Transcript You’ve been WARNED…. Everyday occurrences that landed your colleagues with a Warning Letter from the FDA Laura B.

You’ve been
WARNED….
Everyday occurrences that landed your colleagues
with a Warning Letter from the FDA
Laura B. Cummins, J.D.
Manager, Contract Administration
Office of Clinical Research
UT Medical Group, Inc.
This presentation does not constitute legal advice.
The views expressed are the presenter’s own and do not necessarily express the
views of UT Medical Group, Inc.
1
FDA Warning Letter:
 What
is a FDA Warning Letter?
 What are the common violations cited
by the FDA?
 How can you avoid and correct these
violations?
2
What is a FDA Warning
Letter?
A Warning Letter is an informal advisory,
to a firm or clinical investigator,
communicating the Agency's position on a
matter but does not commit FDA to taking
enforcement action. A Warning Letter is
issued for significant regulatory violations
that require prompt and adequate
corrective actions.
http://www.fda.gov/cder/Offices/DSI/enforcement.htm3
FDA Warning Letter
4
What are the common
violations cited by the FDA?
 Informed
consent
 Investigator responsibilities
 Protocol deviations
 Study records
 IRB approval
5
Informed Consent
6
Informed Consent
You failed to obtain the informed consent of each human subject in
accordance with 21 CFR part 50 [21 CFR 312.60].
FDA Citation:
“we were unable to determine from your
site records if subjects gave informed
consent prior to participation in the study
and/or if subjects were given sufficient
opportunity to consider whether or not to
participate in the study.”
7
Informed Consent
You failed to obtain legally effective informed consent
[21 CFR part 50 and 21 CFR 312.60]
FDA Citation:
“Informed consent documents were dated
by study personnel rather than the legally
authorized representative”
8
Informed Consent
You failed to obtain legally effective informed consent
[21 CFR part 50 and 21 CFR 312.60]
FDA Citation:
“pharmacokinetic samples were collected
from subjects without obtaining informed
consent for blood sampling.”
9
Informed Consent
You failed to obtain legally effective informed consent
[21 CFR part 50 and 21 CFR 312.60]
FDA Citation:
“According to study records,
representatives for subjects 114302 and
114504 were non-English speaking. The
subjects’ representatives signed informed
consent documents written in English
rather than a language understandable to
the representative.”
10
Informed Consent
You failed to obtain legally effective informed consent
[21 CFR part 50 and 21 CFR 312.60]
FDA Citation:
“Subject signed the consent form on
[redacted]; however, the witness signed
the consent on [redacted].”
11
Informed Consent
You failed to provide a copy of the signed and dated written Informed
Consent document, which had been approved by the IRB to the subject or
subject’s legally authorized representative [21 CFR 50.2(a)]
FDA Citation:
“There was no documentation that
subjects who were enrolled in this study
received informed consent.”
12
Informed Consent
Failed to obtain proper assent as determined to be appropriate by the IRB
[21 CFR § 50.55]
FDA Citation:
“the IRB requires that subjects who are 713 years old sign a Research Assent form.
Subject 124501 was seven years old at
the time of consent, but did not sign a
Research Assent form prior to being
enrolled in the study.”
13
How to avoid and correct:






