Disclosure and Registration The Transparency Revolution INSIGHT Toronto April 25 2006 Michael...

Disclosure and RegistrationDisclosure and Registration

The Transparency RevolutionThe Transparency Revolution

INSIGHT Toronto April 25 2006INSIGHT Toronto April 25 2006

Michael Goodyear1, Lisa Golec2

1. Department of Medicine, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax NS2. NICU Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto ON

Learning ObjectivesLearning Objectives

I: Why is there a Crisis in Trust?I: Why is there a Crisis in Trust? II: Where has Science gone Wrong?II: Where has Science gone Wrong? III: Why is there an Ethical Problem?III: Why is there an Ethical Problem? IV: Why Transparency?IV: Why Transparency? V: Why Registration?V: Why Registration?

SummarySummary

Part IPart I

Why is There a Crisis in Trust?Why is There a Crisis in Trust?


Evidence Based MedicineEvidence Based Medicine

Archie Cochrane (1909-1988)


Evidence Based MedicineEvidence Based Medicine– Replaced Opinion, Anecdotes and ExpertsReplaced Opinion, Anecdotes and Experts

EvidenceEvidence


Evidence Based MedicineEvidence Based Medicine– Replaced Opinion, Anecdotes and ExpertsReplaced Opinion, Anecdotes and Experts– Based on Systematic Reviews of High Based on Systematic Reviews of High

Quality Evidence (RCTs)Quality Evidence (RCTs)

When was the first RCT?

Cultural Intermission

Daniel (600 BC) Chapter 1:1-16

First RCT

Michelangelo

Capella Sistina1511


Evidence Based MedicineEvidence Based Medicine– Replaced Opinion, Anecdotes and ExpertsReplaced Opinion, Anecdotes and Experts– Based on Systematic Reviews of high quality Based on Systematic Reviews of high quality

evidence (RCTs)evidence (RCTs)– Practice Based Guidelines Practice Based Guidelines

Graded by Strength of EvidenceGraded by Strength of Evidence– So far, so good, BUTSo far, so good, BUT


Evidence Based MedicineEvidence Based Medicine

A House of Cards Built on Sand?A House of Cards Built on Sand?

Why Is There a Crisis in Trust?Why Is There a Crisis in Trust?

Public Perceptions (1)Public Perceptions (1)– Law Suits against IndustryLaw Suits against Industry

June 3, 2004Spitzer Sues a Drug Maker, Saying It Hid Negative Data By GARDINER HARRIS

In a novel claim testing the way that the $400 billion worldwide pharmaceutical industry is regulated, the New York State attorney general, Eliot Spitzer, sued the British-based drug giant GlaxoSmithKline yesterday, accusing the company of fraud in concealing negative information about its popular antidepressant medicine Paxil. (Paroxetine)

The civil lawsuit, filed in State Supreme Court in Manhattan, contends that GlaxoSmithKline engaged in persistent fraud by failing to tell doctors that some studies of Paxil showed that the drug did not work in adolescents and might even lead to suicidal thoughts. Far from warning doctors, the suit contends, the company encouraged them to prescribe the drug for youngsters.


Public Perceptions (1)Public Perceptions (1)– Law suits against industryLaw suits against industry– Publication Ethics Publication Ethics

Publication BiasPublication Bias Outcome BiasOutcome Bias Altered outcomesAltered outcomes Publication restrictionsPublication restrictions

Selective Reporting in theSelective Reporting in the Medical Literature Medical Literature

Trial 1Trial 1 Trial 3

Systematic review

Meta-analyses

Publication Publication

Outcomes

Selectivestudy

publication Selective outcomereporting

Trial 2 2

26% None13% Abstract39%4% Incomplete

75% Trials

AW ChanK Dickersin

Selective Study PublicationSelective Study PublicationOdds of Publication by SignificanceOdds of Publication by Significance

Dickersin K. AIDS Educ Prev (1997)

2.5

p<0.05p≥0.05

AW Chan

No bias

CIHR (n=30)

REBs(n=50)

MEDLINE(n=161)

Favours p < 0.05Favours p 0.05

0.1 1 10.2 .3 .4 .5 2 3 4 5 6 7

Efficacy outcomes

Selective Reporting of OutcomesSelective Reporting of Outcomes

Chan AW et al, JAMA (2004) CMAJ (2004)

BMJ (2005)


Public Perceptions (1)Public Perceptions (1)– Law suits against industryLaw suits against industry– Publication EthicsPublication Ethics

Publication biasPublication bias Outcome biasOutcome bias Altered OutcomesAltered Outcomes Publication restrictionsPublication restrictions

