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. On a regular basis, we will post a map 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, Infections, and Reports from Consumers (5/14/2008)
The FDA recently announced the addition of a boxed warning, accompanied by a Dear Healthcare Provider letter, regarding tuberculosis and serious infections with the use of etanercept (marketed as ENBREL®).⁶⁰ Enbrel is a Tumor Necrosis Factor blocker used to treat rheumatoid and some other forms of arthritis, as well as psoriasis. The occurrence of tuberculosis and infection had previously appeared in the prescribing information for etanercept, but not in a boxed warning.

An article which describes the technology behind PVmaps⁶¹ made note of the fact that the appearance of a signal of disproportionate reporting (SDR) in the top twelve SDRs for a drug often preceded the escalation of labeling for a serious adverse event. We created a drug-focused PVmap for etanercept to see if this was the case for this particular drug-event combination, using data from the FDA Adverse Event Reporting System (AERS) database from 1997 through the third quarter of 2007.

TThe MedDRA® Preferred Term infection nos appears as the 11th highest-ranked reported term for this drug, when ranked by statistical unexpectedness. (The top ten terms relate to injection site reactions or indications for the drug, plus rhinitis nos and sinusitis nos, which are labeled for the drug.) Thus the escalation to a boxed warning is consistent with the "rule of twelve".

We made a further interesting observation when we clicked on the dot for infection nos using the CLÆRITY® software and examined the demographics of the adverse event reports which contribute to this SDR:

We note a strong gender imbalance in reporting, presumably due to the increased prevalence of rheumatoid arthritis in women. The interesting point here is the distribution of report sources: Three quarters of the reports for this signal of disproportionate reporting came directly from consumers. This is somewhat unusual, since reports from consumers make up less than half of AERS reports overall.

The FDA makes provisions for the collection of adverse event reports directly from consumers, while regulatory agencies in some other countries accept such reports only from healthcare providers, pharmaceutical manufacturers, and other similar sources. The advantages and disadvantages of accepting reports from consumers is an active area of discussion in the drug safety community. There can be strong differences between healthcare providers and consumers as to what adverse events should be reported to the FDA. In the case illustrated here, the FDA and drug manufacturers have chosen to act on an adverse event where reporting to the AERS database is strongly consumer-driven.

About Drug-focused PVmaps
Above is a Drug-focused PVmap, allowing 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. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. PVmaps has been evaluated as a safety signal investigation tool for over two years.

References

60. PAmgen Corp. and Wyeth Pharmaceuticals. Tuberculosis and Infections with ENBREL® (Etanercept). A ccessed on the Internet at This URL , 14 May 2008.
61. Hochberg AM, Reisinger SJ, Pearson, RK, et al. Using Data Mining to Predict Safety Actions from FDA Adverse Event Reporting System Data. Drug Information Journal 2007; 41(5): 633 - 642.