittees538 Standards Activities: 365 National and 173 Other Activities538 Standards Activities: 365 National and 173 Other Activities

A significant number of applications reference consensus standarA significant number of applications reference consensus standardsds

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Guidance DevelopmentGuidance Development

The Review and Inspection of Premarket The Review and Inspection of Premarket Approval Applications under the Bioresearch Approval Applications under the Bioresearch Monitoring ProgramMonitoring ProgramRoles and Responsibilities of Device Clinical Roles and Responsibilities of Device Clinical InvestigatorsInvestigators

A webA web--based training programbased training program

Monitoring of Device Clinical InvestigationsMonitoring of Device Clinical Investigations

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BIMO PMA Review GuidanceBIMO PMA Review Guidance

Draft IssuedDraft IssuedJune 2006June 2006

Final CirculatingFinal CirculatingSeptember 2007?September 2007?

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GoalsGoalsDescribe the sequence of events as the Office of Describe the sequence of events as the Office of Compliance completes a BIMO review of a PMACompliance completes a BIMO review of a PMADescribe the administrative process and the Describe the administrative process and the timeframes involved with each steptimeframes involved with each stepDescribe how the clinical or nonDescribe how the clinical or non--clinical inspections clinical inspections fit into the approval processfit into the approval process

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BIMO inspections issued within 30 daysBIMO inspections issued within 30 daysFor original For original PMAsPMAsBy review division request, for PMA supplementsBy review division request, for PMA supplements

Sites selected may includeSites selected may includeSponsor, study monitor, or CROSponsor, study monitor, or CROClinical investigatorClinical investigatorLaboratory conducting nonLaboratory conducting non--clinical studiesclinical studies

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BIMO Review MilestonesBIMO Review Milestones

PMA Receipt

BIMO Receipt of PMA

BIMO Inspection Assignments Issued

BIMO Inspection Complete

BIMO Inspection Report Received

BIMO Completes Review

FinalBIMORecommendation

0 7 30 70/80 90/100 120/130 140/150

Review Clock in Calendar Days

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BIMO Review DelaysBIMO Review Delays

Submission of incomplete informationSubmission of incomplete informationComplete contact information forComplete contact information for

Clinical InvestigatorsClinical InvestigatorsInstitutional Review BoardsInstitutional Review Boards

IRBIRB--approved informed consent documentsapproved informed consent documentsLocation where clinical study records are maintainedLocation where clinical study records are maintainedStudy protocol including history of changesStudy protocol including history of changesSample case report formsSample case report formsData tabulations (line data) that support key S&E endpointsData tabulations (line data) that support key S&E endpoints

Sorted by site then subject for each pivotal studySorted by site then subject for each pivotal studyStandard acceptable electronic format (e.g., SAS XPT)Standard acceptable electronic format (e.g., SAS XPT)

Site readinessSite readinessAccess to study recordsAccess to study records

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BIMO Review OutcomesBIMO Review Outcomes

Inspection results are usually supportive Inspection results are usually supportive of the review processof the review processSometimes inspection results can have an Sometimes inspection results can have an adverse impact on the review processadverse impact on the review process

Deficiency letterDeficiency letterSubjects failed to meet the inclusion criteriaSubjects failed to meet the inclusion criteriaUnderreporting of unanticipated adverse device effectsUnderreporting of unanticipated adverse device effectsFailure to obtain informed consent Failure to obtain informed consent

Application Integrity PolicyApplication Integrity PolicyPattern or practice of wrongful acts that effect data reliabilitPattern or practice of wrongful acts that effect data reliabilityy

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Guidance for Industry: Guidance for Industry: Guideline for the Guideline for the Monitoring of Clinical Monitoring of Clinical InvestigationsInvestigations

Issued in 1988Issued in 1988Not comprehensiveNot comprehensive

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Draft Guidance for Industry: Monitoring Draft Guidance for Industry: Monitoring of Device Clinical Investigationsof Device Clinical Investigations

FDLI facilitated meeting of research communityFDLI facilitated meeting of research communityMedical device manufacturersMedical device manufacturersHealth care professionalsHealth care professionalsMedical device regulatory consultantsMedical device regulatory consultantsTrade associationsTrade associationsDevice clinical trial expertsDevice clinical trial expertsCompliance officersCompliance officers

Draft circulating for final reviewDraft circulating for final review

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63

Device GLP Program StatusDevice GLP Program Status

Historically, CDRH review divisions Historically, CDRH review divisions have not required animal safety have not required animal safety studies to follow GLPstudies to follow GLPMany marketed devices did not follow Many marketed devices did not follow GLPGLPNot feasible to require current Not feasible to require current manufacturers to follow GLPmanufacturers to follow GLP

