Preparing for Increased FDA Enforcement Activities Impacting Clinical Studies

Michael A. Swit, Esq., Vice President
November 3, 2011
An FX Conferences Audio Conference
Preparing for Increased FDA
Enforcement Activities
Impacting Clinical Studies

What We Will Cover
 Understanding the Warning Letter in FDA’s
Enforcement Arsenal
 GCP Warning Letters – Highlights of 2010 and 2011
 How to Respond if Targeted
 Consequences of Non-Compliance
 Lessons Learned
 Appendices – Details on Warning Letter observations by type
of citation/type of recipient
2

Understanding
FDA’s Use of The
Warning Letter
3

Warning Letters – 2004 to 2008
4

 Total Warning Letters
 2008 – 445
 2009 – 571
 2010 – 616
 2011 -- 537 (as of 10/30)
 Clinical Research –
 2009 – 45
 2010 – 18
 2011 – 24 (as of 10/30)
Source: FDA Warning Letters Website
 Why did they go up after 2008?
FDA, under Commissioner Hamburg, Is on the March …
Warning Letters – 2009 & 2010
5

Hamburg – August 2009
New FDA Enforcement Mandates
 Inspections – The 483 -- Impose clear post-
inspection deadlines
 Generally -- no more than 15 business days to respond 483
 After that, agency can issue warning letter or take other
enforcement action
 Speed the warning letter process -- by limiting review
by FDA Office of Chief Counsel to warning letters that
present significant legal issues
 FDA will be prepared to take immediate action to
respond to public health risks.
 Actions may occur before a formal warning letter – at any time
 Days of multiple responses to inspections -- over 6

New Enforcement Mandates …
 Prioritize follow-up on all warning letters and other
enforcement actions
 FDA will work quickly to assess the corrective action taken by
industry after a warning letter, a major product recall, or other
enforcement action
 Via new inspection or other form of investigation
 Develop and implement a formal warning letter
“close-out” process.”
 If FDA determines a firm fully corrected violations in a
warning letter, agency will issue an official “close-out” notice
and post on FDA Web site.
 Seen as an “important motivator” for corrective action
7

Enhanced Enforcement In Action –
Timely 483 Responses Policy
 Aug. 11, 2009 Federal Register notice – Post-inspection
483 responses timing policy published – 15 business days
 If a Timely Response
 FDA will conduct “detailed review” in deciding any enforcement
action
 If FDA issues a W.L., letter will address sufficiency of response
 If a Late Response
 Response will not be considered by FDA in deciding to take
enforcement action such as a W.L.
 If W.L. issues after a late 483 response, FDA will consider the
483 response in assessing firm’s later reply to W.L.
8

 Purpose of warning letter:
 “to ensure that the seriousness and scope of the
violations are understood … by top management … and
 that the appropriate resources are allocated to fully
correct the violations and prevent their recurrence”
Enhanced Enforcement In Action –
Timely 483 Responses Policy
9

GCP Warning Letters
2010 and 2011
10

Who’s Been Targeted
11
Warning Letter
Recipient
# of
WLs
Total
Allegations
All WLs
Average #
Allegations
Per WL
Clinical Investigator 25 86 3.4
IRB 13 42 3.2
Sponsor 2 18 9
Sponsor/Investigator 1 8 8
Radioactive Drug Research
Committee
1 5 5
Total 42 159 3.8

Citation
Number of WLs
With Citation
Failure to Follow Investigational Plan 25
Inadequate Case Histories 13
Informed Consent Failures 9
Drug Disposition 7
Failure to Protect Subjects Under P.I.’s Care 7
Failure to Personally Conduct or Supervise Study 6
Record Retention Issues 5
Failure to Report Changes in Study Plan to IRB 5
Failure to Get IRB Approval to Study Changes 4
Failure to Assure IRB Involvement in Study 3
Failure to Inform IRB of Risks to Human Subjects 1
Failure to Report IRB Approval Withdrawal 1
Total # 86
Violations – Clinical Investigators
12n = 25

Violations – IRBs
13n = 13
Citation
Number of WLs
With Citation
Failure to Follow Procedures 8
Failure to Have Adequate Procedures for IRB Functions 6
Composition of IRB Issues 6
Failure to Have Adequate Documentation for IRB Functions 5
Failure to Determine Risks to Subjects Minimized 4
Informed Consent 4
Continuing Review 3
Expedited Review 2
Controverted Issues 1
Conflicts of Interest 1
Failure to Ascertain Acceptability of Proposed Research 1
Failure to Ascertain if Studies in Children met Regulation on
Additional Safeguards for Children in Studies
1
42

Citation
Number of WLs
With Citation
Failed to Test Tissue Specimen for Infection 3
Started Study without an IND 2
Failure to Monitor 2
Investigational Product Disposition Records 2
Bar on Advertising an Investigational Device as Safe and
Effective
1
Violated Clinical Hold 1
Tissue Donor Screening Violation 1
Started Study without a Protocol Amendment 1
Failure to Get FDA Approval to Charge for IND Drug 1
Failure to Ensure Investigational Plan Followed 1
Inadequate Informed Consent 1
Failure to Get Investigator Agreements with Sufficient Financial
Disclosure Information
1
Failure to Supply Investigators with the Investigational Plan 1
18
Violations -- Sponsors
14n = 3*

Citations
Number of WLs
With Citation
Failure to Ensure Monitoring 1
Failure to Obtain 1572 1
Failure to Give IB to Other Investigators 1
Failure to Evaluate Evidence of Safety and Effectiveness of
Drug
1
Failure to File IND Annual Report 1
Failure to Keep Adequate Drug Disposition Records 1
Failure to Keep Adequate Drug Disposition Records 1
Records Retention 1
8
Violations – Sponsor/Investigators
15n = 1

