Ethics and Regulations in Ethics and Regulations in Clinical ResearchClinical Research

MCTS C03 (3 credits)MCTS C03 (3 credits)Tuesday Evenings, 4:30Tuesday Evenings, 4:30--7:30pm7:30pm

RWJMS Clinical Academic Building, Room 3403, RWJMS Clinical Academic Building, Room 3403, New Brunswick, NJNew Brunswick, NJ

Course Director: Michael J. Leibowitz, M.D., Ph.D.Course Director: Michael J. Leibowitz, M.D., Ph.D.

Ethics and RegulationsEthics and Regulations

Ethical issues need to be considered in all Ethical issues need to be considered in all clinical studies. Each study is unique and clinical studies. Each study is unique and there often are differing opinions on critical there often are differing opinions on critical issues.issues.On the other hand, Regulations protect On the other hand, Regulations protect subjects, and these must be followed. subjects, and these must be followed. These may vary between countries, These may vary between countries, states, and institutions.states, and institutions.

Course FormatCourse Format

Lecturers include academic and industrial Lecturers include academic and industrial researchers, many with extensive clinical researchers, many with extensive clinical research experience.research experience.GradingGrading

Mock IRB & suggestions for protocol revisionMock IRB & suggestions for protocol revisionStudent seminarsStudent seminarsTerm papersTerm papersCITI (Collaborative IRB Training Initiative) CITI (Collaborative IRB Training Initiative) certification (oncertification (on--line)line)

Ethical Scientific Conduct & Ethical Scientific Conduct & Conflict of Interest Conflict of Interest

Michael J. Leibowitz, M.D., Ph.D.Michael J. Leibowitz, M.D., Ph.D.Professor, Molecular Genetics, Professor, Molecular Genetics,

Microbiology & ImmunologyMicrobiology & ImmunologyUMDNJUMDNJ--Robert Wood Johnson Robert Wood Johnson

Medical SchoolMedical SchoolEmail: Email: leibowit@umdnj.eduleibowit@umdnj.edu

September 8, 2009September 8, 2009

Definition of Scientific MisconductDefinition of Scientific Misconduct

FabricationFabricationFalsificationFalsificationPlagiarismPlagiarismOther definitions (not meeting the Other definitions (not meeting the standards of the scientific community) no standards of the scientific community) no longer widely usedlonger widely used

Experimental DataExperimental Data

Who owns them?Who owns them?Dated and signedDated and signedNot removable or erasableNot removable or erasableHow keep computerized data?How keep computerized data?

Publishing a PaperPublishing a PaperAuthorship is the Authorship is the ““coin of the realmcoin of the realm””When you ready to publish? Tell a complete When you ready to publish? Tell a complete story, reproducible data, significant contributionstory, reproducible data, significant contributionAuthor/contributor: significant contribution to the Author/contributor: significant contribution to the design, experimentation, and reporting of the design, experimentation, and reporting of the workworkRewards and responsibilities of authorship: Rewards and responsibilities of authorship: credit and blamecredit and blameNew initiative to identify contribution of each New initiative to identify contribution of each contributor (not exactly same as author) of a contributor (not exactly same as author) of a paper (paper (RennieRennie et al., JAMA 278:579, 1997)et al., JAMA 278:579, 1997)

Fabrication and FalsificationFabrication and Falsification

Unlike plagiarism, obviously wrong and requires Unlike plagiarism, obviously wrong and requires conscious action by the wrongconscious action by the wrong--doerdoerHow can this be prevented?How can this be prevented?--SupervisorsSupervisors--ReviewersReviewers--Other researchersOther researchers--Responsible Conduct of Research courseResponsible Conduct of Research course--Is reducing pressure feasible and would it Is reducing pressure feasible and would it work?work?

Failure to Publish Negative ResultsFailure to Publish Negative Results

Many more positive than negative results Many more positive than negative results publishedpublishedIs this due to influence of sponsors or Is this due to influence of sponsors or other factors?other factors?Importance in clinical research greater Importance in clinical research greater than in other fieldsthan in other fields

Definition: PlagiarizeDefinition: Plagiarize

““to steal or pass off as oneto steal or pass off as one’’s own (the s own (the ideas or words of another)ideas or words of another)””““to present as oneto present as one’’s own an idea or s own an idea or product derived from an existing source.product derived from an existing source.””

