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, .

Telithromycin and Hepatotoxicity (2/18/2007)
Within the past few days, a revised label was issued for the antibiotic telithromycin, marketed as Ketek^®.¹⁶ The revised label was the final result of a process of balancing drug safety concerns against the need for new antibiotics to fight serious, life-threatening infections, from increasingly antibiotic-resistant organisms. Hepatotoxicity was among the drug safety concerns that led to the label revision.

Hepatotoxicity is considered serious enough that it is a concern even for drugs where it is a rare event, with an incidence of around 1 case per 100,000 patients that may not be seen at all in clinical trials.¹⁷ Data mining of adverse event databases is a way of detecting and investigating these rare events. In the FDA's AERS database, evidence of hepatotoxic adverse events may be identified by looking for various MedDRA terms and combinations. The sensitivity of search strategies for the detection of hepatotoxicity can vary, depending on the severity of the reaction, and on whether the mechanism of injury is hepatocellular, cholestatic, or a mixture of both. Cases may be coded under the term hepatic enzymes increased, as well as terms such as jaundice, aspartate aminotransferase increased, hepatotoxicity, hepatic failure, and blood bilirubin increased, along with many others. This week's case study investigates the MedDRA term hepatic enzymes increased reported for patients who are receiving telithromycin.

The Trajectory PVmap shown above illustrates the emergence of the safety signal hepatic enzymes increased in telithromycin patients, which have 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 trajectory map shows that the number of cases reported under the term hepatic enzymes increased was increasing and marginally significant (statistical unexpectedness level around 5) in the third and fourth quarters of 2005, and then dramatically increased in significance in the first quarter of 2006.

The rapid increase in signal strength during a single quarter is notable. It could represent a large increase in the usage of telithromycin in that timeframe, with a corresponding increase in hepatotoxic adverse events. However, an uncharacteristically rapid increase in signal strength in a single quarter raises the possibility of stimulated reporting. Stimulated reporting is an increase in the reporting of cases following publicity about a drug safety problem, or having to do with related litigation. The first published reports of hepatotoxicity with telithromycin appeared in the peer-reviewed literature early in 2006, thus the data potentially became known to the medical community in a time frame compatible with this dramatic rise in signal strength.

The Trajectory PVmap shown above demonstrates both a strength and limitation of drug-safety data mining of spontaneous-reporting databases. The limitation relates to the inherent lack of information about the total population exposed to the drug. Without this "denominator information", it is difficult for data mining tools to make quantitative assessments of signal strength (such as the rapid increase in signal strength shown above). However, data mining is able to expose subtle and sometimes dramatic patterns found in the data, supporting the primary mission of these databases: The collection of data to investigate evidence of rare but potentially serious adverse drug events, so that well-reasoned plans for risk management can be developed.

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

16. Telithromycin (marketed as Ketek) Information. Accessed on the Internet at http://www.fda.gov/cder/drug/infopage/telithromycin/default.htm, 13 February 2007.
17. Navarro VJ, Senior JR. Drug-Related Hepatotoxicity. NEJM 2006;354;731-739.