Transcript FDA Compliance Enforcement Actions: What you need to know in

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
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Device Firms

Entrepreneurial firms common
 93% have fewer than 100 employees
 Venture capitalized
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Diverse and specialized products
 Principles of operation and intended uses
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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*
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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
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Investigational New Drug (IND) application
Covers all research (drugs and biologics)
 21 CFR Part 312
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Investigational Device Exemption (IDE)
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Covers significant risk research
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Implants, life-threatening, or sight-threatening
21 CFR Part 812
Regulatory Distinctions
 IDE exempt studies
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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
(NDA)
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Innovator
21 CFR Part 314
Abbreviated New Drug
Application (ANDA)
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Substantial equivalence
21 CFR Part 314
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Innovator
21 CFR Part 601
Substantial equivalence
21 CFR Part 807
Humanitarian Device Exemption
(HDE)
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New Use, Technology, or Class III
21 CFR Part 814
Premarket Notification (510(k))
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Biologics Licensing
Application (BLA)
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Premarket Approval Application
(PMA)
Similar to Orphan Product
21 CFR Part 814
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.
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Combination Products
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Types of products
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Products are assigned to lead Center based upon
primary mode of action
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Drug/device, biologic/device, drug/biologic, or
drug/device/biologic
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
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Untitled/Warning letter
Re-inspection
Informal conference
3rd party audits
Rejection of site data
Disqualification
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CI, IRB, or GLP
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Invoke Application
Integrity Policy or Integrity
Hold
Revoke marketing or
research permit
Civil Money Penalties
Injunction
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
FY02
FY03
FY04
332
336
FY05
FY06
300
200
100
CDRH BIMO INSPECTIONS
Fiscal Years 2002 - 2006
Inspected
Entity
2002
2003
2004
2005
2006
72
81
73
70
53
CI
151
170
183
183
200
IRB
128
85
73
48
59
GLP
6
9
19
31
24
Sponsor
CDRH 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
CDRH BIMO Warning Letters
50
3
40
7
30
7
10
1
3
6
7
20
3
3
24
10
2
20
17
18
7
0
FY02
FY03
FY04
FY05
FY06
GLP
IRB
Sponsor
CI
CDRH 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
CDRH BIMO OAI Rates
(with & w/o “For Cause” Inspections)
OAI (NFC)
NFC = No “For Cause”
inspections included
OAI
30%
24%
20%
17%
16%
15%
13%
10%
11%
10%
9%
5%
7%
0%
10 Years
FY03
FY04
FY05
FY06
CDRH Sponsor Compliance Rates
70%
NAI
VAI
OAI
60%
50%
40%
31%
30%
24%
20%
19%
15%
10%
11%
10%
0%
10 Years
FY02
FY03
FY04
FY05
FY06
CDRH Sponsor Compliance Rates
70%
NAI
VAI
OAI
60%
50%
40%
31%
30%
24%
19%
20%
10%
10%
15%
11%
10%
FY06
FY06
(NFC)
0%
10
Years
FY02
FY03
FY04
FY05
Sponsor Deficiencies
Fiscal Years 1999 - 2006
FY
1999 2000 2001 2002 2003 2004 2005 2006
Inadequate
monitoring
65% 68% 65% 33% 37% 40% 24% 23%
Failure to secure
investigator
compliance
27% 44% 27% 19% 24% 21% 15% 13%
Inadequate
device
accountability
23% 28% 19%
Obtain FDA/IRB
approval
7%
19% 16% 18% 15%
4%
18% 11%
8%
5%
CDRH Clinical Investigator
Compliance Rates
70%
60%
50%
NAI
VAI
OAI
40%
30%
21%
20%
15%
17%
17%
11%
11%
10%
0%
10 Years
FY02
FY03
FY04
FY05
FY06
CDRH Clinical Investigator
Compliance Rates
70%
60%
50%
NAI
VAI
OAI
40%
30%
20%
21%
15%
17%
17%
11%
11%
10%
7%
0%
10
Years
FY02
FY03
FY04
FY05
FY06
FY06
(NFC)
Common Investigator
Deficiencies
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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%
NAI
VAI
OAI
40%
30%
17%
20%
10%
14%
13%
9%
0%
10
Years
FY02
8%
7%
FY03
FY04
FY05
FY06
5%
FY06
(NFC)
IRB Deficiencies
Fiscal Years 1999 - 2006
FY
1999
2000
2001
2002
2003
2004
2005
2006
Inadequate initial
&/or continuing
review
64%
56%
39%
24%
25%
50%
37%
38%
Inadequate
minutes
61%
42%
35%
11%
42%
28%
17%
20%
Lack of or
incorrect SR/NSR
determination
58%
42%
57%
10%
16%
34%
22%
7%
Inadequate
membership roster
31%
22%
30%
13%
20%
21%
12%
12%
Addendum: FY06 – Lack of Quorum & Reporting
Non-Compliance 12%
CDRH BIMO OAI
Follow-up Inspections (as of 9/30/06)
Recidivist OAIs
evenly distributed
across program
areas:
18%
52%
GLP = 17%
IRB = 25%
CI
30%
= 33%
S/M = 25%
N = 64
NAI
VAI
OAI
CDRH BIMO Vulnerable
Population Inspections
10%
OAI split among
Sponsor (44%)
and Clinical
Investigator
(56%) programs
32%
NAI
VAI
OAI
58%
N = 164
CDRH BIMO COMPLIANCE RATES
FY06: All Inspections vs. Complaints
All Inspections
Complaints
NAI
11%
35%
36%
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
NAI
14%
26%
31%
VAI
55%
46%
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
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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
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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
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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
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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
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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
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Defer Scientific Review
Issues Letter to Applicant
Conducts Validity Assessment
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Scope, extent of problem
Inspection
Audit Report
Applicant’s Responsibilities
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Cooperation with FDA
Internal Review (Audit)
Independent Outside Consultant
Identify/Remove Individuals
Submit CAP
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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
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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
[email protected]