FDA Warning Letters: Dont Make the Same Mistakes

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FDA Warning Letters Dont Make the Same Mistakes!

• Neysa Rhoads, RN, CCRC
• Preventive Medicine
• nrhoads_at_utmem.edu

October 13, 2009
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Experience is the name everyone gives to their
mistakes --Oscar Wilde
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What are Good Clinical Practices?

• Guidelines for the Investigator
• Guidelines for the Trial Sponsor
• Guidelines for the Clinical Trial Protocol
• Guidelines for the Investigators Brochure

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Fraud

• In the broadest sense, a fraud is a deception
  made for personal gain. The specific legal
  definition varies by legal jurisdiction. Fraud is
  a crime, and is also a civil law violation. Many
  hoaxes are fraudulent, although those not made
  for personal gain are not technically frauds.
  Defrauding people of money is presumably the most
  common type of fraud, but there have also been
  many fraudulent "discoveries" in art,
  archaeology, and science.

From http//en.wikipedia.org/wiki/Fraud
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Objectives

• Identify different types of misconduct and
  falsification in research
• Discuss causes and consequences of misconduct
• Learn from others mistakes

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Synonyms for Fraud Misconduct

• Wrong Doing Deception
• Felony Malpractice
• Unethical Behavior Mischief
• Cheating Felony
• Unprofessional Swindling
• Deceit Crime

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Misconduct

• Three categories of misconduct
• Illusion of Knowledge
• Surprisingly Sloppy
• Malicious Malfeasance
• Detecting, Correcting and Preventing
• FDA Sanctions
• Resources

Woollen, S.W., n.d.
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The Illusion of Knowledge

• Lack of understanding
• Misconduct of the uninformed kind
• Examples Backdating the subjects signature on a
  consent form because the subject forgot to date
  the form, creating source documents from CRFs,
  discarding source document after accurate
  transcription and reporting transcribed data as
  original.

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Surprisingly Sloppy

• Lazy
• Inaction, inattention to detail, inadequate
  staff, lack of supervision
• Examples ICF inadvertently not obtained from
  subjects, blood pressures rounded to the nearest
  10mmHg, data estimated rather than actually
  measured, protocol ignored or shortcuts taken

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Malicious Malfeasance

• Deliberate action to deceive or mislead
• F _ _ _ _
• Examples creating, altering, recording, or
  omitting data
• Data does not represent what actually occurred

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Falsification of Data

• FDA focus Falsification of Data
• Deliberate or repeated noncompliance can be
  considered misconduct and is secondary focus of
  FDA

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Recognizing Research Misconduct

• Research misconduct means falsification of data
  in proposing, designing, performing, recording,
  supervising or reviewing research or in reporting
  research results

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Consequences

• Places subjects at possible safety risk
• Jeopardizes the reliability of the data

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What Causes Fraud

• Study staff that does not have the necessary
  resources and support to accomplish their tasks
• Study staff have unreasonable demands placed upon
  them
• Grand enrollment incentives
• Just tell the truth

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Research for Hire Second of Two Articles. A
Doctors Drug Studies Turned Into Fraud

• New York Times, May 1999
• Dr. Robert Fiddes
• Reports of Fraud by his staff went unnoticed
• June 1996, auditors took notice
• Plead guilty to fraud

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The Emperor Has No Clothes!
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Dos and Donts

• Do
• Fill in all blanks
• Enter date and times
• Make sure information is accurate and matches
  throughout the chart
• Complete documentation the day of the visit
• Write a progress note!
• Do the right thing!

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Dos and Donts

• Dont Cut corners
• Dont Backdate
• Dont use liquid paper or pencil
• Dont re-create
• Dont perform study related procedures before the
  ICF is signed

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FDA Sanctions

• Warning Letters
• Formal Disqualification
• Clinical Hold
• Voluntary Agreements
• Debarment
• Prosecution

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Expectations of an Audit

• Auditors work on the assumption the records are
  bogus and the study is a fraud
• They are taught to carefully review and evaluate
  the Labs, ECGs X-Rays
• Question missing information
• Look out for denial and shifting of blame
• Verify then trust

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FDA Misconduct
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You failed to obtain informed consent of each
human subject in accordance with 21 CRF 50 21
CRF 312.60

• Lab samples drawn prior to signing and dating the
  ICF
• IRB approved ICF required actual time in which
  legally effective IC was obtained. No
  documentation of the actual time. Unable to
  verify subjects signed dated prior to protocol
  specific procedures being conducted on them

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You failed to obtain informed consent of each
human subject in accordance with 21 CRF 50 21
CRF 312.60

• ICF not approved by IRB
• ICF not signed prior to implanting
  investigational device

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You failed to obtain informed consent of each
human subject in accordance with 21 CRF 50 21
CRF 312.60

• No written documentation that IC was obtained
• IRB approved a 3 page document. Found subjects
  who were consented with a 1 page ICF and
  unapproved ICFs
• IRB approved ICF signed after study device was
  utilized

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You failed to obtain informed consent of each
human subject in accordance with 21 CRF 50 21
CRF 312.60

• Subject signed consent form for incorrect study
• Consent not signed until 11 days after study
  related procedure. Handwritten note states, I
  was informed about study and risk-did not sign
  consent 6-26-03
• No documentation that subject was given copy of
  the signed informed consent

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You failed to obtain informed consent of each
human subject in accordance with 21 CRF 50 21
CRF 312.60

• Prior to any study related procedures being
  performed, subject was given a copy of the ICF to
  read. Subject was given the opportunity to have
  her questions answered and wishes to participate
  in the TREAT trial. Subject willingly signed
  consent with witness present and copy of signed
  consent given to subject for her records. Neysa
  Rhoads, RN

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Characteristics of Quality Data

• Accuracy
• Immediacy
• Legibility
• Durability
• Integrity
• Consistency
• Honesty

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Warning Letter

• Most Recent Warning Letters are on the FDA
  website
• Read Them, See What Others Did Wrong
• Learn from the Mistakes of Others

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Summary

• Knowledge is Power
• If it Looks Like a Skunk, Acts like a Skunk and
  Smells Like a Skunk ITS A SKUNK!!!!

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The only real mistake is the one from which we
learn nothing --John Powell
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References

• www.fda.gov/foi/warning_letters
• Wollen, S.W. (2003). Retrieved on 6/13/08 from
  http//www.fda.gov/oc/gcp/slideshows/2003/gcp2003.
  ppt
• Wollen, S.W. Hage, A.E. (2001). Retrieved on
  6/13/08 from http//www.fda.gov/oc/gcp/slideshows/
  misconduct2001/misconduct.ppt
• Eichenwald, K. Kolata G. (1999). A doctors
  drug trials turn to fraud. Retrieved from
  http//www.nytimes.com