Primary Outcomes are Often ChangedBetween Protocol and Publication

Discrepancy in primary outcomes Proportion (%) of trials with inconsistencies

CIHR REBs

Changes to protocol-defined outcome 33% 53%

New publication-defined outcome 24% 33%

Change in power calculation outcome 8% 29%

ANY INCONSISTENCY 40% 63%

None were acknowledged in publications

AW Chan

Primary outcome:Primary outcome:

Withdrawal rateWithdrawal rate

ExampleExample

Diabetes trialDiabetes trialDrug interventionDrug intervention

PP0.050.05

Primary outcome:Primary outcome:

% change in Hgb% change in HgbA1CA1C

ProtocolProtocol

P<0.05P<0.05

PublicationPublication

AW Chan

Neg Pos


Public Perceptions (1)Public Perceptions (1)– Law suits against industryLaw suits against industry– Publication EthicsPublication Ethics

Publication biasPublication bias Outcome biasOutcome bias Altered outcomesAltered outcomes Publication RestrictionsPublication Restrictions

Industry Publication Restrictions Industry Publication Restrictions Facilitate Selective ReportingFacilitate Selective Reporting

““If there are If there are disagreementsdisagreements with the investigators’ with the investigators’

analyses, analyses, new or repeated analysesnew or repeated analyses are required are required

before publication. The before publication. The SponsorSponsor remains sole remains sole

owner of the dataowner of the data.” .”

““Only the Sponsor has the Only the Sponsor has the right to publishright to publish results.” results.”

““Any information which the Sponsor deems Any information which the Sponsor deems

confidentialconfidential must be must be deleted prior to submissiondeleted prior to submission.”.”AW Chan (Gøtzsche P et al JAMA 2006 295: 1645)


Public Perceptions (1)Public Perceptions (1)– Law suits against industryLaw suits against industry– Publication biasPublication bias– Outcome biasOutcome bias– Altered outcomes Altered outcomes – Publication restrictionPublication restriction– Suppressed DataSuppressed Data

Volume 354:1193 March 16, 2006 Number 11 Expression of Concern Reaffirmed

Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D.

On December 8, 2005, we published an expression of concern regarding an article by Bombardier et al. on the Vioxx Gastrointestinal Outcomes Research (VIGOR) study that was published in the Journal on November 23, 2000. Our expression of concern was prompted by evidence that the VIGOR article did not accurately represent the safety data available to the authors when the article was being reviewed for publication.

…critical data on an array of adverse cardiovascular events that were not included in the VIGOR article. These data, which should have raised concern about potential cardiovascular toxicity of rofecoxib…

http://content.nejm.org/cgi/content/short/354/11/1194?query=nextarrow


Public Perceptions (1)Public Perceptions (1)– Law suits against industryLaw suits against industry– Publication biasPublication bias– Outcome biasOutcome bias– Altered outcomes Altered outcomes – Publication restrictionPublication restriction– Suppressed dataSuppressed data– Ghost WritingGhost Writing


Ghost WritingGhost Writing

““Dear Dr …., In order to reduce your workload to a Dear Dr …., In order to reduce your workload to a minimum we have had our Ghost Writers produce minimum we have had our Ghost Writers produce a first draft based on your published work …”a first draft based on your published work …”

The British Journal of Psychiatry (2003) 183: 22-27 Interface between authorship, industry and science in the domain of therapeutics DAVID HEALY, FRCPsych and DINAH CATTELL North Wales Department of Psychological Medicine, University of Wales College of Medicine, Bangor, UK

Unacknowledged editorial or writing assistants to academic authors – so-called ghostwriters – are often employed by medical communication agencies working for pharmaceutical companies. Efforts have been made to quantify the extent to which ghostwriting is happening, with Flanagin et al (1998)1 reporting that up to 11% of articles published in six peer-reviewed journals in 1996 involved the use of ghostwriters.

1. A. Flanagin et al., “Honorary Authors and Ghost Authors in Peer-Reviewed Medical Journals,” JAMA 280 (1998): 222-24

http://bjp.rcpsych.org.ezproxy.library.dal.ca/cgi/content/full/183/1/22#FN1

http://bjp.rcpsych.org.ezproxy.library.dal.ca/cgi/content/full/183/1/22#REF3


Ghost WritingGhost Writing Going price $1,000-1,500/articleGoing price $1,000-1,500/article11

Frequently outnumber original articlesFrequently outnumber original articles22

– 41/55 (75%) articles on 41/55 (75%) articles on SertralineSertraline 1998-2000 1998-2000– More likely to be in prestigious journalsMore likely to be in prestigious journals– Higher citation rate (x 5)Higher citation rate (x 5)– Differ in conclusions from original articlesDiffer in conclusions from original articles

