Fraud & Misconduct at Investigator Sites – A CRA’s Perspective Paul Below Clinical Research...

Fraud & Misconduct at Investigator Sites – A CRA’s Perspective

Paul BelowClinical Research Consultant

P. Below Consulting, Inc.

7th Annual Fall ConferenceResearch Triangle Park Chapter ACRP

November 5, 2005

This presentation and related references are posted on my corporate website at:

www.pbelow-consulting.com/fraud.html

• I have a consulting relationship with the following:

– GlaxoSmithKline

– Boehringer Ingelheim Pharmaceuticals

– Southeast Louisiana Chapter ACRP (web)

– On-Call Clinicians (web)

– Minnesota Eye Consultants (web)

• I have a significant equity interest in the following companies referenced here:

– Pfizer

Disclosure

• The views expressed here are my own and are not necessarily those of the Association of Clinical Research Professionals (ACRP) or its affiliate local chapters.

• I am solely responsible for the content of this presentation.

Disclaimer

• Definition of fraud

• Prevalence

• Consequences

• Reasons why fraud occurs

• Case studies

• Sponsor regulatory responsibilities

Introduction

• Warning signs/identifiers

• Detection strategies

• What to do if fraud is detected

• Fraud prevention

• Questions

Introduction (cont)

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

• The FDA often use the terms “fraud” and “misconduct” interchangeably although dictionary definitions defer

• PHS definition includes plagiarism

FDA Definition of Research Fraud

• Per FDA, falsification includes both acts of omission and commission

• Omission = consciously not revealing all data

• Commission = consciously altering or fabricating data

Definition (cont)

• Fraud does not include honest error or honest differences in opinion

• Per the FDA, deliberate or repeated noncompliance with the protocol and GCP can be considered fraud, but is considered secondary to falsification of data

Definition (cont)

• Investigators

• Study coordinators

• Data management personnel

• Lab personnel

• IRB staff

• CRAs and sponsor personnel

• FDA

Who Commits Fraud?

Who Gets Blamed?

Study Coordinator

Nurse

Hospital

Sponsor

Investigator

Office Staff

Sub-investigator

CRA

39%

17%9%

9%

9%

9%

4% 4%

Source: FDA Presentation, DIA 2000

• Difficult to determine but still considered rare

• Reported to significantly impact 1-5% of pharmaceutical clinical trials – Frank Wells, Medico Legal Investigations (Reuters Health, January 2002)

• Only ~3% of FDA inspections uncover serious GCP violations

Prevalence of Fraud

• Sponsor – data validity compromised, submission jeopardized, additional costs

• Investigator – fines, legal expenses, disqualification/debarment, license revocation, incarceration, ruined career

• Institution – lawsuits

• Subject – safety at risk, loss of trust in clinical trial process

Consequences of Fraud

• Fraudulent investigators are often used by multiple sponsors on multiple trials

• A small number of investigators can have a broad impact on many NDA submissions

• Disqualified investigator, Dr. Fiddes, was involved in 91 submissions with 47 different sponsors

Consequences (cont)

• Lack of resources (staff, time, subjects)

• Lack of GCP training and/or regulatory oversight

• Laziness, loss of interest

• Pressure to perform, publish

• Money, greed

Why Does Fraud Occur?

• Dr. Fiddes was president of a clinical research company in Whittier, CA

• Conducted over 200 studies beginning in the early 1990’s

• Engaged in extensive fabrication and falsification of data

Case Study - Dr. Fiddes

• Removed exclusionary data from medical history in patient charts

• Made up fictitious study subjects

• Fabricated lab results by substituting clinical specimens and manipulating lab instrumentation

Dr. Fiddes (cont)

Fiddes had always found it easy to elude detection by the crews of company monitors and government auditors that visited his offices, even when his employees spelled out their suspicions about what was happening. It wasn't that he was particularly adept at dodging their questions; rather, they seemed reluctant to challenge such a prominent figure in the drug-testing business.

