Medical Device Regulatory Update

Medical Device Regulatory Update Matthew Tarosky Division of Bioresearch Monitoring Office of Compliance Center for Devices and Radiological Health US...
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Medical Device Regulatory Update Matthew Tarosky Division of Bioresearch Monitoring Office of Compliance Center for Devices and Radiological Health US Food and Drug Administration 1

Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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CDRH’s mission is… Getting safe and effective devices to market as quickly as possible…

… while ensuring that devices and radiological products currently on the market remain safe and effective.

Helping the public get science-based accurate information about medical devices and radiological products needed to improve health 3

CDRH’s vision is... Total Product Life Cycle

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Who We Are… CDRH is a team of over 1,000 dedicated, highly skilled, and internationally respected public health employees Our employees are drawn from a wealth of science and public health professions Biologists, chemists, physicists, engineers, microbiologists, statisticians, epidemiologists, physicians, nurses, pharmacologists, veterinarians, toxicologists, and specialists in public health education and communication

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CDRH’s Organizational Chart Office of the Center Director Daniel G. Schultz, M.D., Director Linda Kahan, Deputy Director Lillian Gill, D.P.A., Senior Associate Director

Postmarket Transformation Management Group

Don St. Pierre Diane Mitchell, M.D. Susan Meadows

Office of Compliance

Timothy A. Ulatowski

Les Weinstein

Office of Device Evaluation

DonnaDonna-Bea Tillman, Ph.D.

Office of Management Operations

Ruth E. McKee

Office of Communication, Education, & Radiation Programs

Lynne L. Rice

CDRH Ombudsman

Office of In Vitro Diagnostic Device Evaluation & Safety

Steven I. Gutman, M.D.

Office of Surveillance & Biometrics

Susan N. Gardner, Ph.D.

Office of Science & Engineering Laboratories

Larry Kessler, Sc.D.

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CDRH’s Compliance Office Office of Compliance Tim Ulatowski, Director Larry Spears, Deputy Director Regulatory Kimber Richter, M.D., Deputy Director Medical

Division of Enforcement A

Division of Enforcement B

Betty Collins, Director

Gladys Rodriguez, Director

Division of Bioresearch Monitoring

Division of Risk Management Operations

Michael Marcarelli, Director

Karen Moss, Director

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What does the domestic medical device industry look like? Employees Per Firm* 3%

1%

5% 3% < 10

1% 1%

6% 1%

7% 10 .. 29 30 .. 59

16%

60 .. 99

Smallest Firms 66%

Largest Firms

100 .. 499 500 or more

90%

Total Manufacturers*

Total 2004 Sales

N = 14,937

$320 Billion

* Dun & Bradstreet 2004 Medical Device Firm Data 8

Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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Priorities Medical Device User Fee & Modernization Act Postmarket Transformation Information Technology Staff Development Device Critical Path White Oak Campus

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Medical Device User Fee and Modernization Act of 2002 MDUFMA I Sunsets 9/30/07 Annual public stakeholder meetings

MDUFMA II Negotiations with industry over last 18 months Stronger performance goals More predictable user fee structure Registration, annual reports

Sent to Congress for review/approval 11

Postmarket Transformation

Connecting the dots… Premarket Approval Process

Adverse Event Reporting

Inspections

Problem Assessment Groups

Postmarket Problem Assessment

Postmarket Problem Identification Tools Additional Signals

Internal Data Analysis

Information Education

Post Approval Studies

Laboratory Research & Analysis

Information Dissemination

Postmarket Tools Public Health Response External Data Analysis Enforcement

Public Health Partners

Postmarket Problem Identification

Postmarket Problem Assessment

Postmarket Public Health Response 12

Postmarket Transformation Priorities

1.

Create a matrix organization to optimize medical device regulation across the Total Product Lifecycle

2.

Develop metrics and methods for tracking postmarket issues

3.

Pursue the development of unique identification (UDI)

4.

