+A Case Study in Conflict of Interest, Fraud and AbuseAnn Marie Cisneros, MBA

Western MA Chapter

+ Presentation Topics

- Case Study of fraud in Ketek Study Warning signs of fraud Investigating fraud Lessons Learned- Role of stakeholders

participation/responsibility in fraud cases- Look at how current monitoring methods can

be improved to detect fraud

+

Background- Ketek Study

+ Ketek-Study 3014

A Pivotal Phase III safety study to support NDA to market the drug in US in 2001

Mega trial - 24,000 patients enrolled in 5 months

1,800 PIs, many research naïve

Study was requested by FDA due to previous data showing liver complications

+ Background

• October 2002- After all data from TREAT study was submitted to the FDA, case was handed over to FDA’s Office of Criminal Investigation as a result of several routine FDA regulatory audits.

• August 2003- One PI, Dr. Anne Kirkman Campbell indicted by grand jury of 21 counts of making false claims and mail fraud.

• March 2004- Dr. Campbell was sentenced to 57 months in prison, fined $557,251 and ordered to pay close to 1 million dollar in restitution to the sponsor.

+ Background

- Initially approved in 2004 for acute bacterial sinusitis, acute exacerbation of chronic bronchitis and community acquired pneumonia.

- Approval for sinusitis and AECB was withdrawn 1 day before the Congressional Hearing in Feb. 2007

- November 2005- PI Medical license revoked

+

Background• May 2006- Consented to voluntary disqualification

• Feb 2007- CRA testifies before Congress

• Feb 2008- CRA testifies again

+

Stakeholders

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+ Main Stakeholders

PI convicted of fraud: Dr. Kirkman-Campbell Unqualified PIs: at least 10 other unqualified PIs- many where

highest enrollers CRO CRA’s who identified fraud: Ann Marie Cisneros and others who

wish to remain un-named. Central IRB Global Pharmaceutical company FDA: Approved Ketek despite audit showing noncompliance Patients-post approval: deaths and cases of liver failure US Government: held hearings on Ketek fraud case

+Principal Investigator- Dr. Kirkman-Campbell

Site was located in Gadsden, Alabama, population < 40,000

> 1% of the adult population was enrolled in the trial

Highest enroller with 407 patients, almost all fabricated

Sponsor paid Campbell $400/enrolled subject

Had only conducted 1 previous clinical trial

+ Principal Investigator

Uncooperative with monitoring efforts:

ordered site staff to not talk to CRAs if PI not present

ordered 2 CRAs to leave site

allowed Ms. Cisneros to stay only if sponsor promised her more studies

+ Other PIs

At least 10 other sites, including top 3 enrollers, had serious deviations that affected integrity of data

4 other study sites were referred for criminal activity 2nd highest enrolling PI had never conducted a trial &

was cited by FDA for failing to follow the Protocol & to report AEs

3rd highest enrolling PI conducted study with suspended medical license, did not follow protocol, falsified study records, was addicted to cocaine when conducting study, arrested in 2002 for threatening to kill his wife, had a bag of cocaine and a loaded gun in his pocket when police came to arrest him

+ Study Site Staff

PI employed inexperienced young women untrained in proper conduct of trials

PI did not employ trained employees likely to question her conduct of trial, protect study subjects & alert others

PI controlling of them, forbidding them to talk to monitors PI may have capitalized on their financial dependence on

job, creating a coercive relationship in which staff vulnerable to follow her orders

How many site staff are willing to put their job in jeopardy in to blow the whistle on their PI?

+ CRO

CRO informed sponsor of sites numerous deficiencies Did not contact FDA when neither Sponsor nor IRB took any action CEO testified CRO did not inform FDA because that specific

responsibility was not transferred If it is not actually stated that it is a stakeholder's responsibility to

inform FDA about potential fraud or harm to subjects, may any stakeholder do so?

What about ethical responsibility? Contract = > $20 Million for this study. How much do business

motivations such as desire for repeat business affect such decisions?

+ IRB

Used a for-profit IRB Business with financial & repeat business considerations

Is there a conflict of interest because IRBs are paid by sponsor companies?