Citation
# of WLs
with Citation
Failure to Assure Quality 1
Failure to Ensure AEs Reported Immediately by
Investigators
1
Committee Composition 1
Failure to Submit Special Summary Report to FDA 1
Failure to Secure IRB Approval of Research 1
5
Violations -- Radioactive Drug
Research Committee
16n = 1

Review of Specific Warning
Letter Allegations
17

 Duty – conduct at least annually
 Mother Francis Hospital – Tyler, TX
 Several reviews of device studies were more than two months
late (exact dates are purged in WL)
 Bay Regional Medical Center – Bay City, MI
 One was a month late when FDA showed up for its 2009
inspection
 Red Flag Note – FDA had inspected in March 2009 – after
that, the IRB set up a procedure regarding assignment of
studies to specific IRB members for in-depth review. When
FDA re-inspected in 2010 (leading to the WL), the IRB had
not been following its new procedure
IRB – Continuing Review Failure
18

 Covenant Healthcare – Saginaw, MI
 The ICD entitled “consent to receive (b)(4) to attempt to
prevent (b)(4) in my baby”
 Lack statements that the study involves research; and
 Lack a description of the procedures to be followed with respect to
the investigational drug treatment [21 CFR 50.25(a)(1)]. The
statement in the ICD that the “treatment will be discussed
with you” does not sufficiently meet the regulatory
requirement for a description of procedures.
 Lack explanation of whom to contact for answers to pertinent
questions about research subjects’ rights [21 CFR 50.25(a)(7)].
Contact information for Covenant HealthCare IRB was left blank.
IRB – Informed Consent
19

 Essex IRB – Lebanon, NJ – Allegedly approved a
fictitious investigation
 Fictitious study protocol was for a drug class with well-known
CV risks. However, the IRB did not ensure that those risks
were addressed in the ICD
 Second study – a risk of graft rejection was included in draft
ICD from sponsor.
 Sponsor asked to relocate the graft discussion within ICD.
 IRB – omitted the graft rejection discussion completely in final ICD
IRB – Informed Consent …
20

 Duty – no IRB member with a conflict can participate
in initial or continuing review of a study
 Covenant Healthcare – several examples where
conflicted members took action
 Approving studies where IRB member was an investigator
 Approving SAEs where IRB member was an investigator
 Continuing review of studies where Chairman of the IRB was
an investigator
IRB – Conflicts of Interest
21

 Duty – must have 5 or more members and at least one
“non-scientific” member and one unaffiliated member
 Napoli LLC (dba Precision Reproduction) – Beverly Hills
 IRB had only two members
 Both members were scientists/doctors (an M.D. and an
embryologist)
 Providence Hospital IRB – Washington, D.C.
 took action without a majority of IRB being present
 June 10, 2009 – of 9 members, only 4 present and only 2 were seen
as on IRB (others were IRB coordinator and person not on roster)
 June 20, 2007 – of 9 members, 5 present, but only three seen as on
IRB (same issue as in 2009)
 2009 roster – CVs showed all were affiliated with hospital
IRB – Composition Issues
22

 Duty – investigator must personally conduct or
supervise the clinical investigation
 Note – this is a “catch-all” violation
 Martin Zaiac, M.D. – Miami Beach, FL
 W.L. does not provide specifics re allegation but is replete with
examples of serious protocol deviations including failing to
ensure sexually active women were on contraception ,
 W.L. makes clear that, while delegating specific duties to qualified
personnel is OK, P.I. can not delegate his/her general duties re
conduct of study
 Joel Picus, M.D. – St. Louis, MO (Washington Univ.)
 Failed to ensure Liver Function Tests reviewed before dosing
to set dose or if drug should be withheld (subject later died)
Investigator – Failure to Personally Conduct
23

 John Griffin, M.D. – Virginia Beach, VA
 Research nurse signed his name to:
 1572
 a study protocol
 a confidentiality agreement
 AEs
 Signature and delegation form
 R. Judith Ratzan, M.D. – Miami, FL – failure to
supervise led to:
 chemotherapy misadministration – e.g., 6 cycles after study
closed and AE reporting errors
 Study staff told FDA that Dr. lived outside Florida 6 mos of
year and was absent for majority of study’s conduct
Investigator – Failure to Personally Conduct …
24

 Another “catch-all” violation – cited in all 25
investigator warning letters
 David Scott, M.D. – Spokane, WA
 Randomization to occur after surgery – ten subjects
randomized before surgery
 Physical exam required – none done
 PK samples not collected on 11 subjects – PK measures were
a secondary endpoint of study
 Sant Chawla, M.D. – Santa Monica
 PK samples collected at wrong time (end of drug infusion
when protocol said at start)
Investigator – Fail to Follow Investigational Plan
25

 Duty – no investigator can involve a subject without
first getting legally effective informed consent
 Zaiac – informed consents signed were in English
when other consents by same subjects were in Spanish.
 Robert Deitz, M.D. – San Francisco, CA
 Patient enrolled on Jan. 10, 2005 and given drug. ICD not
signed until May 2005.
 Three subjects signed ICD’s not approved by IRB
 John Simmons, M.D. – Geneva, AL
 Signature on ICD did not match subject diary handwriting; P.I.
said signed by someone else because subject’s hands were
shaking; but P.I. did not verify other was the L.A.R.
Investigator – Informed Consent
26

