Maintaining Integrity in Clinical Maintaining Integrity in Clinical TrialsTrials

Harvey J. Murff MD, MPHHarvey J. Murff MD, MPHDirector of Research SafetyDirector of Research Safety

GCRC, VanderbiltGCRC, Vanderbilt

Bush Misuses Science Data, Bush Misuses Science Data, Report SaysReport Says

New York Times, August 8, 2003New York Times, August 8, 2003

““Rather fail with honor than Rather fail with honor than succeed by fraud”succeed by fraud”

SophoclesSophocles

Federal Definition of Research Federal Definition of Research MisconductMisconduct

Fabrication, falsification, plagiarism, or Fabrication, falsification, plagiarism, or other practices that seriously deviate from other practices that seriously deviate from those commonly accepted within the those commonly accepted within the scientific community scientific community

Traditional Definitions of Traditional Definitions of Research MisconductResearch Misconduct

FalsificationFalsification FabricationFabrication PlagiarismPlagiarism

Traditional Definitions of Traditional Definitions of Research MisconductResearch Misconduct

FalsificationFalsification– Substituting one subject’s record for that of another; Substituting one subject’s record for that of another; – falsely reporting to a data coordinating center that falsely reporting to a data coordinating center that

certain clinical trial staff, who were certified to perform certain clinical trial staff, who were certified to perform the procedures on the subjects, had done so, when they the procedures on the subjects, had done so, when they had not; had not;

– altering the dates and results from subjects’ eligibility altering the dates and results from subjects’ eligibility visits; visits;

– altering the dates on patient screening logs and altering the dates on patient screening logs and or/submitting the same log with altered dates on or/submitting the same log with altered dates on multiple occasions; multiple occasions;

Traditional Definitions of Traditional Definitions of Research MisconductResearch Misconduct

FalsificationFalsification– failing to update the patients’ status and representing failing to update the patients’ status and representing

data from prior contracts as being current; data from prior contracts as being current; – altering the results of particular tests on blood samples altering the results of particular tests on blood samples

to show that the test accurately predicted a disease or to show that the test accurately predicted a disease or relapse; relapse;

– backdating follow-up interventions to fit the time backdating follow-up interventions to fit the time window determined by the study protocol; window determined by the study protocol;

– falsifying the times that blood samples were drawn fro falsifying the times that blood samples were drawn fro subjectssubjects

Traditional Definitions of Traditional Definitions of Research MisconductResearch Misconduct

FabricationFabrication– Creating records of interviews of subjects that Creating records of interviews of subjects that

were never performedwere never performed– Making up progress notes for patient visits that Making up progress notes for patient visits that

never took place and inserting them into the never took place and inserting them into the medical record to support published and medical record to support published and unpublished research recordsunpublished research records

– Preparing records for calls and follow-up Preparing records for calls and follow-up contracts to subjects who had already diedcontracts to subjects who had already died

Traditional Definitions of Traditional Definitions of Research MisconductResearch Misconduct

PlagiarismPlagiarismIncluded both the theft or misappropriation of Included both the theft or misappropriation of

intellectual property and the substantial intellectual property and the substantial unattributed textual copying of another’s workunattributed textual copying of another’s work-This includes use of privileged -This includes use of privileged communications (such as a grant review)communications (such as a grant review)

Not Considered Research Not Considered Research Misconduct by ORIMisconduct by ORI

Failing to report an AE to the sponsor or IRBFailing to report an AE to the sponsor or IRBDeviating from the protocolDeviating from the protocolForging a physician’s signature on medical ordersForging a physician’s signature on medical ordersFailing to obtain or properly document, informed Failing to obtain or properly document, informed

consentconsentBreaching human subjects confidentialityBreaching human subjects confidentialityFailure to obtain IRB and/or FDA approval for Failure to obtain IRB and/or FDA approval for

protocol changesprotocol changes

IOM Definition of Research IOM Definition of Research MisconductMisconduct

Significant misbehavior that improperly Significant misbehavior that improperly appropriates the intellectual property or appropriates the intellectual property or contributions of others, that intentionally contributions of others, that intentionally impedes the progress of research, or that impedes the progress of research, or that risks corrupting the scientific record or risks corrupting the scientific record or compromising the integrity of scientific compromising the integrity of scientific practicespractices

