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Through the Looking Glass:Through the Looking Glass:

Reflections of a Research EthicistReflections of a Research Ethicistoror

The Collapse of Science and Ethics?The Collapse of Science and Ethics?

Michael GoodyearMichael Goodyear

Department of Medicine,Department of Medicine,Queen Elizabeth II Health Sciences Centre, Queen Elizabeth II Health Sciences Centre,

Dalhousie University, Halifax,Dalhousie University, Halifax,Nova Scotia, CanadaNova Scotia, Canada

MSMR Waltham MA, June 2006MSMR Waltham MA, June 2006

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Alice was sitting curled up in a corner of the great arm-chair, half talking to herself and half asleep

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Learning ObjectivesLearning Objectives

I: How Did We Get Here From There?I: How Did We Get Here From There? II: Where are We Now?II: Where are We Now? III: Lessons from TGN1412III: Lessons from TGN1412 IV: Moving ForwardIV: Moving Forward

SummarySummary

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“The aim of science is not to open a door to infinite wisdom but to set a limit to infinite error”Brecht B. The Life of Galileo (Leben des Galilei) 1943

Bertolt Brecht (1898 –1956)

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Part IPart I

How Did We Get Here From How Did We Get Here From There?There?

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We All Know Where We Have We All Know Where We Have Come FromCome From

Or Do We?Or Do We?

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HistoryHistory

Human experimentation since time Human experimentation since time immemorialimmemorial– Generally more vulnerable populationsGenerally more vulnerable populations

Prisoners, slaves, patientsPrisoners, slaves, patients

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HistoryHistory

Thomas Percival (1740-1804) Thomas Percival (1740-1804) Medical Ethics: a Code of Institutes and Medical Ethics: a Code of Institutes and Precepts Adapted to the Professional Precepts Adapted to the Professional Conduct of Physicians and SurgeonsConduct of Physicians and SurgeonsRussell, London 1803Russell, London 1803

Adopted by AMA 1847, modified many timesAdopted by AMA 1847, modified many times

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HistoryHistory

Claude Bernard (Claude Bernard (1813-1878)1813-1878)

– Must have potential benefitMust have potential benefit

– Prisoners not considered humanPrisoners not considered human

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HistoryHistory

William Osler (1849-1918)William Osler (1849-1918)

– ConsentConsent

– Animal experimentationAnimal experimentation

George Bernard Shaw (1856-1950)George Bernard Shaw (1856-1950)

– ““Human Guinea Pigs” (1913)*Human Guinea Pigs” (1913)*

*Disclaimer: No Guinea Pigs were harmed in this production

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HistoryHistory

GermanyGermany– Prussian regulations 1900Prussian regulations 1900– Third Reich 1931Third Reich 1931

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Nürnberg

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Nuremberg CodeNuremberg Code 19471947

Trials of war criminals before the Nuremberg military tribunals under Control Council Law, No 10, Vol 2. Washington DC: US Government Printing Office, 1949: 181.

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Nuremberg CodeNuremberg Code 1947 1947

1.1. Voluntary Consent Essential Voluntary Consent Essential2. Must Yield Valid Results2. Must Yield Valid Results3. Based on Animal Experiments3. Based on Animal Experiments4. Avoid Physical and Mental Suffering4. Avoid Physical and Mental Suffering5. Avoid Injury5. Avoid Injury6. Risk Proportional to Benefit6. Risk Proportional to Benefit7. Subjects Must be Protected7. Subjects Must be Protected8. Qualified Investigators8. Qualified Investigators9. Voluntary Withdrawal9. Voluntary Withdrawal10. Must be Terminated if Necessary10. Must be Terminated if Necessary

Top Secret

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Nuremberg CodeNuremberg Code 1947 1947

3. The experiment should be so designed and based on the results of animal animal experimentationexperimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment.

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(1)The voluntary consent of the person on whom the experiment is to be performed must be obtained

(2)The experiment must be performed under proper medical protection and management.

