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
- ProSanos is not affiliated with the authors of cited references and this
article does not imply endorsement of their findings, content, or offerings.
- 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.
- 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.
- 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.
- 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.
- 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.
- PVmaps has been evaluated as a safety signal investigation tool for over two years.
References
- 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.
- Han ES, Monk BJ. What is the risk of bowel perforation associated with
bevacizumab therapy in ovarian cancer? Gynecol Oncol 2007;105:3-6.