Definition of Research Definition of Research MisconductMisconduct

MisappropriationMisappropriation– PlagiarizePlagiarize– Breach confidentialityBreach confidentiality

InterferenceInterference– Sequester or damage materialSequester or damage material

MisrepresentationMisrepresentation– Reckless disregard for the truthReckless disregard for the truth– Omit facts Omit facts

Other forms of Research Other forms of Research MisconductMisconduct

Obstruction of investigations of research Obstruction of investigations of research misconductmisconduct

Noncompliance with research regulationsNoncompliance with research regulations

Integrity and Public TrustIntegrity and Public Trust

Public fundingPublic funding– Advancement of public goodAdvancement of public good

Support is qualifiedSupport is qualified– Must trust scientistsMust trust scientists– Must trust institutionsMust trust institutions

Institutions are held accountableInstitutions are held accountable

Research MisconductResearch MisconductNumber of Institutions Reporting Misconduct Activities, New Allegations, and Number of Number of Institutions Reporting Misconduct Activities, New Allegations, and Number of New CasesNew Cases

Annual ReportAnnual Report # of Institutions # of Institutions Reporting ActivityReporting Activity

# of Institutions- # of Institutions- New AllegationsNew Allegations

# of New Cases # of New Cases OpenedOpened

20012001 7878 6161 7272

20002000 8282 6060 6262

19991999 7272 4646 6363

19981998 6767 4141 5454

19971997 7373 4848 6464

Research MisconductResearch MisconductTypes of Misconduct and Total Number of New Allegations ReportedTypes of Misconduct and Total Number of New Allegations Reported

Annual Annual ReportReport

FabricationFabrication FalsificationFalsification PlagiarismPlagiarism OtherOther TotalTotal

20012001 3737 4646 1717 2727 127127

20002000 3737 2424 1919 2323 103103

19991999 2121 3737 1313 1818 8989

19981998 1515 2222 1010 2222 6969

19961996 2626 3434 88 2424 9292

Reports not Submitted to ORIReports not Submitted to ORI

> 50% significantly deficient> 50% significantly deficient 57% did not contain information 57% did not contain information

establishing PHS jurisdictionestablishing PHS jurisdiction 57% did not include sufficient information 57% did not include sufficient information

to determine whether a formal inquiry was to determine whether a formal inquiry was necessarynecessary

Who is Being Investigated By Who is Being Investigated By ORIORI

150 investigations from 1993-1997150 investigations from 1993-1997– 76 found misconduct and 74 no misconduct76 found misconduct and 74 no misconduct– Primary sitePrimary site

» Medical Schools 68%Medical Schools 68%» Hospitals 11%Hospitals 11%» Research institutions 10%Research institutions 10%

– Primary funding mechanismPrimary funding mechanism» RO1RO1

– ORI results 71% disbarred (range 18 months to ORI results 71% disbarred (range 18 months to 8 years)8 years)

Who is Being Investigated By Who is Being Investigated By ORIORI

Allegations againstAllegations against» Associate professors 27%Associate professors 27%» Professors 19%Professors 19%» Postdoctoral fellows 19%Postdoctoral fellows 19%» Technicians 13%Technicians 13%

Misconduct findingsMisconduct findings» Associate professors 22%Associate professors 22%» Postdoctoral fellows 28%Postdoctoral fellows 28%

Allegations most frequently supportedAllegations most frequently supported» Students 73%Students 73%» Postdoctoral fellows 66%Postdoctoral fellows 66%» Technicians 62%Technicians 62%» Professors 19%Professors 19%» Assistant professors 29%Assistant professors 29%

Who is Being Investigated By Who is Being Investigated By ORIORI

WhistleblowersWhistleblowers» Senior personnel (Deans, professors, asso prof) Senior personnel (Deans, professors, asso prof)