Dr. Fiddes (cont)

Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

Several former coordinators for Fiddes said they had reported his unethical conduct to Pat Pryor, an independent study monitor working with Pfizer, Inc. Tipped off to the discrepancies, Ms. Pryor sharply challenged Fiddes and his staff in her reviews of their paperwork.

Dr. Fiddes (cont)

Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

Fiddes chafed at the challenges, feigning outrage. ‘Our integrity and reputation for performing high-quality clinical trial work has been injured, and we are justifiably upset,’ Fiddes wrote in a July 1995 letter to Pfizer.

He insisted Pfizer ‘have a new monitor assigned to our site immediately.’

Dr. Fiddes (cont)

Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

What could the watchdogs have seen that would have allowed them to detect his fraud? Nothing, Fiddes replied.

Had it not been for a disgruntled former employee, he would have still been in business.

Dr. Fiddes (cont)

Source: “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999

• Feb. 1997 – Staffers blows the whistle and FDA special agents storm the site

• Aug. 1997 – plead guilty to felony charge of conspiracy to make false statements to the FDA

• Sept. 1998 – sentenced to 15 months in federal prison and ordered to pay $800,000 in restitution

Dr. Fiddes (cont)

• May 1999 – profiled on 60 minutes and in the New York Times

• June 1999 – disqualified as a clinical investigator by FDA

• Mar. 2000 – medical license revoked

• Nov. 2002 – debarred by FDA along with three study coordinators

Dr. Fiddes (cont)

Dr. Fiddes and staff on the FDA Debarment List

Federal Register Notice for Laverne Charpentier Debarment

Office of Criminal Investigations

• Part of Office of Regulatory Affairs

• Conduct FDA criminal investigations

• Thomas Jefferson University, Philadelphia - NIH-funded HIV gene therapy studies - False Claims Act settlement

• Michael McGee, MD - University of Oklahoma - melanoma vaccine trial

• Richard Borison, MD and Bruce Diamond, PhD - Medical College of Georgia – psych and neuro studies

Other Famous Cases

Bruce Diamond, PhD – “The Lessons of Greed,” PharmaVOICE, July 2004

Example “Warning” Letter

Warning Letter - Pg 2: Submission of False Information

• 21 CFR 312.56(b): A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA 1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator’s participation in the investigation.

FDA Regulations

• ICH E6 - 5.20.1:Noncompliance with the protocol, SOPs, GCP and/or applicable regulatory requirement(s) by the investigator / institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance.

ICH Guidance

• ICH E6 - 5.20.2:If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s / institution’s participation in the trial … and promptly notify the regulatory authorities.

ICH Guidance (cont)

• ICH - E6 4.12:If the trial is terminated prematurely or suspended for any reason, the investigator / institution should inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and … should promptly inform the regulatory authority(ies).

ICH Guidance (cont)

• High staff turnover

• Staff are disgruntled, fearful, anxious, depressed, defensive.

• High pressure work environment

• Obsession with study payments

• Absent investigators

• Lack of GCP training

• Unusually fast recruitment

General Warning Signs

• Implausible trends/patterns:

100% drug compliance

Identical lab/ECG results

No SAEs reported

Subjects adhering perfectly to visit schedules

Perfect efficacy responses for all subjects

Data Identifiers

Layout the primary efficacy data for all subjects at a site to look for trends

• Site data not consistent with other centers (statistical outlier)

• Source records lack an audit trail - no signatures and dates of persons completing documentation

• All source records & CRFs completed with the same pen

• Perfect diary cards, immaculate CRFs

Data Identifiers (cont)

Source: British Medical Journal, 2002; 324; 1193-1194

• Subject handwriting and signatures are inconsistent across documents (consents, diaries)

• Questionable subject visit dates (Sundays, holidays, staff vacations)

• Impossible events (eg, subject randomized before IP even available at the site)

Data Identifiers (cont)

• Subject visits cannot be verified in the medical chart or appointment schedule

• Data contains “digit preference” – some digits used more frequently than others (0, 5, and even digits)

