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, .

Bevacizumab, Gastrointestinal Tract Perforation, and Fistula Formation (4/29/2007)
Genentech, Inc., in cooperation with the FDA, recently issued a warning regarding the risk of tracheoesophageal (TE) fistula formation in patients being treated with bevacizumab (marketed as AVASTIN^®) for small cell lung cancer. The warning came after two cases of TE fistula during a trial of bevacizumab for lung cancer.³⁹ Although bevacizumab has only recently (October 2006) been granted approval for use in certain lung cancer patients, it has been approved since February 2004, along with 5-FU, to treat patients with metastatic colorectal cancer.

Understanding the overall picture of a drug's safety profile is helpful when a new potential adverse event appears, and PVmaps can be used to investigate the post-market adverse event profile of bevacizumab, as well as the background of TE fistula as an adverse event. Information gleaned from this investigation can be used to help to put the adverse event into context. We began this investigation with a Drug-focused PVmap.

The PVmap above uses the publicly-available data from the FDA via its Adverse Event Reporting System (AERS) with data covering the period from 2001 through the first quarter of 2006. This is a Drug-focused PVmap that shows the adverse events most strongly associated with bevacizumab in the upper right hand corner of the graph. The PVmap shows the well-documented association of bevacizumab with perforation of the gastrointestinal tract, which appears as a prominent warning on the label for the drug.

A number of mechanisms have been proposed as the cause of this and other, related adverse events. Some of the proposed mechanisms are tied to the effectiveness of the drug in inducing tumor necrosis and others are related to its unique mode of action as a VEGF inhibitor.⁴⁰ It is plausible that the TE fistulas in the recent warning letter are a variation of the previously-observed gastrointestinal perforations, some of which have involved fistula formation.

To further investigate, we searched the results of the Drug-focused PVmap to identify statistically significant occurrences of fistula formation with bevacizumab:

The details of the Drug-Focused PVmap above indicate that four MedDRA Preferred Terms involving fistula formation are statistically significant; however, Tracheo-esophageal (TE) fistula does not appear in any case reports for this drug. TE fistula is an extremely rare adverse event. It is covered by several MedDRA terms, each with less than 20 total occurrences in the AERS database. To illustrate this in more detail, we produced an Event-focused PVmap for the MedDRA term trans-oesophageal fistula.

The Event-focused map above shows that out of 974,050 case reports in the AERS data analyzed, only 20 include trans-oesophageal fistula as an adverse event. Four drugs appear to be significantly associated with this adverse event (above the horizontal blue line): Three of those drugs are based on a single case report; Photofrin has two distinct case reports, but these may represent confounding with the indication for the drug rather than a bona fide adverse event. These reports appear as statistically significant due to the extremely low number of reports of TE fistula overall in the AERS data. While PVmaps alone cannot determine whether these reported occurrences represent true adverse drug reactions, it is able to quickly highlight unusual and unexpected drug / event combinations hidden within the data for further review.

In this Map of the Week, we have investigated the safety profile of bevacizumab, in light of the recent warning regarding TE fistula. Bevacizumab, a VEGF inhibitor with great promise to improve cancer survival by inhibiting angiogenesis, is one of the first fruits of the biotechnology and genomics revolution to reach the clinic. In a recent talk at the 2007 Drug Information Association EuroMeeting, Dr. Simon Day raised an important point regarding the safety of these new drugs: Many of them target signaling systems and fundamentally alter human biology in ways that have not been manipulated before. This raises the potential for unusual and unexpected adverse events as a result of unintended consequences of altering these pathways. PVmaps can play a significant role in the investigation of these adverse events, so that the balance between risk and benefit for these new classes of drugs can be properly assessed.

About Drug-focused PVmaps
Above is a Drug-focused PVmap, allowing you to visualize which adverse events are most highly associated with a particular drug of interest. In the map directly above, the drug is bevacizumab and the red dots represent Adverse Events reported in the AERS database to be associated with bevacizumab. On the horizontal axis of this graph is the reporting ratio that 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 bevacizumab appear at the top and to the right on the PVmap.

About Event-focused PVmaps
The second PVmap shown in the case study above is an Event-focused PVmap that 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 tracheo-oesophageal fistula 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 that a drug is reported with the specified adverse event to 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 drugs with the strongest association to TE fistula appear at the top and to the right on 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. 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

39. Important Drug Warning Regarding Avastin^® (bevacizumab). Accessed on the Internet at: http://www.fda.gov/medwatch/safety/2007/
    Avastin_DHCP_TEF_Final_April2007.pdf, 25 April 2007.
40. Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol 2007;105:3-6.