Propose mandatory electronic MDR reporting

5.

Revise and update the MAUDE system, and expand the premarket data-warehousing

6.

Increase the quality and quantity of Center/ORA/OCC interactions

7.

Develop and implement a risk-communication strategy

8.

Design a pilot project to test the usefulness of quantitative decisionmaking methods

9.

Enhance utility of MedSun programs 13

Matrix Organization

Establish cross-cutting product-related groups over the current functionallybased organization to: Foster information sharing and more effective PH promotion and protection Collaboration as a part of day-to-day operations, not just in crisis situations 14

Information Technology Turbo 510(k) Program http://www.fda.gov/cdrh/oivd/turbo510kcesub1.html

eCopy Initiative http://www.fda.gov/cdrh/elecsub.html May be submitted for any premarket submission Immediately available for CDRH staff

eReview Streamline and facilitate review process

Electronic Medical Device Reporting Electronic adverse device effects as HL7 standard 15

Staff Development New Hires Shared Hires ODE-OC ODE-OSB

Medical Device Fellowship Program (MDFP) Special Government Employees (SGEs) as members and consultants to our 18 Advisory Panels Over 700 SGEs

Contractors Collaborations with the clinical community and professional groups 16

Device Critical Path A serious commitment to make product development more predictable and less costly Work together with industry, academia, and patient care advocates to modernize, develop and disseminate solutions (tools) to address scientific hurdles in product development

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Device Critical Path Market Application

Basic Research

Prototype Design or Discovery

Preclinical Development

Clinical Development

Approval

FDA Filing/ Approval & Launch Preparation

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

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Device Critical Path Drugs

Devices

Pure molecules

Complex components

Toxicology

Biocompatibility

Short half-life

Durable Equipment

Long market life

Rapid product cycles

Drug interactions

Device Malfunction

Wrong Drug / Dose

User Error

Clinical studies

Bench and Clinical studies

Good Manufacturing Practices (cGMP)

Quality Systems (ISO 9000) 19

Device Critical Path Projects Working with a West Coast University on combination products Analyze the development of biomarkers and diagnostics and their application to pharmacogenomics Identify barriers to drug/diagnostic device co-development

Working with the Juvenile Diabetes Research Foundation Accelerate development of a closed-loop system using continuous glucose sensors and insulin pumps linked by a control-algorithm

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Device Critical Path Projects Working with academia on peripheral vascular stent development Computer models of human physiology to test and predict failure (before animal and human studies)

Validating surrogate markers especially in the area of cardiovascular devices “Late loss” via imaging

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White Oak Campus Office of Science & Engineering Laboratories move complete Remaining CDRH staff move anticipated in March 2009

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Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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Initiatives International Harmonization Office of Regulatory Affairs (ORA) Transformation Risk-Based Work Plan Bioresearch Monitoring (BIMO) Modernization Probability Sampling

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International Harmonization Educating Foreign Government Officials on the U.S. Regulatory Process Supporting Global Harmonization, Mutual Recognition Agreements (MRAs) and other International Agreements Managing US/EC Mutual Recognition Agreement www.fda.gov/cdrh/mra 11th Conference of Global Harmonization Task Force, October 3-4, 2007, Washington, DC

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ORA Reorganization Strategic Plan Framework Leveraging Workforce Capability Quality Management Systems Risk Management Information Technology Laboratories Imports

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ORA Reorganization Proposed Organization Chart Consolidate 13 labs and align under Science Directorate Consolidate 19 district offices under Inspection Compliance Directorate Eliminate Regional Offices Hire 100 new consumer safety officers

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Risk-Based BIMO Inspections Allegations of Research Misconduct For Cause Assignments

PMA and Panel Track Supplements Directed Inspections

IDE Early Intervention Inspections Novel technologies Vulnerable populations

Non-compliant history Previously violative (OAI) inspection

Routine surveillance Institutional Review Boards 28

BIMO Modernization HSP/BIMO Council Mandate to systematically and comprehensively reexamine FDA’s approach to human subject protection and bioresearch monitoring 5 Year Charter Oversight and central coordination of all modernization activities related to BIMO and HSP

