Recommendation Letter for a Gun Permit FDA Compliance Enforcement by kbl15758

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									 FDA Compliance Enforcement
Actions: What you need to know
         for clinical device trials
    The 3rd Annual FDA Regulatory and Compliance Symposium
       Track 3- Pharma Product Development and Clinical Trials
                                             August 23, 2007
                                             Cambridge, MA
 The 3rd Annual FDA Regulatory
  and Compliance Symposium
PRESENTED BY:
 Sonali P. Gunawardhana M.P.H., J.D.,
 LL.M.
 Regulatory Counsel
 Food and Drug Administration
 Center for Devices and Radiological
 Health
 Office of Compliance
 Division of Bioresearch Monitoring
            Devices vs. Drugs

   How do studies with investigational
    devices differ from those with drugs and
    biologics?
     Nature of industry
     Statutory distinctions
     Regulatory distinctions
     Research distinctions
                    Device Firms

   Entrepreneurial firms common
     93% have fewer than 100 employees
     Venture capitalized
   Diverse and specialized products
     Principles of operation and intended uses
   Device “developer” often involved
   Minimal clinical trial experience
   Rapid product cycles limiting testing time
             Statutory Distinctions

 Devices lack market exclusivity provisions
    Waxman-Hatch (drugs)
    Orphan drug (drugs/biologics)
 Differences in standards of approval
    “Substantial” adequate and well-controlled trials (drug)
    “Reasonable” valid scientific evidence (device)
 Devices must down regulate
    FDAMA (1997) “least burdensome” provision
        Valid Scientific Evidence*


   Well-controlled investigations
   Partially controlled studies
   Studies and objective trials without matched
    controls
   Well-documented case histories by qualified
    experts
   Reports of significant human experience with
    a marketed device
                                    * 21 CFR 860.7
                Research Applications


   Investigational New Drug (IND) application
     Covers all research (drugs and biologics)
     21 CFR Part 312
   Investigational Device Exemption (IDE)
       Covers significant risk research
            Implants, life-threatening, or sight-threatening
       21 CFR Part 812
      Regulatory Distinctions

 IDE exempt studies
     In vitro diagnostics (IVDs)
     In commercial use before May 28, 1976
     Consumer preference testing
     Solely for veterinary use
     Post Approval Studies
                   Marketing Applications


   New Drug Application             Premarket Approval Application
    (NDA)                             (PMA)
       Innovator                        New Use, Technology, or Class III
       21 CFR Part 314                  21 CFR Part 814
   Abbreviated New Drug             Premarket Notification (510(k))
    Application (ANDA)                   Substantial equivalence
       Substantial equivalence          21 CFR Part 807
       21 CFR Part 314              Humanitarian Device Exemption
   Biologics Licensing               (HDE)
    Application (BLA)                    Similar to Orphan Product
       Innovator                        21 CFR Part 814
       21 CFR Part 601              In Vitro Diagnostics (IVDs)
                                         21 CFR Part 809
 Product Distinctions




vs.
    Charging for Investigational
             Products
 Devices: Always have been able to
  charge in order to recoup the research
  cost. This request for reimbursement is
  generally submitted in the IDE.
 Drugs: Special request is made for
  reimbursement – this was not the norm in
  the past but now there is a move towards
  making it easier for reimbursement.
               Combination Products

   Types of products
       Drug/device, biologic/device, drug/biologic, or
        drug/device/biologic
   Products are assigned to lead Center based upon
    primary mode of action
       Other Centers provide consulting reviews
   Product is required to follow regulation of lead
    Center
   Important to seek early consultation
       FDA’s Office of Combination Products
       Enforcement Actions

  REASONS WHY SOME OF THESE
  ACTIONS ARE IMPLEMENTED:
 Untitled Letters/Warning Letters
 Application Integrity Policy/ Integrity
  Hold
 Notice of Initiation of Disqualification
  Proceedings and Opportunity to Explain
  (NIDPOE)
           Compliance Tools

   Untitled/Warning letter    Invoke Application
   Re-inspection               Integrity Policy or Integrity
   Informal conference         Hold
   3rd party audits           Revoke marketing or
                                research permit
   Rejection of site data
                               Civil Money Penalties
   Disqualification
                               Injunction
       CI, IRB, or GLP
                               Prosecution
         Untitled Letters

■ Untitled Letters are issued when
  substantial violations are documented
  during inspection and requests voluntary
  corrective action.

■Unlike Warning Letters, Untitled Letters
 are not posted on the FDA website.
              Warning Letters

   The Warning Letter is the agency’s principal
    means of notifying regulated industry of
    violations (prior notice) and achieving prompt
    voluntary correction.

