Health Care Compliance Association Research Compliance … · Health Care Compliance Association Research Compliance Conference October 20, 2009 2 CROs -Who is Doing Your Clinical

Health Care Compliance AssociationResearch Compliance Conference

October 20, 2009

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CROs - Who is Doing Your Clinical Research??

Presented by

Bret S. Bissey, MBA, CHC, FACHE

Director, Regulatory Compliance Practice

http://www.biores.org/dir/Companies/Contract_Research_Organizations/

An example (8/18/2009):

• ClinStat, Inc. - Contract research services for general design and conduct of clinical investigations and for specific disorders of extreme stress (PTSD, DES)http://www.clinstat.ca

http://www.clinstat.ca/

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How Many CROs Are There?

• Conflicts of Interest

• Money Flow

• Interrelationships of Companies

• Quality of Principle Investigators

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Why Would We Be Concerned About Who Is Conducting Your Clinical Research??

• Broadly defined as any situation in which a decision maker has a financial or other interest in or maker has a financial or otherinterest in, or relationship with, an entity or person that doesbusiness with the hospital, physician, pharmaceutical/device company (i.e., healthcare provider)

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Conflict Of Interest—Defined

• Conflicts are unavoidable. We are only six degrees of separation from every other human being on the planet. Conflicts of interest are simply a part of life

• But, when are they ok? When are they not?

– Testing Human Subjects would seem to want to be immune from Conflicts of Interest

or

– They should be totally vetted to assure they are ok

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Conflict Of Interest

• I was a non-voting member of a Hospital IRB for 8 ½ years

• We were never informed that someone other than the pharmaceutical, device, or healthcare organization (data collection) was doing the research study

• We didn’t know what a Clinical (or Contract) Research Organization was…

– Were they conducting research on our patients?

– Was this disclosed?

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How Much Are Hospital IRBs Told?

• Is there a conflict of interest of the CRO to enroll patients quickly?

– How is the CRO compensated?

– What relationships does the CRO have with main researching party?

• Should they have any relationships other than conducting research?

• Who is doing QA at the clinical sites?

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Why Would Hospital IRBs Want To Know About CROs?

• If the CRO is involved, did they have involvement in writing theClinical Protocol?

– If so, should they be permitted to conduct, enroll, monitor the research?

– If the protocol is flawed, what is the consequence for future business?

• Why is this important?

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• Good Compliance Officers are taught to be skeptical…

• Good Compliance Officer is taught to “look everywhere..”

• Where is the Compliance function within a CRO?

• Most time the skepticism is validated in future years.

• $$$$ and Egos!!

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Compliance Officer Perspective

• If a CRO is involved, who is really the Principle Investigator (PI)?

– Does the CRO have physicians that are “ghost PIs” (remember ghost writers) for the pharmaceutical or device companies?

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• Who are the physicians leading the study for a CRO?

– Are they in the proper specialty?

– Are they Board Certified?

– Where are they located?

– What Experience?

– Where did they train?

– Could they be credentialed at our hospital?

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Why Would IRBs Want To Know About CROs?

• They are directing care for our patients!

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Why Would IRBs Want To Know About CROs?

• Would I have reviewed a project differently if I knew the PI functions were subcontracted to a CRO who had a non-Board Certified or Board Eligible Physician in charge of the day-to-day functions, including all adverse effects of the study?

– YES!!

– But, if I didn’t know I couldn’t ask the question.

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Back To My IRB Experience

• Why not?

– CROs are compensated many times based upon their performance of concluding studies according to time lines established by the sponsor.

• Inherent pressure to start, enroll, and complete on time.

• I personally have seen studies begin without all T’s crossed and I’s dotted and it concerns me…

– Example : SOPs being delinquent

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Why Question The CRO?

• Majority of CRO’s probably have quality as top priority but do all –all of the time?

• There is always fraud and corruption in every industry…

– Consider the following:

• 1998 – 10 complaints to the FDA regarding clinical drug trial irregularities

• 2006 - 350 complaints to the FDA regarding clinical drug trial irregularities

• Why the increase? Maybe because people are starting to look?

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Cause For Concern?

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Example of a Problem

• Marketed as the next Amoxicillin

– Sinusitis and bronchitis

• Aventis devised Study 3014 – nationwide patient clinical drug trial involving 1800 private physicians

• Aventis sub-contracted the clinical trial work to a third party CRO, PPD, Inc. for $20 million

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Aventis Pharmaceutical – Ketek

(Story from Tampabay.com May 27, 2007)

• PPD Clinical Reviewer sent to QA a high enrolling physician

• Review determined problems

– Doctor had enrolled staff and family members

– Patient consent forms signed every few minutes and when office was closed

– Edits/addendums to medical records that were not appropriate

– 407 patients enrolled by one physician, peer group had 12

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• None of this physician’s patients dropped from trial

• Fraud was concluded by Clinical Reviewer

• Reviewer had teleconference with PPD bosses and drug maker

– “I walked away from that meeting very frustrated” she said, “I’d never seen a sponsor so lackadaisical about a site.”

