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					      Disclosure and Registration

        The Transparency Revolution

             INSIGHT Toronto April 25 2006

              Michael Goodyear1, Lisa Golec2



1. Department of Medicine, Queen Elizabeth II Health Sciences Centre,
    Dalhousie University, Halifax NS
2. NICU Sunnybrook and Women’s College Health Sciences Centre,
    University of Toronto, Toronto ON
          Learning Objectives
   I: Why is there a Crisis in Trust?
   II: Where has Science gone Wrong?
   III: Why is there an Ethical Problem?
   IV: Why Transparency?
   V: Why Registration?

                    Summary
            Part I
Why is There a Crisis in Trust?
Why is There a Crisis in Trust?

     Evidence Based Medicine



                Archie Cochrane
                   (1909-1988)
  Why is There a Crisis in Trust?

 Evidence Based Medicine
  – Replaced Opinion, Anecdotes and Experts
     Evidence
  Why is There a Crisis in Trust?

 Evidence Based Medicine
  – Replaced Opinion, Anecdotes and Experts
  – Based on Systematic Reviews of High
    Quality Evidence (RCTs)
Cultural Intermission




 When was the first RCT?
  First RCT

Daniel (600 BC)
Chapter 1:1-16




  Michelangelo
  Capella Sistina
      1511
  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
June 3, 2004
Spitzer 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
     Selective Reporting in the
         Medical Literature
   Trial 1        Trial 2            Trial 3

                Publication         Selective
Publication
                                     study
                Selective          publication
 Outcomes
                outcome
                reporting
                   75% Trials
 Systematic                           26% None
                                      13% Abstract
   review                             39%
                                      4% Incomplete

Meta-analyses        AW Chan
                     K Dickersin
          Selective Study Publication
          Odds of Publication by Significance




                             2.5




                p≥0.05              p<0.05
                           Dickersin K. AIDS Educ Prev
AW Chan                               (1997)
   Selective Reporting of Outcomes

  Efficacy outcomes                                CIHR
                                                   (n=30)


                                                   REBs
                                                   (n=50)


Chan AW et al, JAMA (2004)
               CMAJ (2004)                         MEDLINE
               BMJ (2005)                          (n=161)

   0.1       .2    .3 .4 .5     1       2   3 4 5 67    10
Favours p  0.05              No bias       Favours p < 0.05
  Why Is There a Crisis in Trust?

 Public Perceptions (1)
  – Law suits against industry
  – Publication Ethics
      Publication bias
      Outcome bias
      Altered Outcomes
      Publication restrictions
Primary Outcomes are Often Changed
     Between Protocol and Publication
                                      Proportion (%) of trials
 Discrepancy in primary outcomes
                                       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
                       Example
                     Diabetes trial
                     Drug intervention

          Protocol                 Publication

    Primary outcome:               Primary outcome:
  % change in HgbA1C                Withdrawal rate



          P0.05       Neg               P<0.05   Pos

AW Chan
  Why Is There a Crisis in Trust?

 Public Perceptions (1)
  – Law suits against industry
  – Publication Ethics
      Publication bias
      Outcome bias
      Altered outcomes
      Publication Restrictions
      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 bias
  – Outcome bias
  – Altered outcomes
  – Publication restriction
  – Suppressed 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…
  Why Is There a Crisis in Trust?

 Public Perceptions (1)
  – Law suits against industry
  – Publication bias
  – Outcome bias
  – Altered outcomes
  – Publication restriction
  – Suppressed data
  – Ghost Writing
  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
Journals,” JAMA 280 (1998): 222-24
    Why Is There a Crisis in Trust?

Ghost Writing
 Going price $1,000-1,500/article1
 Frequently outnumber original articles2
    –   41/55 (75%) articles on Sertraline 1998-2000
    –   More likely to be in prestigious journals
    –   Higher citation rate (x 5)
    –   Differ in conclusions from original articles

1. C Elliott Hast Cent Rep Sep 2004 p18
2. D. Healy and D. Cattell 2003
  Why Is There a Crisis in Trust?

 Public Perceptions (2)
  – Death and Injury of Volunteers
  – Breaches of integrity
  – Conflicts of interest
  – Commercialisation
  – Health Care Industry
  – Globalisation
  – Unnecessary research
                  Ellen Roche


                                    Would Ellen be Alive
                                            Today,
                                   if all Hexamethonium
                                       Trials had been
                                          Registered?




