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, .
Below-Threshold Signal for Pioglitazone and Fracture Risk (4/8/07)
The FDA and Takeda Pharmaceuticals North America recently issued a warning of the
possibility of increased fracture risk in female patients taking pioglitazone
(marketed as ACTOS®, and in fixed-dose combinations as ACTOplus
met® and duetact™.) The warning
was issued as a result of a careful reanalysis of clinical trial databases by
the manufacturer, and indicated an increase in risk of 0.8 fractures per 100
patient-years of use. Fractures were mainly those of the distal upper limb or
distal lower limb.
A Drug-focused PVmap (not shown) for pioglitazone and its combination
formulations showed no fracture-related signals above the statistical significance
limit for this drug. However, when a signal has been detected by other means,
such as analysis of data from controlled trials, it is quite appropriate to use
PVmaps to further investigate the safety issue in question. A feature of
Drug-focused PVmaps allows users to look at reported adverse events for
pioglitazone that have not reached statistical significance. Using this feature,
we found several fracture related reports below the statistical significance
line. The most significant of these was rib fracture: the signal had
16 cases, a Reporting Ratio of 2.7, and a Statistical Unexpectedness of 3.49,
below the significance limit of 4.8. To learn more about the developing evidence
for this drug-event association, we produced a Trajectory PVmap for pioglitazone
and rib fracture.
The Trajectory PVmap shown 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 map shows a typical
pattern for the evolution of signal trajectories for rare but real drug-event
relationships. There is a large amount of "noise" at the beginning
due to the small number of events. Then, as cases accumulate, the amount of
noise decreases, and the trajectory turns more uniformly upward and to the right.
Based on the rate of increase, it is likely that this signal will reach the
statistical-significance threshold of 4.8 within the next year.
Lack of prior suspicion is probably one reason why this signal was first
detected in a clinical trial database by comparison to a control group, rather
than through spontaneous reports. Spontaneous reporting is most sensitive for
events where there is a high suspicion that they are drug-related: hepatotoxicity
and QT prolongation, for instance. Although the signal was not initially
detected through SRS data, PVmaps investigative capabilities can be used to
provide additional corroborating evidence for a drug-event relationship.
Plotting the trajectory of a suspected drug-event combination that has not yet
reached the detection threshold can provide strong visual evidence about the
potential emergence of the event as a statistically-significant signal.
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
- 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
- Observation of an Increased Incidence of
Fractures in Female Patients Who Received Long-Term Treatment with
ACTOS® (pioglitazone HCl) Tablets for Type 2 Diabetes Mellitus.
Accessed on the Internet at http://www.fda.gov/medwatch/safety/2007/Actosmar0807.pdf,
21 March 2007.