   The Warning Letter clearly states that if there is
    a failure to promptly achieve correction the
    FDA may take enforcement action without any
    further notice.
  CDRH BIMO INSPECTIONS
         Fiscal Years 2002 - 2006
500


400    357    353   350
                           332    336

300


200


100
      FY02   FY03   FY04   FY05   FY06
 CDRH 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
       CDRH BIMO Warning Letters

50

45

40

35

30

25
                          44
20

15                 31            30
                                        24
10
     14
5            9

0
     FY01   FY02   FY03   FY04   FY05   FY06
      CDRH BIMO Warning Letters

50


                    3
40
                    7



30                  10     1            GLP
             7             3
                                        IRB
                           6      3     Sponsor
20           7
                                  3     CI


                    24
10           17
                           20
                                  18
      2

      7

0
     FY02   FY03   FY04   FY05   FY06
CDRH BIMO Compliance Rates

70%

60%

50%
                                                    NAI
40%                                                 VAI
30%                            24%                  OAI
                        17%
20%     13%
                                      15%
                 12%                         11%
10%

 0%
      10 Years   FY02   FY03   FY04   FY05   FY06
            CDRH BIMO OAI Rates
      (with & w/o “For Cause” Inspections)

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

30%

                               24%

20%
                   17%
                               16%
                                        15%
                   13%
                                                         11%
10%       10%
                                        9%

        7%                                               5%

0%
      10 Years   FY03        FY04     FY05           FY06
      CDRH Sponsor Compliance Rates

70%
                                                   NAI
60%                                                VAI
                                                   OAI
50%

40%

30%                                31%
                           24%
20%       19%
                                           15%
10%                10%                             11%


0%
      10 Years   FY02    FY03    FY04    FY05    FY06
      CDRH Sponsor Compliance Rates

70%
                                                 NAI
60%
                                                 VAI
50%                                              OAI
40%
                            31%
30%                  24%
      19%
20%
              10%
10%                                15%
                                          11%     10%
0%
       10     FY02   FY03   FY04   FY05   FY06    FY06
      Years                                      (NFC)
             Sponsor Deficiencies
           Fiscal Years 1999 - 2006
                     FY
                    1999 2000 2001 2002 2003 2004 2005 2006

Inadequate          65% 68% 65% 33% 37% 40% 24% 23%
monitoring

Failure to secure   27% 44% 27% 19% 24% 21% 15% 13%
investigator
compliance
Inadequate          23% 28% 19%    7%   19% 16% 18% 15%
device
accountability
Obtain FDA/IRB                     4%   18% 11%   8%   5%
approval
      CDRH Clinical Investigator
         Compliance Rates
70%

60%

50%

40%                                                 NAI
                                                    VAI
30%
                               21%                  OAI
                        17%           17%
20%              15%
        11%                                  11%
10%

0%
      10 Years   FY02   FY03   FY04   FY05   FY06
        CDRH Clinical Investigator
           Compliance Rates
70%
60%
50%
40%                                                      NAI
                                                         VAI
30%
                            21%                          OAI
                     17%           17%
20%           15%
      11%                                 11%
10%                                                 7%
0%
       10     FY02   FY03   FY04   FY05   FY06    FY06
      Years                                      (NFC)
         Common Investigator
            Deficiencies
   Follow investigational plan, investigator
    agreement, or protocol
   Protocol deviations
   Inadequate subject protection or informed
    consent
   Inadequate device accountability
   Lack of FDA or IRB approval
   Inadequate reporting of UADEs to Sponsor or
    IRB
      CDRH IRB Compliance Rates

70%
60%
50%
40%                                                      NAI
                                                         VAI
30%
                                                         OAI
                                   17%
20%
10%   13%                   14%
              9%                                    5%
                     7%                   8%
0%
       10     FY02   FY03   FY04   FY05   FY06    FY06
      Years                                      (NFC)
                 IRB Deficiencies
             Fiscal Years 1999 - 2006
                      FY
                     1999    2000    2001    2002    2003     2004   2005   2006

Inadequate initial   64%     56%     39%     24%      25%     50%    37%    38%
&/or continuing
review
Inadequate           61%     42%     35%     11%      42%     28%    17%    20%
minutes
Lack of or           58%     42%     57%     10%      16%     34%    22%    7%
incorrect SR/NSR
determination
Inadequate           31%     22%     30%     13%      20%     21%    12%    12%
membership roster



                     Addendum: FY06 – Lack of Quorum & Reporting
                                Non-Compliance 12%
                             CDRH BIMO OAI
                     Follow-up Inspections (as of 9/30/06)



Recidivist OAIs               18%
evenly distributed
across program
areas:                                                  NAI
GLP = 17%                                    52%        VAI
                                                        OAI
IRB = 25%                     30%
CI   = 33%
S/M = 25%




