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, .

Gemcitabine and Pneumonitis (6/4/07)

Archives of Internal Medicine recently published an article describing the success of a proactive pharmacovigilance program, Research on Adverse Drug events And Reports (RADAR) in the detection of safety signals for serious adverse events.⁴⁸ This project relies primarily on the medical review of individual cases by academic investigators and uses statistical data mining as an adjunct method of analysis.

For a number of the safety signals studied in the paper, there are strong clues in either the nature or the timing of the event that a drug-induced adverse event has taken place. Others pose more of a challenge in this regard and are further complicated by the nature of the drug indication and by the heavy use of multiple medications. We chose for this week to examine one of the more complicated cases, pneumonitis with gemcitabine. Gemcitabine (marketed as GEMZAR^®) is a deoxycytosine analog that was approved by the FDA in 1996 and has been used for a variety of solid tumors and hematologic malignancies, including lung cancer. According to the article by Bennett, information regarding the association of this drug with pneumonitis was provided by the drug manufacturer on the package insert in 2000, citing post-market experience. Authors from the RADAR project published a review article on gemcitabine-associated lung injury in 2006.⁴⁹

A Drug-focused PVmap (not shown) for gemcitabine, using data from the FDA Adverse Event Reporting System (AERS) database for January 2001 through March 2006, shows statistically-significant associations with the MedDRA preferred terms (PTs) interstitial lung disease, pneumonitis, pulmonary toxicity, pneumonitis nos, pulmonary fibrosis, pulmonary toxicity nos, and others. In addition, there are associations with terms such as pneumonia and dyspnoea that are not specific to drug-associated pneumonitis, but may reflect its presence. These may also reflect the effects of underlying disease, particularly for lung cancer, as well as infection due to immunosuppression.

Below is a Trajectory PVmap for gemcitabine and interstitial lung disease, the term under which the most cases (229 cases) appear.

The data shown begins at the start of 2001, five years after the FDA approval of gemcitabine. By the fourth quarter of 2001, ten cases of interstitial lung disease have accumulated, which is sufficient to create a statistically significant signal for this adverse event, with a Statistical Unexpectedness of 7.98, well above the threshold of 5. The signal increases in strength over subsequent years as further cases accumulate.

In this case, the relationship between gemcitabine and pneumonitis was established on the basis of individual case reports rather than data mining. But we have shown here that, even in this complex clinical setting, a signal of disproportionate reporting could be seen by PVmaps, on the basis of ten cases over the course of four quarters. This suggests that data mining methods such as PVmaps can be a useful "safety net" to call for review of potential safety signals that might not appear to be obviously related to a particular drug when initially reviewed.

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).

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

48. Bennett CL, Nebeker JR, Yarnold PR, et al. Evaluation of Serious Adverse Drug Reactions: A Proactive Pharmacovigilance Program (RADAR) vs Safety Activities Conducted by the Food and Drug Administration and Pharmaceutical Manufacturers. Arch Intern Med 2007;167:1041-1049.
49. Belknap SM, Kuzel TM, Slimack PR, et al. Clinical Features and Correlates of Gemcitabine-Associated Lung Injury. Cancer 2006;106:2051-2057.