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, .
Clozapine-Induced Agranulocytosis and Risk Management (1/29/2007)
Drug safety is not a field where there is a lot of cheerful news. The news tends
to focus on the unintended harm done by therapeutic agents in the course of treating
disease, even if the drug provides a great benefit to a majority of patients
exposed to it. Often, the mechanism of such harm is not clear and the balance
of risk and benefit is even less clear. Implementing a risk-management plan for
a drug under these circumstances is an important but challenging undertaking.
Equally as important, assessing the impact of a risk management plan requires
information about the impact that the plan is having on the exposed population.
This week's case study focuses on clozapine (marketed in the US as
Clozaril®). Clozapine is a treatment for schizophrenia whose
usefulness has been seriously limited by the fact that approximately 1% of
patients can develop agranulocytosis, a serious loss of infection-fighting white
blood cells. Our PVmap of the week is inspired by a press release from a company called PGxHealth™. PGxHealth
announced on January 23 that they had launched a pharmacogenetic test which will
provide information on whether a patient is at higher or lower risk of developing
clozapine-induced agranulocytosis.
This week's Drug-focused PVmap dramatically illustrates the problem of
clozapine-induced agranulocytosis, which has been known for many years9.
The data on clozapine patients comes from the FDA via its Adverse Event Reporting
System (AERS) using data covering the period from 2001 through the first quarter
of 2006. This is a Drug-focused PVmap, which shows strongest (most statistically
significant) signals in the upper right hand corner of the graph. Agranulocytosis
is the second highest, and therefore the second-most statistically significant,
point on the graph. (The top point, personality disorder nos, is most
likely a reflection of underlying schizophrenia rather than an adverse event
due to drug treatment.) The Reporting Ratio, shown on the horizontal axis of the
graph, is about 14, indicating that there are 14 times as many cases of
agranulocytosis for this drug as would be expected by chance alone. The statistical
unexpectedness, shown on the vertical axis, is 234 (e.g. the probability that
there is no statistical relationship between clozapine and
agranulocytosis is 10-234). The large magnitude of this signal
reflects the fact that it corresponds to a previously-known adverse event.
If a test to evaluate patient risk of a known adverse event prior to drug
exposure (such as the screening test described above) became widely used, it is
likely that there would be fewer occurrences of clozapine-induced agranulocytosis,
and the magnitude of the corresponding safety signal would begin to decrease over
time. A trajectory PVmap
can visually track the increase or decrease in the magnitude of a signal over
time. In the example above, a Trajectory PVmap could provide ongoing information
about the impact of the utilization of the proposed screening test as part of a
risk management plan on the subsequent number of cases of clozapine-induced
agranulocytosis that are reported. Information such as this can provide
important evidence to assist in the evaluation and further development of a
risk management plan.
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 this case, the
drug is clozapine and the red dots represent Adverse Events reported
in the AERS database to be associated with clozapine. On the horizontal axis of
this graph is 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. 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 clozapine appear at the top and to the right on the PVmap.
This map is another example (in addition to this one) where the adverse event of interest is spread out
over a number of MedDRA terms, in this case including agranulocytosis,
leukopenia, neutropenia, etc. The advantage of the visual approach of the PVmap
is that it is easy for the safety investigator to recognize this type of
association for a particular drug, even if it involves several organ systems.
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 PGxHealth™, and
discussion of its products in the context of risk management, diagnostics, and
treatment decisions does not imply endorsement of them or validation of their
findings.
- 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
- Idanpaan-Heikkila J, Alhava E, Olkinuora M,
et al. Clozapine and agranulocytosis. Lancet. 1975;2:611.
