As of March 2007, 136 drugs have been granted pediatric exclusivity; the result of over 300 studies. However, rare and serious AEs may be missed due to the trials’ small sample sizes and relatively short durations.17
Although post-marketing surveillance of AEs in millions of children is difficult, continued surveillance in children is of crucial importance for several reasons including: the variation in metabolism, distribution, and elimination across pediatric age groups leading to potentially higher or unpredictable levels; unique toxicities present in children; drug effects on child growth and development; extensive off-label use of drugs in the pediatric population; the limited number of children involved in the initial studies including dose finding and safety studies; lack of appropriate pediatric formulations; unique exposure of children to drugs through breast milk or in utero
exposures; and drug–drug interactions unique to children.18–21
AERS is a passive, voluntary reporting system designed by the FDA as a post-marketing safety surveillance program for approved drugs and biologics in all age groups. The system records both US and foreign reports. All AEs are coded with the Medical Dictionary for Regulatory Activities. Although the AERS system has many critics,17,22–25
its strengths include its relatively low cost, provision of large-scale surveillance, detection of rare events, and clinician contribution.17,24–26
Despite relying on voluntarily submitted reports, the AERS system can be used to infer causality in instances where the AE and drug are temporally related, biologically plausible, and there is a positive de-challenge and/or re-challenge test.27
Occasionally, there is sufficient information to proceed with a labeling recommendation, as seen with the fentanyl transdermal system (Duragesic®). The AERS system may also be analyzed for indications of AEs that are particular to a drug class.27
Physicians should understand that reporting an AE to the FDA does not mean one knows that drug exposure was the cause. Providers should report AEs for which there are temporal or other relationships to the administration of a drug. This approach allows the FDA to develop hypotheses to further investigate these events and their possible relationship to the therapy. As discussed in this paper, post-marketing surveillance is an even more important component of AE identification in the pediatric population. The Health Insurance Portability and Accountability Act (HIPAA) allows for patient and reporter information to be provided, but this information is protected. The FDA will not release any confidential information, and public AERS data do not contain confidential information (names of patients, healthcare professionals, or hospitals). Reporting to the AERS system can be done electronically at www.fda.gov/medwatch/report.htm
or by phone at 1-800-FDA-1088.
Limitations of the AERS system include underreporting because of reliance on passive reporting. It has been estimated that only 1–10% of AEs are reported to AERS.28,29
Other limitations include reporting bias, erroneous reporting, inadequate documentation, duplicate reporting, difficulty establishing causality, and inability to estimate the true rate of events or exposure risks.23,24
The FDA attempts to correct some of these limitations by contracting to acquire large databases of drug use data which provide a context for the AERS reports.
AERS does function as a useful tool that provides signals which can help direct future investigation, as with SSRIs and ADHD medications. Its importance is demonstrated by the finding of the US General Accounting Office that 51% of serious AEs are detected after approval of the drug.30
Since the adoption of the 1992 Prescription Drug User Fee Act, the time for drug approval has decreased from 27 to 14 months.24,31
One might expect the percentage of AEs detected after drug approval to rise as a result. Already the FDA has seen an increase in the number of drug recalls following approval.24,31
In addition, historically for pediatrics, industry has undertaken less than 50% of the post-marketing studies promised as a condition of drug approval.32
Because of the unique challenges involved with drug studies in children, they are often excluded from research.20,33,34
This approach results in off-label use of many drugs for which there is inadequate efficacy, dosing, and safety information. Because serious AEs are often rare and pediatric clinical trials are often performed in limited numbers of patients for short periods of time in controlled circumstances, detection during clinical studies may be difficult. Monitoring during the early post-marketing period is crucial to detect signals of these events, and health care providers can play a more active role in this area. The FDA is able to use AERS along with retrospective safety analysis across previously completed trials (SSRIs and ADHD medications) and sponsor-completed phase IV safety studies to detect serious and rare AEs. Many of the products brought before the PAC have phase 4 safety studies underway. The PAC is made aware of these ongoing studies and is unlikely to ask for additional studies when the results of these studies are still pending. However, the PAC may ask for additional follow-up during this time period.
The BPCA required the FDA to report to the PAC on safety concerns identified in AERS in the 1-year period following the granting of exclusivity, but the PAC found this data required more context if the AE reporting was to be useful. The reauthorization of BPCA expands the reporting review to encompass, if necessary, all AEs since the original marketing of the product. This mechanism ensures that these data are reviewed and carefully considered. As a result, the PAC is able to recommend label changes, MedGuide production, or continued close surveillance. In a short period of time, this provision of the BPCA has made important contributions to the safety of drugs used in pediatric populations. It is important for clinicians using these therapies to report when patients experience AEs that are or are not in the labeling for the product. To learn more about the AEs discussed in this paper, one can go to the FDA’s Web page, click on “Pediatrics,” and then select “Safety Reporting” or check the specific PAC meeting that reviewed the safety reports. The Pediatric Therapeutics web site will also take you to the label changes.