# Presentation: 334085

## Patient Misuse and Investigator Fraud in Clinical Trials: What Can Be Done? Part I

**Stan W. Woollen**
- Deputy Director
- Division of Scientific Investigations
- Center for Drug Evaluation and Research , FDA
- June 14, 2000

## GCP Is a System of Shared Responsibilities 

- Sponsors/Monitors/CRO’s
- Institutional Review Boards
- Clinical Investigator
- FDA

## FDA Monitoring of Clinical Research

- _FDA’s Bioresearch Monitoring Program_ - A comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA regulated research.

## Program Objectives

- Protect the rights and welfare of research subjects
- To verify the quality and integrity of  research data submitted to FDA by industry to support research and marketing permits for new products

## BIMO Inspections Completed

**637**

**627**

**678**

**683**

**675**

**BIMO Inspections Completed**

## Clinical Investigator InspectionsFY 92-99

- 324

- 402

- 338

- FYI            92    93   94   95    96   97   98    99

- 261

- 229

- 182

- 348

- 305

- 6/5/00

## Clinical Inspections - DomesticFY’99

- Clinical Inspections - DomesticFY’99

- n = 241

- 45%

- 50%

- 4%

- 1%

- 6/5/00

## Clinical Investigator Deficiency Categories* - FY 99

- Protocol

- Records

- Drug Acct

- AEs

- Consent

- 27%

- 20%

- 15%

- 9%

- 8%

- n=305

- *Foreign & Domestic

- 6/5/00

## Clinical Investigator Deficiency Categories: FY 97-99

## Regulatory Actions(Clinical Investigations)

- Regulatory Actions(Clinical Investigations)

- Year(s)		       93-96	   97	   98	     99
- Warning
-   Letters			22	     0   	    7	       8
- Disqualifications		  2	     0 	    0	       2
- Consent
- Agreements			  7	     1	    4  	       5
- NIDPOEs* 			 n/a	   n/a	    5	      3**

- *Notice of Initiation of Disqualification Proceedings and Opportunity to Explain	**One resolved in favor of CI

## Inspection Outcomes(1964-1999)

- Disqualifications				99
- 	(via hearing process or consent agreements)
- Restrictions/Assurances			26
- 	(via consent agreements)
- Prosecutions/Convictions			20*

- *Includes some CI’s who signed consent agreements.

## IRB Inspections

- 185

- 150

- 149

- 179

- FY   95      96        97        98        99

- 224

## Institutional Review is a Critical Component of GCP

**Considerable attention has focused on the performance of IRB’s/IEC’s in the U.S.**
**HHS Inspector General Reports**
**Testimony to the National Bioethics Advisory Commission**
**Suspension of clinical research by NIH’s Office of Protection from Research Risks**

## FDA Recognizes the Importance of IRB Inspections to Implementing GCP

**FDA has inspected U.S. IRB’s since 1980**
**FDA performs 250-300 IRB inspections per year from an inventory of approximately 1600**
**4-5% of inspections result in official action**
**Required action is most typically a notification to FDA (15 days) of steps to come into compliance**
**In 3 cases (FY 99):  Sanctions imposed**

## IRB Deficiencies - FY’99

**Quorum**

** ****Minutes**

**Written **
**Procedures**

**Records**

**Roster,**
**Proposals**

**25%**

**21%**

**15%**

**10%**

**8%**

**N= 224**

## IRB’s: What We Observe  

**Leading problems evoking official action**
**For 15 WL’s issued between 1/99 and 3/00**
**Failure to prepare and/or follow written procedures (n=14)**
**Failure to adequately document activities (n=13)**
**Failure to conduct adequate continuing review (n=10)**
**Failure to fulfill requirements for expedited review (n=9)**
**Failure to fulfill the requirements of informed consent (n=7)**

## IRB’s:  Observations as Symptoms

**Heightened Workload Pressures**
**Adverse event reports**
**Protocol amendments**
**Limited Resources**
**Limited Useful Feedback on Multi-Site Trials**
**Limited Feedback on Problem Investigators**
**IRB Membership**** **
**Fluidity; competing commitments; training**

## Human Subject Protection Is Not Just IRBs: Current Issues

**Process of Informed Consent**
**Subject Recruitment Practices**
**Conflicts of Interest**
**Financial interests and arrangements**
**Professional (publications; promotion; stature)**
**Vulnerable Populations**
**Pediatric initiatives**

## Impact of Misconduct

**Impact of Misconduct**

- While scientific misconduct is rare, when it does occur, it affects public confidence in the clinical trial process and raises questions about the effectiveness of trial monitoring and its follow-up by sponsors.

