Challenges for Surveillance of Drug Adverse Events

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Chapter: Pharmacovigilance: Pharmacovigilance in Pediatrics

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.

·                    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.

·    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.

·    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.

·    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.

·    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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