Especially if showing equivalence to predicateEspecially if showing equivalence to predicate

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Device GLP Program StatusDevice GLP Program Status

Inspections may be issued for Inspections may be issued for nonnon--GLP or GLP animal studiesGLP or GLP animal studiesFocus on data audit or verificationFocus on data audit or verification

Less emphasis on GLP requirementsLess emphasis on GLP requirementsMore emphasis on auditing safety More emphasis on auditing safety studies that support highstudies that support high--risk productsrisk products

OAI applies to sites with data OAI applies to sites with data reliability issuesreliability issues

Data falsification, omission, etc.Data falsification, omission, etc.

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66

Device BIMO InspectionsDevice BIMO InspectionsFiscal Years 2002 Fiscal Years 2002 -- 20062006

357 353 350 332 336

0

100

200

300

400

FY02 FY03 FY04 FY05 FY06

67

Device BIMO InspectionsDevice BIMO InspectionsFiscal Years 2002 Fiscal Years 2002 -- 20062006

Inspected Inspected EntityEntity 20022002 20032003 20042004 20052005 20062006

SponsorSponsor 7272 8181 7373 7070 5353

200200

5959

2424

CICI 151151 170170 183183 183183

IRBIRB 128128 8585 7373 4848

GLPGLP 66 99 1919 3131

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Device BIMO Warning LettersDevice BIMO Warning Letters

14

44

3024

9

31

0

5

10

15

20

25

30

35

40

45

50

FY01 FY02 FY03 FY04 FY05 FY06

69

Device BIMO Warning LettersDevice BIMO Warning Letters

7

20 18

10

63

7

33

1

2417

7

2

7

3

0

10

20

30

40

50

FY02 FY03 FY04 FY05 FY06

GLPIRBSponsorCI

70

Device BIMO Compliance RatesDevice BIMO Compliance Rates

13% 12%17%

24%

15%11%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAIVAIOAI

71

Device BIMO OAI RatesDevice BIMO OAI Rates

13%16%

9%

5%

10%

17%

24%

15%

11%

7%

0%

10%

20%

30%

10 Years FY03 FY04 FY05 FY06

OAI (NFC) OAI NFC = No “For Cause”inspections included

72

Device Sponsor Compliance RatesDevice Sponsor Compliance Rates

19%

10%

24%31%

15%11%

0%

10%

20%

30%

40%

50%

60%

70%


NAIVAIOAI

73

Device Sponsor Deficiencies Device Sponsor Deficiencies

FY02FY02 FY03FY03 FY04FY04 FY05FY05 FY06FY06

Inadequate Inadequate monitoringmonitoring

33%33%

19%19%

7%7%

4%4%

23%23%24%24%40%40%37%37%

24%24% 15%15%

19%19%

21%21%

16%16%

18%18% 11%11%

18%18%

8%8%

13%13%

15%15%

5%5%

Failure to secure Failure to secure investigator investigator compliancecompliance

Inadequate device Inadequate device accountabilityaccountability

Obtain FDA/IRB Obtain FDA/IRB approvalapproval

74

Device Clinical Investigator Device Clinical Investigator Compliance RatesCompliance Rates

11%15% 17%

21%

11%17%

0%

10%

20%

30%

40%

50%

60%

70%


NAIVAIOAI

75

Clinical Investigator DeficienciesClinical Investigator Deficiencies

20022002 20032003 20042004 20052005 20062006

Failure to follow Failure to follow investigational investigational plan/regs/IAplan/regs/IA

44%44% 51%51% 54%54% 50%50%

9%9%

29%29%

7%7%

10%10%

Protocol deviations Protocol deviations (R&R)(R&R)

20%20% 38%38% 16%16%

44%44%

22%22%

20%20%

15%15%

Inadequate subject Inadequate subject protection/ICprotection/IC

21%21% 21%21% 24%24%

Inadequate device Inadequate device accountabilityaccountability

26%26% 18%18% 14%14%

Lack of FDA &/or Lack of FDA &/or IRB approvalIRB approval

8%8% 13%13% 13%13% 7%7%

76

Device IRB Compliance RatesDevice IRB Compliance Rates

13%9%

14%8%

17%

7%0%

10%

20%

30%

40%

50%

60%

70%


NAIVAIOAI

77

Device IRB DeficienciesDevice IRB Deficiencies

FY02FY02 FY03FY03 FY04FY04 FY05FY05 FY06FY06

Inadequate initial Inadequate initial &/or continuing &/or continuing reviewreview

