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7/30/2019 Chalumeau & Grimaldi Bensouda
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Lamiae Grimaldi-Bensouda, La-Ser, CNAM
Martin Chalumeau, Necker Hospital for Sick Children, Paris Descartes
University, Inserm U953PRES Paris Sorbonne
Drug evaluation in children:
observational approaches
Methodological Approaches to Overcome the Challenges
of Drug Evaluation in Children
EUCROF/RIPPS/EMA Conference, London, 2013
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Observational approachesto evaluate drugs in pediatrics
2 clinical examples highlighting theimportance of observational studies
to evaluate drugs in pediatrics:- rare adverse events- long term adverse events
These examples allow discussing methods inobservational studies.
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Observational approachesto evaluate drugs in pediatrics
Clinical situation 1
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Ibuprofento treat fever without source
As a physician / pharmacist / parent you prescribe / deliver / giveibuprofen to a 2 years old girl withisolated fever.
72 hours later the patient ishospitalized for acute necrotizingfasciitis related to a Group AStreptococcus infection.
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Biological plausibilityIn vitro and animal studies
Decrease in neutrophil function after exposures to NSAIDs
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Ibuprofento treat fever without source
As a physician / pharmacist / parent you prescribe / deliver / giveibuprofen to a 2 years old girl withisolated fever.
72 hours later the patient ishospitalized for acute necrotizingfasciitis related to a Group AStreptococcus infection.
You report the case to the pharmacovigilance system.
What can you learn from this system?
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Spontaneous reporting of ADRLimitations
Essential for drug monitoring and signal generating butquantitative measures of risk nearly impossible given:
Incomplete numerator (underreporting)
Absence of real denominator (n exposed to the drug)
Others:
- Selection bias / novelty bias- Information bias: data collection is different / exposure- Confusion / inference- Not for delayed events and events with high-baseline risk
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RCT to evaluate rare adverse events
Number of NF at 30 days: 0
Which inference (enough power for rare events)?
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RCT to evaluate rare adverse events
Usual inference drawn:
NF nearly does not exist in the 30 daysafter exposure to ibuprofen in children…
Is it possible to refine this inference?
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Inference / Rare AEBernouilli trial and Binomial distribution
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RCT to evaluate rare adverse events
Given zero events in a sample size of 55785,
the exact inference is:
it is fairly unlikely (< 2.5%) that the trueprobability of adverse events is higher than
1/15000
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RCT to evaluate rare adverse events
>1/15000:rare (or not so rare?)
- Frequency of the treated disease- Existence of safe alternative treatment- Severity of the AE- Severity of the treated disease
Here: which inference on ibuprofen safety after
this huge RCT?
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Observational approachesto evaluate drug safety in pediatrics
To make inference, you need information.
Here, you need cases.
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Observational approachesto evaluate drug safety in pediatrics
Cohort studies
or
Case-control studies
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Observational approachesto evaluate drug safety in pediatrics
Cohort studies would offer similarpower than RCTs
(not useful for rare events)
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Case-controlto evaluate drug safety in pediatrics
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Case-controlto evaluate drug safety in pediatrics
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Case-control studiesavoiding protopathic bias
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Case-controlto evaluate drug safety in pediatrics
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Case-controlto evaluate drug safety in pediatrics
1st inference:
NF does exist in the 30 days afterexposure to ibuprofen in children
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Case-controlto evaluate drug safety in pediatrics
2nd inference:
Exposure to ibuprofen (in the last 7 days) ismore frequent among cases than controls- strenght of the association- statistical significance of the association
- (dose relationship issues)
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Case-control studiesWarning
Selection of controls
Measure of exposure (retrospective)
Recal bias: potentially differential
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Case-control and cohort studiesAre mix approaches possible?
Would it be possible:to gain ‘‘cases’’ (using a case-control design)while avoiding (differential) recal bias
and selection bias?
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Nested case-control studieswithin an automated data-base cohort
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Nested case-control studieswithin an automated data-base cohort
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Nested case-control studieswithin an automated data-base cohort
Statistical power
Less risk of selection biasLess risk of (differential) recal bias
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Nested case-control studiesinside a cohort
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Nested case-control studiesinside a cohort
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Observational studiesfor rare adverse events
Which inference on ibuprofen safety afterthese various observational studies?
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Observational approachesto evaluate drugs in pediatrics
Clinical situation 2
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Prolonged sedation/analgesiain very preterm infants
As a pediatrician, you wonder if youshould prescribe sedative or opioiddrugs to a 3 days old girl, born after30 weeks of gestation, admitted to
the NICU for respiratory distress
Given:- these drugs are not labeled in this age group for this indication(prolonged sedation/analgesia)
- there are concerns about the neurological safety of these drugsrelated to immaturity…
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Prolonged sedation/analgesiathe alert (1/2)
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Prolonged sedation/analgesiathe alert (2/2)
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Inference problemsin observational studies
Confounding
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Confirming the biaslook at covariates
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Theoretical solutionsfor confusion by indication
ethical?
a priori
a posteriori
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Nonrandomized solutionsLimits
n binary confounders2n combinations
logistic regression model:
P(Y/X1,2,3,...n) = 1 / [1 + e-( 0 1 1+ 2 2 3 3 ... n n ]
To avoid ‘‘over adjustment’’: n < Y events /10
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Propensityfor what?
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Why a scoreof propensity?
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Propensity scoreChanging the predicted variable
P(Y/X1,2,3,...n) = 1 / [1 + e-( 0 1 1+ 2 2 3 3 ... n n ]
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Propensity scoreChoosing predicting variables
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Variables includedExample
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How to use the score?3 main approaches
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How to use the score?(1) stratification
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How to use the score?(2) matching
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P(Y/X1,2,3,...n) = 1 / [1 + e-(0 1 1
+2 2 3 3 ]
P(Y/X1,2,3,...n) = 1 / [1 + e-(0 1 1
+2 2 3 3
...n n ]
How to use the score?(3) adjustment - principles
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How to use the score?(3) adjustment - results
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Propensity scoresLimits
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Propensity scoresPotential applications
To study safety and effectiveness of drugs in children:
- when cohort data is available
- with data on potential confounders- with a non homogenous pattern of treatment
Not a magic bullet
Just another way to deal with confounding (by indication)
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Prolonged sedation/analgesiain very preterm infants
As a physician, you wonder if youshould prescribe sedative or opioid toa 3 days old girl, born after 30 weeksof gestation, admitted to the NICU
for respiratory distress.
Questions:
Does the lack of license (or labeled indication) is a limitation to the useof prolonged sedation/analgesia?
Would it be possible to obtain a license without RCTs in this indication?
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Observational approachesto evaluate drugs in pediatrics
In pediatrics,well-performed observational studies are very
important tools to evaluate :
- rare adverse events (no alternative design)- long-term safety (no alternative design)
- effectiveness (no alternative design)
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Observational approachesto evaluate drug efficacy in pediatrics
Existing examples (with license):
- Precocious puberty and GnRH agonists;- Turner Sd and GH;- Burkitt lymphoma and Wollner-MTX = LSAL2.
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Open label, n = 11
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Open
label,n = 4
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Statistical inference with 4 observations
Ob l h
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Observational approachesto evaluate drug efficacy in pediatrics
Candidate situations:- Very serious conditions
- Outcome: in steel- Perfectly known natural history- Effect size: important (visible to the naked eye)