                                    N = 64
                  CDRH BIMO Vulnerable
                   Population Inspections


                       10%


OAI split among
                                       32%
Sponsor (44%)
and Clinical                                 NAI
Investigator                                 VAI
(56%) programs                               OAI

                       58%




                             N = 164
 CDRH BIMO COMPLIANCE RATES
  FY06: All Inspections vs. Complaints

All Inspections                        Complaints

  11%                    NAI
          36%                                      35%

                         VAI
                                      48%
                                                   17%
  53%
                         OAI



    333% higher OAI rate in complaint follow-ups
  CDRH BIMO COMPLIANCE RATES
  FY97-06: All Inspections vs. Complaints

All Inspections                       Complaints

  14%                    NAI
                                               26%
         31%
                         VAI
                                      46%
  55%                                          28%
                         OAI



    230% higher OAI rate in complaint follow-ups
               over a 10 year period
What does AIP mean?
  Application Integrity Policy


■What is “Wrongful Act”?

■What is an “Untrue Statement of
 Material Fact”?
                Wrongful Act

   “…A wrongful act is any act that may subvert
    the integrity of the review process. A wrongful
    act includes but is not limited to, submitting a
    fraudulent application, offering or promising an
    illegal gratuity, or making an untrue statement
    of material fact. A wrongful act also includes
    submitting data that are otherwise due to, for
    example, a pattern of errors whether caused by
    incompetence, negligence, or a practice such as
    inadequate standard operating procedures or a
    system-wide failure to ensure the integrity of
    data submissions…”
    Untrue Statement of Material
                Fact
 “…An “untrue statement of material fact”
  is a false statement, misstatement, or
  omission of fact. A determination that an
  untrue statement is material is necessary
  for purposes of invoking the AIP…”
 Materiality- Under Development
 Agent- Under Development
    Examples of Wrongful Acts

   Submit Fraudulent Application
   Offer Bribe/Illegal Gratuity
   Make Untrue Statement of Material Fact
   Submit Data Otherwise Unreliable
   Omitted Data
   Manufactured Data
   Altered Data
   Other Data Inconsistencies
       Examples of Data Integrity
              Problems
   Falsification of Specific Data or an Entire
    Submission
   Omission of Relevant and Important Data and
    Information
   Inability to Account for Patient Population
   Inability to Account for Investigational Devices
   Failure to Maintain Adequate Investigational
    Records
   Unreported Changes to the Investigational
    Device
    Process: Pre-Discovery Stage

   Tips from Anonymous/Known Informant
   Current/Former Employees
   Former Business Partners
   Patients
   Other Agencies (SEC, FTC, CMS)
   Suspicious Data Found During
    Scientific/Clinical Review
   Observations During Pre-Approval Inspection
        Process: Inspection Stage

   Inspection of Company/ Sponsor
   Inspection of Clinical Sites
   Inspections of CRO’s
   Inspection of Clinical Sites
    •   Data Audit
    •   System Audit
    •   Company Internal Documents
           Invoking the AIP

   Pattern or Practice of Wrongful Conduct
   Significant Question of Data Reliability
   System-wide Failures
   Decision made by Center Director, The
    Division of Bioresearch Monitoring and
    The Office of Device Evaluation Integrity
    Officer
              Agency’s Action

   Defer Scientific Review
   Issues Letter to Applicant
   Conducts Validity Assessment
       Scope, extent of problem
       Inspection
       Audit Report
    Applicant’s Responsibilities
   Cooperation with FDA
   Internal Review (Audit)
   Independent Outside Consultant
   Identify/Remove Individuals
   Submit CAP
       Commit to Safety, Efficacy and Quality
       Describe Ethics/Compliance Programs
       Standard Operating Procedures
       Steps to Address and Prevent Wrongful Acts
   Application Withdrawal, Patient Notification,
    Product Recall etc.
      Global Industry Issues

 Systems to identity and/or address
  regulatory shortcomings
 Systems to correct/prevent recurring
  issues
 Accountable company culture
 Environment of conflict of interest
        FDA Responsibilities

 Review of Corrective Action Plan

 Field Onsite Inspection & Recommendation

 Headquarters Review

 Letter to Applicant
    Center Director’s Signature
 Application Integrity Program

   “Fraud, Untrue Statements of
    Material Facts, Bribery, and Illegal
    Gratuities; Final Policy,”
56 F.R. 46191, 9/10/91
http://www.fda.gov/ora/fr/fraud_ill_grat.html
    Application Integrity Program

   Application Integrity Policy
    RPM Chapter 10
http://www.fda.gov/ora/compliance_ref/rpm_new2/rpm10aip.html