(3)(3)The danger of each experiment must be The danger of each experiment must be previously investigated by previously investigated by animal animal experimentationexperimentation

American Medical AssociationJudiciary Council

December 10th, 1946

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David Rothman PhDDirector, Center for the Study of Society and MedicineColumbia College of Physicians and Surgeons

Strangers at the Bedside: A history of how law and bioethicstransformed medical decision makingNY Basic Books 1991

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““Neither the horrors described at the Neither the horrors described at the Nuremberg trial nor the ethical Nuremberg trial nor the ethical principles that emerged from it had a principles that emerged from it had a significant impact on the American significant impact on the American research establishment” research establishment” because they did not seem “directly because they did not seem “directly relevant to the American Scene”relevant to the American Scene”

Rothman p. 62Rothman p. 62

LF Ross

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“To most Americans, however, Nuremberg addressed madness, not medicine”

Shapiro HT.Waggoner Lecture, U MichiganDec 5 2001Ethical Considerations in Research on Human Subjects:A Time for Change…Again

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Nürnberg, Germany

Tuskegee, Alabama

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Tuskegee, AlabamaTuskegee, Alabama(1932 – 1972)(1932 – 1972)

RIPRIP

“I don’t know what they used us for. I ain’t never understood the study”

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1965

Are humans used as guinea pigs not told?

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(1904-1976)

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“What seem to be breaches of ethical conduct in experimentation are by no means rare, but are almost, one fears, universal”

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““No physician is justified in placing No physician is justified in placing science or the public welfare first and science or the public welfare first and his obligation to the individual, who is his obligation to the individual, who is his patient or subject, second” his patient or subject, second”

““No doctor, however great his capacity No doctor, however great his capacity or original his ideas, has the right to or original his ideas, has the right to choose martyrs for science or for the choose martyrs for science or for the general good”general good” Maurice PappworthMaurice Pappworth

Pappworth M.H. Human Guinea Pigs Penguin 1967, Pappworth M.H. Human Guinea Pigs Penguin 1967, p.27p.27

L Swartz

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The Dark SideThe Dark Side

Willowbrook Hepatitis StudyWillowbrook Hepatitis Study Jewish Hospital Cancer StudyJewish Hospital Cancer Study Tearoom Trade StudyTearoom Trade Study Wichita Jury StudyWichita Jury Study Milgram Obedience StudyMilgram Obedience Study San Antonio Contraceptive StudySan Antonio Contraceptive Study Radiation StudiesRadiation Studies etc…………..etc…………..

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……and the Lightand the Light

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Belmont ReportBelmont Report19791979

Ethical Principles and Guidelines for the Protection of Human Subjects of Research

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

April 18, 1979

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So We Fixed it?So We Fixed it?

Right?Right?

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Advisory Committee on Human Radiation Experiments (1994-5)

Human Radiation ExperimentsAssociated with the

U.S. Department of Energyand Its Predecessors

(1944 – 1974)

X-Files?

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Unfortunately, however, the government's conduct with respect to some research performed in the past has left a legacy of distrust

1.

We did find evidence of some serious problems in the conduct …of human research today

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We realize, however, that regulations and policies are no guarantee of ethical conduct

2.

It is essential that the research community come to increasingly value the ethics of research involving human subjects as central to the scientific enterprise

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The revision of regulations that govern human research (and) professional ethics are necessary, but are not sufficient, means to needed reform. Of at least equal import is the development of a more common understanding among the public of research involving human subjects

3.

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Some of what is regrettable about the past happened… because we

as citizens let it happen

Let the lessons of history remind us all that the best safeguard for the future is an informed and active citizenry

4.

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Part IPart I

Where are We Now? Where are We Now?