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Clinical Research Landscape

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Regulatory Research Landscape

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Evolution of Clinical Trial Practices New trial methods and designs New methods of data collection and processing Electronic data capture

Globalization New arrangements Sponsors and various contractors, among investigators, among institutions, among IRBs, and rise of free-standing for-profit study centers

Greater number of studies in children and other vulnerable populations Combination products 32

FDA’s Oversight Must Evolve Too… How should FDA regulate this new clinical trial paradigm? Responsibilities of investigators Data quality

How should FDA facilitate reasonable & effective IRB oversight of clinical trials? IRB oversight of human subject protection FDA oversight of IRB function

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FDA’s Oversight Must Evolve Too… Common standards and regulatory requirements for electronic data handling Accommodate globalization of clinical trials Comprehensive approach to protection of vulnerable populations

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Internal Challenges BIMO highly decentralized function Units of varying size in review centers Field force; only a few experts in any given district Very small centralized group in OC

Relative lack of guidance and standards Non-automated environment Multiplicity of stakeholders

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Areas of Interest… Risk Management Quality Systems Transparency Critical Path

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Current HSP/BIMO Issues Subject Safety CI training/supervision Oversight of sub- and co-investigators

A Strong IRB System Registration Modernize AE reporting Guidance

Protection of Vulnerable Populations Pediatric Decision-impaired Emergency Research 37

Current HSP/BIMO Issues Data Quality and Integrity Common definition(s) of “high-quality” data Methods to assess Quality systems (build-in vs. inspect-in) Evaluating the role and performance of monitoring, auditing, and inspecting Pursuing falsification and high-risk challenges

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Current HSP/BIMO Issues Advancing Technology CCT (computerized systems used in clinical trials) e-PRO (Patient Reported Outcomes) EHR (Electronic Health Records)

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

GCP Information from/to FDA For Consumers and for Professionals Reporting of and responsiveness to “complaints” 39

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

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

Direct Final Rule and Draft Guidance – INDs: Approaches to Complying with CGMP (1/06) http://www.fda.gov/cder/guidance/6164dft.pdf

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Initial Accomplishments Updated: Five Information Sheet Guidances for Sponsors, Clinical Investigators, and IRBs 2/06 http://www.fda.gov/oc/ohrt/irbs/default.htm

Final Guidance: Using a Centralized IRB Review Process in Multicenter Trials (3/06) http://www.fda.gov/cder/guidance/OC2005201fnl.pdf

Final Guidance: Establishment and Operation of Clinical Trial Data Monitoring Committees (3/06) http://www.fda.gov/cber/gdlns/clintrialdmc.pdf

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

Final Guidance: Informed Consent for IVD device studies using leftover specimens that are not individually identifiable (4/06) http://www.fda.gov/cdrh/oivd/guidance/1588.pdf

Draft Guidance: Adverse Event Reporting – Improving Human Subject Protection (4/07) http://www.fda.gov/cber/gdlns/advreport.pdf

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Data Quality Initiative Joint DIA and FDA Workshop, May 10-11, 2007 Defining and Implementing Quality in Clinical Investigations from Design to Completion

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

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Probability Sampling Why? Develop a science-based report card of the device research community Large device researcher population; scarce agency resources

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Probability Sampling How? Random sample of active IDEs Stratified by device type & geography Completed 199 CI inspections Focus on protocol adherence and human subject protection issues, not data verification Use CI Compliance Program (83811) Analysis, assessment, and interventions 46

Probability Sampling Status Sampling plan complete FDA field investigators to conduct inspections 202 assignments issued (FY04, 05, & 06) 198 inspections classified to date

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Probability Sampling Interim Results

