PVmap™ of the Week

ProSanos has initiated a program to publicly provide a limited set of PVmaps™ generated from the FDA's Adverse Event database. A different map will be posted each week focusing on a drug and adverse event combination that is a current topic of discussion within the industry or in the published literature. For more information about PVmaps or the PVmap of the Week program, .

Etanercept Safety in Children (6/18/2007)

Amgen and Wyeth Pharmaceuticals recently announced the presentation of long-term safety data for children taking etanercept for juvenile rheumatoid arthritis for up to eight years. In the 58 patients studied, "No deaths, lymphomas or other malignancies, tuberculosis or other opportunistic infections were reported."⁵² An abstract of the study has been published.⁵²

The FDA Adverse Event Reporting System (AERS) database contains information on the ages of patients and thus offers an opportunity to compare the safety profile of etanercept in children (for all indications) from compiled spontaneous reports with that obtained in the study described above. We created a Drug-focused PVmap for etanercept using AERS data for individuals aged 0-18 years from the fourth quarter of 1997 through the fourth quarter of 2006.

The most highly statistically-significant signals of disproportionate reporting (above the horizontal dotted line) appear to be injection-site reactions, indication-related MedDRA Preferred terms (such as rheumatoid arthritis), and symptoms of upper-respiratory infections.

A zoomed-in view of the PVmap is shown below.

This view again is dominated by indication-related terms and non-serious adverse events. However, the term sepsis appears. Giannini et al noted that "2 cases of sepsis (ETN and ETN/MTX) were reported" in their study.

An even more detailed view does show a statistically significant signal for tuberculosis (31 cases), as well as tuberculosis skin test positive (15 cases), and joint tuberculosis (4 cases). These rare events are described in the prescribing information for the drug. While AERS lacks precise "denominator information" on the size of the exposed population, the enbrel.com web site states, "More than 460,000 patients have used ENBREL worldwide across indications". It does not give specific numbers for children, but it is unsurprising, given these numbers, that these events were not seen in a 58-patient long-term registry.

By reading the results of the eight-year study in a precisely-defined, carefully-monitored population, along with prescribing information while viewing a display of spontaneous-report data for the same age group, we are able to gain a more comprehensive understanding of the adverse events associated with etanercept in children so that the risks can be weighed against the benefits of this important drug for severe juvenile rheumatoid arthritis.

About Drug-focused PVmaps
Above is a Drug-focused Pvmap, which allows you to visualize which adverse events are most highly associated with a particular drug of interest. In the map directly above, the drug is etanercept and the red dots represent adverse events reported in the AERS database to be associated with etanercept. On the horizontal axis of this graph is the reporting ratio that compares the number of cases of a particular adverse event with the number expected due to chance alone. The vertical axis expresses the statistical significance of the finding. Dots above the horizontal blue line and to the right of the vertical blue line represent "significant signals". The adverse events with the strongest association to etanercept appear at the top and to the right on the PVmap.

Sponsor companies have used ProSanos PVMaps for multiple therapeutic areas. To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with the authors of cited references and this article does not imply endorsement of their findings, content, or offerings.
2. Potential risks highlighted by drug safety analysis must be balanced against the clinical benefit attained by the use of a pharmaceutical product in a given clinical situation. Nothing in these analyses is intended to influence the practice of medicine, nor to weigh the benefits of one product over another.
3. Whether the reporting ratio of an adverse event is high enough to influence the decision to use a given product or products can only be determined by a complete analysis of the benefits, risks, and therapeutic alternatives.
4. Use of the publicly available FDA AERS data does not imply endorsement or agreement of the findings by the FDA Center for Drug Evaluation and Research.
5. There are many factors that can influence how the adverse events are reported in the AERS database and may impact the resulting safety signal. These include but are not limited to: publicity and media attention, litigation, length of time drug is on the market, whether the event in question has been previously attributed to the drug, the source of the report, etc.
6. AERS data must often be "cleaned" prior to analysis. This process may include de-duplication, reconciliation of misspelled product names, mapping of adverse events terms, and other manipulations which could introduce bias into the analysis.
7. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

52. Enbrel safety data for up to 8 years in patients with juvenile rheumatoid arthritis [Press release]. Accessed on the Internet at this URL.
53. Giannini EH, Ilowite NT, Lovell DJ, et al. The Long-Term Safety of Etanercept in Children with Polyarticular or Systemic Juvenile Rheumatoid Arthritis. Abstract SAT0397, Annual European Congress of Rheumatology, Barcelona, Spain, June 13-16, 2007. Accessed on the Internet at this URL.