Webster’s Seventh New Collegiate Dictionary

Definition: CopyrightDefinition: Copyright

““the exclusive legal right to reproduce, publish the exclusive legal right to reproduce, publish and sell the matter and form of a literary, musical and sell the matter and form of a literary, musical or artistic work.or artistic work.””Note that this includes scientific publications.Note that this includes scientific publications.

Webster’s Seventh New Collegiate Dictionary

Who owns a publication?Who owns a publication?

All authors?All authors?Senior (first) author?Senior (first) author?Submitting (PI) author?Submitting (PI) author?Employer(s) of authors?Employer(s) of authors?Funding agencies?Funding agencies?Publisher?Publisher?

Why is plagiarism the most Why is plagiarism the most widespread infraction despite being widespread infraction despite being

the easiest to detect?the easiest to detect?

Many authors may not know the rules!Many authors may not know the rules!Computers make plagiarism easy!Computers make plagiarism easy!““SelfSelf--plagiarismplagiarism”” is still plagiarism!is still plagiarism!

How to use the work of others How to use the work of others appropriatelyappropriately

ReferenceReferenceCitationCitationWhen is permission needed? From When is permission needed? From whom?whom?

Permission to RePermission to Re--Publish is Not Publish is Not AutomaticAutomatic

““The rightsholder did not grant rights to reproduce this item The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original in electronic media. For the missing item, see the original print version of this publication.print version of this publication.

Figure 3. Figure 3. catcat--scratch disease showing inflammation of the scratch disease showing inflammation of the lymph node.lymph node.

Division of Pediatric Surgery, Brown Medical School. Division of Pediatric Surgery, Brown Medical School. Accessed August 17, 2007, at Accessed August 17, 2007, at http://bms.brown.edu/pedisurg/Brown/IBImages/SkinST/http://bms.brown.edu/pedisurg/Brown/IBImages/SkinST/Catscratch.htmlCatscratch.html..””

P.M. Rabinowitz et al., American Family Physician 76: 1318 (2007P.M. Rabinowitz et al., American Family Physician 76: 1318 (2007).).

Plagiarism Checking SitesPlagiarism Checking Sites

Multiple sites and programs are listed at:Multiple sites and programs are listed at:

http://http://plagiarism.phys.virginia.edu/links.htmlplagiarism.phys.virginia.edu/links.html

Conflict of InterestConflict of Interest

Definition of Conflict of InterestDefinition of Conflict of InterestAccording to D.F. Thompson, a conflict of According to D.F. Thompson, a conflict of interest occurs when secondary interests interest occurs when secondary interests (financial and many others, such as promotion, (financial and many others, such as promotion, fame, family, etc.) unduly influence professional fame, family, etc.) unduly influence professional judgment concerning a primary interest (patient judgment concerning a primary interest (patient wellwell--being, research and education).being, research and education).This may be an actual or potential personal or This may be an actual or potential personal or institutional conflict, or the APPEARANCE of institutional conflict, or the APPEARANCE of such a conflict.such a conflict.BayhBayh--Dole Act (1980) mandates Dole Act (1980) mandates commercialization of govt.commercialization of govt.--funded university funded university research discoveries. research discoveries.

Why Such a High Standard?Why Such a High Standard?

Observers cannot easily determine what Observers cannot easily determine what influences an investigatorinfluences an investigatorScience, funding agencies and the public Science, funding agencies and the public depend on trust of research reports; any depend on trust of research reports; any doubt is potentially disastrousdoubt is potentially disastrous

Does funding source matter?Does funding source matter?603 consecutive papers and presentations on 603 consecutive papers and presentations on leg orthopedic prostheses:leg orthopedic prostheses:–– Total hip replacement implantsTotal hip replacement implants

Commercially funded: 93% positiveCommercially funded: 93% positiveIndependently funded: 37%Independently funded: 37%

–– Total knee replacementsTotal knee replacementsCommercial: 75% positiveCommercial: 75% positiveIndependent: 20% positiveIndependent: 20% positive

–– Investigators receiving royalties reported no negative Investigators receiving royalties reported no negative outcomesoutcomes

K.A. K.A. EzzetEzzet, J. , J. ArtrhoplastyArtrhoplasty 18(7 Suppl. 1):13818(7 Suppl. 1):138--45 (2003)45 (2003)

How widespread is COI?How widespread is COI?