1. C Elliott Hast Cent Rep Sep 2004 p18 1. C Elliott Hast Cent Rep Sep 2004 p18 2. D. Healy and D. Cattell 20032. D. Healy and D. Cattell 2003


Public Perceptions (2)Public Perceptions (2)– Death and Injury of VolunteersDeath and Injury of Volunteers– Breaches of integrityBreaches of integrity– Conflicts of interestConflicts of interest– CommercialisationCommercialisation– Health Care IndustryHealth Care Industry– GlobalisationGlobalisation– Unnecessary researchUnnecessary research

Ellen Roche, a Healthy Volunteer

Ellen RocheEllen Roche

Would Ellen be Alive Today,

if all Hexamethonium Trials had been

Registered?

Unnecessary Research


Public Perceptions (2)Public Perceptions (2)– Death and injury of volunteersDeath and injury of volunteers– Breaches of IntegrityBreaches of Integrity– Conflicts of interestConflicts of interest– CommercialisationCommercialisation– Health Care IndustryHealth Care Industry– GlobalisationGlobalisation– Unnecessary research Unnecessary research

Vol 435|9 June 2005 nature

COMMENTARYScientists behaving badlyBrian C. Martinson, Melissa S. Anderson and Raymond de Vries

Serious misbehaviour in research is important for many reasons, not least because it damages the reputation of, and undermines public support for, science.

(n=3,247)Overall, 33% of the respondents said they had engaged in at least one of the top ten behaviours during the previous three years.

Changing the design, methodology or results of a study in response topressure from a funding source 16%


Public Perceptions (2)Public Perceptions (2)– Death and injury of volunteersDeath and injury of volunteers– Breaches of integrityBreaches of integrity– Conflicts of InterestConflicts of Interest– CommercialisationCommercialisation– Health Care IndustryHealth Care Industry– GlobalisationGlobalisation– Unnecessary ResearchUnnecessary Research

Ellen RocheEllen Roche AprotininAprotinin


Public Perceptions (3)Public Perceptions (3)– Inappropriate Sponsor InvolvementInappropriate Sponsor Involvement– Safety issuesSafety issues

Paroxetine (Paxil)Paroxetine (Paxil) Rofecoxib (Vioxx)Rofecoxib (Vioxx) Class I Antiarrhythmic DrugsClass I Antiarrhythmic Drugs

– Disease MongeringDisease Mongering


Public Perceptions (4)Public Perceptions (4)– Claims of large numbers of Unnecessary Claims of large numbers of Unnecessary

Deaths from inappropriate publicationDeaths from inappropriate publication– Consumer group websites publish daily bulletins Consumer group websites publish daily bulletins

on wrongdoing in researchon wrongdoing in research

What is the Impact on Patients?What is the Impact on Patients?

Over-representation of Positive Results in the

Literature

Misguided Healthcare Decisions

Selective ReportingMisinformation

Part IIPart II

Where has Science Gone Where has Science Gone Wrong?Wrong?

Robert K Merton (1910-2003)

Where Has Science Gone Wrong?

CUDOS

Where Has Science Gone Where Has Science Gone Wrong?Wrong?

Scientific Norms (Merton)Scientific Norms (Merton)11 (1) (1)– Science: The objective seeking of universally valid Science: The objective seeking of universally valid

knowledge for the common goodknowledge for the common good

CCommunalism - (Open community) ommunalism - (Open community) UUniversalism - (Does not discriminate) niversalism - (Does not discriminate) DDisinterestedness - (Favors an outward objectivity) isinterestedness - (Favors an outward objectivity) OOriginality - (Gives new contributions) riginality - (Gives new contributions) SSkepticism - (All ideas must be tested) kepticism - (All ideas must be tested)

1. Merton R. J Legal Political Sociol 1942 1: 115-126

Where Has Science Gone Wrong?Where Has Science Gone Wrong?

Scientific Norms (Merton)Scientific Norms (Merton)11 (2) (2)– CollaborationCollaboration– Sharing of KnowledgeSharing of Knowledge– Common Goal of the Common GoodCommon Goal of the Common Good– Findings Belong to the CommunityFindings Belong to the Community– Secrecy is the Antithesis of Normal Secrecy is the Antithesis of Normal

1. The Sociology of Science (1973)


Scientific Norms (2)Scientific Norms (2)– Intellectual Property means RecognitionIntellectual Property means Recognition– New Knowledge must be Rapidly New Knowledge must be Rapidly

DisseminatedDisseminated11

1. Stuart and Ding Academy of Management Conference 2003


Has science lost its way?Has science lost its way?– Collaboration replaced by SecrecyCollaboration replaced by Secrecy– Obsession with CommercialisationObsession with Commercialisation– Lost Sight of Normative ValuesLost Sight of Normative Values

Part IIIPart III

Why is There an Ethical Why is There an Ethical Problem?Problem?