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The Ongoing ProblemsThe Ongoing Problems

Role ConfusionRole Confusion– Mission CreepMission Creep– AdministriviaAdministrivia

The Collapse of Scientific IntegrityThe Collapse of Scientific Integrity Inadequate Resources Increasing Complexity of Science Patchwork Quilt Accountabilty Inflexible

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Gunsalus CK, Bruner EM, Burbules NC, Dash L, Finkin M, Goldberg JP, Greenough WT, Miller GA, Pratt MG

Mission creep in the IRB world.Science. 2006 Jun 9;312(5779):1441.

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Mission Creep in the IRB WorldMission Creep in the IRB World

System endangered by excessive System endangered by excessive paperworkpaperwork– Overregulation and underprotectionOverregulation and underprotection

Overwhelmed by procedures and Overwhelmed by procedures and documentation at expense of thoughtful documentation at expense of thoughtful considerationconsideration

‘‘Ethics Police’Ethics Police’ Researchers equate ‘Human Protection’Researchers equate ‘Human Protection’

– with frustrating delays, expensive paperworkwith frustrating delays, expensive paperwork

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Mission Creep in the IRB WorldMission Creep in the IRB World

*Ethics a Collective Responsibility*Ethics a Collective Responsibility IRBs not a substitute for Ethical Thinking IRBs not a substitute for Ethical Thinking

and Behaviourand Behaviour Should cultivate Ethical CultureShould cultivate Ethical Culture Researchers and IRBs need SupportResearchers and IRBs need Support

– locallocal– central central

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The Ongoing ProblemsThe Ongoing Problems

Role ConfusionRole Confusion The Collapse of Scientific Integrity

– A crisis in trust Inadequate Resources Increasing Complexity of Science Patchwork Quilt Accountabilty Inflexible

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

Evidence Based MedicineEvidence Based Medicine

Archie Cochrane (1909-1988)

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Evidence Based MedicineEvidence Based Medicine

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

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

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

Evidence Based MedicineEvidence Based Medicine

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

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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

data suppressiondata suppression

– Publication ethicsPublication ethics

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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.

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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– Publication EthicsPublication Ethics

Publication BiasPublication Bias Outcome BiasOutcome Bias Altered outcomesAltered outcomes Publication restrictionsPublication restrictions Suppressed dataSuppressed data Ghost writingGhost writing

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This past year has been a bumper year for research and publication misconductCOPE Report 2005

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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– Publication EthicsPublication Ethics

Publication BiasPublication Bias Outcome BiasOutcome Bias Altered outcomesAltered outcomes Publication RestrictionsPublication Restrictions Suppressed dataSuppressed data Ghost writingGhost writing

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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

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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– Publication EthicsPublication Ethics

Publication Bias Outcome Bias Altered outcomes Publication restrictions Suppressed DataSuppressed Data Ghost writing

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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…

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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– Publication EthicsPublication Ethics

Publication Bias Outcome Bias Altered outcomes Publication restrictions Suppressed data Ghost WritingGhost Writing

– David Healey, Carl ElliottDavid Healey, Carl Elliott

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

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 …”

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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 JournalsJAMA 280 (1998): 222-24

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

Public Perceptions (2)Public Perceptions (2)– Death and Injury of VolunteersDeath and Injury of Volunteers– Breaches of integrity– Commercialisation– Unnecessary research

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Ellen Roche, a Healthy Volunteer

Ellen RocheEllen Roche

Would Ellen be Alive Today,

if all Hexamethonium Trials had been

Registered?

