Medical Device Medical Device Regulatory Update Regulatory Update - - PowerPoint PPT Presentation
Medical Device Medical Device Regulatory Update Regulatory Update Matthew Tarosky Tarosky Matthew Division of Bioresearch Monitoring Division of Bioresearch Monitoring Office of Compliance Office of Compliance Center for Devices and
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Matthew Matthew Tarosky Tarosky Division of Bioresearch Monitoring Division of Bioresearch Monitoring Office of Compliance Office of Compliance Center for Devices and Radiological Health Center for Devices and Radiological Health US Food and Drug Administration US Food and Drug Administration
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Getting safe and Getting safe and effective devices effective devices to market as to market as quickly as quickly as possible possible… … … … 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 science Helping the public get science-
based accurate information about medical devices and radiological information about medical devices and radiological products needed to improve health products needed to improve health
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Total Product Life Cycle Total Product Life Cycle
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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 employees health employees Our employees are drawn from a wealth of Our employees are drawn from a wealth of science and public health professions science 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 i pharmacologists, veterinarians, toxicologists, and specialists in n public health education and communication public health education and communication
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CDRH CDRH Ombudsman Ombudsman
Les Weinstein Les Weinstein
Office of the Center Director Office of the Center Director
Daniel G. Schultz, M.D., Director Daniel G. Schultz, M.D., Director Linda Kahan, Deputy Director Linda Kahan, Deputy Director Lillian Gill, D.P.A., Senior Associate Lillian Gill, D.P.A., Senior Associate Director Director
Postmarket Transformation Postmarket Transformation Management Group Management Group
Don S
Don S
Diane Mitchell, M.D. Diane Mitchell, M.D. S usan Meadows S usan Meadows
Office of In Vitro Office of In Vitro Diagnostic Device Diagnostic Device Evaluation Evaluation & Safety & Safety
S teven I. Gutman, M.D. S teven I. Gutman, M.D.
Office of Office of Compliance Compliance
Timothy A. Ulatowski Timothy A. Ulatowski
Office of Device Office of Device Evaluation Evaluation
Donna Donna-
Bea Tillman, Ph.D.
Office of Office of S cience & S cience & Engineering Engineering Laboratories Laboratories
Larry Kessler, S c.D. Larry Kessler, S c.D.
Office of Office of Communication, Communication, Education, & Education, & Radiation Radiation Programs Programs
Lynne L. Rice Lynne L. Rice
Office of Office of Surveillance & Surveillance & Biometrics Biometrics
S usan N. Gardner, Ph.D. S usan N. Gardner, Ph.D.
Office of Office of Management Management Operations Operations
Ruth E. McKee Ruth E. McKee
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Office of Compliance Office of Compliance
Tim Tim Ulatowski Ulatowski, Director , Director Larry Spears, Deputy Director Regulatory Larry Spears, Deputy Director Regulatory Kimber Kimber Richter, M.D., Deputy Director Medical Richter, M.D., Deputy Director Medical
Division of Enforcement A Division of Enforcement A
Betty Collins, Director Betty Collins, Director
Division of Enforcement B Division of Enforcement B
Gladys Rodriguez, Director Gladys Rodriguez, Director
Division of Risk Management Division of Risk Management Operations Operations
Karen Moss, Director Karen Moss, Director
Division of Bioresearch Division of Bioresearch Monitoring Monitoring
Michael Michael Marcarelli Marcarelli, Director , Director
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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 = 14,937 Total 2004 Sales $320 Billion
Smallest Smallest Firms Firms Largest Largest Firms Firms Employees Per Firm*
* Dun & Bradstreet 2004 Medical Device Firm Data * Dun & Bradstreet 2004 Medical Device Firm Data
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Sunsets 9/30/07 Sunsets 9/30/07 Annual public stakeholder meetings Annual public stakeholder meetings
Negotiations with industry over last 18 months Negotiations with industry over last 18 months Stronger performance goals Stronger performance goals More predictable user fee structure More predictable user fee structure
Registration, annual reports Registration, annual reports
Sent to Congress for review/approval Sent to Congress for review/approval
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Public Health Partners
Information Education Adverse Event Reporting Additional Signals
Postmarket Problem Assessment