 Yale Cohen, M.D. – Hollywood, FL
 Re-consenting by mail and phone approved by IRB only for
subjects not actively participating in study. P.I. used
mail/phone process for active subjects.
 Samya Nasr, M.D. – Ann Arbor, MI
 Gave out tote bags, diary cards, and calendars to subjects
without IRB approval
 Timothy Summers, M.D. – Meridian, MS
 Hand-altered a consent form without IRB approval
Investigator – Changes to Study
Without IRB Approval
27

 TCA Cellular Therapy, LLC – Covington, LA
 The TCA letter attempts to justify a lack of monitoring by
explaining that the contracted monitor could no longer
perform monitoring as of January 2011 and negotiations
were ongoing with another company to begin monitoring in
March 2011. The TCA letter further explains that after the
inspection, Dr. Lasala, TCA Managing Member, discovered
that the last monitoring visit was August 26, 2008.
Sponsor – Failure to Monitor Study
28

 TCA Cellular –
 Started study without an IND in effect -- told at an End-of-
Phase 2 meeting that use of allogeneic cells would need a new
IND. Started study with allogeneic cells without IND.
 Violated clinical holds – had two studies on hold, but
administered same test product to individuals who were not
even enrolled in the study (not clear how FDA figured this
out)
 Cayman Chemical Company – Ann Arbor, MI
 Administered study drug without an IND in effect
Sponsor – Illegally Starting Study
29

 FDA alleges all studies done from April 2005 to
June 2010 at Houston bioanalytical facility were
based on fraudulent data
 Problem with trying to salvage:
 FDA -- can’t audit fraudulent data
 retained samples may not be subject to stability
 Result -- could undermine approved and pending applications
 No warning letter issued – untitled letter on July 26,
2011
 MDS – 2007 – somewhat similar, but pervasive fraud
not alleged, allowing for audits to verify study work
Special Case Study -- Cetero
30

How to Respond When
Enforcement Hits
31

When FDA An FDA Warning Letter Hits …
 Who FDA Can Target: any individual within the
company that has a position of responsibility for the
violative aspect of the company’s operation,
including:
President/CEO/COO
General Counsel
VP or Director of QA, QC, RA, Mfg., etc.
Managers
Technicians (rare)
32

When Warning Letter Hits -- Assessing
 Assess each allegation/observation
 Focus on specifics
 Focus on system-wide implications
 Focus on global implications
 Consider affected products
 Consider root-cause analysis
 Focus on the regulatory requirement(s) associated
with each allegation/observation
 Develop action plan to achieve immediate, short-term,
and long-term correction and to prevent recurrence
 Know when to seek outside assistance
33

When Warning Letter Hits –
Keys to Responding
 Include a commitment/statement from senior leadership
 Address each allegation/observation separately
 Never agree with the allegation/observation – state what
you are doing regarding the allegation
 Provide corrective action accomplished and/or planned;
tell FDA the plan
 Be specific (e.g. observation-by-observation)
 Be complete
 Be realistic
 Be able to deliver what you promise
 Address affected products
34

When Warning Letter Hits –
Keys to Responding …
 Provide time frames for correction
 Describe method of verification and/or monitoring for
corrections
 Submitting documentation of corrections where
reasonable & feasible
 Be Timely and Thorough – deliver what you promised
when you promised it
35

FDA Expectations for Your W.L. Response
 Wants to Hear Your D.R.U.M. – expects your
response to have these qualities:
 Direct – i.e., address the items directly raised in warning letter
 Related – go beyond those to potentially related problems
 Universal – expand to review those issues company-wide
 Management & Monitoring – show that you will stay on
top of the issues and that management is involved
Source: “Compliance and Enforcement.” Presentation by David K.
Elder, Director, FDA Office of Enforcement, at the Orange County
Regulatory Affairs (OCRA)/FDA Joint Educational Conference. June
15, 2005. Irvine, California.
36

Potential Consequences
of FDA Enforcement
After a Warning Letter
37

Direct Possible Consequences
of Non-Compliance
 Clinical holds – study stopped
 AIP – application reviews suspended
 Import Alerts – product can’t be imported into U.S.
 Civil Money Penalties -- $$$
 Seizures – product can’t be sold
 Injunctions – selling/manufacturing could be halted
for years
 Disgorgement -- $$$ returned for “ill-gotten gains”
38

 Prosecutions
 Fines -- $$$
 Imprisonment
 Disqualification proceedings
 FDA
 HHS – Federal Health Programs – “the Death Penalty”
 Approval withdrawal proceedings
Direct Possible Consequences
of Non-Compliance …
39

Collateral Consequences
of Non-Compliance
 Financial consequences
 Lost sales – you can bet your competitors will be waving your
W.L. in faces of your customers …
 Stock price drops – market capitalization – ability to use capital
markets
 Shareholders sue the company, its officers and directors
 Other companies may sue the company if reason for non-
compliance gave you a competitive edge
 Federal government may suspend or “debar” company from
selling to government
 “Qui Tam” actions under the False Claims Act -- e.g., Neurontin
case -- “whistle blower” cases -- leading to civil damages and
may also spawn a criminal prosecution
 Financing covenants may be violated 40

Collateral Consequences of
Non-Compliance …
 Other Consequences
 State license actions – could pull your manufacturing license
 Lay-offs
 Damage to corporate reputation
 Lost time – interruption with normal operations
 Consequences for Individuals
 Job loss
 Reputation
 Expense of defending – and your company may not have to pay
 Impact of convictions
 Deportation if not U.S. citizen
 Imprisonment
 Fine
 Right to vote/run for public office
41

 Vigorous site qualification -- essential
 Robust training required -- even for non-naïve
investigators and their staff
 Contracts – essential to drive compliance
 Sponsors must stay on top of their CROs or sites
(if sponsor-controlled)
 Co-monitoring
 Independent site audits
 Try to ensure study site personnel have an avenue to
communicate issues directly to you
 Don’t overlook clinical labs
 MDS – 2007-- & Cetero -- 2011
What Is Our Take Away Today?
43

44
Call, e-mail, fax or write:
Michael A. Swit, Esq.
Vice President
The Weinberg Group Inc.
1422 Caminito Septimo
Cardiff by the Sea, CA 92007
Phone 760.452.6568
Fax 760.454.2979
Cell 760.815.4762
michael.swit@weinberggroup.com
www.weinberggroup.com
Questions?