Survey of medical school/teaching hospital Survey of medical school/teaching hospital faculty (1663 at 50 schools, 2007)faculty (1663 at 50 schools, 2007)–– 52% had 52% had ““any relationshipany relationship”” with industrywith industry–– 41% had relationship that contributed to most 41% had relationship that contributed to most

important researchimportant research–– 20% had industrial funding (48% clinical trials)20% had industrial funding (48% clinical trials)–– Average industry funding per year: $33,417Average industry funding per year: $33,417–– Average industry funding of clinical trial Average industry funding of clinical trial PIPI’’ss: :

$110,869$110,869DE DE ZinnerZinner, EG Campbell, JAMA 302:969, EG Campbell, JAMA 302:969--76 (Sept. 2, 2009)76 (Sept. 2, 2009)

COI Importance in Clinical COI Importance in Clinical ResearchResearch

Potential of harm to subjectsPotential of harm to subjectsStudy defects may harm future patients as Study defects may harm future patients as well as future researchwell as future researchExposure reduces public trust, reducing Exposure reduces public trust, reducing willingness of public to serve as subjectswillingness of public to serve as subjectsRisk of lack of faith by funding sourcesRisk of lack of faith by funding sourcesBASIC research still has rules, but not as BASIC research still has rules, but not as strict as CLINICAL researchstrict as CLINICAL research

Secondary Interests Define Types Secondary Interests Define Types of Conflictsof Conflicts

Institutional conflict of interestInstitutional conflict of interest–– Growing problem as universities profit from Growing problem as universities profit from

inventionsinventionsIntellectual biasIntellectual biasConflict of commitmentConflict of commitmentIndividual investigator conflicts: financial Individual investigator conflicts: financial easiest to recognize and measure, but easiest to recognize and measure, but there may be othersthere may be others

Financial Conflict of InterestFinancial Conflict of Interest

Any monetary value including, but not Any monetary value including, but not limited to:limited to:–– Salary or other payments (e.g. fees or Salary or other payments (e.g. fees or

honoraria); NIH threshold=$10K/yearhonoraria); NIH threshold=$10K/year–– Equity; NIH threshold $10K or 5%Equity; NIH threshold $10K or 5%–– Intellectual property rights (patents or Intellectual property rights (patents or

royaltiesroyalties–– Investigator or a spouse or relativeInvestigator or a spouse or relative–– Other institutions may use different thresholds Other institutions may use different thresholds

(Harvard threshold is (Harvard threshold is de de minimisminimis level)level)

Remedies for COIRemedies for COI

SelfSelf--regulation: Has not worked!regulation: Has not worked!Disclosure: Disclosure: ““Sunshine as a disinfectantSunshine as a disinfectant””–– May cause subject stress and anxietyMay cause subject stress and anxiety–– Is it sufficient? Will subjects understand?Is it sufficient? Will subjects understand?Mediation/Management: blind trust, Mediation/Management: blind trust, proceeds to charity, outside supervisor for proceeds to charity, outside supervisor for research, etc.research, etc.Prohibition: Some conflicts are prohibited Prohibition: Some conflicts are prohibited by journals or institutions, not manageableby journals or institutions, not manageable

DisclosureDisclosureMay not be sufficient, but is requiredMay not be sufficient, but is requiredEarly disclosure can prevent later Early disclosure can prevent later embarrassment!embarrassment!Includes all payments (received or planned), Includes all payments (received or planned), equity interest, fiduciary responsibility, personal equity interest, fiduciary responsibility, personal financial interest including relatives (spouse, financial interest including relatives (spouse, parent, child, siblings, domestic partner, parent, child, siblings, domestic partner, including including ““step,step,”” ““half,half,”” ““inin--law,law,”” etc.)etc.)Size and nature of a financial conflict of interest Size and nature of a financial conflict of interest affects how it should be managedaffects how it should be managed

Who Needs to Disclose?

Investigator = principal investigator and any other person who is responsible for the design, conduct, analysis or reporting of research.Not just PI, it can be anyone (key personnel, even tech) who is involved in design, conduct, or reporting of sponsored researchTerm also includes investigator’s spouse and family

Federal COI Reporting Federal COI Reporting RequirementsRequirements

At time of application, all investigators At time of application, all investigators must submit information to institutionmust submit information to institutionPrior to expenditure, institution reports COI Prior to expenditure, institution reports COI to NIH & assures management, reduction to NIH & assures management, reduction or elimination of COIor elimination of COIFinancial COI identified after initial report Financial COI identified after initial report must be reported within 60 days of must be reported within 60 days of discovery and managed, reduced or discovery and managed, reduced or eliminatedeliminated

How to Decide if COI is a Problem?How to Decide if COI is a Problem?