Epistemic and UtilitarianEpistemic and Utilitarian

Collective Fiduciary Duty of CareCollective Fiduciary Duty of Care– Decision Making Based on Disclosure of FactsDecision Making Based on Disclosure of Facts

PriorPrior Continuing Continuing PostPost

Janus


PresumptionsPresumptions Prior: InceptionPrior: Inception

– The totality of prior informationThe totality of prior information Continuing: ExecutionContinuing: Execution

– New information that might bear on decision New information that might bear on decision Post: LegacyPost: Legacy

– Information acquired for societal benefitInformation acquired for societal benefit

Why is There an Ethical Problem?Why is There an Ethical Problem?

A PRIOREA PRIORE– Right to believe that information disclosed is Right to believe that information disclosed is

based on based on allall knowledge – But; knowledge – But; Prior Knowledge is Incomplete and SelectivePrior Knowledge is Incomplete and Selective Research may be Unnecessarily DuplicativeResearch may be Unnecessarily Duplicative11

(1) Young C, Horton R. Lancet 3666: 107, 2005

Cumulative Meta-analysis of Aprotinin for Perioperative

Bleeding1

Where was Equipoise?

1 Fergusson, Glass, Hutton, Shapiro: Clinical Trials 2:218, 2005


CONTINUINGCONTINUING– Subjects have Subjects have rightright to know about other to know about other

relevant trials (new information)relevant trials (new information) Currently very difficult to find that informationCurrently very difficult to find that information


A POSTERIOREA POSTERIORE– Consent implies contribution to knowledgeConsent implies contribution to knowledge

Less than half of randomised trials are publishedLess than half of randomised trials are published11

Many not indexed, therefore ‘lost’Many not indexed, therefore ‘lost’22

Negative trials delayedNegative trials delayed inin publicationpublication11

Publication BiasPublication Bias11

Outcome Reporting BiasOutcome Reporting Bias33

1. Tumber and Dickersin J Int Med 2004 256: 2712. Hopewell Stat Med 2002 21: 1625 3. Chan et al JAMA 2004 291: 2457


A POSTERIOREA POSTERIORE– Consent implies contribution to knowledgeConsent implies contribution to knowledge– Probability of real benefit to an individual is Probability of real benefit to an individual is

lowlow– Subjects usually motivated by AltruismSubjects usually motivated by Altruism

Immanuel Kant (1724-1804)

Critique of Practical Reason 1778

‘Highest Derived Good’Summum Bonum

“What's the worst that can happen to me? …I die, and it's for the babies.“1

1 New York Times, 28 Nov 1999

Jesse GelsingerJesse Gelsinger


““The Covenant between Researcher and The Covenant between Researcher and Patient…between Ethical Review Boards and Patient…between Ethical Review Boards and

Patients, is Broken”Patients, is Broken”11

““Underreporting Research is Scientific Underreporting Research is Scientific Misconduct”Misconduct”2 2 and Unethicaland Unethical33

1. Dickersin K, Rennie D 2003 290(40): 5162. Chalmers I JAMA 1990 263: 14053. Antes G, Chalmers I Lancet 2003 361: 978

Part IVPart IV

Why Transparency?Why Transparency?


Trust and confidence can only be restored Trust and confidence can only be restored by a guaranty of transparencyby a guaranty of transparency

““his call for a culture of greater openness in his call for a culture of greater openness in medical research is, I think, both powerful medical research is, I think, both powerful and timely”.and timely”.11

1. Gunn A USA TODAY March 27 2006, on: Goodyear M Learning from the TGN1412 trial. BMJ. 2006 Mar 25


Subjects have the Subjects have the rightright to see all aspects of to see all aspects of a trial they are contributing toa trial they are contributing to

Subjects have the Subjects have the rightright to believe that to believe that anyany information derived from their participation information derived from their participation will be fully and freely disclosed for the will be fully and freely disclosed for the Common Good Common Good


Commitment to transparency provides a Commitment to transparency provides a common data base for allcommon data base for all

Part VPart V

Why Registration?Why Registration?