Do not date for subjects
If someone forgets to date the consent form,
write a signed and dated note-to-file explaining
how and when the subject was consented,
report to IRB
Write a signed and dated note-to-file explaining
why dates are different
Always give subject a copy of the signed and
dated consent form
Document the informed consent process
Always maintain the original signed and dated
consent form in the research file
14
Investigator
Responsibilities
15
Investigator Responsibilities
You failed to conduct the studies according to the signed investigator statement
[21 CFR 312.60]
FDA Citation:
“You failed to adequately supervise
individuals to whom you delegated study
tasks.”
16
Investigator Responsibilities
You failed to conduct the studies according to the signed investigator
statement [21 CFR 312.60]
FDA Citation:
“you did not list the names of all
subinvestigators who would be assisting in
the conduct of the investigation, as
required by the Statement of Investigator,
Form FDA 1572.”
17
Investigator Responsibilities
You failed to personally conduct or to supervise the clinical investigation
[21 CRF 312.60]
FDA Citation:
“You did not personally conduct or
supervise this study.”
18
Investigator Responsibilities
You failed to personally conduct or to supervise the clinical
investigation [21 CRF 312.60]
FDA Citation:
“We also note that during the
inspection you admitted that you are
conducting many studies that you are
not able to remember all of them. This
suggests that you are not as involved
as we would expect of a Principal
Investigator.”
19
Investigator Responsibilities
You failed to maintain adequate case histories that record all observations
and other data pertinent to the investigation on each individual
[21CFR 312.62(b)]
FDA Citation:
“You misrepresented your presence at the
Institution by signing and dating source
documents and consent forms on days
you were, in fact, absent from the
Institution.”
20
How to avoid and correct:
 Stay
involved
 Document your involvement
 Only delegate responsibilities to
appropriate individuals who are
qualified, trained and supervised
 Maintain documentation of training for
all staff
21
Read the small print of the 1572
Supervise
Maintain Records
Adhere to Protocol
Learn Investigator
Brochure
Let FDA inspect
RePort Adverse Events
Retain Records
Inform Subjects
Notify IRB
Train Staff
22
Protocol Deviations
23
Protocol Deviations
You failed to conduct the studies or to ensure they were conducted
according to the investigational plans [21 CFR 312.60]
FDA citation:
“The protocol specified that women of
childbearing potential were to be excluded
from the study. The protocol further specified
that pregnancy tests were to be taken at the
Visits P1 and T1. Protocol-specified
pregnancy tests were not performed for
subjects [(b)(6)] and [(b)(6)] on one and/or
both of these visits.”
24
Protocol Deviations
You failed to conduct the studies or to ensure they were conducted
according to the investigational plans [21 CFR 312.60]
FDA citation:
“Subject [(b)(6)] did not meet the protocol
specified blood pressure inclusion criterion at
either Visit P2, Visit P3, or Visit P4, but was
randomized into that study. That the study
sponsor ultimately permitted this subject to
remain in the trial does not mitigate this initial
failure to follow the protocol.”
25
How to avoid and correct:

Report all protocol deviations to the IRB
according to the reporting guidelines
 Develop and implement an adequate
corrective plan to avoid future deviations
 Retrain study team
 Create checklist of procedures to be
performed at each visit
26
Study Records
27
Study Records
You failed to maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation of each individual
administered the investigational drug or employed as a control in the
investigation [21 CFR 312.62(b)]
FDA citation:
“on the source document for the
administration of (infusion) maintenance
dose was recorded as “1:1” or “0.5:1”.
Based on this documentation, the actual
drug concentration is uncertain.”
28
Study Records
You failed to maintain adequate and accurate case histories that
record all observations and other data pertinent to the investigation
of each individual administered the investigational drug or employed
as a control in the investigation [21 CFR 312.62(b)]
FDA citation:
“The CRFs contained blank fields.”
29
Study Records
You failed to maintain adequate and accurate case histories that
record all observations and other data pertinent to the investigation
of each individual administered the investigational drug or employed
as a control in the investigation [21 CFR 312.62(b)]
FDA citation:
“All medical records/case reports
audited had numerous write-over
corrections which lacked dates and
initials.”
30
How to avoid and correct:

All information entered on a CRF or data collection
sheet must be supported by source documents
 A signed and dated note-to-file can be used to
explain:
 How information was obtained
 Who obtained information
 Any discrepancies
 Missing or incomplete data
 Use a single line to cross-out the incorrect
information; enter the correct information next to it,
and initial and date (time) the change
 Never obscure the initial entry
 Sign/initial and date all entries
 Always use ink to enter data
31
IRB
Requirements/Approval
32
IRB Requirements/Approval
You failed to promptly report to the IRB all unanticipated problems involving
risk to human subjects or others [21 CFR 312.66]
FDA citation:
“You failed to notify the IRB per IRB
requirements within three business days of
becoming aware of this serious adverse
event, and you reported this event to the
IRB as a protocol deviation rather than an
adverse event.”
33
IRB Requirements/Approval
You failed to assure that an Institutional Review Board (IRB) complying with
applicable regulatory requirements was responsible for the continuing
review and approval of the clinical study [121 CFR 312 .66].
FDA citation:
“Specifically, our investigation revealed that
IRB approval for the above-referenced study
expired on October 7, 2005, and was not
renewed until October 19, 2006. During this
time period, when IRB approval was lapsed
you screened, enrolled, or randomized 16
subjects and continued to perform research
activities (study visits and phone contacts).”
34
FDA citation:
“You failed to obtain IRB approval for
the media advertisements used to
recruit and enroll Subjects for the
protocol.”
35
FDA citation:
“Revised case report forms identifying
additional data to be collected.., for
which IRB approval was not
documented, were used after initiation
of the study.”
36
How to avoid and correct:

Obtain IRB approval prior to initiating
study
 Report all adverse events to the IRB
according to the IRB’s guidelines
 Do not allow study to lapse. Submit
continuing review prior to expiration
 Obtain prior IRB approval for any
changes made during the course of the
study
37
Clinical Researchers
and Criminal Liability
38
FDA Definition of Fraud:

