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.
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.
What is a FDA Warning Letter?
What are the common violations cited by the FDA?
How can you avoid and correct these violations?
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.
“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.”
“Informed consent documents were dated by study personnel rather than the legally authorized representative”
“pharmacokinetic samples were collected from subjects without obtaining informed consent for blood sampling.”
“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.”
You failed to obtain legally effective informed consent [21 CFR part 50 and 21 CFR 312.60]
“Subject signed the consent form on [redacted]; however, the witness signed the consent on [redacted].”
“There was no documentation that subjects who were enrolled in this study received informed consent.”
“the IRB requires that subjects who are 7-13 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.”
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
“You failed to adequately supervise individuals to whom you delegated study tasks.”
“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.”
“You did not personally conduct or supervise this study.”
“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.”
“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.”
Document your involvement
Only delegate responsibilities to appropriate individuals who are qualified, trained and supervised
Maintain documentation of training for all staff
Adhere to Protocol
Let FDA inspect
RePort Adverse Events
“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.”
“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.”
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
“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.”
“The CRFs contained blank fields.”
“All medical records/case reports audited had numerous write-over corrections which lacked dates and initials.”
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
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
“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.”
“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).”
“You failed to obtain IRB approval for the media advertisements used to recruit and enroll Subjects for the protocol.”
“Revised case report forms identifying additional data to be collected.., for which IRB approval was not documented, were used after initiation of the study.”
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
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
Barry D. Garfinkel, M.D.
Maria C. Palazzo, M.D.
“Drug Money,” 48 hours, July 31, 2000
“Of Mice and Men”, 60 Minutes, April 1, 2001
“Abuses Endangered Veterans in Cancer Drug Experiments,” New York Times, February 6, 2005
Delegate responsibility appropriately
Seek out more education in “GCPs”
Develop strong partnership between investigator and study coordinator
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/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 ‘checks and Balances’ Failed” By Steve Stecklow and Laura Johannes, August 18, 1997
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)
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
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
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
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