The Good, The Bad and The Ugly of Clinical Research Sites.

The Good, The Bad and The Ugly

of Clinical Research Sites

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

Features Clint Eastwood films

Titles

Phrases

Music

Photos

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

“Hang ‘Em High”

Objectives

Warning! Warning! Warning! Letter1. Dr “Dirty Harry” Bear Investigator

“True Crime(s)”2. The Borison – Diamond Affair

3. Dr. Robert “Every Which Way But Loose” Fiddes

“Make My Day”

Cases

AND

Music Titles

Pictures Quotes

Film Clues

Prizes

Correctly guess:

1. Total number of film clues in presentation– 12 clues, so far

2. Total number of unique film clues– 9 clues, so far

The “Good Clinical Practice” Definition

ICH: “Perfect World” for Clinical Trials

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

Investigator Obligations

FDA Form 1572

“Absolute Power”

“Read the SMALL PRINT of the 1572” [Investigator Commitments: Box 9]

S _______ M ______ ______ A _____ to _______ L ____ __________ ________ L et FDA Inspect

__P__ _______ _______ R etain Records I _____ _______ N ____ _ _ _ T ____ ______

upervise

aintain Recordsdhere Protocolearn Investigator’s Brochure

Re ort Adverse Events

nform Subjects

otify I R Brain Staff

“Sudden Impact” GCP Document

How many clues do you have now?

Harry D. Bear M.D., Ph.D.(Virginia Commonwealth University)

Case #1

Investigator with unqualified coordinators

“Dirty Harry’s” 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

“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]

“Dirty Harry’s” Warning Letter

S upervise– “It is your responsibility to monitor

all personnel…”– “There are several examples of…

reports 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…”

Dr. Bear: “High Plains Drifter”

“Several study visits were conducted by personnel not medically qualified to evaluate the subject’s disease status, including the study coordinator…”

“The study coordinator signed the “Request to Transfer Patient” form…even though the “Site Reference Manual” requires that “the investigator must review and sign…”

: “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

FDA Timeline for Dr. Bear

Inspection ended 29 Apr 2002

Warning Letter posted 27 Sep 2002

Disqualification process starts? Unknown

More Clues Ahead!

Richard Borison M.D. and Bruce Diamond Ph.D

(Medical College of Georgia?)

Case #2

Investigators with “Rookie” Coordinators

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

“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

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

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

“For a Few Dollars More”

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

“Thunderbolt and Lightfoot”

Borison Diamond Guilty!

54 36 Felony Counts

150K 125K Fines

$4.26M $1.1M Restitution

15 5 Imprisonment

15 10 Probation

FDA Timeline for Dr. Borison

Inspection ended 22 Apr 1997

[No warning letter issued]

Prison term started 09 Oct 1998

Disqualified 10 Nov 1998

Debarred (10 yrs) 30 Sep 2003

Robert Fiddes, M.D.(Southern California Research Institute)

Case #3

Investigator with his “Beguiled” band of Coordinators

News Article in FDA Consumer

“Physician Sentenced for Doctoring Drug Data” by Tamar Nordenberg

“For a Few Dollars More”

New York Times (17 May 1999) Headlines

A Doctor’s 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.”

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. Fiddes’s research center, Ms. C found herself being pushed to break the rules.”

NYT: 17 May 1999

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. Fiddes’s coordinators, paid bonuses for recruiting patients into studies, soon began improperly enrolling themselves and members of their families.”

NYT: 17 May 1999

“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

“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

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

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.

FDA Timeline for Dr. Fiddes

Inspection ended 28 Feb 1996

[No Warning Letter issued]

Pleaded guilty Aug 1997

Sentenced to prison Sep 1998

Disqualified 01 Jun 1999

Debarred (20 yrs) 06 Nov 2002

FDA Disqualification and Debarment Lists

Disqualification:– http://www.fda.gov/ora/compliance_ref/bimo/disqlist.

htm

Debarment:– http://www.fda.gov/ora/compliance_ref/debar/default

.htm

Some Final Thoughts

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

Clint Eastwood Film Clues

Photos– The Outlaw Josey Wales– Dirty Harry– Hang ‘Em High– Space Cowboys – Pink Cadillac– The Bridges of Madison

County– Kelly’s 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)

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)

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