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, .

Proton-Pump Inhibitors and Community-Acquired Pneumonia (5/21/07)
A recent article by Gulmez et al. in Archives of Internal Medicine describes a population-based case control study of the relationship between the use of proton-pump inhibitors and the subsequent development of community-acquired pneumonia.⁴⁵ Proton-pump inhibitors are the mainstay of treatment for acid-related disorders of the upper gastrointestinal tract and are generally viewed as safe drugs. Because these drugs are so widely used, we are now in a position to detect rare adverse events associated with them (for example, see Map of the Week #4, and with PVmaps, we can also detect their influence on the rate of occurrence of a common medical condition such as pneumonia.

A Drug-focused PVmap (not shown here) using publicly-available data from the FDA Adverse Event Reporting System (AERS) covering the period from 2001 through the first quarter of 2006, yields a statistically-significant signal of disproportionate reporting (SDR) for the MedDRA Preferred Term (PT) pneumonia for three proton-pump inhibitors: omeprazole, pantoprazole, and lansoprazole. The SDR for an additional PPI, rabeprazole, was below the statistical significance limit at SU=3.4 vs. a threshold of 4.8 as of first-quarter 2006. Rabeprazole is a newer drug, and there are far fewer adverse event reports for it than for other PPIs (5,846 vs. 23,905 for omeprazole, for instance). In a full-scale investigation of this adverse event, rather than the illustration given here, additional cases under other preferred terms, such as bronchopneumonia, pneumonia nos, lobar pneumonia, etc, would have increased the signal strength. Presumably, the susceptibility to pneumonia is a class effect, though we cannot rule out drug-to-drug differences in the extent of the effect. Note that the AERS database does not distinguish between community-acquired and hospital-acquired pneumonia.

Choosing omeprazole as the PPI with the greatest base of clinical experience, a Trajectory PVmap for Omeprazole and the MedDRA PT pneumonia is shown below.

This Trajectory PVmap traces the evolution of a SDR generated from the AERS database over time. It becomes statistically significant in AERS data from the second quarter of 2004 onward. The reporting ratio remains very stable at around 1.6, while the statistical significance increases as case reports accumulate.

In this Map of the Week, we have an interesting example of an unexpected relationship between a drug and a relatively common medical condition, pneumonia. The relationship provides further evidence to corroborate a recent case-control study. When studying relationships between drugs and common medical conditions with PVmaps, we frequently find statistically-significant SDRs that have a reporting ratio of less than 2.0, as drug effects are generally not strong enough to double the background rate for such conditions. The level of 2.0 is a recommended threshold for several data-mining algorithms other than PVmaps.⁴⁶ In our experience, the PVmaps algorithm identifies these statistically-significant SDRs with reporting ratios less than 2.0, and does so in a way that does not produce an unacceptable number of "false positives". We routinely investigate SDRs with reporting ratios of 1.6, such as in the example shown here, or even lower, provided that they reach the Statistical Unexpectedness threshold. As this case study illustrates, these SDRs can represent valid and unexpected drug-safety signals.

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, a Statistical Unexpectedness level of 5 or more (corresponding to a p-value of 10^-5) is considered statistically significant.

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

45. Gulmez SE, Holm A, Frederiksen H, et al. Use of Proton-Pump Inhibitors and the Risk of Commmunity-Acquired Pneumonia. Arch Intern Med. 2007;167:950-955.
46. Evans SJ, Waller P, Davis S. Proportional reporting ratios: the uses of epidemiological methods for signal generation. Pharmacoepidemiol Drug Saf 1998;7(Suppl 2):S102.