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, .

Vasculitis and Warfarin (1/21/2007)
In this week's case study, we focus attention on how statistical and graphical techniques can be used to assist in safety signal investigation— that is, to provide additional information about the real-world context of a known safety signal.

A recently published case report from Tunisia describes a case of vasculitis associated with the drug, acenocoumarol, not used widely in the United States⁶. This report prompted our interest regarding a closely related and widely used drug, warfarin, and vasculitis. Warfarin (marketed as Coumadin^® and as a generic) is an anticoagulant widely used to prevent formation of harmful blood clots. Current literature indicates that vasculitis is a known rare adverse event of warfarin use. The causal relationship between the drug and the event has been established on the basis of case reports that include de-challenge and re-challenge testing: noting the improvement of the adverse event upon discontinuation of the drug, and its reappearance upon restarting the drug⁷.

In the above example, we are faced with a case report or a small case series that leaves little doubt about the existence of a drug-event relationship. However, in situations such as this, there are a number of follow-on questions that may be important to ask, including:

• "How often does this event occur?"
• "Is the event occurrence increasing in frequency over time?"

To answer the first question, ProSanos produced a Drug-focused PVmap to investigate whether a statistically significant number of vasculitis cases for warfarin had been reported to the FDA via its Adverse Event Reporting System (AERS), using data covering the period from 2001 through the first quarter of 2006. The drug-focused PVmap (not shown here) for warfarin shows no statistical evidence for an association with vasculitis (For this illustration, we used MedDRA term vasculitis. For further investigation additional terms would be used.). In the AERS data, there are 27 cases of vasculitis with warfarin, which is very close to the number expected within the AERS database due to coincidence alone (Reporting Ratio = 1.08 , Statistical Unexpectedness = 0.435). This signal is orders of magnitude below the threshold for statistical significance. The fact that this drug / event combination is not being reported in statistically significant numbers to the FDA provides further evidence that vasculitis is in fact a rare adverse event.

To answer the second question, ProSanos produced a Trajectory PVmap to determine if the incidence of this event is increasing in frequency over time in a way that indicates that it might cross the threshold of statistical significance in the near future. The Trajectory Map shown above traces the evolution of the vasculitis signal in the AERS database over time. It shows no upward trend in either Reporting Ratio or Statistical Unexpectedness.

Signals that do show upward trending might be cause for concern that the incidence of a specific drug-event combination is growing. An upward trend could be due to such things as:

• changes in the indication
• changes in dosing for a drug
• changes in rate of use in susceptible populations
• the appearance of new concomitant medications
• stimulated adverse event reporting caused by increased publicity

In the example described here, PVmaps are used with the AERS database for signal investigation, rather than detection. While AERS does not contain denominator information that can be used to compute incidence rates directly, it can be used, along with information on the seriousness of the event in question, to provide additional information about the real-world context of a signal to aid in the determination of what follow-up action (if any) is appropriate for a given signal.

Trajectory PVmap
A Trajectory PVmap traces the evolution of a potential drug safety signal over time. The horizontal axis represents the reporting ratio, which 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. Thus significant drug safety signals show an upward trajectory over time, sometimes with some small statistical fluctuation. Generally, it is important to investigate signals when they reach a Statistical Unexpectedness level of 5 or more (corresponding to a p-value of 10^-5), which is represented by the yellow and red-shaded portion of the trajectory when you move your cursor over 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

6. Aouam K, Gassab A, Khorchani H, et al. Acenocoumarol and vasculitis: a case report. Pharmacoepidemiology and Drug Safety 2006;16:113-114.
7. Yaghoubian B, Ngo B, Mak M, et al. Warfarin-induced leukocytoclastic vasculitis. Cutis. 2005;75:329-38.
8. Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmaco-vigilance. Drug Saf. 2005;28:981-1007.