Part I

Where are We Now?

The Ongoing Problems

• Role Confusion– Mission Creep– Administrivia

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

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.

Mission Creep in the IRB World

• System endangered by excessive paperwork– Overregulation and underprotection

• Overwhelmed by procedures and documentation at expense of thoughtful consideration

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

– with frustrating delays, expensive paperwork

Mission Creep in the IRB World

• *Ethics a Collective Responsibility

• IRBs not a substitute for Ethical Thinking and Behaviour

• Should cultivate Ethical Culture

• Researchers and IRBs need Support– local– central

The Ongoing Problems

• Role Confusion• The Collapse of Scientific Integrity

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

Why is There a Crisis in Trust?

Evidence Based Medicine

Archie Cochrane (1909-1988)

Evidence Based Medicine

Why is There a Crisis in Trust?

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

evidence (RCTs)– Practice Based Guidelines

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

Why is There a Crisis in Trust?

• Evidence Based Medicine

A House of Cards Built on Sand?

Why Is There a Crisis in Trust?

• Public Perceptions (1)– Law Suits Against Industry

• data suppression

– Publication ethics

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.

Why Is There a Crisis in Trust?

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

• Publication Bias• Outcome Bias• Altered outcomes• Publication restrictions• Suppressed data• Ghost writing

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

Why Is There a Crisis in Trust?

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

• Publication Bias• Outcome Bias• Altered outcomes• Publication Restrictions• Suppressed data• Ghost writing

Industry Publication Restrictions Facilitate Selective Reporting

“If there are disagreements with the investigators’

analyses, new or repeated analyses are required before

publication. The Sponsor remains sole owner of the

data.”

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

“Any information which the Sponsor deems confidential

must be deleted prior to submission.”AW Chan, Gøtzsche P et al JAMA 2006 295: 1645

Why Is There a Crisis in Trust?

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

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

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…

Why Is There a Crisis in Trust?

• Public Perceptions (1)– Law suits against industry

– Publication Ethics • Publication Bias

• Outcome Bias

• Altered outcomes

• Publication restrictions

• Suppressed data

• Ghost Writing– David Healey, Carl Elliott

Why Is There a Crisis in Trust?

Ghost Writing

“Dear Dr …., In order to reduce your workload to a minimum we have had our Ghost Writers produce 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 JournalsJAMA 280 (1998): 222-24

Why Is There a Crisis in Trust?

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

Ellen Roche, a Healthy Volunteer

Ellen Roche

Would Ellen be Alive Today,

if all Hexamethonium Trials had been

Registered?

Unnecessary Research

“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 Gelsinger

Why Is There a Crisis in Trust?

• Public Perceptions (2)– Death and Injury of Volunteers– Breaches of integrity– Commercialisation– 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%

Why Is There a Crisis in Trust?

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

• Conflicts of interest

• Health Care Industry

• Globalisation

– Unnecessary research

Global Corruption Report 2006

Special focus:CORRUPTION AND HEALTH

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

Testing new drugson the world’s poorest patients

Why Is There a Crisis in Trust?

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

• Ellen Roche

• Aprotinin

Cumulative Meta-analysis of Aprotinin for Perioperative

Bleeding1

Where was Equipoise?

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

Why Is There a Crisis in Trust?

• Public Perceptions (3)– Inappropriate sponsor involvement– Safety issues

• Paroxetine (Paxil)

• Rofecoxib (Vioxx)

• Class I Antiarrhythmic Drugs

– Disease Mongering

“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

Why Is There a Crisis in Trust?

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

Deaths from inappropriate publication– Consumer group websites publish daily

bulletins on wrongdoing in research

Rofecoxib

Cardiovascular Risk Factors

VIGOR Trial (4%)

Increased Risk: 38% CV events

Risk Ratio: 2.5

Event Rate 1.5%

Tennessee Medicaid Study (40%)

Event Rate 11.6

NNH: 556 v 70 (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

Why Is There a Crisis in Trust?

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

from inappropriate publication– Consumer Group Websites publish daily

bulletins on wrongdoing in research

Vera Hassner Sharav, M.L.S.

Where Has Science Gone Wrong?

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

Has Science lost its Way?

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

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

• Are IRBs legitimising fraud?

Sponsor always Wins!

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

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

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

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

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

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

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

Department of Family MedicineVirginia Commonwealth University