Unnecessary Research

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“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

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

Public Perceptions (2)Public Perceptions (2)– Death and Injury of Volunteers– Breaches of integrityBreaches of integrity– Commercialisation– Unnecessary research

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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%

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

Public Perceptions (2)Public Perceptions (2)– Death and Injury of Volunteers– Breaches of integrity– CommercialisationCommercialisation

Conflicts of interest Health Care Industry Globalisation

– Unnecessary research

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Global Corruption Report 2006Global Corruption Report 2006

Special focus:CORRUPTION AND HEALTH

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Editorial Corruption in health care costs lives Volume 367, 11 February 2006 447

The word corruption—abuse of entrusted power for private gain—rarely enters health professionals' vocabulary and is frequently softened to unethical or unprofessional behaviour

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Testing new drugson the world’s poorest patients

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

Public Perceptions (2)Public Perceptions (2)– Death and Injury of Volunteers– Breaches of integrity– Commercialisation– Unnecessary ResearchUnnecessary Research

Ellen RocheEllen Roche AprotininAprotinin

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Cumulative Meta-analysis of Aprotinin for Perioperative

Bleeding1

Where was Equipoise?

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

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

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

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“Widening the boundaries of treatable illness in order to expand markets for those who sell and deliver treatments” Moynihan R, Heath I, Henry D Selling sickness: The pharmaceutical industry and disease mongering. BMJ 2002 324: 886–891

Vol 3(4) April 2006

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

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

on wrongdoing in research

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Rofecoxib

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Cardiovascular Risk FactorsCardiovascular Risk Factors

VIGOR Trial (4%)VIGOR Trial (4%)

Increased RiskIncreased Risk: 38% CV events: 38% CV events

Risk Ratio: 2.5 Risk Ratio: 2.5

Event Rate 1.5%Event Rate 1.5%

Tennessee Medicaid Study (40%)Tennessee Medicaid Study (40%)

Event Rate 11.6Event Rate 11.6

NNH: 556 v 70NNH: 556 v 70 (8 fold) (8 fold)““It is not until drugs go out into the world and they are used in real It is not until drugs go out into the world and they are used in real patients” EMEApatients” EMEA

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

Public Perceptions (4)Public Perceptions (4)– Claims of large numbers of unnecessary deaths

from inappropriate publication– Consumer Group Websites publish daily Consumer Group Websites publish daily

bulletins on wrongdoing in researchbulletins on wrongdoing in research

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Vera Hassner Sharav, M.L.S.

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

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

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Has Science lost its Way?Has Science lost its Way?

The majority of new products since 1990 The majority of new products since 1990 have not improved health care compared to have not improved health care compared to less costly and better understood drugsless costly and better understood drugs

Many are analogues (Many are analogues (me-toome-too) and ) and reformulations designed to improve market reformulations designed to improve market share and prolong patentsshare and prolong patents

Are IRBs legitimising fraud?Are IRBs legitimising fraud?

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Sponsor always Wins!Sponsor always Wins!

Heres S, Davis J, Maino K, Jetzinger E, Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S.Kissling W, Leucht S.

Why olanzapine beats risperidone, Why olanzapine beats risperidone, risperidone beats quetiapine, and risperidone beats quetiapine, and quetiapine beats olanzapine: an quetiapine beats olanzapine: an exploratory analysis of head-to-head exploratory analysis of head-to-head comparison studies of second-comparison studies of second-generation antipsychotics.generation antipsychotics.

Am J Psychiatry. 2006 Feb;163(2):185-94.Am J Psychiatry. 2006 Feb;163(2):185-94.

If A > B, and B > C, then why is C > A?

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Unhealthy Medicine: All Breakthrough,No Follow-ThroughBy Steven H. WoolfSunday, January 8, 2006 We spend far more money on inventing new

treatments than on research into how to deliver them

Developing new treatments often does less good than ensuring the delivery of older drugs to all those in need

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Beyond dissatisfaction, the larger problem with our Beyond dissatisfaction, the larger problem with our focus on medical breakthroughs is that more focus on medical breakthroughs is that more Americans will die as a resultAmericans will die as a result

We have reached a point when progress in providing We have reached a point when progress in providing good care – when needed, with compassion and skill good care – when needed, with compassion and skill and without errors -- would impress the public as a and without errors -- would impress the public as a more meaningful "medical advance" than the rollout of more meaningful "medical advance" than the rollout of the latest device or pill.the latest device or pill.