$ amount of payment/equity$ amount of payment/equityResponsibility of investigator in entity with Responsibility of investigator in entity with a competing interest (Board Member a competing interest (Board Member greater than consultant)greater than consultant)Decision making power in the research. Decision making power in the research. COI influences decisions.COI influences decisions.

Examples Allowed at UMDNJExamples Allowed at UMDNJ

UMDNJ employee receiving royalties from UMDNJ employee receiving royalties from publications or licensure of inventionspublications or licensure of inventionsEquity in a company whose sole purpose Equity in a company whose sole purpose is to accommodate employeeis to accommodate employee’’s outside s outside consultingconsultingNominal compensation for service to Nominal compensation for service to professional associations, review panels, professional associations, review panels, presentations of scholarly work, presentations of scholarly work, accreditation reviewsaccreditation reviews

DecisionDecision--making is the problem in making is the problem in conflict of interestconflict of interest

What to testWhat to testPlacebo vs. active controlPlacebo vs. active controlEndpoint selectionEndpoint selectionInclusion/exclusion criteriaInclusion/exclusion criteriaDesign of informed consent documentDesign of informed consent documentRules for stopping trial for proven efficacy or Rules for stopping trial for proven efficacy or adverse eventsadverse eventsDecision on stopping trial due to evidence from Decision on stopping trial due to evidence from other trialsother trialsWhich eligible patients will be enrolledWhich eligible patients will be enrolled

Reporting of Negative ResultsReporting of Negative ResultsEssential in clinical researchEssential in clinical researchOften against the interests of the corporate Often against the interests of the corporate sponsorsponsorIt is generally unacceptable for a sponsor to ban It is generally unacceptable for a sponsor to ban (or impede or delay) the publication of negative (or impede or delay) the publication of negative results.results.Required registry of clinical trials (Internal. Required registry of clinical trials (Internal. Comm. Med. J. Editors, 2005) may alleviate this Comm. Med. J. Editors, 2005) may alleviate this problem, but not eliminate; publications are problem, but not eliminate; publications are more visible than registry.more visible than registry.

Selective Outcome Reporting Selective Outcome Reporting Remains a ProblemRemains a Problem

323 trials in cardiology, rheumatology, GI in 10 323 trials in cardiology, rheumatology, GI in 10 top journals in 2008top journals in 2008–– 45.5% registered before end with outcomes45.5% registered before end with outcomes–– 27.6% not registered27.6% not registered–– 13.9% registered after completion13.9% registered after completion–– 10.8% without clear outcomes10.8% without clear outcomes–– 31% discrepancy between outcomes registered and 31% discrepancy between outcomes registered and

outcomes published (reported new outcome or did not outcomes published (reported new outcome or did not report original outcome)report original outcome)

S. Mathieu et al., JAMA 302:977S. Mathieu et al., JAMA 302:977--84 (Sept. 2, 2009)84 (Sept. 2, 2009)

Other COI IssuesOther COI Issues

Fees for patient recruitment. General Fees for patient recruitment. General covering costs OK, but profit is a problemcovering costs OK, but profit is a problemFinderFinder’’s fees (payment for referral of s fees (payment for referral of patients) considered unethical (illegal in patients) considered unethical (illegal in clinical practice)clinical practice)

COI ResourcesCOI Resources

UMDNJ Policies UMDNJ Policies http://www.umdnj.edu/oppmweb/university_policihttp://www.umdnj.edu/oppmweb/university_policies/Academic_affairs/PDF/00es/Academic_affairs/PDF/00--0101--2020--89_00.pdf89_00.pdf42 CFR Part 50, Subpart F 42 CFR Part 50, Subpart F http://grants.nih.gov/grants/compliance/42_CFRhttp://grants.nih.gov/grants/compliance/42_CFR_50_Subpart_F.htm_50_Subpart_F.htmAAMC site AAMC site http://http://www.aamc.org/research/coi/start.htmwww.aamc.org/research/coi/start.htmNJ Law: NJSA 52:13DNJ Law: NJSA 52:13D--19.119.1