Chalumeau & Grimaldi Bensouda

7/30/2019 Chalumeau & Grimaldi Bensouda

http://slidepdf.com/reader/full/chalumeau-grimaldi-bensouda 1/58

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

http://www.inserm.fr/



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.




Clinical situation 1



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.



Biological plausibilityIn vitro and animal studies

Decrease in neutrophil function after exposures to NSAIDs



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?



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



RCT to evaluate rare adverse events

Number of NF at 30 days: 0

Which inference (enough power for rare 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?



Inference / Rare AEBernouilli trial and Binomial distribution




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




>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?



Observational approachesto evaluate drug safety in pediatrics

To make inference, you need information.

Here, you need cases.




Cohort studies

or

Case-control studies




Cohort studies would offer similarpower than RCTs

(not useful for rare events)



Case-controlto evaluate drug safety in pediatrics



Case-control studiesavoiding protopathic bias




1st inference:

NF does exist in the 30 days afterexposure to ibuprofen in children




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)



Case-control studiesWarning

Selection of controls

Measure of exposure (retrospective)

Recal bias: potentially differential



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?



Nested case-control studieswithin an automated data-base cohort




Statistical power

Less risk of selection biasLess risk of (differential) recal bias



Nested case-control studiesinside a cohort



Observational studiesfor rare adverse events

Which inference on ibuprofen safety afterthese various observational studies?




Clinical situation 2



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…



Prolonged sedation/analgesiathe alert (1/2)



Prolonged sedation/analgesiathe alert (2/2)



Inference problemsin observational studies

Confounding



Confirming the biaslook at covariates



Theoretical solutionsfor confusion by indication

ethical?

a priori

a posteriori



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



Propensityfor what?



Why a scoreof propensity?



Propensity scoreChanging the predicted variable

P(Y/X1,2,3,...n) = 1 / [1 + e-( 0 1 1+ 2 2 3 3 ... n n ]



Propensity scoreChoosing predicting variables



Variables includedExample



How to use the score?3 main approaches



How to use the score?(1) stratification



How to use the score?(2) matching



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



How to use the score?(3) adjustment - results



Propensity scoresLimits



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)



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?




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)



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.



Open label, n = 11



Open

label,n = 4



Statistical inference with 4 observations

Ob l h



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)

Chalumeau & Grimaldi Bensouda

Documents

Transcript of Chalumeau & Grimaldi Bensouda