45
About your Speaker …
Michael A. Swit, Esq., is a Vice President at The Weinberg Group, where he develops and ensures the execution of
a broad array of regulatory and other services to clients, both directly and through outside counsel. His expertise
includes regulated product development strategies, compliance and enforcement initiatives, recalls and crisis
management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical
research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the food and
dietary supplement industries.
Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and multi-faceted
experience includes serving for three and a half years as corporate vice president, general counsel and secretary of
Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and
commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as
CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products
for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel
in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food &
Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first
practiced FDA regulatory law with the D.C. office of Burditt & Radzius.
Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial
activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and
editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the
Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences
sponsored by such organizations as RAPS, FDLI, and DIA. He received his A.B., magna cum laude, with high
honors in History, from Bowdoin College and his law degree from Emory University School of Law. Mr. Swit is a
member of the California Bar.

Appendices
GCP Warning Letters
January 2010 to September 2011
Types of Citations
46

47
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
IRB -- Controverted Issues
The IRB failed to prepare and maintain adequate documentation of IRB activities
including a written summary of the discussion of controverted issues and their
resolution [21 CFR 56.115(a)(2)], making it appear that the IRB failed to determine
that risks to subjects were minimized and reasonable in relation to anticipated
benefits [21 CFR 56.115(a)(2)]
[21 CFR 56.111(a)(1)
and(2)]
Covenant Healthcare
#1
IRB -- Failure to Determine Risks to Subjects Minimized
The IRB failed to prepare and maintain adequate documentation of IRB activities
including a written summary of the discussion of controverted issues and their
resolution [21 CFR 56.115(a)(2)], making it appear that the IRB failed to determine
that risks to subjects were minimized and reasonable in relation to anticipated
benefits [21 CFR 56.115(a)(2)]
[21 CFR 56.115(a)(2)] Covenant Healthcare
#1
The IRB failed to determine that risks to subjects are minimized. [21 CFR 56.111(a)(1)] Essex Institutional Review Board
#1
[same as above] [21 CFR 56.111(a)(1)] Brookwood Medical Center
#3
In approving research covered by the regulations, the IRB failed to determine that
risks to subjects are minimized, risks to subjects are reasonable in relation to
anticipated benefits, if any, to subjects, and the importance of the knowledge that
may be expected to result.
[21 CFR 56.111(a)(1),
(a)(2)]
Independent Review Consulting,
Inc. # 4
IRB -- Expedited Review
The IRB failed to follow FDA regulations regarding expedited review procedures [21 CFR 56.110(b)] Covenant Healthcare
#2

48
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
Failure to use expedited review procedures only for certain kinds of research
involving no more than minimal risk or for minor changes in approved research.
[21 CFR 56.110, 21 CFR
56.108(c)].
Independent Review Consulting,
Inc. # 1
IRB – Continuing Review
Failure to follow written procedures for conducting continuing review of research at
least annually.
[21 CFR 56.108(a)(1) and
56.109(f)]
Mother Frances Hospital IRB #2
The IRB failed to conduct continuing review of research at intervals of not less than
once per year,
[21 CFR 56.109(f)]. Bay Regional Medical Center IRB
#2
Failure to conduct continuing review of research at least annually. [21 CFR 56.109(f)] Centra Health Inc IRB #1
IRB—Informed Consent
The IRB failed to ensure that information given to subjects as part of informed
consent is in accordance with 21 CFR Part 50.25
[21 CFR 56.109(b)] Covenant Healthcare
#3
[same as above] [21 CFR 56.109(b)] Independent Review Consulting,
Inc. #3
The IRB failed to ensure that basic elements of informed consent are included in the
IRB-approved consent form.
[21 CFR 56.109(b)] Essex Institutional Review Board
#4
Failure to ensure that informed consent will be sought from each prospective
subject, in accordance with 21 CFR Part 50.
[21 CFR 56.111(a)(4)] American Assn. of Acupuncture and
Bio-Energetic Medicine #1
IRB – Conflicts of Interest
The IRB failed to ensure that no member participated in the initial or continuing
review of a project in which the member had a conflicting interest, except to provide
information requested by the IRB.
[21 CFR 56.107(e)] Covenant Healthcare
#4
IRB – Failure to Follow Procedures
The IRB failed to follow its written procedures for conducting continuing review of
research.
[21 CFR 56.108(a)(1)] Covenant Healthcare
#5
[same as above] [21 CFR 56.108(a)(1)] Bay Regional Medical Center IRB
#1
[same as above] [21 CFR 56.108(a)(1)] Brookwood Medical Center
#1