24%24% 25%25% 50%50% 37%37%

17%17%

22%22%

12%12%

Inadequate minutesInadequate minutes 11%11% 42%42% 28%28%

38%38%

20%20%

7%7%Lack of or incorrect Lack of or incorrect SR/NSR SR/NSR determinationdetermination

10%10% 16%16% 34%34%

Inadequate Inadequate membership rostermembership roster

13%13% 20%20% 21%21% 12%12%

FY06 – Lack of Quorum & Reporting Non-Compliance 12%

78

Allegations of Research MisconductAllegations of Research Misconduct

15

41 41

136

72

154

82

020406080

100120140160

FY02 FY03 FY04 FY05 FY06Red = # of inspections

79

FY06 BIMO Compliance RatesFY06 BIMO Compliance Rates

NAI

VAI

OAI

11%

36%

53%

All Inspections Complaints

17%

35%48%

COMPLAINTSALL INSPECTIONS

80

FY06 Special InvestigationsFY06 Special Investigations

Application Integrity Policy (i.e. multiple applications)Application Integrity Policy (i.e. multiple applications)Lifted from 2 firmsLifted from 2 firms

Integrity Holds (i.e., single application)Integrity Holds (i.e., single application)Lifted from 2 firmsLifted from 2 firmsReapplied to 1 firmReapplied to 1 firm

Rescission, Withdrawal, NSERescission, Withdrawal, NSE1 Ortho firm had 510(k)s WD1 Ortho firm had 510(k)s WD3 IVD firms had 510(k)s WD or NSE3 IVD firms had 510(k)s WD or NSE

DisqualificationsDisqualificationsLevied against 1 Clinical InvestigatorLevied against 1 Clinical Investigator

Administrative Restrictions on IRBsAdministrative Restrictions on IRBsLevied against 1 IRBLevied against 1 IRB

81



82

How can a Sponsor Prepare a How can a Sponsor Prepare a Site for a BIMO Inspection?Site for a BIMO Inspection?

Inform the site that the FDA may inspect their Inform the site that the FDA may inspect their study site, and that they be prepared for an FDA study site, and that they be prepared for an FDA inspection at any timeinspection at any timeEnsure that the site understands that the preEnsure that the site understands that the pre--announcement is not announcement is not ““an appointmentan appointment”” to be to be scheduled at the sitescheduled at the site’’s convenience, but a s convenience, but a courtesy precourtesy pre--notification to allow the site time to notification to allow the site time to collect records and notify relevant study collect records and notify relevant study personnelpersonnelMDUFMA mandates specific review deadlines, and MDUFMA mandates specific review deadlines, and inspections often cannot be postponed without inspections often cannot be postponed without jeopardizing this timely reviewjeopardizing this timely review

83

How can a Sponsor Prepare a How can a Sponsor Prepare a Site for a BIMO Inspection?Site for a BIMO Inspection?

Inform the site at the beginning of the study what Inform the site at the beginning of the study what actions to take if they receive notification of an actions to take if they receive notification of an upup--coming inspectioncoming inspection

Immediately notify the sponsor, monitor, IRB, etc.Immediately notify the sponsor, monitor, IRB, etc.Ask sufficient questions so that they clearly understand which Ask sufficient questions so that they clearly understand which study will be inspected, who will be conducting the inspection, study will be inspected, who will be conducting the inspection, and the contact information for that personand the contact information for that person

Consider doing a mock FDA inspection especially Consider doing a mock FDA inspection especially at sites where monitoring identified problemsat sites where monitoring identified problems

84

How can a Site Prepare for a How can a Site Prepare for a BIMO Inspection?BIMO Inspection?

Make all study records availableMake all study records availableRegulatory documentsRegulatory documents

Study protocols, protocol amendments, IRB approvals and reports,Study protocols, protocol amendments, IRB approvals and reports,study device accountability records, monitoring logs, site persostudy device accountability records, monitoring logs, site personnel nnel logs, study subject enrollment logs, etc.logs, study subject enrollment logs, etc.

Sponsor correspondenceSponsor correspondenceLetters, newsletters, memos, work instructions, eLetters, newsletters, memos, work instructions, e--mails, monitoring mails, monitoring visit reports, telephone contacts, etc.visit reports, telephone contacts, etc.

Study subject recordsStudy subject recordsConsent forms, Case Report Forms/Consent forms, Case Report Forms/CRFsCRFs, clinic charts, subject , clinic charts, subject diaries, lab reports, hospital records, data queries, adverse evdiaries, lab reports, hospital records, data queries, adverse event ent records, etc.records, etc.

