Fraud & Misconduct at Investigator Sites

Paul BelowMedical Affairs - 3M Pharmaceuticals

Presented to the Great Plains Chapter ACRPMarch 27, 2003

• The views and opinions expressed by the presenter are not necessarily those of the 3M Company, 3M Pharmaceuticals or its subsidiaries

• The presenter does not have a significant equity interest (>$50,000) in any of the companies or products cited in this presentation.

Disclaimer / Disclosure

• Definition of fraud

• Prevalence

• Consequences

• Reasons why fraud occurs

• Case studies

• Sponsor regulatory responsibilities

Introduction

• Warning signs/identifiers

• Detection strategies

• 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 uses the terms “fraud” and “misconduct” interchangeably

FDA Definition of Research Fraud

• Per FDA, falsification includes acts of omission and commission

• Omission = consciously not revealing all data

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

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 secondary to falsification of data

Definition (cont)

• Investigators

• Study nurses / coordinators

• Data management personnel

• CRAs / sponsors

• Lab personnel

• IRB staff

Who Commits Fraud?

• Bristol-Myers concedes accounting practices for wholesale earnings “inappropriate” (3/11/03). Also settled with FTC over allegations of patent protection abuse (3/10/03).

• Schering-Plough CEO being investigated by SEC for insider trading (3/13/03).

• ImClone CEO settled with SEC over insider trading violations (3/11/03).

Recent Examples of Pharma Corporate Fraud

• TAP Pharmaceuticals paid $875 M fine over pricing/marketing practices w/ Lupron (2001)

• J&J’s LifeScan paid $60 M in fines over SureStep glucose monitoring device; deficient labeling, failure to report problems and submission of false reports (2000).

• Genentech paid $50 M to settle charges of illegal promotion of Protropin growth hormone for unapproved uses (1999).

Pharmaceutical Corporate Fraud Examples (cont)

Who Gets Blamed?

Study Coordinator

Nurse

Hospital

Sponsor

Self

Office Staff

Sub-investigator

CRA

39%

17%9%

9%

9%

9%

4% 4%

Source: FDA Presentation, DIA 2000

• Difficult to determine but considered rare

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

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

Prevalence of Fraud

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

• Investigator – disqualification, fines, incarceration, legal expenses, 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 submissions made by sponsors

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

Consequences (cont)

• Not enough time or staff

• Not enough subjects

• Lack of GCP training and/or regulatory oversight

• Laziness, loss of interest

• Money, greed

• Pressure to perform, publish

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

• Made up fictitious study subjects

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

• Prescribed prohibited medications to manipulate data

Dr. Fiddes (cont)

• 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

• June 1999 - disqualified as a clinical investigator by FDA

Dr. Fiddes (cont)

• November 2003 - debarred by FDA along with three staff (study coordinators)

• Profiled on 60 Minutes and in the New York Times in 1999

Dr. Fiddes (cont)

Recent additions to the FDA Debarment List

Federal Register Notice for Laverne Charpentier Debarment

• Richard Borison, MD and Bruce Diamond, PharmD - Medical College of Georgia - psych studies

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

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

Other Famous Cases

Recent “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

Perfect efficacy responses for all subjects

Identical lab/ECG results

No SAEs reported

Subjects adhering perfectly to visit schedules

Data Identifiers

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

• Perfect diary cards, immaculate CRFs

• All source records & CRFs completed with the same pen

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

Data Identifiers (cont)

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

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

• Impossible events (eg, randomization before drug delivery)

• Data contains “digit preference”

Identifiers (cont)

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

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

Cherlynn Mathias - University of Oklahoma Melanoma Trial Whistle-Blower

• 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 -Tips for Sponsors/CRAs

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

• Emphasize company policy on fraud at the initiation visit

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

Fraud Prevention (cont)

• Minimize the use of enrollment incentives and pressure to enroll

• Don’t place needless requirements or unreasonable demands on sites

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

Fraud Prevention (cont)

• “Who’s in Charge Anyway? Responsibility in Today’s Clinical Trial Environment”, Stan Wollen, DIA Meeting, June 2000.

• “Patient Misuse and Investigator Fraud in Clinical Trials: What Can Be Done?”, Stan Wollen, DIA Meeting, June 2000.

• “Detecting and Handling Scientific Misconduct and Persistent Noncompliance”, Stan Wollen, DIA Meeting, June 2000.

• “Scientific Misconduct – The ‘F’ Word”, Stan Wollen and Antoine El Hage, FDA Clinical Trials Meeting, October 2001.

References - Presentations

• “A Doctor's Drug Studies Turn Into Fraud,” New York Times, May 17, 1999, K. Eichenwald and G. Kolata.

• “Drug Money,” CBS News 48 Hours, July 31, 2000.

• “At Your Own Risk,” Time Magazine, April 22, 2002, M. Lemonick and A. Goldstein.

• “Alleged Abuse of Research Grant Money Led to False Claims Settlement”, Report on Medicare Compliance, May 25, 2000.

Other References

• HHS Guidance (Office of Research Integrity): Guidelines for Assessing Possible Research Misconduct in Clinical Research and Clinical Trials, January 2001(available at ori.dhhs.gov/multimedia/acrobat/ clinicaltrialsguidelines.pdf)

• Book: Fraud and Misconduct in Medical Research, Lock S, Wells F, eds., London: BMJ Publishing, 1996.

Other References (cont)

• This presentation and related reference material is posted on the Minnesota ACRP website at:

www.mnacrp.org/fraud.html

Current Presentation

• “Fraud and Non-Compliance: How Should an Independent Consultant Respond?”

Ann Begely, JD, RN, Attorney, Kirkpatrick & Lockhart

John Isidor, JD, CEO, Shulman Associates IRB

Session #49 - Tuesday, April 8, 10:30 am - 12:00 noon

Related Sessions at ACRP

• “Disqualification of a Clinical Investigator by the FDA’s CDRH”

Gary Yingling, MS, JD, Kirkpatrick & Lockhart

Rodney Allnutt, Consumer Safety Officer, ORA, FDA

Session #67 - Tuesday, April 8, 3:30 pm - 5:00 pm

ACRP Sessions (cont)

• “Fraud and Misconduct: Who’s Doing It and How Can We Stop Them”

Stan Woollen, Associate Director for Biomedical Research, FDA

Session #71 - Wednesday, April 9, 8:30 am - 10:00 am

ACRP Sessions (cont)

• “The Risks Never Outweigh the Benefits”

Bruce Diamond & AttorneyChaired by Bart Denys, MD, FACC, FSCAI, CCRI

Closing Session (#81)Wednesday, April 91:30 pm - 3:00 pm

ACRP Sessions (cont)

• “FDA Bioresearch Workshop for Investigators, CRAs, CRCs, IRBs, and Sponsors”

Antonie El-Hage, PhD, Branch Chief, Good Clinical Practices II, CDER, FDA

Pre-session workshop #21-24Sunday, April 6, 8:30 am - 5:00 pm (free - included in full registration fee)

ACRP Sessions (cont)

Questions

• 3M Pharmaceuticals

• Minnesota Chapter - ACRP

• Volunteers of the Great Plains Chapter - ACRP

Thanks

• Email: paul@pbelow-consulting.com or vicepresident@mnacrp.org

• Home office phone: (952) 882-4083

• Don’t hesitate to call me with follow-up questions!

Contact Information