49
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
Failure to prepare, maintain, and follow required written procedures governing the
functions and operations of the IRB.
[21 CFR 56.108(a)(1), 21
CFR 56.108(b)(1)-(3), and
21 CFR 56.115(a)(6)]
Centra Health Inc IRB #2
The IRB failed to follow its written procedures for ensuring that changes in
approved research, during the period for which IRB approval has already been given,
may not be initiated without IRB review and approval except where necessary to
eliminate apparent immediate hazards to the human subjects
[21 CFR 56.108(a)(4)]. Brookwood Medical Center
#2
The IRB failed … to follow written procedures as required by 21 CFR 56.108(a) and
(b) [21 CFR 56.115(a)(6)].
[21 CFR 56.108(a)] Ephraim McDowell Regional
Medical Center IRB #1
Failure to follow written procedures for conducting initial and continuing review of
research and for reporting your findings and actions to the investigator and the
institution.
[21 CFR 56.108(a)] American Assn. of Acupuncture and
Bio-Energetic Medicine #2
Failure to follow written procedures for ensuring prompt reporting to the appropriate
institutional officials and FDA of any instance of serious or continuing
noncompliance with 21 CFR Part 56 or determinations of the IRB, and of any
suspension or termination of IRB approval.
[21 CFR 56.108(b)]. American Assn. of Acupuncture and
Bio-Energetic Medicine #3a
IRB – Failure to Ascertain Acceptability of Proposed Research
The IRB failed to demonstrate its ability to ascertain the acceptability of the
proposed research in terms of institutional commitments, regulations, applicable
law, and standards of professional conduct and practice
[21 CFR 56.107(a)] Essex Institutional Review Board
#2
IRB – Failure to Ascertain if Studies in Children met Regulation
on Additional Safeguards for Children in Studies
The IRB failed to determine at the time of initial review that studies involving
children are in compliance with 21 CFR Part 50, Subpart D, Additional Safeguards
for Children in Clinical Investigations
[21 CFR 56.109(h)] Essex Institutional Review Board
#3
IRB – Failure to Have Adequate Procedures for IRB Functions
Failure to have adequate written procedures governing the functions and operations
of the IRB.
[21 CFR 56.108 (b)(1), (2)
and (3)]
Mother Frances Hospital IRB #1

50
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 56.108(a), (b), and
(c)]
Napoli LLC (dba Precision
Reproduction) #2
[same as above] [21 CFR 56.108(a), (b), and
(c)]
North Memorial Medical Center #1
Failure to prepare, maintain, and follow required written procedures governing the
functions and operations of the IRB.
[21 CFR 56.108(a)(1), 21
CFR 56.108(b)(1)-(3), and
21 CFR 56.115(a)(6)]
Centra Health Inc IRB #2
Failure to have adequate written procedures governing the functions and operations
of the IRB.
[21 CFR 56.108(a), (b) and
(c)]
Providence Hospital Institutional
Review Board #1
The IRB failed to prepare and maintain written procedures for the IRB … [21 CFR 56.108(a) & (b) 21
CFR 56.115(a)(6)].
Ephraim McDowell Regional
IRB – Failure to Have Adequate Documentation for IRB
Functions
Failure to prepare and maintain adequate documentation of IRB activities, including
minutes of IRB meetings.
[21 CFR 56.115(a)(2)] Mother Frances Hospital IRB #3
Failure to … maintain minutes of IRB meetings in sufficient detail. [21 CFR 56.107(d) and 21
CFR 56.115(a)(2)]
Review Board #2
Failure to prepare and maintain adequate documentation of IRB activities, including
minutes of IRB meetings, which shall be in sufficient detail to show attendance at the
meetings, actions taken by the IRB, the vote on these actions including the number
of members voting for, against and abstaining, the basis for requiring changes in or
disapproving research, and a written summary of the discussion of controverted
issues and their resolution.
[21 CFR 56.115(a)(2)] Independent Review Consulting,
Inc. #2
Failure to prepare and maintain adequate documentation of IRB activities. [21 CFR 56.115(a)(2) and
(5)]
North Memorial Medical Center #3

51
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
Failure to prepare and maintain adequate documentation of IRB activities. Such
documentation must include minutes of IRB meetings which shall be in sufficient
detail to show the vote on actions taken by the IRB, including the number of
members voting for, against, and abstaining. Such documentation also must include
a list of IRB members identified by name, earned degrees, representative capacity,
indications of experience, and any employment or other relationship between each
member and the institution.
[21 CFR 56.115(a)(2) and
21 CFR 56.115(a)(5)]
Wayne State University IRB
#1
IRB – Composition of IRB Issues
Failure to ensure that the IRB is composed of at least five members; at least one IRB
member's primary concerns are in nonscientific areas; and no IRB member
participates in the initial or continuing review of any projects in which the member
has a conflict of interest.
[21 CFR 56.107(a), (c), and
(e)]
Napoli LLC (dba Precision
Reproduction)
#1
Failure to … ensure that the IRB reviews proposed research at convened meetings at
which a majority of the members are present including at least one member whose
primary concerns are in nonscientific areas.
[21 CFR 56.108(a), (b) and
(c)]
Review Board #1
Failure to include at least one member of the IRB who is not affiliated with the
institution …
[21 CFR 56.107(d) and 21
CFR 56.115(a)(2)]
Review Board #2
The IRB failed to prepare and maintain a list of IRB members identified by name;
earned degrees; representative capacity; indications of experience sufficient to
describe each member’s chief anticipated contributions to IRB deliberations; and any
employment or other relationship between each member and the institution.
[21 CFR 56.115(a)(5)]. Ephraim McDowell Regional
The IRB failed to review proposed research at convened meetings at which a
majority of the members of the IRB are present, including at least one member
whose primary concerns are in nonscientific areas.
[21 CFR 56.108(c)] Ephraim McDowell Regional
[same as above] [21 CFR 56.108(c)] North Memorial Medical Center #2
[same as above] [21 CFR 56.108(c)] Wayne State University IRB
#2

