PVmap^® of Interest

ProSanos has initiated a program to publicly provide a limited set of data mining results generated from the FDA's Adverse Event database. On a periodic basis, we will post results 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 CLÆRITY^®, PVmaps or the PVmap of Interest program, .

Didanosine and Portal Hypertension (10/30/2009)
In early October the FDA posted the report: Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January - March 2009. One of the drug/event pairs included in this report is Didanosine with Portal hypertension,. In the discussion below, we investigate this potential signal further using CLÆRITY software to visualize the relationship, and put it into context.

We start our investigation by producing a "Drug-focused PVmap" for Didanosine, using the FDA AERS database from the fourth quarter of 1997 through the second quarter of 2009. Observe the yellow highlighted point in the chart below (for clarity, we have zoomed in on the portion of this PVmap that contains our event of interest, portal hypertension):

Looking at the result details in the graphic below, we observe that out of the 8,486 adverse events that have been reported for this drug, there are 82 reports of Portal Hypertension, with a Reporting Ratio of 31.62 and a Statistical Unexpectedness of 91.94 Additionally, this drug / event combination produces a Proportional Reporting Ratio (PRR) of 35.48, Chi-Square of 2,410.27 and an EB05 score > 7.6. All of these metrics represent Statistics of Disproportionate Reporting (SDRs) which indicate that Portal Hypertension is being reported disproportionately with the drug Didanosine compared to other drugs.

To investigate the behavior of this over time, we can produce a Trajectory PVmap. The Trajectory PVmap below shows the Statistical Unexpectedness and Reporting Ratio by AERS quarter for Didanosine and Portal hypertension:

These results indicate that the combination of didanosine and Portal hypertension first produced an SDR from the AERS data in late 2002, and that the signal has been steadily increasing in strength over time.

To gain further perspective on the size of this signal, we produced an "Event-Focused PVmap" for the MedDRA Preferred Term (PT) Portal hypertension. The PVmap below shows the drugs that are most disproportionately reported with this adverse event:

We note that didanosine is the drug most strongly associated in the AERS database with this adverse event. The relative rank of a particular drug on an Event-focused PVmap can provide useful perspective as to the relative strength of an SDR, with respect to all of the other drugs found within AERS.

Here we have shown the use of CLÆRITY to produce a number of different PVmap investigations - Drug-Focused, Trajectory, and Event-Focused - which paint a picture of a drug-event relationship. In this particular case, we were able to rapidly investigate the potential signal for didanosine and Portal hypertension, as described in the FDA's report.

About Drug-focused PVmaps
A Drug-focused PVmap allows you to visualize which adverse events are most highly associated with a particular drug of interest. In this case, the drug is didanosine and the red dots represent Adverse Events reported in the AERS database to be associated with didanosine. On the horizontal axis of this graph is 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. 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 didanosine appear at the top and to the right on the PVmap.

About Event-focused PVmaps

An Event-focused PVmap allows you to visualize which drugs are most highly associated with a particular adverse event (rather than the other way around). In this case, the adverse event is the MedDRA term portal hypertension and the red dots represent drugs reported in the AERS database to be associated with this condition. On the horizontal axis of this graph is the reporting ratio, which compares the number of times a drug is reported with the specified adverse event to the number expected due to chance a lone. 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 drugs with the strongest association to portal hypertension appear at the top and to the right on the PVmap.

About Trajectory PVmaps

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).

Sponsor companies have used CLÆRITY Software for multiple therapeutic areas. To learn more about CLÆRITY 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.