Good Clinical Practice Guidelines

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The Good, The Bad and The Ugly

• of Clinical Research Sites

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Includes FDA Documents as Learning Tools

• Form 1572
• Warning Letters
• Notice of Observations (483s)
• Publications (FDA Consumer)
• Investigator Lists
• Debarment
• Disqualification
• Federal Register Notices

AND
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Features Clint Eastwood films

• Titles
• Phrases
• Music
• Photos

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Hang Em High Objectives

• Define Good Clinical Practice requirements with
  investigator obligations
• Review 3 cases of research misconduct
• Read public documents available from FDA
• Highlight some signs and symptoms of the
  misconduct
• Examine investigator-study coordinator
  interactions

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Make My Day Cases

• Warning! Warning! Warning! Letter
• Dr Dirty Harry Bear Investigator
• True Crime(s)
• The Borison Diamond Affair
• Dr. Robert Every Which Way But Loose Fiddes

AND
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(No Transcript)
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Prizes

• Correctly guess
• Total number of film clues in presentation
• 12 clues, so far
• Total number of unique film clues
• 9 clues, so far

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The Good Clinical Practice Definition

• ICH Perfect World for Clinical Trials

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Good Clinical Practice (GCP)

• A standard for the design, conduct, performance,
  monitoring, auditing, recording, analyses, and
  reporting of clinical trials that provides
  assurance that
• the Data and Reported Results are Credible, and
  Accurate, and that
• the Rights, Integrity, and Confidentiality of
  Trial Subjects are Protected.

Quality Data
Ethics
Quality Data Ethics GCPs
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Investigator Obligations

• FDA Form 1572
• Absolute Power

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Read the SMALL PRINT of the 1572 Investigator
Commitments Box 9
upervise

• S _______
• M ______ ______
• A _____ to _______
• L ____ __________ ________
• L et FDA Inspect
• __P__ _______ _______
• R etain Records
• I _____ _______
• N ____ _ _ _
• T ____ ______

aintain Records
dhere Protocol
earn Investigators Brochure
Re ort Adverse Events
nform Subjects
otify I R B
rain Staff
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How many clues do you have now?
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Harry D. Bear M.D., Ph.D.(Virginia Commonwealth
University)

• Case 1
• Investigator with unqualified coordinators

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Dirty Harrys Warning Letter

• A Sep 27, 2002 FDA communication for violations
  which are regulatory significant and that failure
  to adequately and promptly make corrections may
  expect enforcement action by FDA if the
  violation(s) continue.
• FDA as Enforcer and Dr Bear as High Plains
  Drifter
• http//www.fda.gov/foi/warning_letters/g3537d.htm

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Any Which Way You Can

• People issues are noted often in the warning
  letter
• Not qualified, inexperienced, unauthorized
• Need to supervise, monitor, train
• S M A L L P R I N T
  
• of the FDA Form 1572

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Dirty Harrys Warning Letter

• S upervise
• It is your responsibility to monitor all
  personnel
• There are several examples ofreports that were
  not signed or dated by you or a subinvestigator
  responsible to you.
• please explain how you will supervise study
  staff to ensure
• Your response is therefore inadequate to explain
  how a different person was granted the authority
  to

• T rain staff
• individuals who have prepared study drugs have
  not been registered pharmacists qualified by
  training and experience
• visits were conducted by personnel not
  medically qualified to evaluate the subject
  disease status,
• attributes these errors to the initial
  inexperience of the person who

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Dr. Bear High Plains Drifter

• Several study visits were conducted by personnel
  not medically qualified to evaluate the subjects
  disease status, including the study coordinator
• The study coordinator signed the Request to
  Transfer Patient formeven though the Site
  Reference Manual requires that the investigator
  must review and sign

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The Enforcer

• These errors reflect a pattern of insufficient
  training and experience that may impact the
  safety and welfare of subjects, and the ability
  to determine the safety and efficacy of the study
  drug.

ethics
data quality
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FDA Timeline for Dr. Bear
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More Clues Ahead!
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Richard Borison M.D. and Bruce
Diamond Ph.D (Medical College of Georgia?)

• Case 2
• Investigators with Rookie Coordinators

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Form FDA 483 Inspectional Observations for
Richard L. Borison

• Inspection Dates 06 Nov 1996 22 Apr 1997
• 20 Significant Findings (I.e., 4 pages)
• Added note Dr Diamond received a separate Form
  FDA 483 with 13 of the exact same findings

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A Fistful of Dollars

• Wall Street Journal (15 Aug 1997) Headlines
• Drug Makers Relied on Clinical Researchers Who
  Now Await Trial
• Two Professors Are Accused of Endangering
  Patients and Stealing 10 Million
• Checks and Balances Failed

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The Rookie Coordinators

• Two of their study coordinators had been hired
  after working as Girl Scout administrators
  another had recently been a Delta Airlines flight
  attendant.
• Ms. A who began working as a study
  coordinator , also had no medical training, yet
  was put to work interpreting electrocardiograms
  and blood tests.

