Scientific Integriy in Medical Research Partnerships and Ethical Implications

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Scientific Integriy in Medical ResearchPartnershi
ps and Ethical Implications
J. Lobo Antunes MD, Ph.D.President Portuguese
Academy of Medicine

• FEAM Conference December 15th Lisbon

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• Scientific has become an all purpose term of
  epistemic praise meaning strong, reliable, good
• and yet...
• like all human enterprises it is thoroughly
  fallible, imperfect, uneven in its achievements,
  often fumbling, sometimes corrupt, and of course
  incomplete

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The History of the Decline and Fall of the Roman
Empire
Consider me not as a contemptible thief but as
an honest and industrious manufacturer
Edward Gibbon (1737-1794)?
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Gregor Johan Mendel (1822-1884)?
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Louis Pasteur (1822-1895)?
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Robert A. Millikan (1868-1953)?
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Some key ideas

• Legally scientific fraud is a deliberate
  misrepresentation of truth (misconduct may be a
  better term)?

• Sloppy science
• Contradicted or misguided interpretations
• Mistakes
• Poor scientific and unprofessional practices
• Negligence

• It is different from

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Non-intentional
Misconduct
Error
Fraud

• Wrong observations
• Wrong analysis
• Undeclared conflict of interest
• Publication bias
• Undeserved authorship
• Supressing data
• Plagiarism
• Falsification
• Fabricacion

Intentional
M. Nylenna, S. Simonsen Lancet 3671882, 2006
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Science does not exist until it is published.
Drummond Rennie. Lancet 1998352SII18
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The Audit Society

• Publications are fundamental units of information
  exchange, proof of productivity and creativity,
  and bases for future research and development

Productivity (quantity)? Independence (first or
senior authorship)? Significance (impact factors)?
Academic promotion
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• 27 of the scientific papers are never cited
• Papers published
• Papers published in Nature 1999
• citations in 2001 10 (80 papers) half of
  citations

A few interesting numbers
1955 1987 55.7 79,9
30 million 1 citation no more than 4
If 2/3 of accepted papers were replaced by 2/3 of
the rejected, the quality of the journal would
not alter (Adair et al. Phys Rev Letters 431969,
1979)?
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There are more gt16000 medical journals
Authors/article and Editors do NEJM
Manuscripts submitted to NEJM
Drummond Rennie. Lancet 1998352SII18
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972 authors 2 words/author
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Committee on Publication Ethics (COPE)?
TAXONOMY OF MISCONDUCT

• Falsification
• Fabrication
• Plagiarism
• Failure to get ethical approval
• Not admitting that some data are missing
• Ignoring outliers without declaring it
• Not including data on side effects on a clinical
  trial
• Conducting research without informed consent
• Publication of post-hoc analysis without
  declaring it
• Gift /honorary authorship
• Not attributing other authors
• Redundant publication
• Not disclosing conflicts interest
• Not attempting to publish completed research
• Failure to do an adequate search of existing
  research before beginning new research
• Shotgunning - simultaneous submission of a
  manuscript to more than one journal.

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Fraud in Publishing
More common

• Major research institutions and high impact
  journals
• Biological sciences
• Clinical research

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You catch them in the NET
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What happens after

• Retraction ignore it
• Expression of concern we are looking into it
• Correction substitute information
• papers continue to be quoted after retraction

but
ExampleJam Hendrik Schön, Nature published 2000
retracted 2003
cited 17X after that!
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The Peer-review system
Gate-Keepers

• JAMA 9
• Academic Medicine 15
• Nature 5

Rate of acceptance
Remote Mysterious Crude Understudied
but
indispensable
86 of unpublished trials have negative results
45 of published trials have negative results
Confirmatory bias Bias against negative
results Give disproportionate credit to the
already famous Orientation and theoretical
persuasion Conflicts of interest competitors
/ antagonists Agreement between referees 10-15
The pitfalls
The politically correct
Blinding is not the solution. The authors can be
guessed in 46 of manuscripts!
(JAMA 272 143, 1994)?
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The Malefices of Covert Duplicate Publication
Example

• Ondasetron on post-operative emesis
• 9 trials published in 14 further reports
  duplicating data from 3325 patients
• Inclusion of duplicate data in meta-analysis led
  to a 23 overestimation of the drugs antiemetic
  efficacy

Tramer et al. Brit Med J 315635, 1997
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Pressure to publishUnhealthy competition?
The Schön Scandal

• They chose reviewers who they knew to be
  positive (...) They did not allow their
  experiments to be reproduced
• Robert Laughlin
• (Nobel Prize physics)
• Given the exciting claims made by the papers, we
  were certainly hoping that the outcomes would be
  positive
• Karl Ziemeli
• (Chief physical sciences editor, Nature)?