PS CI Inspections 7%

All CI Inspections NAI

15%

37%

37%

VAI 48%

56%

OAI 48

Probability Sampling Interim Results

PS CI Inspections 7%

All CI Inspections* NAI

9%

37%

39%

VAI 52%

56%

OAI *Excluding For Cause Inspections

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Probability Sampling Interim Results 72 hrs per operation (79 hrs planned) 53% (105/198) issued 483s (51% for all CIs) 7% (13/198) OAI Rate (15% for all CIs) Inspection findings similar Possible explanations for OAI disparity Studies involve smaller number of subjects Outreach having impact (i.e., active studies) Higher rate for directed / for cause

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Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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Guidance and Standards Guidance Development CDRH has instituted guidance prioritization CDRH frequently reaches out to industry for drafts of guidance that would be useful CDRH added guidance development to its performance scorecard FY 06 goal was 32 guidances out of CDRH Results - 46 guidances out of CDRH

Standards Development Standards Participation 38 Development Organizations 238 Liaison Reps: 220 National Committees and 128 International Committees 538 Standards Activities: 365 National and 173 Other Activities

A significant number of applications reference consensus standards 52

Guidance Development The Review and Inspection of Premarket Approval Applications under the Bioresearch Monitoring Program Roles and Responsibilities of Device Clinical Investigators A web-based training program

Monitoring of Device Clinical Investigations

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BIMO PMA Review Guidance Draft Issued June 2006

Final Circulating September 2007?

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BIMO PMA Review Guidance Goals Describe the sequence of events as the Office of Compliance completes a BIMO review of a PMA Describe the administrative process and the timeframes involved with each step Describe how the clinical or non-clinical inspections fit into the approval process

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BIMO PMA Review Guidance BIMO inspections issued within 30 days For original PMAs By review division request, for PMA supplements

Sites selected may include Sponsor, study monitor, or CRO Clinical investigator Laboratory conducting non-clinical studies

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BIMO Review Milestones BIMO BIMO BIMO Inspection PMA Inspection Receipt Assignments Receipt Complete of PMA Issued

0

7

30

70/80

BIMO BIMO Inspection Completes Report Review Received

Final BIMO Recommendation

90/100 120/130 140/150

Review Clock in Calendar Days 57

BIMO Review Delays Submission of incomplete information Complete contact information for Clinical Investigators Institutional Review Boards IRB-approved informed consent documents Location where clinical study records are maintained Study protocol including history of changes Sample case report forms Data tabulations (line data) that support key S&E endpoints Sorted by site then subject for each pivotal study Standard acceptable electronic format (e.g., SAS XPT)

Site readiness Access to study records 58

BIMO Review Outcomes Inspection results are usually supportive of the review process Sometimes inspection results can have an adverse impact on the review process Deficiency letter Subjects failed to meet the inclusion criteria Underreporting of unanticipated adverse device effects Failure to obtain informed consent

Application Integrity Policy Pattern or practice of wrongful acts that effect data reliability 59

Guidance Development Guidance for Industry: Guideline for the Monitoring of Clinical Investigations Issued in 1988 Not comprehensive

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Guidance Development Draft Guidance for Industry: Monitoring of Device Clinical Investigations FDLI facilitated meeting of research community Medical device manufacturers Health care professionals Medical device regulatory consultants Trade associations Device clinical trial experts Compliance officers

Draft circulating for final review 61

Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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Device GLP Program Status Historically, CDRH review divisions have not required animal safety studies to follow GLP Many marketed devices did not follow GLP Not feasible to require current manufacturers to follow GLP Especially if showing equivalence to predicate 63

Device GLP Program Status Inspections may be issued for non-GLP or GLP animal studies Focus on data audit or verification Less emphasis on GLP requirements More emphasis on auditing safety studies that support high-risk products

OAI applies to sites with data reliability issues Data falsification, omission, etc. 64

Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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Device BIMO Inspections