Laboratory Research & Analysis Problem Assessment Groups Post Approval Studies External Data Analysis Internal Data Analysis
Postmarket Tools Public Health Response
Enforcement Information Dissemination
Premarket Approval Process
Postmarket Problem Identification Tools
Inspections
Postmarket Public Health Response Postmarket Problem Identification Postmarket Problem Assessment
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1. 1. Create a matrix organization to optimize medical device regulati Create a matrix organization to optimize medical device regulation
across the Total Product Lifecycle across 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 data data-
warehousing 6. 6. I ncrease the quality and quantity of Center/ ORA/ OCC interactions I ncrease the quality and quantity of Center/ ORA/ OCC interactions 7. 7. Develop and implement a risk Develop and implement a risk-
communication strategy 8. 8. Design a pilot project to test the usefulness of quantitative de Design a pilot project to test the usefulness of quantitative decision cision-
making methods 9. 9. Enhance utility of MedSun programs Enhance utility of MedSun programs
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Establish cross Establish cross-
cutting product-
related groups over the current functionally groups over the current functionally-
based organization to:
Foster information sharing and more effective PH Foster information sharing and more effective PH promotion and protection promotion and protection Collaboration as a part of day Collaboration as a part of day-
to-
day operations, not just in crisis situations not just in crisis situations
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Turbo 510(k) Program Turbo 510(k) Program
http://www.fda.gov/cdrh/oivd/turbo510kcesub1.html http://www.fda.gov/cdrh/oivd/turbo510kcesub1.html
eCopy eCopy I nitiative I nitiative
http:// http:// www.fda.gov/cdrh/elecsub.html www.fda.gov/cdrh/elecsub.html May be submitted for any premarket submission May be submitted for any premarket submission Immediately available for CDRH staff Immediately available for CDRH staff
eReview eReview
Streamline and facilitate review process Streamline and facilitate review process
Electronic Medical Device Reporting Electronic Medical Device Reporting
Electronic adverse device effects as HL7 standard Electronic adverse device effects as HL7 standard
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New Hires New Hires Shared Hires Shared Hires
ODE ODE-
OC ODE ODE-
OSB
Medical Device Fellowship Program (MDFP) Medical Device Fellowship Program (MDFP) Special Government Employees ( Special Government Employees ( SGEs SGEs) as members and ) as members and consultants to our 18 Advisory Panels consultants to our 18 Advisory Panels
Over 700 Over 700 SGEs SGEs
Contractors Contractors Collaborations with the clinical community and professional Collaborations with the clinical community and professional groups groups
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A serious commitment to make product A serious commitment to make product development more predictable and less costly development 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 development hurdles in product development
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Basic Research Prototype Design or Discovery Clinical Development FDA Filing/ Approval & Launch Preparation Preclinical Development
Critical Path Critical Path
Approval Approval Market Market Application Application
The journey from medical product candidate to full-scale production and marketing
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Drugs Drugs Devices Devices
Pure molecules Pure molecules Complex components Complex components Toxicology Toxicology Biocompatibility Biocompatibility Short half Short half-
life Durable Equipment Durable Equipment Long market life Long market life Rapid product cycles Rapid product cycles Drug interactions Drug interactions Device Malfunction Device Malfunction Wrong Drug / Dose Wrong Drug / Dose User Error User Error Clinical studies Clinical studies Bench and Clinical studies Bench and Clinical studies Good Manufacturing Practices Good Manufacturing Practices (cGMP) (cGMP) Quality Systems Quality Systems (I SO 9000) (I SO 9000)
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Working with a West Coast University on Working with a West Coast University on combination products combination products
Analyze the development of biomarkers and diagnostics and Analyze the development of biomarkers and diagnostics and their application to their application to pharmacogenomics pharmacogenomics Identify barriers to drug/diagnostic device co Identify barriers to drug/diagnostic device co-
development
Working with the Juvenile Diabetes Research Working with the Juvenile Diabetes Research Foundation Foundation
Accelerate development of a closed Accelerate development of a closed-
