Bianca Hemmingsen

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Components associated with systematic
underestimation of harm

• Bianca Hemmingsen
• Lina Saem Støy

Copenhagen Trial Unit (CTU) Centre for Clinical
Intervention Research
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• Overview
• Definitions
• Phases of harm evaluation
• Extent of underreporting
• Components
• Solutions

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Definitions

• Harm
• The totality of possible adverse
• consequences of an intervention or therapy
• Safety
• Substantive evidence of an absence of harm

Definitions by the CONSORT
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Definition

• Adverse event (AE)
• Any untoward medical occurrence in a
• patient or clinical trial participant
• administered a medicinal product and
• which does not necessarily have a
• causal relationship with this
• intervention 

Definitions from the DMA
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Definition

• Adverse reaction (AR)
• All untoward and unintended
• responses to an investigational
• medicinal product related to any dose
• administered

Definitions from the DMA
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Definition

• Serious adverse event (SAE)
• Any untoward medical occurrence or
• effect that at any dose results in
• death
• life-threatening
• requires hospitalisation or prolongation of
• hospitalisation
• results in significant disability or incapacity
• is a congenital anomaly or birth defect

Definitions from the DMA
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Definition
Serious adverse reactions (SAR) If a serious
adverse event is related to the medical
intervention used in trial
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Definition

• Suspected unexpected serious adverse
• reaction (SUSAR)
• An adverse reaction, the nature or
• severity of which is not consistent with
• the product resume or investigators
• brochure

Definitions from the DMA
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(No Transcript)
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Estimation of harm

• Principles of monitoring safety in trials
• include
• Phase 1 establishes maximum tolerated dose few
  participants, often including placebo group
• Phase 2 determines biological effect and adverse
  events, patient with specified condition (often
  randomised)

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Estimation of harm

• Phase 3 evaluate efficacy, adverse events,
  compared to placebo or standard of care (always
  randomised)
• Phase 4 evaluates long-term effectiveness and
  safety, post-marketing (often observational
  studies)

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Extent of underestimation

• Evidence of underestimation of harm in clinical
  research
• Papanikolaou et al CMAJ 2006 AE in randomised
  clinical trials and non-randomised studies
• Hazel et al. Drug Saf 2006 AR in randomised
  clinical trials
• Nuovo et al. Pharmacoepidemiol Drug Saf 2007 AE
  and AR in publications of randomised clinical
  trials

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Papanikolaou et al. 2006

• Data from large scale (gt4000 participants)
  randomised trials and non-randomised studies
• Comparing of risk differences for 13 harms
  regarding medical and surgical interventions

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Papanikolaou et al. 2006

• Risk difference in AE in randomised trials are
  two fold higher than in non-randomised studies
  for 7/13 harm topics
• Conclusion non-randomised studies are often more
  conservative in estimating risks of harm than
  randomised trials

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Extent of underestimation Hazell et al. 2006
Method used to estimate underreporting
Number of reported AR
of estimated underreporting

Number of AR should have been reported

• Number of AR should have been reported
• Monitoring
• Resume of product
• Other

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Extent of underestimationHazel et al. 2006
Median underreporting across 37 studies (from 12
countries) was 94 (IQR 82-98) compare to actual
number of known adverse reactions
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Extent of underestimationHazel et al. 2006
Median average percentage of underreporting was
95 with no significant difference in
underreporting for general practitioners compared
to hospital doctors
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Extent of underestimationHazel et al. 2006
Median underreporting across 14 trials involving
specific AR was 83 (IQR 66-95) when compared to
actual number of known adverse reactions
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Extent of underreportingNuovo et al. 2007

• Of 521 RCTs, AE is mentioned in
• 63 in Abstract
• 73 in Method
• 89 in Results section

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Components associated with underestimation of
harm

• Study design
• Lack of time
• Difficulties in accessing reporting form
• Uncertainty of drug causality

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Components associated with underestimation of
harm

• Short duration of trial
• Small number of participants
• Selective inclusion criteria
• Selective exclusion criteria
• Lack of reporting in articles

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Components associated with underestimation of
harm

• Lack of awareness of requirements of reporting
• Lack of understanding the purpose of spontaneous
  reporting system
• Lack of transparency

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Solutions

• Education
• Improve accessibility of reporting form
• Standardised guidelines for reporting system

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Solutions

• Increased use of large randomised clinical trials
  
• Standardised guidelines for article reporting
  (CONSORT checklist)
• Public access to reporting registers

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Thank you!
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References
Hazel L, Shakir SAW. Under-reporting of adverse
drug reactions a systematic review. Drug Safety
2006 29(5) 385-396
Nuovo et al. Reporting adverse events in
randomized controlled trials. Pharmacoepidemiology
and Drug Safety 200716 349-351
Papanikolaou, et al. Comparison of evidence on
harms of medical interventions in randomized and
nonrandomized sutdies. Canadian Medical
Association Journal 2006 174 (5) 635-641
Ionnidis, JPA et al. Better reporting of harms in
randomized trials an extension of the CONSORT
statement. Annals of Internal Medicine 2004 141
(10) 781-788