Department of Family MedicineDepartment of Family MedicineVirginia Commonwealth UniversityVirginia Commonwealth University

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Part IIIPart III

Lessons from TGN1412Lessons from TGN1412

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TGN1412TGN1412

““A Watershed Incident”A Watershed Incident”

Fiona Godlee, Editor BMJFiona Godlee, Editor BMJ

A line in the sand?A line in the sand?

A cautionary tale from Waltham MA

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Hell of human guinea pigsHow the drug trial horror unfoldedBy MICHAEL SEAMARK, Daily Mail 17th March 2006

We saw human guinea pigs explodeVictims tearing at shirtsBy NICK PARKER, EMMA MORTON and JACQUI THORNTON 16th March 2006

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Peer ReviewPeer Review

Wood AJ, Darbyshire J.Wood AJ, Darbyshire J.

Injury to research volunteers--the clinical-research Injury to research volunteers--the clinical-research nightmare.nightmare.

N Engl J Med. 2006 May 4;354(18):1869-71N Engl J Med. 2006 May 4;354(18):1869-71

Ho MW, Cummins J.Ho MW, Cummins J.

London Drug Trial Catastrophe – London Drug Trial Catastrophe – Collapse of Science Collapse of Science and Ethicsand Ethics: Postmortem on the TGN1412 disaster: Postmortem on the TGN1412 disaster

Science in Society. 2006 Summer 30: 44-5Science in Society. 2006 Summer 30: 44-5

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SUN: A VOLUNTEER who escaped the drug test disaster told last night how he saw six healthy young men turn into wailing wrecks within minutes.

Human guinea pig Raste Khan — who did not know he had been given a harmless placebo in the test — said it was like a horror film unfolding before his eyes.

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RASTE KHAN

“The test ward turned into a living hell minutes after we were injected. The men went down like dominoes.First they began tearing their shirts off complaining of fever, then some screamed out that their heads felt like they were about to explode”

“After that they started fainting, vomiting and writhing around in their beds”

“It was terrifying because I kept expecting it to happen to me at any moment. But I felt fine and didn’t know why. An Asian guy next to me started screaming and his breathing went haywire as though he was having a terrible panic attack”

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RASTE KHAN

“They put an oxygen mask on him but he kept tearing it off, shouting ‘Doctor, doctor, please help me!’ He started convulsing, shouting that he was getting shooting pains in his back.”

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TGN1412TGN1412

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TGN 1412TGN 1412

CD28 T Cell Receptor SuperAgonistCD28 T Cell Receptor SuperAgonist

Humanised IgG4 Monoclonal Antibody

CD28

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TGN 1412TGN 1412

By-passes Costimulation byBy-passes Costimulation by

Antigen Presenting CellAntigen Presenting Cell

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TGN 1412TGN 1412

First Time in ManFirst Time in Man Phase I March 13 2006Phase I March 13 2006 8 Subjects in first cohort8 Subjects in first cohort

– Healthy Male VolunteersHealthy Male Volunteers– 2 Placebo2 Placebo– 6 Active6 Active

All 8 treated in rapid successionAll 8 treated in rapid succession Dose based on NOAELDose based on NOAEL $4,000$4,000

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TGN 1412TGN 1412

NNo o OObserved bserved AAdverse dverse EEffect ffect LLevelevel Primates tested up to 50mg/kg (NOAEL)Primates tested up to 50mg/kg (NOAEL) Clinical testing started at 0.1mg/kg Clinical testing started at 0.1mg/kg

– 1/500 NOAEL 1/500 NOAEL

(NOAEL (NOAEL ≠ P≠ Pharmacologically effect)harmacologically effect)0.3 – 5.0mg/kg0.3 – 5.0mg/kg

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TGN 1412TGN 1412

Rapid onset Rapid onset – Cytokine Release SyndromeCytokine Release Syndrome– AngioedemaAngioedema

