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

Paul Below Clinical Research Consultant P. Below Consulting, Inc.

Advanced Monitoring & Site Management Workshop Atlanta Chapter - ACRP October 15, 2005

Disclosure

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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 company referenced here:

– Pfizer

Disclaimer

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I am solely responsible for the content of this presentation.

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The views expressed by me are my own and are not necessarily those of the Association of Clinical Research Professionals or its affiliate local chapters.

Introduction

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Definition of fraud

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Prevalence

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Consequences

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Reasons why fraud occurs

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Case studies

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Sponsor regulatory responsibilities

Introduction (cont)

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Warning signs/identifiers

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Detection strategies

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What to do if fraud is detected

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Fraud prevention

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Questions

FDA Definition of Research Fraud

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

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The FDA often use the terms “fraud” and “misconduct” interchangeably

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PHS definition includes plagiarism

Definition (cont)

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Per FDA, falsification includes acts of omission and commission

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Omission = consciously not revealing all data

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Commission = consciously altering or fabricating data (eg, lab values, lesion counts, etc)

Definition (cont)

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Fraud does not include honest error or honest differences in opinion

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

Who Commits Fraud?

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Investigators

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Study coordinators

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Data management personnel

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Lab personnel

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CRAs and sponsors

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IRB staff

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FDA

9% 9% 4% 4% 9%

Who Gets Blamed?

39% Study Coordinator Nurse Hospital Sponsor Self Office Staff Sub-investigator CRA 9% 17%

Source: FDA Presentation, DIA 2000

Prevalence of Fraud

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Difficult to determine but still considered rare

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

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Only ~3% of FDA inspections uncover serious GCP violations

Consequences of Fraud

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Sponsor

– data validity compromised, submission jeopardized, additional costs

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Investigator

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

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Institution

– lawsuits

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Subject

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

Consequences (cont)

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Fraudulent investigators are often used by multiple sponsors on multiple trials

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

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

Why Does Fraud Occur?

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Lack of resources (staff, time, subjects)

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Lack of GCP training and/or regulatory oversight

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Laziness, loss of interest

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Pressure to perform, publish

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Money, greed

Case Study - Dr. Fiddes

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

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Conducted over 200 studies beginning in the early 1990’s

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Engaged in extensive fabrication and falsification of data

Dr. Fiddes (cont)

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Removed exclusionary data from medical history in patient charts

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Made up fictitious study subjects

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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.

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

Dr. Fiddes (cont)

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.

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

Dr. Fiddes (cont)

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.’

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

Dr. Fiddes (cont)

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.

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

Dr. Fiddes (cont)

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Feb. 1997 – Staffers blows the whistle and federal agents storm the site

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

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

Dr. Fiddes (cont)

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

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June 1999 – disqualified as a clinical investigator by FDA

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Mar. 2000 – medical license revoked

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

Dr. Fiddes and staff on the FDA Debarment List

Federal Register Notice for Laverne Charpentier Debarment

Other Famous Cases

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

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

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

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

Example “Warning” Letter

Warning Letter - Pg 2: Submission of False Information

FDA Regulations

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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.

ICH Guidance

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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 (cont)

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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)

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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).

General Warning Signs

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High staff turnover

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

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High pressure work environment

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Obsession with study payments

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Absent investigators

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Lack of GCP training

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Unusually fast recruitment

Data Identifiers

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Implausible trends/patterns:

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100% drug compliance

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Perfect efficacy responses for all subjects

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Identical lab/ECG results

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No SAEs reported

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Subjects adhering perfectly to visit schedules

Data Identifiers (cont)

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Site data not consistent with other centers (statistical outlier)

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Perfect diary cards, immaculate CRFs

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All source records & CRFs completed with the same pen

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

Identifiers (cont)

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

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

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

Identifiers (cont)

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

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

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

CRA Strategies for Detecting Fraud

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

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Accept no copies – review originals whenever possible

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

Detection Strategies (cont)

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

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

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

Detection Strategies (cont)

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

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

Annual Complaints Received by FDA

200 106 118 131 145 100 11 9 13 11 8 15 9 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002P

Source: FDA Office of Compliance, CenterWatch

Complaints to FDA

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Reporting is encouraged

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All complaints assumed to be credible

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Prioritized evaluation according to subject safety concerns

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

Source of Complaints

53% 17

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30% 1999 Sponsors Anonymous Other

Source: FDA - DIA 2000

Complaints Categories

40% 35% 1998-2001 24% 19% 20% 14% 8% 0% Protocol Violations Falsification of Data Informed Consent Noncompliance Poor AE Reporting Poor Drug Accountability

Source: FDA, CenterWatch

False Claims Act

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

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Unlawful to submit false or fraudulent claim for payment to the United States government

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False claim includes acts of “deliberate ignorance” or “reckless disregard” of the truth

False Claims Act (cont)

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

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

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Suit is filed confidentially under seal

False Claims Act (cont)

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

Recent article about False Claims Act Settlement with Mayo Clinic (Rochester, MN)

Cherlynn Mathias - University of Oklahoma Melanoma Trial Whistle-Blower

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

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Follow your company SOP

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Be a detective - collect evidence

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Challenge but do not accuse

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Conduct the rest of the visit as usual

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Call your manager away from the site

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Write a fact-based summary of findings

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

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Follow your institutional SOP

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Be a detective - collect evidence

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Do not gossip about your suspicions with co-workers

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Write a fact-based summary of your findings

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

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

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

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If still no action, consider your exit strategy

Fraud Prevention (CRAs)

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

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Interest in the study

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Stability of the staff

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Investigator/staff interactions

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Workload

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Level of training

Fraud Prevention (CRAs)

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

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

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Emphasize company policy on fraud at the initiation visit

Fraud Prevention (CRAs)

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Eliminate the use of enrollment incentives and minimize pressure to enroll

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Don’t place unreasonable demands on the sites

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

Fraud Prevention (Sites)

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Don’t overload your staff

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Don’t over-emphasize enrollment in performance evaluations

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Do not accept sponsor bonus payments for enrollment incentives

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Demand regular GCP training by staff and investigators

Fraud Prevention (Sites)

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Discontinue work with problem investigators

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Create an internal QA plan or hire outside consultants to regularly audit

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Develop positive relationships with IRB, internal compliance, legal depts

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Encourage whistle blowers and create institutional policies to protect them

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

www.pbelow-consulting.com/fraud.html

Minnesota Chapter ACRP – www.mnacrp.org

Contact Information

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Office: (952) 882-4083

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E-mail: [email protected]