• “Halo” around the date or test value indicating the original was obliterated with correction fluid

Data Identifiers (cont)

• Ask for all information (data) pertinent to the study (CRFs, study specific source worksheets, clinic charts, sign-in sheets, lab requisitions, shipping records)

• Accept no copies – review originals whenever possible

• Get technical – read lab reports, x-rays, ECGs – don’t just inventory

CRA Strategies for Detecting Fraud

• Expect fraud – start from the assumption that records are bogus and work backwards

• Question missing, altered, and/or inconsistent data – offer to retrieve records yourself, keep pulling on loose ends and see what unravels

• Don’t be intimidated – challenge the site to explain suspicious data

Detection Strategies (cont)

• Be suspicious of blame shifting –remind the investigator that he/she is responsible for study conduct

• Cultivate whistleblowers – pay attention to staff complaints, listen to grievances, establish rapport, and be approachable

Detection Strategies (cont)

Annual Complaints Received by FDA

145131

118

159

106

81113911

0

100

200

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002P

Source: FDA Office of Compliance, CenterWatch

• Reporting is encouraged

• All complaints assumed to be credible

• Prioritized evaluation according to subject safety concerns

• 25% of complaints are evaluated by an on-site inspection (audit)

Complaints to FDA

Source of Complaints

Sponsors

Anonymous

Other

17%

30%53%

1999

Source: FDA - DIA 2000

Complaints Categories

35%

24%

19%

14%

8%

0%

20%

40%

ProtocolViolations

Falsification ofData

InformedConsent

Noncompliance

Poor AEReporting

Poor DrugAccountability

Source: FDA, CenterWatch

1998-2001

• Civil war-era law created to protect government from unscrupulous defense contractors

• FCA says that it is unlawful to submit a false or fraudulent claim for payment to the United States government

False Claims Act

• Private citizens who know of people or companies that are defrauding the government may sue on the government's behalf (qui tam relators)

• Plaintiff shares in the proceeds of the suit (15-30% of amount recovered by government)

• Suit is filed confidentially under seal

False Claims Act (cont)

• FCA contains protections for whistleblowers who are harassed, threatened, discharged or otherwise discriminated against in their employment because of their whistle blowing

False Claims Act (cont)

Recent article about False Claims Act Settlement with

Mayo Clinic (Rochester, MN)

Cherlynn Mathias - University of Oklahoma Melanoma Trial Whistle Blower

• Follow your company SOP

• Be a detective - collect evidence

• Challenge but do not accuse

• Conduct the rest of the visit as usual

• Call your manager away from the site

• Write a fact-based summary of findings

What Should I Do If I Detect Fraud?

• Turn over your findings to your manager/QA and step out of the scene

• If your complaint is not taken seriously and followed-up, keep pressing and find others willing to listen (including the government)

• If still no company action, develop your exit strategy

What Should I Do If I Detect Fraud? (cont)

• During the pre-study evaluation, carefully scrutinize sites in the following areas:

Interest in the study

Stability of the staff

Investigator/staff interactions

Workload

Level of training

Fraud Prevention

• Conduct GCP training at the start and throughout the study as necessary

• Be expert on the protocol particularly with parameters that determine eligibility (inclusion/exclusion criteria) and primary efficacy endpoints

• Emphasize company policy on fraud at the initiation visit

Fraud Prevention (cont)

• Eliminate the use of enrollment incentives and minimize pressure to enroll

• Don’t place unreasonable demands on the sites

• Maintain frequent interaction with sites through regular monitoring visits and phone calls

Fraud Prevention (cont)

This presentation and related references are posted on my corporate website at:

www.pbelow-consulting.com/fraud.html

• Kerrin Young, Study Manager, Takeda, and Jeri Weigand, Quality Assurance Auditor, 3M Pharmaceuticals, for their collaboration in the development of this presentation

• Gail Celik and the Research Triangle Park Chapter ACRP

Thanks

• Office: (952) 882-4083

• E-mail: paul@pbelow-consulting.com

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