IRB received 83 deviations from Campbell’ site & reports from CRO re: IC violations, but never reviewed them

+ IRB

President of IRB, testified IRB’s SOPs did not require review

Are SOPs used as a way to avoid responsibilities?

In the course of the investigation several high ranking IRB experts said IRB’s could not contact patients directly. Why?

CEO of IRB, informed Committee that the record of the call had been found shortly before the Congressional Hearings.

+ Sponsor

No Pre-Study or Site Initiation Visits were performed

Training was conducted via a training video even for research naïve Pis

So many PIs were needed (1,800) that sponsor allowed research-naïve physicians to conduct this safety study

Sponsor increased enrollment cap from 50 to 500 subjects without a protocol amendment or notifying the IRB.

+ Sponsor

Sponsor was responsible for ensuring PI’s compliance Sponsor response to the multitude of GCP issues was

to “generate numerous memos to file” to be used as training tools

Sponsor management later admitted the memos were often generated after the site was closed to enrollment

Sponsor’s representative testified that this secured compliance, which the committee challenged

Do memos amount to remedying?

+ Subjects / Patients

12 cases of acute liver failure 23 cases of serious liver injury 4 people died 1 patient required a liver transplant 53 cases of hepatotoxic events by end of

2006 Some patients not aware their medical

information was used to ‘enroll’ them in a trial fraudulently

+ FDA

FDA issued a 483 Warning letter to Sponsor after approving Ketek

This was years after FDA became aware of fraud & had approved Ketek anyway – does this make sense?

4 FDA safety officials raised warnings about safety of Ketek but were ignored

Email from Dr. Graham “It’s as if every principle governing the review and approval of new drugs was abandoned”

+ FDA / Government

HHS said it would not comply with a subpoena to provide the briefing book used by FDA Commissioner Andrew C. von Eschenbach on Ketek.

Stupak: “There appears to be a continued effort to keep

secret the documents we have requested. This only causes members to further question what could be so damaging in the materials that the administration wants to stonewall our bipartisan subpoena.”

+ Conflict of Interest at FDA?

Dr. David Ross, former safety reviewer at the FDA, ended a 10-year career with the agency due to the Ketek case: “The agency's growing reliance on industry dollars has fostered a culture of approval. There is pressure on managers that gets transmitted down to reviewers to find some way of approving it. There's been a cultural shift at the FDA, and the pharmaceutical industry is now viewed as the client."

+

Monitoring Findings

23

+ Red Flags Noted Before Monitoring Visit

No SAE’s reported Limited # of AE’s reported for 407 subjects, only 5

reported at the time of my monitoring visit Blood test results were not medically feasible Reported that almost all subjects 100% compliant with

study drug. No lost to follow up subjects

+ Red Flags Noted Before Monitoring Visit

All site staff & some relatives were ‘enrolled’ in the study. Subjects enrolled when site not open ( site was closed 1

day/week and 2 hours for lunch) IVRS records showed subjects enrolled too rapidly to be

possible, every few minutes, > 30 subjects/day Same site in Gadsden, Alabama enrolled only 12 subjects

+ Monitoring findings

On most consents, subject’s initials & date not in subject’s handwriting

Compared handwriting to subjects’ signature on documents in chart (Medicare Form / Drivers License) Noted one forgery where patient handwriting didn’t match consent signature

Date of study visit vs. date of consent vs. date of lab draw not always consistent.

+ Monitoring Findings

Adding study diagnosis in different colored ink in Medical record, ex. Subject was seen for HTN, Acute Sinusitis x3 added next to original chart note.

Subject sign in log contained several sets of patients with the same last name, appeared to be husband and wife.

Office waiting room did not appear to be that busy for a site that could enroll 400 subjects.

+ Study Team Findings

Blood splitting MD in charge of reviewing lab data realized results

for subjects not feasible from one visit to another Looked not only at each subject’s lab results, also

results for all subjects drawn on that dayOdd Randomization patterns• Tracked by In-house CRA who noted subjects being

enrolled when the office was closed and upwards of 30/day often when site didn’t have any drug.