loop system using continuous glucose sensors and insulin pumps linked by a continuous glucose sensors and insulin pumps linked by a control control-
algorithm
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Working with academia on peripheral vascular Working with academia on peripheral vascular stent development stent 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 devices area of cardiovascular devices
“ “Late loss Late loss” ” via imaging via imaging
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Office of Science & Engineering Laboratories move complete Office of Science & Engineering Laboratories move complete Remaining CDRH staff move anticipated in March 2009 Remaining CDRH staff move anticipated in March 2009
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I nternational Harmonization I nternational Harmonization Office of Regulatory Affairs (ORA) Transformation Office of Regulatory Affairs (ORA) Transformation Risk Risk-
Based Work Plan Bioresearch Monitoring (BI MO) Modernization Bioresearch Monitoring (BI MO) Modernization Probability Sampling Probability Sampling
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Educating Foreign Government Officials on the Educating Foreign Government Officials on the U.S. Regulatory Process U.S. Regulatory Process Supporting Global Harmonization, Mutual Supporting Global Harmonization, Mutual Recognition Agreements ( Recognition Agreements ( MRAs MRAs) and other ) and other I nternational Agreements I nternational Agreements Managing US/ EC Mutual Recognition Agreement Managing US/ EC Mutual Recognition Agreement www.fda.gov/ cdrh/ mra www.fda.gov/ cdrh/ mra 11 11 th
th Conference of Global Harmonization Task
Conference of Global Harmonization Task Force, October 3 Force, October 3-
4, 2007, Washington, DC
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Leveraging Leveraging Workforce Capability Workforce Capability Quality Management Systems Quality Management Systems Risk Management Risk Management Information Technology Information Technology Laboratories Laboratories Imports Imports
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Consolidate 13 labs and align under Science Consolidate 13 labs and align under Science Directorate Directorate Consolidate 19 district offices under Inspection Consolidate 19 district offices under Inspection Compliance Directorate Compliance Directorate Eliminate Regional Offices Eliminate Regional Offices Hire 100 new consumer safety officers Hire 100 new consumer safety officers
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Allegations of Research Misconduct Allegations of Research Misconduct
For Cause Assignments For Cause Assignments
PMA and Panel Track Supplements PMA and Panel Track Supplements
Directed Inspections Directed Inspections
I DE Early I ntervention I nspections I DE Early I ntervention I nspections
Novel technologies Novel technologies Vulnerable populations Vulnerable populations
Non Non-
compliant history
Previously violative (OAI) inspection Previously violative (OAI) inspection
Routine surveillance Routine surveillance
Institutional Review Boards Institutional Review Boards
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Mandate to systematically and comprehensively Mandate to systematically and comprehensively reexamine FDA reexamine FDA’ ’s approach to human subject s approach to human subject protection and bioresearch monitoring protection and bioresearch monitoring 5 Year Charter 5 Year Charter Oversight and central coordination of all Oversight and central coordination of all modernization activities related to BIMO and HSP modernization activities related to BIMO and HSP
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New trial methods and designs New trial methods and designs New methods of data collection and processing New methods of data collection and processing
Electronic data capture Electronic data capture
Globalization Globalization New arrangements New arrangements
Sponsors and various contractors, among investigators, among Sponsors and various contractors, among investigators, among institutions, among IRBs, and rise of free institutions, among IRBs, and rise of free-
standing for-
profit study centers study centers
Greater number of studies in children and other Greater number of studies in children and other vulnerable populations vulnerable populations Combination products Combination products
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How should FDA regulate this new clinical trial How should FDA regulate this new clinical trial paradigm? paradigm?
Responsibilities of investigators Responsibilities of investigators Data quality Data quality
How should FDA facilitate reasonable & effective How should FDA facilitate reasonable & effective I RB oversight of clinical trials? I RB oversight of clinical trials?