Fiscal Years 2002 - 2006 400

357

353

350

FY02

FY03

FY04

332

336

FY05

FY06

300

200

100

0 66

Device BIMO Inspections Fiscal Years 2002 - 2006 Inspected Entity

2002

2003

2004

2005

2006

Sponsor

72

81

73

70

53

CI

151

170

183

183

200

IRB

128

85

73

48

59

GLP

6

9

19

31

24 67

Device BIMO Warning Letters 50 45 40 35 30 25

44

20

31

15

30 24

10 5

14

9

0

FY01

FY02

FY03

FY04

FY05

FY06 68

Device BIMO Warning Letters 50

3 40

7 30

7 7

20

10

10

24 2

17

1 3 6

3 3

20

18

FY05

FY06

GLP IRB Sponsor CI

7 0

FY02

FY03

FY04

69

Device BIMO Compliance Rates 70% 60% 50% NAI VAI OAI

40% 30% 20%

24% 17%

13%

12%

10 Years

FY02

15%

11%

10% 0% FY03

FY04

FY05

FY06 70

Device BIMO OAI Rates OAI (NFC)

OAI

NFC = No “For Cause” inspections included

30% 24% 20% 17%

16%

13% 10%

10%

15% 9%

11% 5%

7% 0% 10 Years

FY03

FY04

FY05

FY06

71

Device Sponsor Compliance Rates 70%

NAI VAI OAI

60% 50% 40% 31%

30% 20%

24% 19%

10%

15% 10%

11%

0% 10 Years

FY02

FY03

FY04

FY05

FY06 72

Device Sponsor Deficiencies FY02

FY03

FY04

FY05

FY06

Inadequate monitoring

33%

37%

40%

24%

23%

Failure to secure investigator compliance

19%

24%

21%

15%

13%

Inadequate device accountability

7%

19%

16%

18%

15%

Obtain FDA/IRB approval

4%

18%

11%

8%

5% 73

Device Clinical Investigator Compliance Rates 70% 60% 50% NAI VAI OAI

40% 30% 20%

11%

15%

17%

FY02

FY03

21%

17% 11%

10% 0% 10 Years

FY04

FY05

FY06 74

Clinical Investigator Deficiencies

2002

2003

2004

2005

2006

Failure to follow investigational plan/regs/IA

44%

51%

54%

50%

44%

Protocol deviations (R&R)

20%

38%

16%

9%

22%

Inadequate subject protection/IC

21%

21%

24%

29%

20%

Inadequate device accountability

26%

18%

14%

7%

15%

8%

13%

13%

10%

7%

Lack of FDA &/or IRB approval

75

Device IRB Compliance Rates 70% 60% 50% NAI VAI OAI

40% 30% 17%

20% 10%

13%

0% 10 Years

14% 9%

7%

FY02

FY03

8% FY04

FY05

FY06 76

Device IRB Deficiencies FY02

FY03

FY04

FY05

FY06

Inadequate initial &/or continuing review

24%

25%

50%

37%

38%

Inadequate minutes

11%

42%

28%

17%

20%

Lack of or incorrect SR/NSR determination

10%

16%

34%

22%

7%

Inadequate membership roster

13%

20%

21%

12%

12%

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

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Allegations of Research Misconduct 160

154 136

140 120 100 80

72

82

60 40 20

41

41

FY03

FY04

15

0 FY02

FY05

Red = # of inspections

FY06 78

FY06 BIMO Compliance Rates AllINSPECTIONS Inspections ALL

Complaints COMPLAINTS NAI

11%

17%

36%

VAI

48% 35%

53%

OAI

79

FY06 Special Investigations Application Integrity Policy (i.e. multiple applications) Lifted from 2 firms

Integrity Holds (i.e., single application) Lifted from 2 firms Reapplied to 1 firm

Rescission, Withdrawal, NSE 1 Ortho firm had 510(k)s WD 3 IVD firms had 510(k)s WD or NSE

