Docstoc

Presentation Katholieke Universiteit Leuven

Document Sample
Presentation Katholieke Universiteit Leuven Powered By Docstoc
					Independent medical
     research?
 Jos WM van der Meer
    Martijn B Katan
 Jan P Vandenbroucke
   Jos WM van der Meer
Conflicts of interest
• None
      Focus on
pharmaceutical industry
Industry & medical research
Major journal editors:
• Is academic medicine for sale?
   [NEJM,2000]
• Western Medicine: a confidence trick, driven by
  the drug industry [BMJ,2002]
• Journals have devolved into information laundering
  operations for pharmaceutical industry [Lancet
  2004]
• Medical journals are an extension of the
  marketing arm of the pharmaceutical industry
  [PLOS Medicine 2005]
• Industry sponsored medical research: a broken
  system [JAMA 2008]
    Randomised controlled
     clinical trial (RCT)
• Most objective kind of investigation
  regarding the effect of drugs
• Double blinding
• Chance determines who gets what

• Requested for registration
Pharma sponsoring: from 20-30% to 50-60%

                 Ioannidis, BMJ 2006
           Sponsored RCT

• Trial design together with industry
• Authors often consultant to industry
• Recruiting physicians and patients, data
  retrieval and storage by industry or a
  dedicated bureau
• Data analysis by industry
• Manuscript written by/with industry ( or
  “ghost writing” Wall Street Journal 2005 )
• Warrantees: authors have access to data
  and agree on publication
  The “uncertainty principle”
           in RCT
• RCT should be done under circumstances of
  uncertainty
   – It is unclear which arm is superior
   – The design should be such that both arms
     have a maximal chance of superiority.

• The expectation is that results of RCT are
  50 - 50 on average
Is there 50 - 50 outcome?
• Children’s Oncology Group (non-profit
  collaboration of US National Cancer
  Institute) compare new promising therapy
  with the best existing therapy
• 40 years 126 trials
 average: 50%
 superiority
 Sponsored vs. Non-sponsored




Djulbegovic, Lancet 2000   New drug superior
Meta-analysis
• Sponsored studies:
  the drug of the
  sponsor is 4x more
  often superior
  than the
  comparator drug!
 Lexchin, British Medical
 Journal 2003
Better performance of the
    sponsor’s product
• Cardiovascular drugs
    Ridker and Torres, Reported outcomes in
     major cardiovascular clinical trials funded by
     for-profit and not-for-profit organizations:
     2000-2005. JAMA. 2006;295:2270-4.
• Nutritional intervention
    Lenard et al, Relationship between funding
    source and conclusion among nutrition-related
    scientific articles. PloS Medicine 2007
    Jan;4(1):e5


  How can we explain this skewing?
Three levels of explanation
1. The comparator drug is a placebo
   (while an effective comparator is
   available)
2. The comparator drug is used in an
   unfavorable situation (suboptimal
   dose, selection of patients,...)
3. Selective publication
Use of placebo




                 Djulbegovic
                 Lancet
                 2000
    Suboptimal comparison
Why drug A is better than drug B
drug B better than drug C,
and drug C better than drug A...
 (Why olanzapine beats risperidone, risperidone
 beats quetiapine, and quetiapine beats
 olanzapine: an exploratory analysis of head-to-
 head comparison studies of second-generation
 antipsychotics.
 Heres et al. Am J Psychiatry 2006 )
Stand alone
publication

Submitted,
significant

Submitted,
Non-significant

Pooled
publication
      What happens after
         publication?
• The investigator as a vehiculum for
  promotional activities
• Industrial influence on standards,
  protocols and guidelines
  – e.g. Surviving Sepsis Campaign
  – 87% of experts has (often undisclosed) ties
    with industry
• Industrial influence on Ethical
  committees
  – 36% of members has ties with industry;
    disclosure often not asked for.
          Daily practice
• Pharmaceutical industry often has
  more impact on prescribing
  behaviour than authorities and
  reliable literature.       Beads & mirrors
Are they devils?
        • No...
        • Their primary
          commitment is to
          create shareholder
          value,not to maintain
          an altruistic
          commitment to
          patients
        • Trials are driven by
          marketing
       [Brennan, JAMA 2007
       Hill, Ann Int Med 2008]
And the journals?
         • They gain from
           advertisements,
           reprints,
           sponsored special
           issues
         • Large trials raise
           the impact factor
         • They are biased
           towards positive
           studies
        ...and science?
• Which role is left for the academic
  scientist?
• How about the open scientific
  debate?
• Can these large RCT’s ever be
  replicated?
              Solutions
1. No unnecessary placebo-controlled
   trials (optimal comparator drug)
2. Trial with the best possible design
  (investigator-driven; independent
      funding)
3. Clinical trial registration
   www.clinicaltrials.gov
       Further solutions
• Code of conduct
  – Contract between sponsor and
    investigator at the start of the study


                                ‘WETENSCHAP
                                OP BESTELLING’
                                KNAW 2005*


                                *www.knaw.nl
Declaration of independence
1.The structure of the research shall not be geared towards
  producing the desired outcome for the client
2.The assignment and its objective shall preferably be
  formulated jointly by the client and the researcher
3.Remuneration and other tokens of appreciation shall never
  depend on the outcome or interpretation of the research
4.The results of the scientific research shall be published
  irrespective of whether they are favourable to the client
5.The scientist shall always be free to publish the findings of
  the research within a specified reasonable period of time, In
  this context 2 months can be regarded as a reasonable
  period, with 6 months generally the maximum (this period
  being calculated from the moment that the final results are
  submitted to the client). An exception should be made where
  there are issues of intellectual property in which case a
  period of no longer than 12 months would be acceptable.
Declaration of independence(2)
  6. The method of publication shall be stipulated in the
     contract. Publication in a scientific journal shall take place
     in consultation with the client, but the researcher shall
     have the final say on the contents, the authors, the form
     of publication and where the research will be published.
  7. External financiers of research assignments and/or other
     sponsors shall be mentioned by name in publications and
     other forms of disclosure.
  8. Relevant interests and/or advisory relations of the
     researcher(s) shall be cited in publications and other
     forms of disclosure.
  9. The text of the contract shall be available for inspection
     in confidence by the National Council on Research
     Integrity
              Conclusions
• Serious problem
• Medical science, industry and
  journals are seriously entangled
• Limited solutions
  –   Study design
  –   Conduct
  –   Agreement
  –   Funding
  –   Publishing