85

How can the Sponsor or Site How can the Sponsor or Site Manage a BIMO Inspection?Manage a BIMO Inspection?

Provide information/records that are clear and Provide information/records that are clear and responsive to questions from the investigator, as responsive to questions from the investigator, as appropriateappropriateDocument the inspectional coverageDocument the inspectional coverageDocument what information or records were Document what information or records were provided to the investigatorprovided to the investigatorBe cordial and cooperativeBe cordial and cooperative

86


Take notes on everything discussed by the FDA Take notes on everything discussed by the FDA investigator during the inspection and at the investigator during the inspection and at the closeout meetingcloseout meetingRespond in writing to all the violations cited on Respond in writing to all the violations cited on the Form FDA 483 and the issues discussed the Form FDA 483 and the issues discussed verballyverballySubmit the response to FDA as soon as possible Submit the response to FDA as soon as possible after the completion of the inspection, so it can after the completion of the inspection, so it can evaluated before inspection classificationevaluated before inspection classificationAdequate responses may have a favorable impact Adequate responses may have a favorable impact on the final classification of the inspection on the final classification of the inspection

87


It may be helpful to provide support staff or It may be helpful to provide support staff or information that may be required in order to information that may be required in order to assist the site to appropriately respond to the assist the site to appropriately respond to the observationsobservations

88

How can the Sponsor or Site How can the Sponsor or Site Respond to an Inspection?Respond to an Inspection?

If no FDA 483 or significant problems, then no If no FDA 483 or significant problems, then no response necessaryresponse necessaryIf FDA 483 issued, submit prompt written If FDA 483 issued, submit prompt written response response

Assess the root cause of the problemAssess the root cause of the problemExplain actions to correct the problemExplain actions to correct the problemEvaluate the extent of the problemEvaluate the extent of the problemImplement preventative actions to avoid recurrenceImplement preventative actions to avoid recurrenceInclude supporting documentationInclude supporting documentationTimelines for implementationTimelines for implementation

89

How can the Sponsor or Site How can the Sponsor or Site Respond to a FDA 483?Respond to a FDA 483?

Consider requesting a meeting with the District Consider requesting a meeting with the District Office or the Center whenOffice or the Center when

Inspection found significant violationsInspection found significant violationsThere were communication concerns with the investigator, i.e., There were communication concerns with the investigator, i.e., major disagreements or misunderstandingsmajor disagreements or misunderstandingsThere are complex product, process, or study issuesThere are complex product, process, or study issues

90

Closing PerspectiveClosing Perspective……

Collaboration Built on Trust Ensures SuccessCollaboration Built on Trust Ensures SuccessThe American Public is our customerThe American Public is our customerWe work together to serve our customerWe work together to serve our customerCollaboration between FDA, researchers, and industry is Collaboration between FDA, researchers, and industry is vitalvitalSafe and effective products is a collaborative goalSafe and effective products is a collaborative goalConsumers expect safe and effective products Consumers expect safe and effective products Public confidence is influenced by use of productsPublic confidence is influenced by use of productsResult is better health for allResult is better health for all

91

Thank youThank you

FDA looks forward to working with FDA looks forward to working with you to improve public healthyou to improve public health

92

Plenary Session Question #4Plenary Session Question #4

For a multiFor a multi--site study, if the sponsor receives an site study, if the sponsor receives an UADE from one site, should the sponsor report UADE from one site, should the sponsor report this information directly to all this information directly to all IRBsIRBs or report to or report to CIsCIs with request that they notify their with request that they notify their IRBsIRBs??

See FDA Information Sheets: Sponsor, Investigator, IRB InterSee FDA Information Sheets: Sponsor, Investigator, IRB Inter--relationshipsrelationshipsSponsor can report to all Sponsor can report to all CIsCIs with request for CI to notify IRBwith request for CI to notify IRBOr, sponsor can report to Or, sponsor can report to IRBsIRBs with with ““cccc”” to to CIsCIs

93

Plenary Session Question #12Plenary Session Question #12

How would FDA evaluate a nonHow would FDA evaluate a non--clinical device clinical device study in which instudy in which in--vivo and exvivo and ex--vivo study vivo study components are conducted under noncomponents are conducted under non--GLP GLP (in(in--vivo) and GLP (exvivo) and GLP (ex--vivo) compliance?vivo) compliance?

CDRH does not apply GLP to nonCDRH does not apply GLP to non--clinical studiesclinical studiesCDRH evaluates the controls in place to assure accuracy CDRH evaluates the controls in place to assure accuracy and completeness of dataand completeness of dataCDRH may conduct an audit of the dataCDRH may conduct an audit of the data