52
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
IRB – Failure to Notify Investigators of Research Decisions
The IRB failed to notify investigators and the institution in writing of its
decision to approve or disapprove proposed research activities, or of
modifications required to secure IRB approval of the research activity.
[21 CFR 56.109(e)] Ephraim McDowell Regional
IRB – Failure to Notify FDA of Suspension/Termination of
Research Approval
Failure to report promptly to the FDA any suspension or termination of
approval.
[21 CFR 56.113] American Assn. of Acupuncture
and Bio-Energetic Medicine #3b
Investigator – Failure to Personally Conduct or Supervise Study
You failed to personally conduct or supervise the clinical investigation. [21 CFR 312.60] Zaiac, Martin Dr.
#1
[same as above] [21 CFR 312.60] Simmons, John F, M. D.
#1
[same as above] [21 CFR 312.60] Ratzan, Judith M.D.
#1
[same as above] [21 CFR 312.60] Picus, Dr. Joel
#1
You failed to ensure that the investigation was conducted according to the
signed investigator statement, in that you failed to personally conduct or
supervise the clinical investigation
[21 CFR 312.60] Griffin, John M.D.
#1
[same as above] [21 CFR 312.60] Snow, Lamar L. M.D.
#1
Investigator – Failure to Follow Investigational Plan
You failed to ensure that the investigation was conducted according to the
investigational plan
[21 CFR 312.60] Caton, John Jr., M.D.
#1
[same as above] [21 CFR 312.60] Cohen, Yale M.D.
#1

53
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 312.60] Bosserman, Linda MD
#1
[same as above] [21 CFR 312.60] Bosserman, Linda MD
#3
[same as above] [21 CFR 312.60] Michelson, Joseph B., M.D.
[same as above] [21 CFR 312.60] Deitz, Robert, M.D.
#4
[same as above] [21 CFR 312.60] Horowitz, Jeffrey M.D.
#3
[same as above] [21 CFR 312.60] Mancha, Vaughn H Jr.,
M. D. #1
[same as above] [21 CFR 312.60] Ratzan, Judith M.D.
#2
[same as above] [21 CFR 312.60] O'Barr, Thomas Jr., M.D. --
(reissued) #1
#3
#2
You failed to conduct the studies or ensure they were conducted according to the
investigational plan ….
[21 CFR 312.60] Zaiac, Martin Dr.
#2
[same as above] [21 CFR 312.60] Chawla, Sant P., M.D.
#1
[same as above] [21 CFR 312.60] Griffin, John M.D.
#2
[same as above] [21 CFR 312.60] Thurmond-Anderle, Margaret E.
M.D. #1

54
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
#2
[same as above] [21 CFR 312.60] Nasr, Samya, M.D.
#2
[same as above] [21 CFR 312.60] Punjwani, Sohail S., M.D.
#1
You failed to ensure that the investigations were conducted according to the signed
investigator statements and the investigational plans.
[21 CFR 312.60] Scott, David F., M.D.
#1
#1
[same as above] [21 CFR 312.60] Nemechek DO PA, Patrick
#1 [WL is closed]
[same as above] [21 CFR 312.60] Summers, Timothy, MD
#1
Failure to conduct an investigation according to the signed agreement, the
investigational plan, and FDA regulations. [Device Study]
[21 CFR 812.100 and 21
CFR 812.110(b)]
Harlin, Stuart MD
#1
You failed to ensure that the investigation was conducted according to the signed
investigator statement, the investigational plan, and the applicable regulations in
order to protect the rights, safety, and welfare of subjects under your care.
[21 CFR § 312.60]. Toledo, Charles H., M.D.
#1 [WL is closed]
Investigator – Drug Disposition
You failed to maintain adequate records of the disposition of the drug, including
dates, quantity, and use by subjects.
[21 CFR 312.62(a)] Caton, John Jr., M.D.
#2
[same as above] [21 CFR 312.62(a)] Deitz, Robert, M.D.
#5
[same as above] [21 CFR 312.62(a)] Horowitz, Jeffrey M.D.
#4
[same as above] [21 CFR 312.62(a)] O'Barr, Thomas Jr., M.D. --
(reissued) #3

55
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 312.62(a)] Picus, Dr. Joel
#4
[same as above] [21 CFR 312.62(b)] Toledo, Charles H., M.D.
#3 [WL is closed]
[same as above] [21 CFR 312.62(b)] Cayman Chemical Company #6
[also a sponsor]
Investigator – Failure to Inform IRB of Risks to Human Subjects
You failed to promptly report to the IRB all unanticipated problems involving risk to
human subjects or others
#3
Investigator – Failure to Assure IRB Involvement in Study
You failed to assure that an Institutional Review Board (IRB) that complies with the
requirements set forth in part 56 was responsible for the initial and continuing review
and approval of Protocol.
#5
You failed to assure that an Institutional Review Board (IRB) that complies with the
requirements set forth in part 56 was responsible for the initial review and approval
of Protocol.
[21 CFR 312.66] Lippton, Howard M.D.
#1
You failed to ensure that an IRB complying with the requirements set forth in 21
clinical study.
[21 CFR 312.66] Cayman Chemical Company #5
[also a sponsor]
Investigator – Informed Consent
You failed to obtain informed consent in accordance with the provisions of 21 CFR
part 50
#4
[same as above] [21 CFR 312.60] Deitz, Robert, M.D.
#2
#4
#3