 “Points  to Consider for Internal
    Reviews and Corrective Action
    Operating Plans”
http://www.fda.gov/ora/compliance_ref/aip_points.html
    Program Offices/Contacts

   ODE/OIVD Integrity Officer
   Carl DeMarco: 240-276-3993
   Division of Bioresearch Monitoring,
    Office of Compliance
   Michael Marcarelli: 240-276-0125
   Application Integrity Policy Committee
   FDA Office of Criminal Investigations
  Notice Of Initiation Of Disqualification
 Proceedings And Opportunity To Explain

 Applies to Clinical Investigators
 Some clinical investigators may have
  already received a Warning Letter but in
  some cases violations discovered on the
  first inspection are serious enough for the
  Center to issue the NIDPOE.
 Disqualification Of
Clinical Investigators
                Disqualification Of
               Clinical Investigators



A NIDPOE letter informs the recipient clinical investigator that
FDA is initiating an administrative proceeding to determine
whether the clinical investigator should be disqualified from
receiving investigational products pursuant to the Food and Drug
Administration's regulations. Generally, FDA issues a NIDPOE
letter when it believes it has evidence that the clinical investigator
repeatedly or deliberately violated FDA's regulations governing the
proper conduct of clinical studies involving investigational
products or submitted false information to the sponsor.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   Definition under CFR 812.119

   If FDA has information indicating that an investigator
    has repeatedly or deliberately failed to comply with the
    requirements of part 812, part 50, or part 56 of this
    chapter, or has repeatedly or deliberately submitted
    false information either to the sponsor of the
    investigation or in any required report, the Center for
    Devices and Radiological Health will furnish the
    investigator written notice of the matter under
    complaint and offer the investigator an opportunity to
    explain the matter in writing, or, at the option of the
    investigator, in an informal conference.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   If an explanation is offered and accepted by the
    Center for Devices and Radiological Health, the
    disqualification process will be terminated. If
    an explanation is offered but not accepted by
    the Center for Devices and Radiological Health,
    the investigator will be given an opportunity for
    a regulatory hearing under part 16 of this
    chapter on the question of whether the
    investigator is entitled to receive investigational
    devices.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   After evaluating all available information, including
    any explanation presented by the investigator, if the
    Commissioner determines that the investigator has
    repeatedly or deliberately failed to comply with the
    requirements of this part, part 50, or part 56 of this
    chapter, or has deliberately or repeatedly submitted
    false information either to the sponsor of the
    investigation or in any required report, the
    Commissioner will notify the investigator, the sponsor
    of any investigation in which the investigator has been
    named as a participant, and the reviewing IRB that the
    investigator is not entitled to receive investigational
    devices. The notification will provide a statement of
    basis for such determination.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   Each investigational device exemption (IDE)
    and each cleared or approved application
    submitted under this part, subpart E of part 807
    of this chapter, or part 814 of this chapter
    containing data reported by an investigator who
    has been determined to be ineligible to receive
    investigational devices will be examined to
    determine whether the investigator has
    submitted unreliable data that are essential to
    the continuation of the investigation or essential
    to the approval or clearance of any marketing
    application.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   Consent Agreements
   List specific responsibilities of the Clinical
    Investigator in terms of coming into
    compliance.
   Can last for a specific amount of time or can be
    an agreement the disqualification is permanent.
   Can be viewed as a tool to bring the Clinical
    Investigator into compliance which in turn
    serves as a way to educate the Clinical
    Investigator as to their regulatory responsibility
    for the current and future clinical trials.
     Notice Of Initiation Of Disqualification
    Proceedings And Opportunity To Explain

   What does disqualification mean for the
    Sponsor?
      The data from the disqualified clinical site
       can not be used in their submission.
       (Monetary and Ethical considerations)
      Sponsor is responsible for oversight of all
       clinical investigators so there might be some
       serious issues in terms of monitoring which
       can lead to further regulatory action.
 Notice Of Initiation Of Disqualification
Proceedings And Opportunity To Explain

   What does disqualification mean for the
    clinical investigator?
     Their name is added to a list on the FDA
      website that indicates that they are
      disqualified from participation in any type of
      clinical trial.
     Generally it means that they have incurred
      legal fees and it can open them up to more
      eminent liability.
     Some might feel that it has had a negative
      impact on their reputations.
          Web Sites


Device Advice
www.fda.gov/cdrh/devadvice


CDRH BIMO site
www.fda.gov/cdrh/comp/bimo.html
          Contact Information

Sonali P. Gunawardhana
FDA, CDRH, Office of Compliance
9200 Corporate Blvd
HFZ-310
Rockville, MD 20850
(240)276-0246
sonali.gunawardhana@fda.hhs.gov

								
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