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. For more information about PVmaps or the PVmap of the Week program, .

Tamoxifen Side Effects and Adherence to Therapy (2/11/2007)
An article that appeared last week in the Los Angeles Times¹² focuses on the issue of non-adherence to long-term therapy for breast cancer. The author of the article quotes experts¹³ who discuss several studies^14,15 that indicate that drug side effects can lead to non-adherence, and that non-adherence can have serious medical consequences.

This article prompted us to examine the side effect profile of the breast cancer drug tamoxifen using the PVmaps™ software. We produced a Drug-focused PVmap for tamoxifen using the publicly-available data from the FDA via its Adverse Event Reporting System (AERS), with data covering the period from 2001 through the first quarter of 2006.

This is a Drug-focused PVmap, which shows strongest (most statistically significant) signals in the upper right hand corner of the graph. At the top of the list is the known side effect hot flushes nos, followed by a number of potentially painful bone disorders. (The event breast cancer stage iv appears due to confounding with the drug indication.)

To more fully investigate the entire list of statistically significant adverse events reported for tamoxifen, we can also choose the Results Detail View of the Drug-focused PVmap. A portion of the list appears below.

The Results Detail listing for a Drug-focused PVmap (shown above) allows the adverse events that appear on a Drug-focused PVmap to be examined one-by-one in table form. In this case the drug is tamoxifen, and each row of the table represents an Adverse Event term reported in the AERS database to be associated with tamoxifen. Further down this list (not shown), we find other known side effects of the drug, including muscle cramps, headache, and rash.

The AERS database was developed with the goal of aiding in the detection of serious, unexpected adverse events. However, the database contains potentially important information regarding events which may not be serious in their own right, but could lead to non-compliance with ultimately serious consequences (Among the most commonly-reported adverse-event terms in AERS are nausea, pyrexia, myalgia, malaise, and headache). While the primary focus of most drug safety investigators is on more serious conditions, it is worth considering how the AERS data and PVmaps data-mining software can be used to learn more about these less-serious conditions. These "non-serious" adverse events may, through a mechanism of non-compliance, play an important role in determining the practical effectiveness of drug therapy.

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 this case the drug is tamoxifen and the red dots represent Adverse Events reported in the AERS database to be associated with tamoxifen. 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 tamoxifen appear at the top and to the right on the PVmap.

PVmap Results Detail (Drug-focused PVmaps)
The Results Detail listing for a Drug-focused PVmap (shown above) allows the adverse events that appear on a Drug-focused PVmap to be examined one-by-one in table form. In this case the drug is tamoxifen and each row of the table represents an Adverse Event term reported in the AERS database to be associated with tamoxifen. The number of cases for each drug-event combination is shown in blue in the third table column, and in the PVmaps software provides a hyperlink to a listing of details for the corresponding safety reports. The fourth column, Total Reaction Count (Nb), contains the total number of safety reports for the listed adverse event in the entire AERS database. The fifth column contains the reporting ratio (Rab), which compares the number of cases of a particular adverse event with the number expected due to chance alone. The sixth and seventh columns, Uab, and its logarithm log10Uab, express the statistical significance of the finding. The final column contains the serial "ranking" of the signal on the basis of statistical significance. The adverse events with the strongest statistical association to tamoxifen appear at the top of the list. The "Map Totals" near the top of the screen indicate that there are 137 adverse event terms which have a statistically significant relationship to tamoxifen and that the cutoff for statistical significance is a Uab value greater than or equal to 4.7465.

To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with the Los Angeles Times or any authors or institutions who are cited 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

12. Roan S. Cancer drugs: Too toxic? Los Angeles Times 29 Jan 2007. Accessed on line at http://www.latimes.com/features/health/la-he-breastcancer29jan29,1,4899446.story, 6 Feb 2007.
13. Partridge AH. Non-adherence to endocrine therapy for breast cancer. Ann Oncol. 2006 Feb;17:183-4.
14. Fallowfield L, Atkins L, Catt S et al. Patients' preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol 2006; 17: 205-210.
15. Avorn J, Monette J, Lacour A et al. Persistence of use of lipid-lowering medications: a cross-national study. J Am Med Assoc 1998; 279:1458-1462.