Ellen Roche, a Healthy Volunteer
                                   Unnecessary Research
  Why Is There a Crisis in Trust?

 Public Perceptions (2)
  – Death and injury of volunteers
  – Breaches of Integrity
  – Conflicts of interest
  – Commercialisation
  – Health Care Industry
  – Globalisation
  – Unnecessary research
Vol 435|9 June 2005                                                     nature


                                                           COMMENTARY
Scientists behaving badly
Brian 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 to
pressure from a funding source                                                   16%
  Why Is There a Crisis in Trust?

 Public Perceptions (2)
  –   Death and injury of volunteers
  –   Breaches of integrity
  –   Conflicts of Interest
  –   Commercialisation
  –   Health Care Industry
  –   Globalisation
  –   Unnecessary Research
        Ellen Roche
        Aprotinin
  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
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
What is the Impact on Patients?

         Selective Reporting
           Misinformation


        Over-representation of
        Positive Results in the
               Literature



    Misguided Healthcare Decisions
        Part II
Where has Science Gone
        Wrong?
Where Has Science Gone
       Wrong?



           Robert K Merton
             (1910-2003)


                     CUDOS
       Where Has Science Gone
              Wrong?

 Scientific Norms (Merton)1 (1)
  – Science: The objective seeking of universally valid
    knowledge for the common good

      Communalism - (Open community)
      Universalism - (Does not discriminate)
      Disinterestedness - (Favors an outward objectivity)
      Originality - (Gives new contributions)
      Skepticism - (All ideas must be tested)


                     1. Merton R. J Legal Political Sociol 1942 1: 115-126
Where Has Science Gone Wrong?


 Scientific Norms (Merton)1 (2)
  – Collaboration
  – Sharing of Knowledge
  – Common Goal of the Common Good
  – Findings Belong to the Community
  – Secrecy is the Antithesis of Normal



                 1. The Sociology of Science (1973)
Where Has Science Gone Wrong?


 Scientific Norms (2)
  – Intellectual Property means Recognition
  – New Knowledge must be Rapidly
    Disseminated1




        1. Stuart and Ding Academy of Management Conference 2003
Where Has Science Gone Wrong?


 Has science lost its way?
  – Collaboration replaced by Secrecy
  – Obsession with Commercialisation
  – Lost Sight of Normative Values
        Part III
Why is There an Ethical
       Problem?
       Why is There an Ethical
             Problem?
          Epistemic and Utilitarian

 Collective Fiduciary Duty of Care
  – Decision Making Based on Disclosure of Facts
      Prior
      Continuing
                                          Janus
      Post
        Why is There an Ethical
              Problem?

                  Presumptions
 Prior: Inception
  – The totality of prior information
 Continuing: Execution
  – New information that might bear on decision
 Post: Legacy
  – Information acquired for societal benefit
Why is There an Ethical Problem?

 A PRIORE
  – Right to believe that information disclosed is
    based on all knowledge – But;
      Prior Knowledge is Incomplete and Selective
      Research may be Unnecessarily Duplicative1




                        (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
Why is There an Ethical Problem?

 CONTINUING
 – Subjects have right to know about other
   relevant trials (new information)
    Currently very difficult to find that information
 Why is There an Ethical Problem?

 A POSTERIORE
 – Consent implies contribution to knowledge
    Less than half of randomised trials are published1
    Many not indexed, therefore ‘lost’2
    Negative trials delayed in publication1
    Publication Bias1
    Outcome Reporting Bias3



                    1. Tumber and Dickersin J Int Med 2004 256: 271
                    2. Hopewell Stat Med 2002 21: 1625
                    3. Chan et al JAMA 2004 291: 2457
Why is There an Ethical Problem?