+Have to “Think Smart & Work Smart”

The entire study team must ‘work smart’ Think beyond the superficial level of information Not only what is stated, but what is not stated Does everything make sense? Delve deeper Takes time, training, intuition, observational skills

+ Action Items

Increase training in critical thinking & clinical research ethics, rather than narrow focus on concrete regulations

CRAs must be very “smart” when monitoring, looking at qualitative (soft) information as well as quantitative (data) information

Monitoring is more than checking concrete information

Clinical research professionals must utilize critical thinking and have excellent communication skills

Change of Perspective

Old NewConcrete Tasks•Comparing data to CRFs•Checking off boxes on reports

Critical thinking•Think critically about the feasibility of the data•Question what is NOT documented as well as what IS

Discrete Tasks•Focus on specific tasks•See the trees but not the forest

Overall Picture•Put pieces together to see real situation•See both the forest & the trees

Focus on knowledge of Regulations•Citing Reg number, wording•Concrete interpretation•May limit ethical action

Understanding of rationale for regulations•Overall perspective •Knowledge of all aspects of conduct of trials•Add ethics and judgment to approach

SOP, Regulatory Based•Focus on legal, regulatory actions

Integrates Research Ethics•Priority is safety & welfare of subjects

Clearly defined reference point•Regulations, SOPs, Guidances

Soft skills•Communication, observation, intuition

+ System of Checks & Balances

Ensuring trials are conducted properly not just CRAs’ responsibility

We are all responsible Overlapping responsibilities If one party fails, others are present to identify

noncompliance & take action

+

Blowing the Whistle

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+ Motivators of Not “Blowing the Whistle”

Fear of repercussion Fear of loss of job Fear of losing ability to support family Fear of loss of financial security Fear of difficulty securing employment in the future Fear of marred professional reputation Fear of the unknown Fear of person conducting fraud Greed Conflicts of interest Business goals (earnings, repeat business, corporate

pressures, promotions) Lack of knowledge about research ethics/whistleblowing Lack of ethics Lack of motivation to do the right thing due to fear or

greed

+ “Blowing the Whistle”

Many cases uncovered by whistleblowers Many research societies include

commitment to report fraud in their ethical code of conduct

Many institutions have an Office of Compliance with reporting hotlines

Government encourages whistleblowers through False Claims Act awards

+ “Blowing the Whistle”

Should only be considered when it apparent no action is going to be taken.

Lose credibility if processes in place aren’t given an opportunity to work.

Never discuss your decision with co-workers people you think you can trust are more likely to show allegiance with the company.

When calling the FDA you can request that your name be kept confidential

www.whistleblower.org or the Government Accountability Project works with whistleblowers in the pharmaceutical industry.

+References

Congressional Testimony http://energycommerce.house.gov/cmte_mtgs/110-oi-hrg.021208.Ketek.shtml

Ross, D. B. (2007). The FDA and the case of Ketek. The New England Journal of Medicine 356(16), 1601–1604. Retrieved July 18, 2008 from http://content.nejm.org/cgi/content/full/356/16/1601

Hundley, K. (2007, May 27). Drug’s chilling path to market: How a broken FDA approved a cold antibiotic despite a wide trail of alarms. St. Petersburg Times. Retrieved July 19, 2008 from http://www.sptimes.com/2007/05/27/Worldandnation/Drug_s_chilling_path.shtm

+ References

Pringle, E. (2006, December 6). Ketek fraud investigation derails confirmation of new FDA commissioner. Retrieved July 18, 2008 from http://www.lawyersandsettlements.com/articles/00484/ketek-data.html

CIRCARE http://www.circare.org/foia5/ketek.htm "Red Flags in the Study Office“ Goldfarb, N.

http://firstclinical.com/journal/2007/0708_Cisneros.pdf FDA Office of Criminal Investigations - Report of Investigations

http://energycommerce.house.gov/Investigations/KetekExhibitBinder/10001.PDF

"Research, Investigator Conduct Under Scrutiny“ Applied Clinical Trials http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=506843&sk=&date=&pageID=2&searchString=ketek

+ Thank you!

Ann Marie Cisneros, BS, MBA has over 14 years of diverse experience in the clinical research industry, having held a variety of positions as an Independent Consultant and is currently working as a Recruiter at Catalyst Clinical Resourcing, Inc.

.

Ann Marie Cisneros may be contacted at (919) 604-4399 or annmarie@catalystcr.com