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The Editors Pressure

• Manipulation of the impact factor of the journal,
  encouraging the citation of other papers
  published in the journal ()?
• and yet
• Impact factors tell you more about sociology of
  science than about science itself
• S. Brenner

() (M. Farthing, Science and Engineering Ethics
1245-52, 2006)?
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Date withholding

• Protect priority races
• Strictures of commercial funding
• Material and financial costs of responding to
  requests for biomaterials
• Scientists in trainning are discouraged to show
  data
• 42 genetic
• 38 of OLS

Blumenthal et al Academ Med 81 137, 2006
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Industry support of biomedical research

• USA
• 1980 32
• 2000 62
• Lead authors 1 every 3 articles hold relevant
  financial interests.
• In biomedicine, with rare exceptions, is the
  private sector, not academics that develops
  diagnostic, therapeutic and preventive products
  and brings them to market.
• 2/3 of academic institutions hold equity in
  start-up businesses that sponsor research by
  their faculty

Quoted in Bekelman et al. JAMA 289454, 2003
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Industrial support and academic productivity

• - Industry supported faculty is as productive as
  
• those who do not receive support
• - more productive commercially
• - 2 x trade secrecy or withhold results from
  colleagues
• -encourage research with commercial
  applicability and may reduce fundamental
  research.
• Blumenthal et al. N Engl J Med 3351734, 1996

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Competing goals in medical research

• Academic investigators
• Industry

Publication in peer-reviewed journals
Approval and marketing of drug. Without approval,
publication is not worth a cent. Publication in
prestigious journals important for the marketing
No drug company gives away its stockholders
money in an act of desinterested generosity
Journal of Commercial Molecular Biology Journal
of Commercial Neurobiology Sidney Brenner My
life in Science
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Concerns about industrial funding of medical
research

• - Death of volunteer in phase I gene therapy
  trial doctor and institution had financial
  interest in therapy
• Publication biases
• Authors whose work support safety of calcium
  channel antagonists had more frequently financial
  ties with industries.
• Results favoring new therapy over traditional one
  are more likely if study is funded by therapy
  manufacturer.
• 5 of industry supported pharmoeconomic studies
  of cancer drugs reached unfavourable conclusions
  non funded studies reached the same conclusion
  in 38 of the studies.

Stelfox et al. N Engl J Med 338101,
1998 Davidson J Gen Int Med 1 155,
1986 Friedberg et al. JAMA 282 1453, 1998
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Amount (dollars)?
Therapeutic effect. A news report on angiostatin
and endostatins promise did wonders for
WEntreMeds stock
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Conflict of Interest

• Does declaration of competing interests affect
  readers perceptions? A randomized trial
• Results of study on impact of pain in herpes
  were found less interesting , important,
  relevant, valid and believable when the authors
  were employees of fictitious pharmaceutical
  company than with ambulatory care centers.

Chaudhry et al. B M J 3251391, 2002
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Biomedical Research, what is the public interest?

• The research that it supports is for the search
  of truth, uncontaminated by any bias
• Discoveries with potential therapeutic benefit
  are rapidly translated into practice by clinical
  trials.
• Participation in development of new therapies
  will be safe, with full informed consent, and
  access to outcome and follow-up.
• Right to know about potential side effects that
  might influence decision to participate
• Must be assumed that decision to ask patients to
  participate or the assessment of risks will not
  be determined by pressure on the investigator.

J B Martin et al. New England J Med 3431646, 2000
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A convenient omission
A 4x increase in heart atacks was ommitted

• The journal sold 929.000 offprints
• (Revenue 679.000 to 836,000)?

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What does academy have to do?(little scholarship
on this topic!)?

• - Protection of human participants safety and
  welfare
• Academic freedom
• Objectivity
• Data integrity
• Right to publish
• Financial and non financial incentives should
  address institutional, senior and junior
  investigator needs
• - Separate human research responsibilities from
  investment management and technology transfer

Task force Am Ass Med Colleges 2003
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Sponsorship, authorship, and accountability (1)?

• (The Editors of Ann Int Med, JAMA, New England J
  Med, Canad MAJ, J Danish M A, Lancet, Medline,
  etc, Sep 2001)?
• When authors submit manuscript they are
  responsible for disclosing all financial and
  personal relationships that might bias their work
• Researchers should not enter in agreements that
  interfere
• Their access to the data
• Ability to analyze data independently
• Prepare manuscripts
• Publish them

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Sponsorship, authorship, and accountability (2)?

• Should describe the role of the study sponsor
• Collection, analysis and interpretation of data
• Writing the report The non-author writer
  syndrome, the guest author.
• Avoid selecting external peer reviewers with C.I.
  (e.g. same department)?
• Reviewers must disclosed C.I.
• (Drug therapy reviews)?
• Editors most have no personal, professional or
  financial involvement in any issues they might
  judge.

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How to improve

• Research Funding agencies establish research
  grant programs to identify, measure, and assess
  those factors that influence integrity in
  research.
• Institutional Commitment Institutions to
  develop and implement comprehensive programs
• Education Effective educational programs
• Self-assessment Implement self-assessment and
  external review process. If possible this should
  be part of existing processes accreditation

Adapted from Integrity in Scientific Research.
Institute of Medicine. National Research Council,
2002
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• Many people say that is the intellect which
  makes a great scientist.
• They are wrong it is character.