## Current Compliance Concerns

- Failure analysis of monitoring in recent notorious cases
- Six cases were selected based on serious problems
- Source documents completely absent
- Study subjects  completely fabricated
- Study staff performing tasks for which they were unqualified
- Other significant deviations from regulations

## Current Compliance Concerns

- _CI__	__	__Applications  __	__Sponsors__	_
-  A	  	  	91	      	      47
-  B	  	  	49	      	      25
-  C	  	  	43	               21
-  D	  	  	21	               17
-  E	  	  	12		        6
-  F	    	    	  6                      6

## Complaints Received: 92-99*

- 92      93     94      95     96      97     98     99

- 11

- 9

- 13

- 11

- 8

- 15

- 9

- 101

- *calendar years

## Detecting and Handling Scientific Misconduct and Persistent Noncompliance 

- The FDA’s Perspective
- By
- Stan W. Woollen
- Deputy Director Division of Scientific Investigations

## Detecting and Handling Scientific Misconduct

-  **The Fiddes Case "lessons learned”**
- What we observed,
- What we didn't,
- Why
**How we can improve**
- Tips for Detecting  Serious misconduct
- Systems for handling complaints of misconduct
- Reporting misconduct to the FDA
- Sharing information on Misconduct

## Fiddes Case Background

- Dr. Fiddes president of a clinical research company in Whittier California
- Conducted over 200 studies for as many as 47 drug companies beginning in the early 1990’s
- Engaged in extensive fabrication and falsification of data
- Aug. 1997 plead guilty to felony charge of conspiracy to make false statements to the FDA in connection with the Drug approval process

## Fiddes Case Background

- Sept. 1998 sentenced to 15 months in federal prison
- Ordered to pay $800,000 in restitution
- June 1999 Disqualified as a clinical investigator by Commissioner of FDA

## Fiddes Case Background

- Examples of misconduct
- Made up fictitious study subjects
- Fabricated lab results by substituting clinical specimens and manipulating lab instrumentation
- Prescribed prohibited medications to manipulate data

## New York TimesMay 17, 1999RESEARCH FOR HIRE: SECOND OF TWO ARTICLES 

- A Doctor's Drug Studies Turn Into Fraud
- By KURT EICHENWALD and GINA KOLATA

## NY Time Allegations100% source data verification = False sense of security

- Letter from one of the testing company's study monitors. "CONGRATULATIONS on meeting your enrollment deadline!" the monitor, (***YOUR NAME HERE***), wrote in a letter dated Feb.. "_*I performed a 100 percent source document verification,(x-rays) and found no outstanding issues." *_

## Tip for Detecting Serious Misconduct

**Get Technical**- Read and evaluate X-rays, EKGs, lab results, don’t just inventory the source document

## NY Times AllegationThe Slight of Hand Maneuver

-  When a monitor hired by (***YOUR COMPANY NAME HERE***) asked to see the patient's medical chart, a study staff member quickly fetched the patient's medical chart, and pulled out every page that made reference to the disqualifying lung disease. Then, according to investigative documents, she turned the remaining records over to the monitor. The violation went undetected.

## Tip for Detecting Serious Misconduct

**Fill in the Blanks**- Question missing dates, times, information, offer to retrieve records yourself.  Keep pulling on loose ends and see what unravels.

## NY Times AllegationThe Emperor has no clothes Syndrome

- “Even when his employees spelled out their suspicions (to monitors) 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.”

## Tip for Detecting Serious Misconduct

**Don’t be intimidated**- Tell the emperor he has no clothes and see if he tries to cover up.

## NY Times AllegationBLAMETHEMONITOR Maneuver

- “Several former coordinators for Fiddes said they had reported his unethical conduct to an independent study monitor working with (***YOUR COMPANY NAME HERE***). The Study Monitor sharply challenged Fiddes and his staff in her reviews of their paperwork. Fiddes chafed at the challenges, feigning outrage.”

## NY Times AllegationBLAMETHEMONITOR Maneuver

- "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 the sponsor, complaining about the monitor’s demand. He insisted the sponsor "have a new monitor assigned to our site immediately."

## Tip for Detecting Serious Misconduct

**Don’t shoot the messenger**- Believe the monitor, put the burden of proof on the Clinical Investigator.

## NY Times AllegationTHENURSEDIDIT Maneuver The last refuge of a scoundrel

-  "Dr. Fiddes replied that they were going to blame the study nurse for all of the problems, and he was going to say he had no knowledge of what was going on."

