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, .

Comparison of Side Effects between Two EGFR Inhibitors (2/25/07)
The Medscape Hematology-Oncology newsletter¹⁸ this week highlights an article in the European Journal of Cancer¹⁹ on the management of side effects for epidermal growth factor receptor (EGFR) inhibitors. These drugs have produced significant advances in the treatment of certain solid tumors. Unfortunately, as a consequence of their mode of action, they are associated with a significant incidence of side effects, particularly diarrhea and skin- and nail-related conditions. These side effects, while not life-threatening or generally meeting the technical definition of "serious", can be dose-limiting or can lead to discontinuation of therapy and are well represented in the AERS database under a variety of MedDRA terms.

EGFR inhibitors come in two types. There are monoclonal antibodies directed against the EGF receptor itself such as cetuximab (marketed as Erbitux^®), and there are small-molecule tyrosine kinase inhibitors that act intracellularly, such as erlotinib (marketed as Tarceva^®). There are both similarities and differences in the side-effect profiles of the two drugs, and we can use PVmaps to illustrate these similarities and differences.

The Comparative Drug-focused PVmap provides a visual illustration of the similarities and differences between the side effect profiles of these drugs as reflected in the reporting of adverse events in the FDA AERS database through the first quarter of 2006. Adverse events reported for cetuximab shown with red circles, and those for erlotinib are shown with green triangles. Arrows are drawn from the cetuximab adverse event to the corresponding adverse event for erlotinib.

In general, dots on the map that are higher and farther to the right indicate stronger safety signals. Thus, rashes which are coded in MedDRA as dermatitis acneiform are much more commonly reported with cetuximab; hypomagnesaemia and infusion-related reactions appear stronger with cetuximab as well. These findings are consistent with the product insert data²⁰. Erlotinib shows a higher rate for diarrhea, as well as a higher rate for rashes coded as rash. However a more accurate comparison for this particular side effect would require a more thorough study of the various terms that can be used to code rashes, as discussed by Jones in the reference listed below.

There is good qualitative agreement between the Comparative Drug-Focused PVmap above, and information regarding the drugs obtained from randomized, controlled studies. However, opinions vary on whether valid drug comparisons can be made using data mining techniques. The FDA-PhRMA Collaborative Working Group on Safety Evaluation Tools has stated:

In spite of these caveats, a number of drug comparisons using data mining have appeared in the drug-safety literature. The FDA recently performed and disclosed a safety comparison of several antibiotics using data mining²², in order to shed light on an urgent and important drug safety issue.

Our position at ProSanos is that data-mining-based drug-vs.-drug comparisons can be useful for hypothesis generation or corroboration, provided it is performed thoughtfully and certain conditions are met. Based on our experience, below are some of the conditions that we consider before creating a Comparative PVmap (we may also consider additional potential confounders on a case by case basis):

• The drugs being compared are used in similar patient populations.
• The drugs are generally used for the same indication or spectrum of indications.
• The drugs are generally used with the same spectrum of concomitant medications.
• There are no systematic coding differences for adverse events for one drug vs. the other. (This condition generally holds, but may be an issue if there is a large amount of study data or literature data in AERS for a given drug.)
• There is no known cause of stimulated reporting (publicity, litigation), which applies to one of the drugs and not the other.
• There is no great disparity in the time that the two drugs have been on the market, which could lead to unequal reporting via the "Weber effect" (a phenomenon of enhanced safety reporting early in the market life of a drug.)

Drawing valid safety comparisons between drugs is one of the most challenging areas for data mining, but also one of the areas where there is great potential to shed light on patient care practices.

About Comparative Drug-focused PVmaps
Above is a Comparative Drug-focused PVmap, allowing you to compare two drugs in order to visualize which adverse events are most highly associated with each. In this case the drugs are cetuximab and erlotinib. The red circles represent adverse events reported in the AERS database to be associated with cetuximab, while the green triangles represent adverse events reported to be associated with erlotinib. 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 a drug appear at the top and to the right on the PVmap. Arrows indicate the difference in the reporting ratio and statistical unexpectedness between the two drugs for a given designated adverse event. In this case, an arrow pointing to the right indicates a higher reporting ratio for erlotinib, and an arrow pointing to the left indicates a higher reporting ratio for cetuximab.

To learn more about PVMaps projects in your therapeutic area or indication, please .

Disclaimers

1. ProSanos is not affiliated with any authors or institutions who are cited 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

18. Gandey A. Ease Discomfort of EGFR Toxicities. Medscape Medical News 2007. Accessed on the Internet at http://www.medscape.com/viewarticle/552303, 21 February 2007.
19. Galimont-Collen AFS, Vos LE, Laurijsen APM, et al. Classification and management of skin, hair, nail, and mucosal side effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer (2007), doi:10.1016/j.ejca.2006.11.016 .
20. Jones SF. Role of the Pharmacist in the Management of Anti-EGFR Adverse Events. Accessed on the Internet at http://www.oncolink.org/tv/flash/egfr/, 21 February 2007.
21. Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmaco-vigilance. Drug Saf. 2005;28:981-1007.
22. Szarfman A, Levine J. Memorandum: NDA 21-144 KETEK (Telithromycin) 400MG Tablets^® (Sanofi-Aventis): Data Mining Analysis of Adverse Events and Outcomes Reported for Telithromycin and 15 Comparator Drugs (AERS Data), accessed on the Internet at http://www.fda.gov/ohrms/dockets/AC/06/briefing/2006-4266b1-02-06-FDA-appendic-f.pdf, 21 February 2007.