Testing continuedTesting continued Multiple Organ FailureMultiple Organ Failure All subjects admitted to ICUAll subjects admitted to ICU Prolonged immunosuppressionProlonged immunosuppression 1 still hospitalised, dry gangrene1 still hospitalised, dry gangrene

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TGN 1412TGN 1412

Medicines and Healthcare Products AgencyMedicines and Healthcare Products Agency(MHRA)(MHRA)

Suspended CTASuspended CTA Immediate InquiryImmediate Inquiry ReleasedReleased

– protocol, review and inquiryprotocol, review and inquiry

UK Government announces expert inquiryUK Government announces expert inquiry

No review of ethical review to dateNo review of ethical review to date

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TGN 1412TGN 1412

Expert Inquiry (Terms of Reference)Expert Inquiry (Terms of Reference) What may be necessary in transition from pre-clinical What may be necessary in transition from pre-clinical

to first-in-man Phase 1 studies, specifically:to first-in-man Phase 1 studies, specifically:

– Biological molecules with novel mechanisms of action Biological molecules with novel mechanisms of action – New agents with highly species-specific action New agents with highly species-specific action – New drugs for immune system targets New drugs for immune system targets

Interim report within 3 months (August) Interim report within 3 months (August) Minutes of meetings and interim findings to be made Minutes of meetings and interim findings to be made

public public

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (11))

RecruitmentRecruitment– Financial IncentivesFinancial Incentives

Adequacy of Information Choice of Subject in Phase I Number of Subjects Timing of Administration

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (11))

Recruitment Adequacy of Information

– Consent

Choice of Subject in Phase I– Healthy volunteers

Number of Subjects Timing of Administration

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (22))

Sources of Information ReviewedSources of Information Reviewed– Regulatory ReviewRegulatory Review– Ethical ReviewEthical Review

Place of Independent Expert ReviewPlace of Independent Expert Review Relevance of Preclinical TestingRelevance of Preclinical Testing

– Interspecies difference (Maccaca)Interspecies difference (Maccaca)

Transparency in DevelopmentTransparency in Development– Publishing preclinical workPublishing preclinical work

Transparency of ReviewsTransparency of Reviews Response to DisastersResponse to Disasters

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (33))

Caution inCaution in– developing immunomodulatorsdeveloping immunomodulators– agonistsagonists– bypassing regulatory mechanisms (super)bypassing regulatory mechanisms (super)

Assumptions about Dose-ResponseAssumptions about Dose-Response– non-linearnon-linear– bell shaped (optimum dose was 5mg/kg)bell shaped (optimum dose was 5mg/kg)

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (44))

Homology may not mean affinityHomology may not mean affinity Affinity may not translate downstream Affinity may not translate downstream Even monoclonals are not specificEven monoclonals are not specific Standards for preclinical testingStandards for preclinical testing

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (44))

The Immune System is a The Immune System is a Capricious Pandora’s Capricious Pandora’s Box! Box!

Pandora 1898. John William WaterhouseBritish Pre-Raphaelite1849-1917Private collection Oil on canvas

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Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (55))

Relationships with industryRelationships with industry Adequacy of training of staffAdequacy of training of staff Adequacy of facilitiesAdequacy of facilities Adequacy of liability insuranceAdequacy of liability insurance

Plan for the worst, hope for the bestPlan for the worst, hope for the best

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The Relevance of Animal Testing?The Relevance of Animal Testing?

Bhogal N, Combes R. Bhogal N, Combes R.

TGN1412: time to change the paradigm for TGN1412: time to change the paradigm for the testing of new pharmaceuticals.the testing of new pharmaceuticals.Altern Lab Anim. 2006 May;34(2):225-3Altern Lab Anim. 2006 May;34(2):225-3

Fund for the Replacement of Animals in Medical Experiments

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a) The normal co-stimulatory mechanism of T-cell activation b) TGN1412 recognises single CD28 on receptor

Bhogal, Combes 2006

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a) CD28 monomer and corresponding TGN1412 binding epitopeb) 3-D model of CD28 extracellular domainTGN1412 binding epitope circled

Bhogal, Combes 2006

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Conservation of amino acid sequences of CD28.