## The Blame GameWho gets the blame?

- n (parties blamed) = 23
- n (cases) = 20

- 39%

- 17%

- 9%

- 9%

- 9%

- 9%

- 4%

- 4%

## Tip for Detecting Serious Misconduct

**Be suspicious of blame shifting- **Tell the Clinical Investigator he/she is responsible for the conduct of the study and is accountable for the results.

## NY Times Allegation

**“****Monitors for the **_***government and the industry***_** never noticed any problems with Fiddes' bogus paperwork, which they reviewed during routine audits.”**** **

## NY Times Article Allegation

- “Why was Fiddes able to fool the monitors so easily? Because the oversight system is mostly designed to catch errors, not fraud”.

## Tip for Detecting Serious Misconduct

**Expect Fraud**- Start from the assumption the records are bogus and the study is a fraud, and work back.  Verify then trust.

## NY Times AllegationFabrication the undetectable crime?

- “Another study on an antibiotic required that patients have a certain type of bacteria growing in their ear. No problem for Fiddes. He bought the bacteria from a commercial supplier and shipped them to testing labs, saying they had come from his patients' ears.”

## NY Times Allegation

-  The FDA investigators asked (Fiddes), what evidence of fraud is there in the records reviewed by monitors and the government? What could the watchdogs have seen that would have allowed them to detect his fraud?

## NY Times Allegation

_***“***__***Nothing,***_ Fiddes replied. Had it not been for a disgruntled former employee, he would have still been in business.”

## Tip for Detecting Serious Misconduct

**Cultivate Whistleblowers**- Establish rapport with study staff, be approachable and available, listen to grievances, observe working conditions.

## How we can improveTips for Detecting Serious Misconduct

**Get Technical**-Read x-rays, EKGs, lab results, don’t just inventory
**Fill in the Blanks**-Question missing dates, times, information,offer to retrieve records yourself
**Don’t be intimidated**-tell the emperor he has no clothes

## How we can improveTips for Detecting Serious Misconduct

**Don’t shoot the messenger**-believe the monitor, put the burden of proof on the CI
**Be suspicious of blame shifting-**tell CI he/she is totally responsible for the conduct of the study
**Expect Fraud**-Start from the assumption the records are bogus and the study is a fraud, and work back

## How we can improveTips for Detecting Serious Misconduct

**Cultivate Whistleblowers**-establish rapport with study staff, be approachable and available, listen to grievances, observe working conditions

## NY TIMES Allegations

-  Avoiding Detection: The F.D.A. Ignores an Early Warning -The government had its _*first solid lead*_ on what was happening in Fiddes' office fully _*17 months before Ms. X exposed his crimes to an FDA auditor*_. FDA Investigators wrote memos about Ms. X’s allegations, and forwarded them from Los Angeles to  (_***MY***_*** COMPANY NAME HERE***) of the FDA.

## How we can improveTips for Dealing with Serious Misconduct

**        ****Be Prepared- **have a system in place to capture, document and deal with complaints of misconduct in a timely fashion. Follow your SOPs!!!!

## Complaint Handling SystemPoints to Consider

**Policy on Complaints of Misconduct**
**Procedures for Complaint Handling **
**Receiving, reviewing, reporting and processing**
**Procedures for Documenting**
**Complaint files, forms, etc.**

## Complaint Handling SystemPoints to Consider

**Policy**
- All complaints should be ***assumed*** to be credible unless demonstrated* *to the contrary after thorough evaluation and supervisory review
- All decisions on the follow-up action required for a complaint should have documented supervisory review and approval

## Complaint Handling SystemPoints to Consider

**Policy**
_**All**_ complaints should be documented and evaluated for follow-up upon receipt
- Complaints requiring action should be followed up ASAP

## Complaint Handling System Points to Consider

**Policy**
- Identify complaints that will be followed-up on a high priority basis e.g.
**Reports of gross abuse of subjects’ rights that result or have the potential to result in death or injury**
**Reports of fraud, falsification or other criminal activity**
- Assign due date to ensure that complaints are evaluated and acted on immediately,

## Complaint Handling SystemPoints to Consider

**Policy**
**The receipt, follow-up, and action on all complaints should be documented from cradle to grave so that all decisions and actions can be reconstructed from the complaint handling documentation**

## FDA Believes Sponsors should Promptly Report...

**Any information they have that any person involved in human subject trials committed research misconduct**
**Whenever the sponsor discovers misconduct**
**Not just for clinical investigators and not just when a clinical investigator is terminated**