IRB oversight of human subject protection IRB oversight of human subject protection FDA oversight of IRB function FDA oversight of IRB function
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Common standards and regulatory requirements Common standards and regulatory requirements for electronic data handling for electronic data handling Accommodate globalization of clinical trials Accommodate globalization of clinical trials Comprehensive approach to protection of Comprehensive approach to protection of vulnerable populations vulnerable populations
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Units of varying size in review centers Units of varying size in review centers Field force; only a few experts in any given district Field force; only a few experts in any given district Very small centralized group in OC Very small centralized group in OC
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Subject Safety Subject Safety
CI training/supervision CI training/supervision Oversight of sub Oversight of sub-
and co-
investigators
A Strong I RB System A Strong I RB System
Registration Registration Modernize AE reporting Modernize AE reporting Guidance Guidance
Protection of Vulnerable Populations Protection of Vulnerable Populations
Pediatric Pediatric Decision Decision-
impaired Emergency Research Emergency Research
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Common definition(s) of Common definition(s) of “ “high high-
quality” ” data data Methods to assess Methods to assess Quality systems (build Quality systems (build-
in vs. inspect-
in) Evaluating the role and performance of monitoring, Evaluating the role and performance of monitoring, auditing, and inspecting auditing, and inspecting Pursuing falsification and high Pursuing falsification and high-
risk challenges
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Advancing Technology Advancing Technology
CCT (computerized systems used in clinical trials) CCT (computerized systems used in clinical trials) e e-
PRO (Patient Reported Outcomes) EHR (Electronic Health Records) EHR (Electronic Health Records)
Research Enterprise Research Enterprise
Regulatory expectations (e.g., site management organizations, Regulatory expectations (e.g., site management organizations, AE Adjudication) AE Adjudication) International Harmonization and Standardization International Harmonization and Standardization
GCP I nformation from/ to FDA GCP I nformation from/ to FDA
For Consumers and for Professionals For Consumers and for Professionals Reporting of and responsiveness to Reporting of and responsiveness to “ “complaints complaints” ”
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Part 15 Hearing: AE Reporting to Part 15 Hearing: AE Reporting to I RBs I RBs (3/ 05) (3/ 05)
http://www.fda.gov/OHRMS/DOCKETS/98fr/05 http://www.fda.gov/OHRMS/DOCKETS/98fr/05-
2300.pdf
Final Guidance: Exploratory I ND Studies (1/ 06) Final Guidance: Exploratory I ND Studies (1/ 06)
http://www.fda.gov/cder/guidance/7086fnl.pdf http://www.fda.gov/cder/guidance/7086fnl.pdf
Direct Final Rule and Draft Guidance Direct Final Rule and Draft Guidance – – I NDs: I NDs: Approaches to Complying with CGMP (1/ 06) Approaches to Complying with CGMP (1/ 06)
http://www.fda.gov/cder/guidance/6164dft.pdf http://www.fda.gov/cder/guidance/6164dft.pdf
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Updated: Five I nformation Sheet Guidances for Updated: Five I nformation Sheet Guidances for Sponsors, Clinical I nvestigators, and I RBs 2/ 06 Sponsors, Clinical I nvestigators, and I RBs 2/ 06
http:// http:// www.fda.gov/oc/ohrt/irbs/default.htm www.fda.gov/oc/ohrt/irbs/default.htm
Final Guidance: Using a Centralized I RB Review Final Guidance: Using a Centralized I RB Review Process in Multicenter Trials (3/ 06) Process in Multicenter Trials (3/ 06)
http://www.fda.gov/cder/guidance/OC2005201fnl.pdf http://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.pdf www.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: I nformed Consent for I VD device Final Guidance: I nformed Consent for I VD 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.pdf http://www.fda.gov/cdrh/oivd/guidance/1588.pdf
Draft Guidance: Adverse Event Reporting Draft Guidance: Adverse Event Reporting – – I mproving Human Subject Protection (4/ 07) I mproving Human Subject Protection (4/ 07)
http:// http:// www.fda.gov/cber/gdlns/advreport.pdf www.fda.gov/cber/gdlns/advreport.pdf
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Joint DI A and FDA Workshop, May 10 Joint DI A and FDA Workshop, May 10-
11, 2007
Defining and Implementing Quality in Clinical Investigations fro Defining and Implementing Quality in Clinical Investigations from m Design to Completion Design to Completion
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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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Studies involve smaller number of subjects Studies involve smaller number of subjects Outreach having impact (i.e., active studies) Outreach having impact (i.e., active studies) Higher rate for directed / for cause Higher rate for directed / for cause
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Introduction Introduction Priorities Priorities Initiatives Initiatives
Guidance Documents Guidance Documents
