Ensuring a Favourable Benefit/Risk Ratio For Marketed Drugs Used In Pediatrics: Challenges For Surveillance Of Drug Adverse Events
ENSURING A FAVOURABLE
BENEFIT/RISK RATIO FOR MARKETED DRUGS USED IN PEDIATRICS: CHALLENGES FOR
SURVEILLANCE OF DRUG ADVERSE EVENTS
A
product may be considered safe if it has an appropri-ate benefit/risk balance
for its intended population and use. However, this balance is not static as
information on the benefits and risks emerge continually during the
post-approval phase as more patients are exposed to the drug. These new data
can reflect the results of both labelled and off-label uses (used in unapproved
age groups and/or for unapproved new indications) which can shift the
benefit/risk balance of drugs from favourable to unfavourable. Therefore, new
informa-tion from postmarketing surveillance data or studies revealing new
safety signals or new benefits (e.g., new indications or pediatric-appropriate
formulations) should be incorporated into professional labelling. This
continuous process of updating the product labelling with new information will
help guide the safe and effective use of products and help to minimize the
risks and maximize the benefits of drugs in clinical practice.
The continuous maintenance of a favourable bene-fit/risk ratio for pediatric patients is challenged by the limitations of postmarketing data on safety as well as the effectiveness of drugs in real life use. There-fore, multi-faceted efforts to ameliorate the short-comings of our current data systems and process are needed.
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The AERS system has distinct strengths in that it covers all
marketed drug and biologic prod-ucts and can receive reports from around the
world. Although it is the largest database of adverse events, underreporting is
considered to be a significant problem. Programmatic enhance-ments to improve
the quality of reports and to encourage reporting of suspected adverse reactions
via professional and public outreach efforts are needed. Particularly for
pediatrics, data resources to provide accurate estimate of exposed patients
(denominator data) are lacking. Without valid and complete data on the
numerator (number of patients with adverse events) and better databases and
projection methodology to estimate the number of pediatric patients exposed to
a suspect drug, it becomes very difficult to quantify the risks of drugs.
Ideally, pediatric drug use data will be linked to outcomes data in a defined
pediatric population.
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The time has come for initiating pilot programs for active
postmarketing drug adverse event surveil-lance for all marketed drugs and
biologics. Such pilot programs should evaluate the feasibility of several
promising strategies including establish-ing patient exposure registries,
health-care setting-based (health maintenance organization, pharmacy benefit
management organizations) or population or community-based sentinel reporting
sites. A system of sentinel sites must have the capacity and expertise to
monitor specific populations at risk such as infants, children and adolescents,
and ascertain adverse events specific to those popu-lations including growth,
neurocognitive devel-opment, pubertal development, birth defects and adverse
pregnancy outcomes.
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Post-approval sponsor studies or phase 4 studies should be
more aggressively pursued by regula-tory agencies when there are potentially
serious safety concerns that may affect pediatric patients as this may
represent the only opportunity to have the drug sponsor evaluate drug safety in
pediatrics after approval.
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Require the sponsor to submit pediatric-specific safety
assessments in the post-approval period. The periodic safety updates (PSURs)
would include an analysis to update the benefit/risk ratio for a drug’s use for
its approved indication and its off-label use in pediatric patients.
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Finally, efforts to mine automated claims databases and the
design and conduct of epidemiological drug safety studies need to be encouraged.
Of specific relevance to pediatrics will be the design and conduct of
epidemiological studies to assess the long-term effect of drug exposures on
growth and development.
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