## Source of Complaints about CIs FY 1999

- 17%

- 30%

- 53%

- n = 77

## Sponsor reports to DSI

- Of the 13 complaints received from sponsors in FY 1999 related to clinical investigators, the reasons given were as follows:
- 7 - falsification
- 1 - no reason given
- 5 - other problems

## Sponsor Reports to DSI

- FDA follows up on every complaint.  Outcomes of 13 complaints received:
- 4 - Pending receipt of more information
- 2 closed out after evaluation with no further action indicated
- 1 - OAI
- 4 - VAI
- 2 - assignments pending in field

## How you can help

**Recognizing Research Misconduct**
-  Research misconduct means fabrication or falsification in proposing, designing, performing, recording, or reviewing research, or in reporting research results.  Research misconduct does not include honest error or honest differences of opinion.

## How you can help

**Reporting Research Misconduct**
**Name of the person(s) **
**Contact information  **
**Specific identity of the affected research**
**IND/IDE #, protocol, study title, and study dates**
**As much information regarding the research misconduct as is available to the sponsor.**

## We’re from the Government, how can we help?

- Timely Sharing of information on problem investigators
- Amended Privacy Act notice
- Bioresearch Monitoring Information System (BMIS)/ CI Inspection list
- NIDPOE Letters
- Misconduct Websites

## Privacy Act Systems of Records

- Revision published October 19, 1998; effective November 18, 1998
- New routine use added:
- Provides for disclosure of covered records to sponsors and Institutional Review Boards (IRBs) involved with studies affected by a clinical investigator’s violative or potentially violative conduct

## Bioresearch Monitoring Information System (BMIS)

- BMIS lists all clinical investigators, CROs, and IRBs involved in the conduct of Investigational New Drug Studies with human investigational drugs.
- Abstracted from FDA Forms 1571 and 1572, or other pertinent IND submission documents (CVs, cover letters, investigator lists)
- File contains a separate entry for each time an investigator, CRO or IRB is identified in a new submission (i.e.,  if an investigator is named in 10 INDs, his/her name will appear 10 times in this file).

## Notice of Initiation of Disqualification Proceeding and Opportunity to Explain

- NIDPOE Letter
- Notice of matters complained of required under 312.70
- When FDA has information indicating that an investigator has
- repeatedly or deliberately failed to comply OR
- has submitted false information to FDA or sponsor

## Misconduct Website

- FDA Homepage
_*www.fda.gov/ora/compliance.ref/default.htm*_
- FDA Debarment list
- Disqualified/Restricted/Assurances list
- PHS Administrative Actions List

## Where to Report Misconduct 

**Drugs**
**Division of Scientific Investigations (HFD-45), Office of Medical Policy, Center for Drug Evaluation and Research, FDA, 7520 Standish Place, Room 103, Rockville, Maryland 20855-2773, (301) 594-0020, fax (301) 594-1204.**

## Where to Report Misconduct 

**Biological Products**
**Office of Compliance and Biologics Quality, Division of Inspections and Surveillance, Center for Biologics Evaluation and Research, (HFM-650), FDA, 1401 Rockville Pike, Room 400S, Rockville, Maryland 20852-1448, (301) 827-6221, fax (301) 443-6748.**

## Where to Report Misconduct 

**Medical Devices**
-  **Office of Compliance, Division of Bioresearch Monitoring, (HFZ-310), Center for Devices and Radiological Health, FDA, 2098 Gaither, Room 130, Rockville, Maryland 20850, (301) 594-4718, fax (301) 594-4731.**

## How You can help

**FDA Wants ****You**** to Recognize and Report Research Misconduct**

## Classification of IRB Inspections

**FY95**

**FY96**

**FY97**

**19%**

**78%**

**3%**

**84%**

**13%**

**3%**

**78%**

**21%**

**1%**

## IRB Classifications - FY’99

- n=224

- 65%

- 19%

- 15%

- 0.5%

## IRB Deficiencies - FY’97

**Quorum**

**Review **
**Period**

**Written **
**Procedures**

**Report **
**Study**
**Changes**

**49%**

**35%**

**31%**

**28%**

**28%**

**Notify  **
**FDA**

**N=149**

## IRB Deficiencies - FY’98

**Quorum**

** ****Minutes**

**Written **
**Procedures**

**Notify**
** ****FDA**

**Roster**

**26%**

**23%**

**22%**

**17%**

**15%**

**N=179**