Non Non-
clinical (GLP) Program Update Inspection Metrics Inspection Metrics BIMO Inspection Preparation BIMO Inspection Preparation
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Guidance Development Guidance Development
CDRH has instituted guidance prioritization CDRH has instituted guidance prioritization CDRH frequently reaches out to industry for drafts of guidance t CDRH frequently reaches out to industry for drafts of guidance that hat would be useful would be useful CDRH added guidance development to its performance scorecard CDRH added guidance development to its performance scorecard
FY 06 goal was 32 guidances out of CDRH FY 06 goal was 32 guidances out of CDRH Results Results -
46 guidances out of CDRH
Standards Development Standards Development
Standards Participation Standards Participation
38 Development Organizations 38 Development Organizations 238 Liaison Reps: 220 National Committees and 128 International 238 Liaison Reps: 220 National Committees and 128 International Committees Committees 538 Standards Activities: 365 National and 173 Other Activities 538 Standards Activities: 365 National and 173 Other Activities
A significant number of applications reference consensus standar A significant number of applications reference consensus standards ds
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The Review and I nspection of Premarket The Review and I nspection of Premarket Approval Applications under the Bioresearch Approval Applications under the Bioresearch Monitoring Program Monitoring Program Roles and Responsibilities of Device Clinical Roles and Responsibilities of Device Clinical I nvestigators I nvestigators
A web A web-
based training program
Monitoring of Device Clinical I nvestigations Monitoring of Device Clinical I nvestigations
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June 2006 June 2006
September 2007? September 2007?
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Describe the sequence of events as the Office of Describe the sequence of events as the Office of Compliance completes a BIMO review of a PMA Compliance completes a BIMO review of a PMA Describe the administrative process and the Describe the administrative process and the timeframes involved with each step timeframes involved with each step Describe how the clinical or non Describe how the clinical or non-
clinical inspections fit into the approval process fit into the approval process
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For original For original PMAs PMAs By review division request, for PMA supplements By review division request, for PMA supplements
Sponsor, study monitor, or CRO Sponsor, study monitor, or CRO Clinical investigator Clinical investigator Laboratory conducting non Laboratory conducting non-
clinical studies
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PMA Receipt BIMO Receipt
BIMO Inspection Assignments Issued BIMO Inspection Complete BIMO Inspection Report Received BIMO Completes Review Final BIMO Recommendation
7 30 70/80 90/100 120/130 140/150 Review Clock in Calendar Days
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Submission of incomplete information Submission of incomplete information
Complete contact information for Complete contact information for Clinical Investigators Clinical Investigators Institutional Review Boards Institutional Review Boards IRB IRB-
approved informed consent documents Location where clinical study records are maintained Location where clinical study records are maintained Study protocol including history of changes Study protocol including history of changes Sample case report forms Sample case report forms Data tabulations (line data) that support key S&E endpoints Data tabulations (line data) that support key S&E endpoints
Sorted by site then subject for each pivotal study Sorted by site then subject for each pivotal study Standard acceptable electronic format (e.g., SAS XPT) Standard acceptable electronic format (e.g., SAS XPT)
Site readiness Site readiness
Access to study records Access to study records
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Deficiency letter Deficiency letter
Subjects failed to meet the inclusion criteria Subjects failed to meet the inclusion criteria Underreporting of unanticipated adverse device effects Underreporting of unanticipated adverse device effects Failure to obtain informed consent Failure to obtain informed consent
Application Integrity Policy Application Integrity Policy
Pattern or practice of wrongful acts that effect data reliabilit Pattern or practice of wrongful acts that effect data reliability y
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Issued in 1988 Issued in 1988 Not comprehensive Not comprehensive
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Medical device manufacturers Medical device manufacturers Health care professionals Health care professionals Medical device regulatory consultants Medical device regulatory consultants Trade associations Trade associations Device clinical trial experts Device clinical trial experts Compliance officers Compliance officers
Draft circulating for final review Draft circulating for final review
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357 353 350 332 336 100 200 300 400 FY02 FY03 FY04 FY05 FY06