 A POSTERIORE
 – Consent implies contribution to knowledge
 – Probability of real benefit to an individual is
   low
 – Subjects usually motivated by Altruism
‘Highest Derived Good’
   Summum Bonum




            Immanuel Kant
              (1724-1804)




            Critique of Practical Reason 1778
        Jesse Gelsinger


“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
Why is There an Ethical Problem?
    “The Covenant between Researcher and
   Patient…between Ethical Review Boards and
              Patients, is Broken”1

     “Underreporting Research is Scientific
          Misconduct”2 and Unethical3




                  1. Dickersin K, Rennie D 2003 290(40): 516
                  2. Chalmers I JAMA 1990 263: 1405
                  3. Antes G, Chalmers I Lancet 2003 361: 978
      Part IV
Why Transparency?
        Why Transparency?
 Trust and confidence can only be restored
  by a guaranty of transparency

 “his call for a culture of greater openness in
  medical research is, I think, both powerful
  and timely”.1


                 1. Gunn A USA TODAY March 27 2006, on:
                    Goodyear M Learning from the TGN1412 trial.
                    BMJ. 2006 Mar 25
        Why Transparency?
 Subjects have the right to see all aspects of
  a trial they are contributing to

 Subjects have the right to believe that any
  information derived from their participation
  will be fully and freely disclosed for the
  Common Good
       Why Transparency?
 Commitment to transparency provides a
  common data base for all
     Part V
Why Registration?
           Why Registration?
 It is easier to get accurate statistics on baseball
  than on medical research1
 “The result of not knowing who has performed
  what, is loss and distortion of the evidence, waste
  and duplication of trials, inability of funding
  agencies to plan, and a chaotic system …which is
  invariably against the interest of those who offered
  to participate in trials and of patients in general”.1


                           1. Dickersin K, Rennie D 2003 290(40): 516
            Why Registration?
 An Old Idea
  – NIMH Registry 1967
  – Mary Lasker 1974
      “War Against Cancer”
  – NIH Registry 1975-9
  – John Simes 1986
      Publication bias. J Clin Oncol 4: 1529
  – Cochrane Collaboration 1993
  – Ottawa Statement 2005 BMJ
  – WHO
         Why Registration?
 Portal for searching and access of clinical
  research information
  – Unique identifiers: UTRN (ISBNs)

 Tool for evidence based medicine
  – Evolving informatics
  – Guideline development and maintenance
  – Guide for editors and reviewers
  – Cumulative Meta-analyses
Volume 364, Number 9450, 04 December 2004

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis
Jüni P et al
         Why Registration?
 Honours Social Contract with Subjects
 Informs Public
 Enhances Recruitment
         Why Registration?
 Tool for ethical review
 Provides linkage between investigators and
  between ethical review bodies
 Joins the dots
 From Silos to Networks
         Why Registration?
 Why Not?
  – Competitive advantage
  – Burden
  – Cost
  – Proliferation
  – Compliance and enforcement
     Poor to date, but improving
     From Voluntary to Mandatory
     Publication leverage
       – ICMJE
http://www.who.int/ictrp
                        Opening Address to World
                        Health Assembly, May 2005

                               "We are ready to move
                               forward with an
                               International Clinical Trials
        Dr J.W. Lee
        WHO Director-General   Registry. This will do much
                               to strengthen the research
                               process and its ability to win
                               public trust"

I Sim
                                        Registry Platform Overview

                                                    WHO Search Portal
  WHO International Clinical
   Trials Registry Platform




                                                        country specific
                               clinicaltrials.gov             ...          ISRCTN   Registers



                                                                                    Journals


                                                                                    Results
                                                                                    Databases


I Sim
           Why Registration?
 Issues
     Holding “commercially sensitive” items in temporary
      escrow in register
     Burden of proof on sponsor
     How long?
     Who Decides?
     Opposed by consumer groups, academics, funders,
      ethicists, health lawyers
                Summary I/III
   Crescendo of failed trust
   Evidence Based Medicine in crisis
   Science has lost its way and its roots
   Scientific, moral and ethical imperative to
    transparency
             Summary II/III
 Registration restores trust
 Registration restores order out of chaos
 Registration is an efficient tool for the
  furtherance of knowledge
           Summary III/III
 Benefits of registration outweigh
  disadvantages
 Requires commitment and collaboration
  from all partners
 Legislative 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
                  Thank You!

Authors




                 Michael Goodyear   Lisa Golec
                 Dalhousie          Toronto




Collaborators (and many more!)


             Sabina Watts           Elisabeth Clark
             McMaster               McGill

				
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