Scientific Integriy in Medical Research Partnerships and Ethical Implications FEAM Conference – December 15th Lisbon J. Lobo Antunes MD, Ph.D. President Portuguese Academy of Medicine

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

Edward Gibbon ( ) 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

Gregor Johan Mendel ( )

Louis Pasteur ( )

Robert A. Millikan ( )

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

Wrong observations Wrong analysis Undeclared conflict of interest Publication bias Undeserved authorship Supressing data Plagiarism Falsification Fabricacion Non-intentional Intentional Error Misconduct Fraud M. Nylenna, S. Simonsen Lancet 367:1882, 2006

Science does not exist until it is published. Drummond Rennie. Lancet 1998;352:SII18

Publications are fundamental units of information exchange, proof of productivity and creativity, and bases for future research and development Academic promotion Productivity (quantity) Independence (first or senior authorship) Significance (impact factors) The Audit Society

27% of the scientific papers are never cited Papers published Papers published in Nature 1999 citations in 2001 – 10 % (80 papers) = half of citations 1955 – % 79,9% A few interesting numbers… 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 43:1969, 1979)

There are more >16000 medical journals Authors/article and Editors do NEJM Manuscripts submitted to NEJM Drummond Rennie. Lancet 1998;352:SII18

972 authors 2 words/author

Committee on Publication Ethics (COPE) 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. TAXONOMY OF MISCONDUCT

Fraud in Publishing Major research institutions and high impact journals Biological sciences Clinical research More common

You catch them in the NET

What happens after Retraction – ignore it Expression of concern – we are looking into it Correction substitute information papers continue to be quoted after retraction retracted 2003 Example:Jam Hendrik Schön, Nature published 2000 cited 17X after that! but

The Peer-review system JAMA 9% Academic Medicine 15% Nature 5% butindispensable Remote Mysterious Crude Understudied – 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% 86% of unpublished trials have negative results 45% of published trials have negative results The politically correct Blinding is not the solution. The authors can be guessed in 46% of manuscripts! (JAMA 272: 143, 1994) Gate-Keepers Rate of acceptance The pitfalls

The Malefices of Covert Duplicate Publication 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 315:635, 1997 Example

Pressure to publish Unhealthy competition? 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) The Schön Scandal

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 12:45-52, 2006)

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

Industry support of biomedical research USA % % -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 289:454, 2003

- 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 335:1734, 1996 Industrial support and academic productivity

Academic investigators – Industry – Competing goals in medical research 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

- 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 338:101, 1998 ** Davidson – J Gen Int Med 1: 155, 1986 *** Friedberg et al. – JAMA 282: 1453, 1998 Concerns about industrial funding of medical research

+++Teirstein ++Williams ++Kereiakes +++Fitzgerald +++Popma +++Leon +++Moses StockholderFinancingSpeakerConsultant

Amount (dollars) Therapeutic effect. A news report on angiostatin and endostatins promise did wonders for WEntreMeds stock

-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 325:1391, 2002 Conflict of Interest

Biomedical Research, what is the public interest? 1.The research that it supports is for the search of truth, uncontaminated by any bias 2.Discoveries with potential therapeutic benefit are rapidly translated into practice by clinical trials. 3.Participation in development of new therapies will be safe, with full informed consent, and access to outcome and follow-up. 4.Right to know about potential side effects that might influence decision to participate 5.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 343:1646, 2000

A convenient omission A 4x increase in heart atacks was ommitted The journal sold offprints (Revenue $ to $ 836,000)

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

(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 Sponsorship, authorship, and accountability (1)

-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. Sponsorship, authorship, and accountability (2)

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]

Many people say that is the intellect which makes a great scientist. They are wrong: it is character.