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I nspected I nspected Entity Entity 2002 2002 2003 2003 2004 2004 2005 2005 2006 2006 Sponsor Sponsor 72 72 81 81 73 73 70 70 53 53 200 200 59 59 24 24 CI CI 151 151 170 170 183 183 183 183 I RB I RB 128 128 85 85 73 73 48 48 GLP GLP 6 6 9 9 19 19 31 31
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14 44 30 24 9 31
5 10 15 20 25 30 35 40 45 50
FY01 FY02 FY03 FY04 FY05 FY06
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7 20 18 10 6 3 7 3 3 1 24 17 7 2 7 3
10 20 30 40 50
FY02 FY03 FY04 FY05 FY06
GLP IRB Sponsor CI
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13% 12% 17% 24% 15% 11% 0% 10% 20% 30% 40% 50% 60% 70% 10 Years FY02 FY03 FY04 FY05 FY06 NAI VAI OAI
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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
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19% 10% 24% 31% 15% 11% 0% 10% 20% 30% 40% 50% 60% 70% 10 Years FY02 FY03 FY04 FY05 FY06 NAI VAI OAI
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FY02 FY02 FY03 FY03 FY04 FY04 FY05 FY05 FY06 FY06 I nadequate I nadequate monitoring monitoring 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 compliance compliance I nadequate device I nadequate device accountability accountability Obtain FDA/ I RB Obtain FDA/ I RB approval approval
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11% 15% 17% 21% 11% 17% 0% 10% 20% 30% 40% 50% 60% 70% 10 Years FY02 FY03 FY04 FY05 FY06 NAI VAI OAI
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2002 2002 2003 2003 2004 2004 2005 2005 2006 2006 Failure to follow Failure to follow investigational investigational plan/ regs/ I A plan/ regs/ I A 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% I nadequate subject I nadequate subject protection/ I C protection/ I C 21% 21% 21% 21% 24% 24% I nadequate device I nadequate device accountability accountability 26% 26% 18% 18% 14% 14% Lack of FDA &/ or Lack of FDA &/ or I RB approval I RB approval 8% 8% 13% 13% 13% 13% 7% 7%
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13% 9% 14% 8% 17% 7% 0% 10% 20% 30% 40% 50% 60% 70% 10 Years FY02 FY03 FY04 FY05 FY06 NAI VAI OAI
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FY02 FY02 FY03 FY03 FY04 FY04 FY05 FY05 FY06 FY06 I nadequate initial I nadequate initial &/ or continuing &/ or continuing review review 24% 24% 25% 25% 50% 50% 37% 37% 17% 17% 22% 22% 12% 12% I nadequate minutes I nadequate 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 determination determination 10% 10% 16% 16% 34% 34% I nadequate I nadequate membership roster membership roster 13% 13% 20% 20% 21% 21% 12% 12%
FY06 – Lack of Quorum & Reporting Non-Compliance 12%
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15 41 41 136 72 154 82 20 40 60 80 100 120 140 160 FY02 FY03 FY04 FY05 FY06
Red = # of inspections
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NAI VAI OAI
11% 36% 53%
17% 35% 48%
COMPLAINTS ALL INSPECTIONS
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Application I ntegrity Policy (i.e. multiple applications) Application I ntegrity Policy (i.e. multiple applications)
Lifted from 2 firms Lifted from 2 firms
I ntegrity Holds (i.e., single application) I ntegrity Holds (i.e., single application)
Lifted from 2 firms Lifted from 2 firms Reapplied to 1 firm Reapplied to 1 firm
Rescission, Withdrawal, NSE Rescission, Withdrawal, NSE
1 Ortho firm had 510(k)s WD 1 Ortho firm had 510(k)s WD 3 IVD firms had 510(k)s WD or NSE 3 IVD firms had 510(k)s WD or NSE
Disqualifications Disqualifications
Levied against 1 Clinical Investigator Levied against 1 Clinical Investigator
Administrative Restrictions on I RBs Administrative Restrictions on I RBs
Levied against 1 IRB Levied against 1 IRB
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I nform the site that the FDA may inspect their I nform 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 time inspection at any time Ensure that the site understands that the pre Ensure that the site understands that the pre-
announcement is not “ “an appointment an appointment” ” to be to be scheduled at the site scheduled at the site’ ’s convenience, but a s convenience, but a courtesy pre courtesy pre-
notification to allow the site time to collect records and notify relevant study collect records and notify relevant study personnel personnel MDUFMA 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 review jeopardizing this timely review
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I nform the site at the beginning of the study what I nform 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 up up-
coming 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 person and 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 problems at sites where monitoring identified problems
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Make all study records available Make all study records available
Regulatory documents Regulatory documents
Study protocols, protocol amendments, IRB approvals and reports, Study protocols, protocol amendments, IRB approvals and reports, study device accountability records, monitoring logs, site perso study device accountability records, monitoring logs, site personnel nnel logs, study subject enrollment logs, etc. logs, study subject enrollment logs, etc.