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• Why was this case public?

– “Concerned Employee”

• Are CRO employees encouraged to talk about problems?

• I do not know the answer

• This is where compliance is needed

• What is the Compliance Structure at CRO’s

– Is it focused on SOP’s or the seven elements of compliance?

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• Seven Elements that offer you protection from the OIG Model Compliance Program & US Sentencing Guidelines:

– Compliance Officer & Program Oversight

– Policies and Procedures

– Education

– Audit

– Corrective Actions to Identified Problems ***

– Open Communications ***

– Enforce Violations

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Compliance Is Pretty Basic

• What happened with this study?

– FDA approved the study

• Conjecture/debate about information they had and whether they complied with their responsibilities

– FDA approved drug on April 1, 2004

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• Less than a year later

– Young Mexican construction worker in Charlotte went to doctor with cold

– Prescribed Ketek

– Three weeks later died of liver failure

• US Attorney’s office in Birmingham Alabama indicated the study physician on 21 counts of fraud

– Physician sentenced to 57 months in prison

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• FDA part of the problem

• How much does a CRO contribute to the problem

• Are there conflicts of interest

If you are a IRB member, do you want to know if a CRO is involved in a study?

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• Physicians’ quote “they seemed to want to rush you through everything, they didn’t care how you did it. They wanted the trial over so they could get the data to the FDA”

• How was the CRO paid?

– Even after the trial deviations were reported, Aventis hired thesame physician for a second study and flew the physician to San Diego so she could learn how to “market” Ketek to other physicians.

• Does this concern anyone else?

• Does this sound like the “old days” of pharmaceutical/physician relationships? What happened to those?

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• CRO second-biggest investor in Accentia BioPharmaceutical and also runs trials for the company’s sinus drugs

• If the product is approved, the CRO stands to earn 14% of royalties…

– Is this a conflict of interest?

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Should A CRO Invest In Drugs It Tests?

• St. Petersburg Times, July 2, 2007:

– “Protocol violations are much more common than data suggest, they have an underestimated impact on drug development. They are not readily detectable. And conventional measures to prevent them are ineffective” -- CRO Executive

– “The FDA does not have the resources to inspect all clinical trial sites or even a major fraction of them. And if you don’t look for fraud, you won’t find it”-- former FDA medical reviewer

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Should A CRO Invest In Drugs It Tests?

• For-profit !!!

• How are Senior Executives paid?

– Portion Salary, Stock, and Bonus

• Is this appropriate for Clinical Trials??

• Research it Yourself?

• “CROs stay in business by hitting the numbers, that is a big ethical no-no. They should never be reviewing anything in which they have a direct financial interest.” -- Executive from a Center for BioEthics

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CRO Business Model

• Covance and Merck & Co., Inc. Finalize Strategic Agreement PRINCETON, N.J., Aug. 18 /PRNewswire-FirstCall/ -- Covance (NYSE: CVD) today announced that it has closed its transaction with Merck to provide a broad array of genomics analysis services under a five-year $145 million contract and to acquire Merck's Seattle-based Gene Expression Laboratory. Effective August 17, 2009, Covance assumed control of the facility and the Seattle team has joined Covance.

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CRO and Pharmaceutical Relationships

• Fraud against the IRB

– Known failure to request and obtain IRB approval

– Known failure to notify the IRB of protocol changes

– Known failure to comply with subject disclosures & protections

– Known failure to comply with third-party review entities or non-governmental directives.

– Conflicts of Interest

– Bad Science

• Why ?

– Several studies have found that more than 40% of surveyed researchers were aware of misconduct but did not report it

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Where Are The Feds Looking For Fraud?

• Awareness of research challenges is important

• Compliance professionals need to become engaged in IRB activities

– Begin asking the questions and requiring answers

• The healthcare industry needs to understand the value and the risk of CROs

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Conclusions

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Contact Information

Two Christy Drive, Suite 219

Chadds Ford, PA 19317

Bret S. Bissey, MBA, CHC, FACHE

Director, Regulatory Compliance Practice

[email protected]

(484) 844-3327

Documents

Health Care Compliance Association Research Compliance … · Health Care Compliance Association Research Compliance Conference October 20, 2009 2 CROs -Who is Doing Your Clinical