Substitution of Glutamate (E) in Macacca mulatta (Rhesus) for Glycine (G) in human, could have profound conformal implications, and hence affect affinity binding and downstream effects.

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The Relevance of Animal TestingThe Relevance of Animal Testing

Need to establish validityNeed to establish validity Staggered timingStaggered timing MicrodosingMicrodosing Ex-vivoEx-vivo

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Learning from MistakesLearning from Mistakes

We have been assured repeatedly that proper procedures were We have been assured repeatedly that proper procedures were followed, when the the real question is whether they were the followed, when the the real question is whether they were the right procedures.right procedures.

Goodyear M. BMJ March 25Goodyear M. BMJ March 25thth 2006 2006

Nor will a collective claim of ‘not-guilty’ likely lead to Nor will a collective claim of ‘not-guilty’ likely lead to understanding and correctionunderstanding and correction

Goodyear M. CMAJ In pressGoodyear M. CMAJ In press

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"Is there any point to which you would wish to draw my attention?"

"To the curious incident of the dog in the night-time."

"The dog did nothing in the night-time."

"That was the curious incident," remarked Sherlock Holmes.

Conan-Doyle A. Silver Blaze 1892

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Part IVPart IV

Moving Forward?Moving Forward?

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Moving Forward?Moving Forward?

Adaptation in a Changing World

– Regulation and ethics always lags behind technology

TransparencyTransparency Governance Support

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Moving Forward?Moving Forward?

TransparencyTransparency– One of the biggest threats to research One of the biggest threats to research

integrityintegrity

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

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Moving Forward?Moving Forward? Response to TGN1412Response to TGN1412

– This tragedy creates one more imperative for an open culture This tragedy creates one more imperative for an open culture in medical research, a culture that many fear is increasingly in medical research, a culture that many fear is increasingly losing its waylosing its way Goodyear M. BMJ March 25Goodyear M. BMJ March 25thth 2006 2006

His call for a culture of greater openness in medical research His call for a culture of greater openness in medical research is, I think, both powerful and timelyis, I think, both powerful and timelyGunn A USA TODAY March 27Gunn A USA TODAY March 27thth 2006 2006

– Maximum transparency to reaffirm trust in clinical trials and Maximum transparency to reaffirm trust in clinical trials and their regulation. Commercial confidentiality should not their regulation. Commercial confidentiality should not obstruct independent scrutinyobstruct independent scrutiny Lancet March 25Lancet March 25thth 2006 2006

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Clinical trial registration: transparency is Clinical trial registration: transparency is the watchwordthe watchword

Sim I et al. May 20Sim I et al. May 20thth 2006 2006

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"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 Jong-wook LeeWHO Director-Generaldied May 22

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

I Sim

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Robert K Merton (1910-2003)

Restoring Normative Values

CUDOS

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Moving Forward?Moving Forward?

Adaptation in a Changing World

– Regulation and ethics always lags behind technology

Transparency GovernanceGovernance Support

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Michael K Walsh, John J McNeil and Kerry J BreenImproving the governance of health researchMJA 2005; 182: 468–471

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SummarySummary

Research ethics has come a long wayResearch ethics has come a long way In many ways it is unworkable, and unable to In many ways it is unworkable, and unable to

adaptadapt The whole scientific endeavour has come off the The whole scientific endeavour has come off the

railsrails Collaboration must replace competitionCollaboration must replace competition The process must be transparent and accountableThe process must be transparent and accountable Responsible research is a collective cultureResponsible research is a collective culture

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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

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Medical hubris...has overvalued the state of our knowledge and failed to acknowledge the extent of our ignoranceMcCormick J. Medical hubris and the public health: the ethical dimension.J Clin Epidemiol. 1996 49:619

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