WSJ 15 Aug 1997
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The Rookie Coordinators

• Ms. B who coordinated Borison-Diamond drug
  trials at the VA hospital says Dr Diamond pushed
  her so to hard to recruit and retain subjects for
  a Sandoz study of a schizophrenia drug that she
  misled patients claiming the experimental
  medicine may be the next wonder drug.

WSJ 15 Aug 1997
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For a Few Dollars More

• CBS 48 Hours, The Ultimate Risk, aired on 15 Apr
  1999
• Whistleblower was a study coordinator

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Thunderbolt and Lightfoot
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FDA Timeline for Dr. Borison
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Robert Fiddes, M.D.(Southern California Research
Institute)

• Case 3
• Investigator with his Beguiled band of
  Coordinators

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News Article in FDA Consumer

• Physician Sentenced for Doctoring Drug Data by
  Tamar Nordenberg

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For a Few Dollars More

• New York Times (17 May 1999) Headlines
• A Doctors Drug Trials Turn Into Fraud
• Companies large and small showered him not only
  with more than 170 studies to conduct, but with
  millions of dollars in compensation for his work.

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Band of Beguiled Coordinators

• Few employees other than the study coordinators
  mostly women of limited financial means aware
  of the magnitude of the swindle.
• Like every other study coordinator who passed
  through Dr. Fiddess research center, Ms. C found
  herself being pushed to break the rules.

NYT 17 May 1999
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Band of Beguiled Coordinators

• Again and again, study coordinators were
  instructed by Dr. Fiddes and his top aide, Ms.
  Charpentier, to ignore the requirements of the
  drug studies.
• Dr. Fiddess coordinators, paid bonuses for
  recruiting patients into studies, soon began
  improperly enrolling themselves and members of
  their families.

NYT 17 May 1999
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Blood Work Fraud

• Bodily fluids that met certain lab values were
  kept on hand in the office refrigerator, ready to
  be substituted for the urine or blood of patients
  who did not qualify for studies.

NYT 17 May 1999
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In The Line of Fire

• Dr Fiddes laid much of the blame for everything
  that happened on his study coordinators again,
  without providing evidence to support the
  assertion.
• He told them that fraud was rampant in the
  research industry. He named names of doctors he
  suspected of engaging in practices similar to his
  own.

NYT 17 May 1999
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Fiddes Unforgiven?

• But, the investigators asked, What could the
  watchdogs have seen that would have allowed them
  to detect his fraud?
• Nothing, Dr Fiddes replied.
• Had it not been for a disgruntled employee, he
  would have still been in business.
• Disgruntled employee was a study coordinator

NYT 17 May 1999
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The Final Gauntlet

• Dr. Fiddes was sentenced to 15 months in prison,
  ordered to repay 800,000, and debarred.
• 3 study coordinators were found guilty.
• One study coordinator was debarred.

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FDA Timeline for Dr. Fiddes
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FDA Disqualification and Debarment Lists

• Disqualification
• http//www.fda.gov/ora/compliance_ref/bimo/disqlis
  t.htm
• Debarment
• http//www.fda.gov/ora/compliance_ref/debar/defaul
  t.htm

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Some Final Thoughts
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Final Advice

• Conduct ethical clinical research
• Protect the needs of and risks to patients
• Generate quality data
• Follow GCP responsibilities of the 1572
• Seek out more education in GCPs
• Develop strong partnerships between investigator
  and study coordinator

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Clint Eastwood Film Clues

• Photos
• The Outlaw Josey Wales
• Dirty Harry
• Hang Em High
• Space Cowboys
• Pink Cadillac
• The Bridges of Madison County
• Kellys Heroes
• Unforgiven (Oscar Night)

• Music
• The Good, The Bad, and The Ugly (title theme)
• A Perfect World (End Credits Medley)
• Quote
• Make My Day (Dirty Harry)

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Clint Eastwood Film Clues (Titles)

• The Good, the Bad, and the Ugly
• Dirty Harry (2)
• Hang Em High
• Paint Your Wagon
• Absolute Power
• Sudden Impact

• A Perfect World
• True Crime
• Every Which Way But Loose
• Rookie (3)
• A Fistful of Dollars
• For a Few Dollars More (2)

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Clint Eastwood Film Clues (Titles)

• Thunderbolt and Lightfoot
• Enforcer (2)
• High Plains Drifter (2)
• Any Which Way You Can

• Beguiled (3)
• Blood Work
• In the Line of Fire
• Unforgiven
• Gauntlet