47%47%» Junior personnel 21%Junior personnel 21%

Support rate for whistleblowersSupport rate for whistleblowersAcademic faculty 50%Academic faculty 50%Students 100%Students 100%Technicians 20%Technicians 20%

Handling MisconductHandling Misconduct

Few institutions have much experienceFew institutions have much experience Investigations have profound implicationsInvestigations have profound implications Are emotionally chargedAre emotionally charged For ORI from Allegation to final decision For ORI from Allegation to final decision

approximately 480 daysapproximately 480 days

Impact of Research MisconductImpact of Research Misconduct

Scope of MisconductScope of Misconduct Length of time of the MisconductLength of time of the Misconduct Prestige of Institution or IndividualPrestige of Institution or Individual Impact of Clinical TreatmentImpact of Clinical Treatment Mishandling or retaliation associated with Mishandling or retaliation associated with

allegationsallegations Media CoverageMedia Coverage

Guilt by AssociationGuilt by Association

Preventive StrategiesPreventive Strategies1.1. Make it clear that fabrication will get caughtMake it clear that fabrication will get caught

• Personally verify dataPersonally verify data• Question strong marks or erasuresQuestion strong marks or erasures

2.2. Consider re-contacting participants for quality Consider re-contacting participants for quality purposespurposes

• Did data collector contact youDid data collector contact you• Eligibility criteriaEligibility criteria• Aquatinted with recruiterAquatinted with recruiter

3.3. Promote respect for the protocolPromote respect for the protocol• Johns HopkinsJohns Hopkins• Do not promote attitude of “data no matter what”Do not promote attitude of “data no matter what”

Preventive StrategiesPreventive Strategies

4.4. Allow staff to discuss potential protocol changes Allow staff to discuss potential protocol changes but do not alter the experimentbut do not alter the experiment

• Educate about biasesEducate about biases• Institutional policiesInstitutional policies

5.5. Look for outliersLook for outliers• Data collection too fastData collection too fast• One RA recruits faster than othersOne RA recruits faster than others

6.6. Promote research integrityPromote research integrity• Explicitly educate staffExplicitly educate staff• Discuss rules of authorship, data ownership prior to Discuss rules of authorship, data ownership prior to

studystudy

Limitations to RegulationsLimitations to Regulations

Rigid regulations that dictate process often Rigid regulations that dictate process often limiting flexibility without enhancing resultslimiting flexibility without enhancing results

Rules imposed by multiple agencies have Rules imposed by multiple agencies have inconsistent requirementsinconsistent requirements

Regulation of science by nonscience agencies Regulation of science by nonscience agencies often leads to additional and nonproductive often leads to additional and nonproductive regulatory burdenregulatory burden

Poor communication between regulators and Poor communication between regulators and research institutionsresearch institutions

Integrity in ResearchIntegrity in Research

Individual LevelIndividual Level1.1. Intellectual honestyIntellectual honesty2.2. Accuracy in Accuracy in

contributionscontributions3.3. CollegialityCollegiality4.4. TransparencyTransparency5.5. Protection of subjectsProtection of subjects6.6. Humane careHumane care7.7. Adherence to mutual Adherence to mutual

responsibilitiesresponsibilities

Institutional LevelInstitutional Level1.1. Provide leadershipProvide leadership2.2. Encourage respectEncourage respect3.3. Promote productive Promote productive

interactionsinteractions4.4. Advocate adherence to Advocate adherence to

rulesrules5.5. Manage COIManage COI6.6. Investigate allegationsInvestigate allegations7.7. EducateEducate8.8. MonitorMonitor

Research Organization

External Environment

Inputs/ResourcesFunding -Level and sourceHuman Resources -Training -Experience -Sociocultural and psychological

Outputs/ OutcomesResearch related activities -Quality/quantity of activityResearch Integrity -Knowledge and Attitudes toward ethical standards