Sponsor correspondence Sponsor correspondence
Letters, newsletters, memos, work instructions, e Letters, newsletters, memos, work instructions, e-
mails, monitoring visit reports, telephone contacts, etc. visit reports, telephone contacts, etc.
Study subject records Study subject records
Consent forms, Case Report Forms/ Consent forms, Case Report Forms/ CRFs CRFs, clinic charts, subject , clinic charts, subject diaries, lab reports, hospital records, data queries, adverse ev diaries, lab reports, hospital records, data queries, adverse event ent records, etc. records, etc.
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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 appropriate appropriate Document the inspectional coverage Document the inspectional coverage Document what information or records were Document what information or records were provided to the investigator provided to the investigator Be cordial and cooperative Be cordial and cooperative
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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 meeting closeout meeting Respond 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 verbally verbally Submit 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 classification evaluated before inspection classification Adequate responses may have a favorable impact Adequate responses may have a favorable impact
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I t may be helpful to provide support staff or I t 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
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I f no FDA 483 or significant problems, then no I f no FDA 483 or significant problems, then no response necessary response necessary I f FDA 483 issued, submit prompt written I f FDA 483 issued, submit prompt written response 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 Timelines for implementation Timelines for implementation
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Consider requesting a meeting with the District Consider requesting a meeting with the District Office or the Center when Office or the Center when
Inspection found significant violations Inspection found significant violations There were communication concerns with the investigator, i.e., There were communication concerns with the investigator, i.e., major disagreements or misunderstandings major disagreements or misunderstandings There are complex product, process, or study issues There are complex product, process, or study issues
90
The American Public is our customer The American Public is our customer We work together to serve our customer We work together to serve our customer Collaboration between FDA, researchers, and industry is Collaboration between FDA, researchers, and industry is vital vital Safe and effective products is a collaborative goal Safe and effective products is a collaborative goal Consumers expect safe and effective products Consumers expect safe and effective products Public confidence is influenced by use of products Public confidence is influenced by use of products Result is better health for all Result is better health for all
91
92
For a multi For a multi-
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 I RBs I RBs or report to
CI s CI s with request that they notify their with request that they notify their I RBs I RBs? ?
See FDA Information Sheets: Sponsor, Investigator, IRB Inter See FDA Information Sheets: Sponsor, Investigator, IRB Inter-
relationships Sponsor can report to all Sponsor can report to all CIs CIs with request for CI to notify IRB with request for CI to notify IRB Or, sponsor can report to Or, sponsor can report to IRBs IRBs with with “ “cc cc” ” to to CIs CIs
93
How would FDA evaluate a non How would FDA evaluate a non-
clinical device study in which in study in which in-
vivo and ex-
vivo study components are conducted under non components are conducted under non-
GLP (in (in-
vivo) and GLP (ex-
vivo) compliance?
CDRH does not apply GLP to non CDRH does not apply GLP to non-
clinical studies CDRH evaluates the controls in place to assure accuracy CDRH evaluates the controls in place to assure accuracy and completeness of data and completeness of data CDRH may conduct an audit of the data CDRH may conduct an audit of the data