56
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 312.60] Nemechek DO PA, Patrick
#2 [WL is closed]
[same as above] [21 CFR 312.60] Cayman Chemical Company #3
[also a sponsor]
You failed to obtain informed consent of each subject in accordance with the
provisions of 21 CFR part 50.
#4
#1
#3
Investigator – Inadequate Case History
You failed to prepare and maintain adequate and accurate case histories that record
all observations and other data pertinent to the investigation on each individual
administered the investigational drug or employed as a control in the investigation.
[21 CFR 312.62(b)] Cohen, Yale M.D.
#2
[same as above] [21 CFR 312.62(b)]. Horowitz, Jeffrey M.D.
#2
You failed to maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation on each individual
administered the investigational drug or employed as a control in the investigation.
[21 CFR 312.62(b)] Bosserman, Linda MD
#2
[same as above] [21 CFR 312.62(b)] Deitz, Robert, M.D.
#1
[same as above] [21 CFR 312.62(b)] Mancha, Vaughn H Jr.,
M. D. #2
[same as above] [21 CFR 312.62(b)] Ratzan, Judith M.D.
#3
[same as above] [21 CFR 312.62(b)] Scott, David F., M.D.
#3
[same as above] [21 CFR 312.62(b)] O'Barr, Thomas Jr., M.D. --
(reissued) #2

57
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 312.62(b)] Snow, Lamar L. M.D.
#2
[same as above] [21 CFR 312.62(b)] Summers, Timothy, MD
#2
You failed to maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation.
[21 CFR 312.62(b)] Chawla, Sant P., M.D.
#2
[same as above] [21 CFR 312.62(b)] Toledo, Charles H., M.D.
#2 [WL is closed]
Failure to maintain accurate and complete records of each subject's case history
and to maintain required records for a period of 2 years after the date on which the
investigation was terminated. [Device study]
[21 CFR 812.140(a)(3) and
(d)]
Harlin, Stuart MD
#2
Investigator – Failure to Get IRB Approval to Study Changes
You failed to obtain IRB approval before making changes in the research. [21 CFR 312.66] Cohen, Yale M.D.
#3
You … made changes in the research without IRB approval. [21 CFR 312.66] Nasr, Samya, M.D.
#3
[same as above] 21 CFR 312.66] Summers, Timothy, MD
#4
You failed to obtain Institutional Review Board approval for changes in the
research prior to implementing the changes
[21 CFR 312.66] Scott, David F., M.D.
#2
Investigator – Failure to Report Changes in Study Plan to IRB
You failed to promptly report to the IRB all changes in the research activity. [21 CFR 312.66] Deitz, Robert, M.D.
#3
#3
[same as above] 21 CFR 312.66] Summers, Timothy, MD
#4
#3

58
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
#2
Investigator – Failure to Protect Subjects Under P.I. Care
You … failed to protect the rights, safety, and welfare of subjects under the
investigator's care.
#2
[same as above] [21 CFR 312.60] Thurmond-Anderle, Margaret E.
M.D. #1
#2
[same as above] [21 CFR 312.60] Lippton, Howard M.D.
#2
#2
#1
#1
Investigator – Record Retention
You failed to retain records required to be maintained under 21 CFR part 312 until 2
years after the investigation was discontinued and FDA was notified.
[21 CFR 312.62(c)] Deitz, Robert, M.D.
#6
[same as above] [21 CFR 312.62(c)] Horowitz, Jeffrey M.D.
#1
Failure to … maintain required records for a period of 2 years after the date on which
the investigation was terminated. [Device study]
[21 CFR 812.140(a)(3) and
(d)]
Harlin, Stuart MD
#2
You failed to retain records required to be maintained for the period of two years
following the date a marketing application is approved for the indication for which
the drug is being investigated; or, if no application is filed or if the application is not
approved for such indication, until two years after the investigation is discontinued.
[21 CFR § 312.62(c)]. Nemechek DO PA, Patrick
#3 [WL is closed]

59
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
[same as above] [21 CFR 312.62(c)] Toledo, Charles H., M.D.
#4 [WL is closed]
Investigator – Failure to Report IRB Approval Withdrawal
Failure to submit a timely report of withdrawal of Institutional Review Board
approval to the sponsor. [Device study]
[21 CFR 812.150(a)(2)] Harlin, Stuart MD
#3
Sponsor – Failure to Ensure Investigational Plan Followed
You failed to fulfill the general responsibilities of sponsors to ensure that
investigations were conducted according to the investigational plan …
[21 CFR §§ 312.50] TCA Cellular Therapy, LLC #1
Sponsor – Failure to Supply Investigators with the Investigational
Plan
Failure to supply all investigators participating in the study with copies of the
investigational plan. [Device study]
[21 CFR 812.45] Pioneer Surgical Technology #3
Sponsor – Failure to Monitor
… and you failed to monitor the progress of ongoing investigations. [21 CFR 312.56(a)] TCA Cellular Therapy, LLC #1
Failure to ensure adequate monitoring of the investigation. [21 CFR 812.40] [Device
study]
[21 CFR 812.40] Pioneer Surgical Technology #3
Sponsor – Failure to Get FDA Approval to Charge for IND Drug
You failed to obtain prior written authorization from FDA prior to charging for an
investigational drug.
[21 CFR 312.8(a)(3)] Cayman Chemical Company #2
Sponsor –Bar on Advertising an Investigational Device as Safe
and Effective
Failure to comply with FDA regulation that prohibits the promotion and
advertisement of an investigational device as safe and effective. [Device study]
[21 CFR 812.7(d)] Pioneer Surgical Technology #1
Sponsor – Inadequate Informed Consent
Failure to include all elements of informed consent. [21 CFR 50.25(a) and
(b)]
Pioneer Surgical Technology #2