Falsification of data in proposing, designing,
performing, recording, supervising or reviewing
research, or in reporting research results
 Falsification includes both acts of omission
(consciously not revealing all data) and
commission (consciously altering or fabricating
data)
 Fraud does not include honest errors or honest
differences in opinion
 Deliberate or repeated noncompliance with the
protocol and GCPs can be considered fraud, but
is considered secondary to falsification of data
39
Investigators
40
Ronald C. Smith, M.D.
Barry D. Garfinkel, M.D.
Maria C. Palazzo, M.D.
41
Richard Borison, M.D.
Bruce Diamond, Ph.D
“Drug Money,” 48 hours, July 31, 2000
42
Robert Fiddes, M.D.
“Of Mice and Men”, 60 Minutes, April 1, 2001
43
Study Coordinators
44
Anne Butkovitz
45
Paul H. Kornak
“Abuses Endangered Veterans in Cancer Drug Experiments,”
New York Times, February 6, 2005
46
Now that you have been WARNED
Always:
 Stay
involved
 Delegate responsibility appropriately
 Document
 Report
 Seek out more education in “GCPs”
 Develop strong partnership between
investigator and study coordinator
47
References:
Warning Letters:
Christopher Chappel, M.D. Ref #: 09-HFD-45-01-02
Charles J. Cote, M.D. Ref: 09-HFD-45-02-04
http://www.fda.gov/oc/ohrt/IRBS/faqs.html (#41,47,51)
http://www.hhs.gov/ohrp/investigatefaq.html
http://www.fda.gov/ora/ftparea/compliance/48_811.pdf (page 15)
Risa TAKAYANAGI, Kaori WATANABE, Ayako NAKAHARA, Hitoshi NAKAMURA, Yasuhiko
YAMADA, Hiroshi SUZUKI, Yoshihiro ARAKAWA, Masao OMATA and Tatsuji ISA, “Items of
Concern Associated with Source Document Verification of clinical Trials for New Drugs”,
YAKUGAKU ZASSHI, Vol. 124, 89-92 (2004).
F. Well, Reuters Health, January 2002
U.S. v. Smith 740 F.2d 734 (9th Cir. 1984)
U.S. v. Garfinkel 29 F.3d 451 (8th Cir. 1994)
U.S. v. Palazzo 2007 WL 3124697, 7n.7 (E.D. La. 2007)
The Wall Street Journal Europe, “test Case: Drug Makers Relied on Two Researchers Who Now
Await Trial. The Americans Are Accused of Endangering Patients and Stealing $10 million
48
‘checks and Balances’ Failed” By Steve Stecklow and Laura Johannes, August 18, 1997
References:
Ex-Profs Charged in Psych Department Research Scam by Michael Jonathan Grinfeld,
Psychiatric Times, April 1997, Vol. XIV Issue 4
A doctor’s Drug Trials Turn Into Fraud, New York Times, By KURT EICHENWALD and GINA
KOLATA, Published: Monday, May 17, 1999
United States v. Butkovitz, Case No. 05-CR-10128-DPW (D. Ma.)
Meredith Wadman, One in Three Scientists Confesses to Having Sinned, 435 Nature 718
(2005)
http://www.nytimes.com/2005/02/06/nyregion/06vets.html
http://ori.dhhs.gov/misconduct/cases/Kornak.shtml
http://www.circare.org/lex/03cr436.pdf
References:
Partners Human Research, Quality Improvement Program, Quick Bite Series
September 2, 2004, Lessons Learned from FDA Warning Letters
Warning! Warning! Warning! Letters, Lecture by Erich Jensen and Judy Nowack
University of Michigan - Center for the Advancement of Clinical Research, and Office of Vice
President for Research, 17 November 2003
http://www.wlap.org/browser.php?ID=20031117-annarbor-01-jensen
Read the SMALL PRINT of the 1572, The Essential GCP Document
http://www.wlap.org/file-archive/cacr/CACR_CRE_2.ppt#256,1,Read the SMALL PRINT of the
1572
The Good , The Bad and The Ugly of Clinical Research Sites
http://www.wlap.org/wl-repository/umich/cacr/cre/20031215-annarbor-01jensen/realaudio/sld001.htm
Fraud & Misconduct at Investigator Sites, Paul Below, Clinical Research Consultant P. Below
Consulting, Inc., Chicagoland Chapter ACRP Clinical Research Conference & Career Fair,
Schaumburg, IL, November 10, 2006
http://www.pbelow-consulting.com/power_point/fraud_chicago_10-2006.ppt#259,1,Fraud &
Misconduct at Investigator Sites
Contact Information:
Phone: (901) 448.2406
Email: [email protected]