It is easier to get accurate statistics on baseball It is easier to get accurate statistics on baseball than on medical researchthan on medical research11

““The result of not knowing who has performed The result of not knowing who has performed what, is loss and distortion of the evidence, waste what, is loss and distortion of the evidence, waste and duplication of trials, inability of funding and duplication of trials, inability of funding agencies to plan, and a chaotic system …which is agencies to plan, and a chaotic system …which is invariably against the interest of those who offered invariably against the interest of those who offered to participate in trials and of patients in general”.to participate in trials and of patients in general”.11

1. Dickersin K, Rennie D 2003 290(40): 516


An Old IdeaAn Old Idea– NIMH Registry 1967NIMH Registry 1967– Mary Lasker 1974Mary Lasker 1974

““War Against Cancer”War Against Cancer”

– NIH Registry 1975-9NIH Registry 1975-9– John Simes 1986John Simes 1986

Publication bias. J Clin Oncol 4: 1529Publication bias. J Clin Oncol 4: 1529

– Cochrane Collaboration 1993Cochrane Collaboration 1993– Ottawa Statement 2005 BMJOttawa Statement 2005 BMJ– WHOWHO


Portal for searching and access of clinical Portal for searching and access of clinical research informationresearch information– Unique identifiers: UTRN (ISBNs)Unique identifiers: UTRN (ISBNs)

Tool for evidence based medicineTool for evidence based medicine– Evolving informaticsEvolving informatics– Guideline development and maintenanceGuideline development and maintenance– Guide for editors and reviewersGuide for editors and reviewers– Cumulative Meta-analysesCumulative Meta-analyses

Risk of cardiovascular events and rofecoxib: cumulative meta-analysisJüni P et al

Volume 364, Number 9450, 04 December 2004


Honours Social Contract with SubjectsHonours Social Contract with Subjects Informs PublicInforms Public Enhances RecruitmentEnhances Recruitment


Tool for ethical reviewTool for ethical review Provides linkage between investigators and Provides linkage between investigators and

between ethical review bodiesbetween ethical review bodies Joins the dotsJoins the dots From Silos to NetworksFrom Silos to Networks


Why Not?Why Not?– Competitive advantageCompetitive advantage– BurdenBurden– CostCost– ProliferationProliferation– Compliance and enforcementCompliance and enforcement

Poor to date, but improvingPoor to date, but improving From Voluntary to MandatoryFrom Voluntary to Mandatory Publication leveragePublication leverage

– ICMJEICMJE

http://www.who.int/ictrp

"We are ready to move

forward with an

International Clinical Trials

Registry. This will do much

to strengthen the research

process and its ability to win

public trust"

"We are ready to move

forward with an

International Clinical Trials

Registry. This will do much

to strengthen the research

process and its ability to win

public trust"

Dr J.W. LeeWHO Director-General

Opening Address to World Opening Address to World Health Assembly, May 2005Health Assembly, May 2005

I Sim

Registry PlatformRegistry Platform Overview OverviewW

HO

In

tern

ati

on

al C

lin

ical

Tri

als

Reg

istr

y P

latf

orm

Journals

ResultsDatabases

WHO Search Portal

RegistersISRCTNclinicaltrials.gov . . .country specific

I Sim


IssuesIssues Holding “commercially sensitive” items in temporary Holding “commercially sensitive” items in temporary

escrow in registerescrow in register Burden of proof on sponsorBurden of proof on sponsor How long?How long? Who Decides?Who Decides? Opposed by consumer groups, academics, funders, Opposed by consumer groups, academics, funders,

ethicists, health lawyersethicists, health lawyers

Summary I/IIISummary I/III

Crescendo of failed trustCrescendo of failed trust Evidence Based Medicine in crisisEvidence Based Medicine in crisis Science has lost its way and its rootsScience has lost its way and its roots Scientific, moral and ethical imperative to Scientific, moral and ethical imperative to

transparencytransparency

Summary II/IIISummary II/III

Registration restores trustRegistration restores trust Registration restores order out of chaosRegistration restores order out of chaos Registration is an efficient tool for the Registration is an efficient tool for the

furtherance of knowledgefurtherance of knowledge

Summary III/IIISummary III/III

Benefits of registration outweigh Benefits of registration outweigh disadvantagesdisadvantages

Requires commitment and collaboration Requires commitment and collaboration from all partnersfrom all partners

Legislative requirementLegislative requirement

A Fundamental Cultural Shift is required to move from Competition to Collaboration, and from Secrecy to Transparency, if we are to move forward and restore Normative Values to Science, and Ethical Integrity to Research

Genève

Authors

Collaborators (and many more!)

Michael GoodyearDalhousie

Sabina WattsMcMaster

Lisa GolecToronto

Elisabeth ClarkMcGill

Thank You!

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