60
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
Sponsor – Started Study without an IND
You initiated clinical investigations without an IND in effect. [21 CFR §§ 312.20 and
312.40]
TCA Cellular Therapy, LLC #2
You failed to comply with the requirements for use of an investigational new drug in
a clinical investigation by administering the investigational new drugs Compounds
1,2, and 3 to subjects without an IND in effect.
[21 CFR 312.40] Cayman Chemical Company #1
Sponsor – Started Study without a Protocol Amendment
You initiated clinical investigations without either submitting a protocol amendment
or a new IND to FDA.
[21 CFR §§ 312.20, 312.30
and 312.40]
Sponsor – Violated Clinical Hold
You administered an investigational product in violation of a clinical hold. [21 CFR § 312.42(a) and
(e)]
Sponsor – Failure to Get Investigator Agreements with Sufficient
Financial Disclosure Information
Failure to obtain signed investigator agreements that include sufficient
accurate financial disclosure information.
[21 CFR 812.43(c)(5) and
21 CFR Part 54]
Pioneer Surgical Technology #4
Sponsor – Tissue Donor Screening Violation
You failed to determine whether an HCT/P donor is eligible based on the results of
donor screening in accordance with 21 CFR § 1271.75 and donor testing in
accordance with 21 CFR §§ 1271.80 and 1271.85.
[21 CFR § 1271.50(a)] TCA Cellular Therapy, LLC #5
Sponsor – Failed to Test Tissue Specimen for Infection
You failed to test a specimen from the donor for evidence of infection due to relevant
communicable diseases agents, to adequately and appropriately reduce the risk of
transmission of relevant communicable diseases.
[21 CFR § 1271.85(a)(5)] TCA Cellular Therapy, LLC #6
You failed to test a specimen from the donor of viable, leukocyte-rich cells to
adequately and appropriately reduce the risk of transmission of relevant cell-
associated communicable diseases including Human T-lymphotropic virus (HTLV)
types I and II.
[21 CFR § 1271.85(b)(1)] TCA Cellular Therapy, LLC #7

61
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
You failed to test a specimen from the donor of viable, leukocyte-rich cells for
evidence of infection due to Cytomegalovirus (CMV) to adequately and
appropriately reduce the risk of transmission
[21 CFR § 1271.85(b)(2)] TCA Cellular Therapy, LLC #8
Sponsor – Product Disposition Records
You failed to maintain adequate records showing the receipt, shipment or other
disposition of an investigational drug.
[21 CFR 312.57(a)] Cayman Chemical Company #3
Failure to maintain accurate, complete, and current device shipment records. [21 CFR 812.140(b)(2)] Pioneer Surgical Technology #5
Sponsor/Investigator – Failure to Ensure Monitoring
Failure to ensure proper monitoring of the clinical investigations. [21 CFR 312.50 and
312.56(a)]
Lin, Henry, M.D.
#1
Sponsor/Investigator – Failure to Obtain 1572
You failed to obtain a signed investigator statement, Form FDA 1572, before
permitting an investigator to participate in an investigation.
[21 CFR 312.53(c)(1)] Lin, Henry, M.D.
#2
Sponsor/Investigator – Failure to Give IB to Other Investigators
You failed to give each participating investigator an investigator brochure
containing the information described in 312.23(a)(5).
[21 CFR 312.55(a)] Lin, Henry, M.D.
#3
Sponsor/Investigator – Failure to Evaluate Evidence of
Safetyand Effectiveness of Drug
You failed to review and evaluate the evidence relating to the safety and
effectiveness of the drug as it is obtained from the investigator.
[21 CFR 312.56(c)] Lin, Henry, M.D.
#4
Sponsor/Investigator – Failure to File IND Annual Report
You failed to submit to the FDA an annual report of the investigation. [21 CFR 312.33 &
312.56(c)]
Lin, Henry, M.D.
#5
Sponsor/Investigator – Failure to Keep Adequate Drug
Disposition Records
You failed to maintain adequate records showing the receipt, shipment, or other
disposition of the investigational drug
[21 CFR 312.57(a)] Lin, Henry, M.D.
#6

62
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
Sponsor/Investigator – Failure to Keep Adequate Drug
Disposition Records
You failed to maintain complete and accurate records showing any financial interests
of investigators subject to 21 CFR Part 54
[21 CFR 312.57(b)] Lin, Henry, M.D.
#7
Sponsor/Investigator – Records Retention
You failed to retain records and reports for two years after shipment and delivery of
the drug is discontinued and FDA has been so notified
[21 CFR 312.57(c)] Lin, Henry, M.D.
#8
Radioactive Drug Research Committee –Failure to Assure
Quality
The RDRC failed to assure the quality of radioactive drugs [21 CFR 361.1(d)(6)] Columbia University Medical Ctr.
Committee #1
Radioactive Drug Research Committee –Failure to Ensure AEs
Reported Immediately by Investigators
The RDRC failed to assure that investigators immediately report all adverse events
(effects) associated with the use of the radioactive drug in the research study.
[21 CFR 361.1(d)(8)] Columbia University Medical Ctr.
Committee #2
Radioactive Drug Research Committee –Committee Composition
The RDRC failed to review and approve research at meetings at which a quorum,
defined as more than 50% of the membership (including appropriate representation
from the required fields of specialization), is present
[21 CFR 361.1(c)(2)] Columbia University Medical Ctr.
Committee #3
Radioactive Drug Research Committee –Failure to Submit
Special Summary Report to FDA

63
Citation
Regulatory
Violation
Warning Letter
Recipient/
Observation #
The RDRC failed to submit a special summary report to FDA immediately after
approving research proposals which involve exposure of more than thirty research
subjects.
[21 CFR 361.1(c)(3)] Columbia University Medical Ctr.
Committee #4
Radioactive Drug Research Committee –Failure to Secure IRB
Approval of Research
The RDRC failed to assure research was reviewed and approved by an institutional
review board (IRB).
[21 CFR 361.1(d)(9)] Columbia University Medical Ctr.
Committee #5

64
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Preparing for Increased FDA Enforcement Activities Impacting Clinical Studies

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