Disqualifications Levied against 1 Clinical Investigator

Administrative Restrictions on IRBs Levied against 1 IRB 80

Presentation Topics Introduction Priorities Initiatives Guidance Documents Non-clinical (GLP) Program Update Inspection Metrics BIMO Inspection Preparation

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How can a Sponsor Prepare a Site for a BIMO Inspection? Inform the site that the FDA may inspect their study site, and that they be prepared for an FDA inspection at any time Ensure that the site understands that the preannouncement is not “an appointment” to be scheduled at the site’s convenience, but a courtesy pre-notification to allow the site time to collect records and notify relevant study personnel MDUFMA mandates specific review deadlines, and inspections often cannot be postponed without jeopardizing this timely review 82

How can a Sponsor Prepare a Site for a BIMO Inspection? Inform the site at the beginning of the study what actions to take if they receive notification of an up-coming inspection Immediately notify the sponsor, monitor, IRB, etc. Ask sufficient questions so that they clearly understand which study will be inspected, who will be conducting the inspection, and the contact information for that person

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

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How can a Site Prepare for a BIMO Inspection? Make all study records available Regulatory documents Study protocols, protocol amendments, IRB approvals and reports, study device accountability records, monitoring logs, site personnel logs, study subject enrollment logs, etc.

Sponsor correspondence Letters, newsletters, memos, work instructions, e-mails, monitoring visit reports, telephone contacts, etc.

Study subject records Consent forms, Case Report Forms/CRFs, clinic charts, subject diaries, lab reports, hospital records, data queries, adverse event records, etc.

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How can the Sponsor or Site Manage a BIMO Inspection? Provide information/records that are clear and responsive to questions from the investigator, as appropriate Document the inspectional coverage Document what information or records were provided to the investigator Be cordial and cooperative

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How can the Sponsor or Site Manage a BIMO Inspection? Take notes on everything discussed by the FDA investigator during the inspection and at the closeout meeting Respond in writing to all the violations cited on the Form FDA 483 and the issues discussed verbally Submit the response to FDA as soon as possible after the completion of the inspection, so it can evaluated before inspection classification Adequate responses may have a favorable impact on the final classification of the inspection 86

How can the Sponsor or Site Manage a BIMO Inspection? It may be helpful to provide support staff or information that may be required in order to assist the site to appropriately respond to the observations

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How can the Sponsor or Site Respond to an Inspection? If no FDA 483 or significant problems, then no response necessary If FDA 483 issued, submit prompt written response Assess the root cause of the problem Explain actions to correct the problem Evaluate the extent of the problem Implement preventative actions to avoid recurrence Include supporting documentation Timelines for implementation

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How can the Sponsor or Site Respond to a FDA 483? Consider requesting a meeting with the District Office or the Center when Inspection found significant violations There were communication concerns with the investigator, i.e., major disagreements or misunderstandings There are complex product, process, or study issues

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Closing Perspective… Collaboration Built on Trust Ensures Success The American Public is our customer We work together to serve our customer Collaboration between FDA, researchers, and industry is vital Safe and effective products is a collaborative goal Consumers expect safe and effective products Public confidence is influenced by use of products Result is better health for all

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Thank you FDA looks forward to working with you to improve public health 91

Plenary Session Question #4 For a multi-site study, if the sponsor receives an UADE from one site, should the sponsor report this information directly to all IRBs or report to CIs with request that they notify their IRBs? See FDA Information Sheets: Sponsor, Investigator, IRB Interrelationships Sponsor can report to all CIs with request for CI to notify IRB Or, sponsor can report to IRBs with “cc” to CIs

92

Plenary Session Question #12 How would FDA evaluate a non-clinical device study in which in-vivo and ex-vivo study components are conducted under non-GLP (in-vivo) and GLP (ex-vivo) compliance? CDRH does not apply GLP to non-clinical studies CDRH evaluates the controls in place to assure accuracy and completeness of data CDRH may conduct an audit of the data

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