Organizational Structure Policies, procedures, code Roles and responsibilities Decision making practices Missions and goals, objectives Technology Organizational Processes Leadership Competition

Supervision Communication Socialization Organizational learning

Ethical Culture and Climate

Feedback

Research Organization

Government regulation

Policies and practices of

scientific societies

Journal policies and procedures

Human resources Job market

Funding for Scientific Work

General Sociocultural, Political, and Economic Environment

Recommendations of Commission on Recommendations of Commission on Research IntegrityResearch Integrity

Uniform Federal definitionUniform Federal definition Institutional AssurancesInstitutional Assurances Promote EducationPromote Education Organization and Journal Code of EthicsOrganization and Journal Code of Ethics Responsible Whistle blowingResponsible Whistle blowing Administrative processes and InvestigationsAdministrative processes and Investigations Effective Oversight of Misconduct AllegationsEffective Oversight of Misconduct Allegations Impose Federal SanctionsImpose Federal Sanctions

Recommendations of IOM Recommendations of IOM

Establish research grantsEstablish research grants Institution develop comprehensive program Institution develop comprehensive program

to promote integrityto promote integrity Institute develop educational programsInstitute develop educational programs Self-evaluationSelf-evaluation AccreditationAccreditation Public databasePublic database

Institutional Measures to Foster Institutional Measures to Foster IntegrityIntegrity

Establish organizational components to Establish organizational components to comply with regulationscomply with regulations

Offer educational programsOffer educational programs Implement policies and proceduresImplement policies and procedures

– Delineate the normative practices of Delineate the normative practices of responsible conductresponsible conduct

Establish criteria for rewardsEstablish criteria for rewards

Measuring IntegrityMeasuring Integrity

Quality Improvement TechniquesQuality Improvement Techniques Self-AssessmentSelf-Assessment Accredited not regulatedAccredited not regulated Lack of measuresLack of measures

ORI Core ContentORI Core Content

1.1. Data acquisition,management, sharing, and Data acquisition,management, sharing, and ownershipownership

2.2. Mentor-trainees relationshipsMentor-trainees relationships3.3. Publication practices and responsible authorityPublication practices and responsible authority4.4. Peer reviewPeer review5.5. Collaborative scienceCollaborative science6.6. Human subjectsHuman subjects7.7. Research involving animalsResearch involving animals8.8. Research misconductResearch misconduct9.9. Conflicts of interestsConflicts of interests

Performance-based ModelPerformance-based Model

Public display of institutional goalsPublic display of institutional goals Create a bonus planCreate a bonus plan Mentorship opportunitiesMentorship opportunities Public accountability of actions inconsistent Public accountability of actions inconsistent

with institutional missionwith institutional mission

FAQ for ORIFAQ for ORI Who is covered?Who is covered?

– Any institution or individual supported with PHS fundsAny institution or individual supported with PHS funds ConfessionsConfessions

– Must be fully documentedMust be fully documented– Must contact ORIMust contact ORI– No specific deals can be madeNo specific deals can be made– May not need full investigationMay not need full investigation

Standard of proofStandard of proof– ““preponderance of evidence”preponderance of evidence”

Panel membersPanel members– No COINo COI

FAQ for ORIFAQ for ORI

Good faith whistleblowersGood faith whistleblowers– Cannot retaliate againstCannot retaliate against

Ownership of dataOwnership of data– Generally the institutionGenerally the institution

Credentials and PublicationsCredentials and Publications– May not fabricate thisMay not fabricate this

FAQ for ORIFAQ for ORI

Foreign studentsForeign students– US standards applyUS standards apply– ““No one told me” not acceptableNo one told me” not acceptable

ConfidentialityConfidentiality– Confidential treatment to the maximum extent Confidential treatment to the maximum extent

possiblepossible DisbarmentDisbarment

– 3 years generally3 years generally

““Most people say that it is the Most people say that it is the intellect which makes a great intellect which makes a great scientist. They are wrong: it is scientist. They are wrong: it is

character”character”Albert EinstienAlbert Einstien