Levels of evidence

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Levels of evidence

• Ia Meta-analysis or systematic review of RCTs
• Ib Randomised trial
• IIa Controlled non-randomised study
• IIb Cohort study
• III Case-control study
• IV Descriptive study
• Non-systematic review
• Consensus report
• Leading article

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Survey of 85 physicians (36 from internal
medicine)Very important in influencing my
prescribing

• Own training and experience 88
• Scientific papers 62
• Advice from colleagues 48
• Detail men 20
• Drug adds 4
• Patient preference 2

(Avorn J. Am J Med 1982734-8)
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Is impaired cerebral blood flow a major cause of
senile dementia?

• Yes 71
• No 14
• No opinion 15
• 32 found cerebral vasodilators useful in
  managing confused geriatric patients

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Survey of 85 physicians (36 from internal
medicine)Very important in influencing my
prescribing

• Own training and experience 88
• Scientific papers 62
• Advice from colleagues 48
• Detail men 20
• Drug adds 4
• Patient preference 2

(Avorn J. Am J Med 1982734-8)
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Drug adds

• 287 advertisements for anti-hypertensive or
  lipid-lowering drugs
• - 125 promotional claims with references
• - 23 refs. unretrievable (data on file,
  monographs)
• - 45 of 102 claims not supported by reference
• (Lancet 200336127)

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Randomised trials

• Unclear randomisation method
• - effect exaggerated by 30, on average
• No blinding
• - effect exaggerated by 14, on average

(BMJ 200132342-6)
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Outcome reporting bias

• 102 RCTs approved by the Copenhagen
  Frederiksberg Ethics Review Committee 1994-95
• and subsequently published
• Incompletely reported outcomes for meta-analysis
• 50 for efficacy, 65 for safety

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Outcome reporting bias

• Unreported outcomes
• 86 of trialists denied unreported outcomes
  despite evidence in publications protocols
• Only half of the trialists responded to the
  question

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Outcome reporting bias

• Full outcome reporting is associated with plt0.05
• Odds ratio 2.4 (1.4 - 4.0) for efficacy
• Odds ratio 4.7 (1.8 - 12) for safety

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Are primary outcomes consistent between
protocols and publications?
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Conclusions

• Trial outcomes are often inadequately reported
  for inclusion in meta-analyses
• Reporting of outcomes is biased to favour plt0.05
• Primary outcomes are omitted, changed, or
  newly-introduced in over 60 of trials

Protocols should be publicly available
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Positive studies are more likely to be
published than negative studies

• Hazard ratio for 130 clinical trials
• positive (Plt0.05) vs negative (Pgt0.10)
• 3.13 (1.76 to 5.58), P0.0001
• Median time to publication 4.7 vs 8 years

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Cochrane Reviews

• Freely available from
• www.cochrane.dk

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Based on Cochrane Reviews when possible
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NSAIDs

• Systematic reviews of RCTs have found no
  important differences in effect between different
  NSAIDs or doses but have found differences in
  toxicity related to increased doses and possibly
  to the nature of the NSAID itself.
• The only meta-analysis that found one drug to be
  more effective than another was funded by the
  manufacturer
• Clinical Evidence 19992

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Clinical Evidence(NSAIDs)

• We have favoured systematic reviews that have not
  been sponsored or authored by industry ...
• it is easy to seemingly follow the rules for
  systematic reviews and yet adopt inclusion and
  exclusion criteria that omit inconvenient
  studies. In fact, it is hard to find a systematic
  review sponsored by, or co-authored by, industry
  that concludes that the companys product is not
  better than those of its competitors.

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Celecoxib

• Conclusion, industry supported meta-analysis
• Celecoxib ... has significantly improved
  gastrointestinal safety and tolerability (BMJ
  Sept 2002)
• Conclusion, Cochrane Review
• For an individual with RA the potential benefits
  of celecoxib need to be balanced against the
  uncertainty that the short-term reduced incidence
  of upper GI complications are maintained in the
  long-term and its increased cost in comparison to
  traditional NSAIDs.

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Industrisponsorerede forsøg med lægemidler

• Ofte problemer med
• Design
• Data-analyse
• Afrapportering
• Konklusion

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Forsøg med psykofarmaka

• Gamle præparater
• - Alt for høj dosis, alt for hurtig dosisøgning.
• Nye præparater tilsyneladende lige så gode,
• med langt færre bivirkninger.
• Men udbredt manipulation med dosis, data-analyse
  og afrapportering.
• (J Nerv Ment Dis 2002190583)
• (BMJ 20033261171)

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Behandling for skizofreni

• Olanzapin 17.000 kr/år
• Haloperidol 2.400 kr/år
• Forbrug i primærsektoren
• Olanzapin 216 mio kr i 2002
• Haloperidol 4 mio kr i 2002
• the new drugs have no unequivocal advantages for
  first line use (BMJ 20003211371)

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Industrisponsoreret forskning versus offentligt
sponsoreret forskning

• Chancen for et positivt udfald 4 gange så stor
  for forsøg eller systematiske oversigter over
  flere forsøg.
• (BMJ 20033261167)
• Chancen for en positiv konklusion 5 gange så stor
  for forsøg, trods samme effekt.
• (JAMA 2003290921)

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Cochrane Reviews
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Hvilken forskning mangler vi?

• - Sammenligninger med gamle, billige præparater,
  og på en fair måde (offentlig finansiering)
• - Sammenligninger med andet end lægemidler
• Forebyggelse af ikke-insulinkrævende sukkersyge
• - metformin 31 effekt
• - motion og vægttab 56 effekt
• (N Engl J Med 2002346393)
• - Forskning i skadevirkninger

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