Epoetin and Pure Red-Cell Aplasia
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《新英格兰医药杂志》
To the Editor: Bennett et al. (Sept. 30 issue)1 calculated the "incidence" of pure red-cell aplasia among patients receiving epoetin therapy by reviewing reports from the Adverse Event Reporting System of the Food and Drug Administration (FDA). The calculation of incidence rates of pure red-cell aplasia requires complete ascertainment of new cases of this condition in a defined population at risk per unit of time. The completeness of case ascertainment when the FDA's system is used is usually low because that system is based on passive reporting. In addition, some of the 208 cases lacking antibody data and excluded by Bennett et al. may indeed have represented true cases of pure red-cell aplasia, thus resulting in further underestimation of the incidence of pure red-cell aplasia; it would be interesting to see the temporal distribution of the excluded reports. Moreover, the authors do not provide sufficient information on the denominators used to calculate their rates. Draft FDA guidelines make the important distinction between "reporting rates," such as those calculated by Bennett et al., and incidence rates.2 Comparisons and inferences based on analyses of reporting rates should be made cautiously and ideally should be confirmed with the use of data from rigorous epidemiologic studies.
M.M. Braun, M.D., M.P.H.
Robert P. Wise, M.D., M.P.H.
Jennifer J. Wood, Ph.D.
Food and Drug Administration
Rockville, MD 20852
braunm@cber.fda.gov
References
Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351:1403-1408.
Guidance for industry: good phamacovigilance practices and pharmacoepidemiologic assessment: draft guidance. (Accessed January 14, 2005, at http://www.fda.gov/cder/guidance/5767dft.pdf.)
The authors reply: Considering the variability of criteria for reporting "suspected" pure red-cell aplasia, our analysis was facilitated by limiting it to antibody-positive cases. Our incidence estimates are similar to those reported by the Canadian PRCA [Pure Red-Cell Aplasia] Focus Group, which were based on information independently obtained from epoetin manufacturers1 (Table 1). Varying the number of cases of pure red-cell aplasia or of patient exposures for each product did not alter their main findings. Reporting of these estimates allowed health authorities to make timely recommendations about the safety of epoetin products. As outlined in the FDA guidelines, a prospective study is essential. Johnson & Johnson, the manufacturer of Eprex, has initiated a multisite study in Canada in which hemoglobin levels and antiepoetin antibodies will be measured in 20,000 patients with chronic kidney disease, but there is concern that a much larger study is needed, given that the incidence of this phenomenon is probably low.
Table 1. Exposure to Epoetin Products and Incidence of Antibody-Associated Pure Red-Cell Aplasia According to Formulation and Route of Administration.
Charles Bennett, M.D., Ph.D., M.P.P.
Jesse Brown Veterans Affairs Medical Center
Chicago, IL 60611
Nicole Casadevall, M.D.
H?pital H?tel-Dieu
75004 Paris, France
Denis Cournoyer, M.D.
McGill University Health Centre
Montreal, QC H36 IA4, Canada
References
Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-erythropoietin antibody-mediated pure red-cell aplasia after treatment with recombinant erythropoietin products: recommendations for minimization of risk. J Am Soc Nephrol 2004;15:2728-2734.
M.M. Braun, M.D., M.P.H.
Robert P. Wise, M.D., M.P.H.
Jennifer J. Wood, Ph.D.
Food and Drug Administration
Rockville, MD 20852
braunm@cber.fda.gov
References
Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351:1403-1408.
Guidance for industry: good phamacovigilance practices and pharmacoepidemiologic assessment: draft guidance. (Accessed January 14, 2005, at http://www.fda.gov/cder/guidance/5767dft.pdf.)
The authors reply: Considering the variability of criteria for reporting "suspected" pure red-cell aplasia, our analysis was facilitated by limiting it to antibody-positive cases. Our incidence estimates are similar to those reported by the Canadian PRCA [Pure Red-Cell Aplasia] Focus Group, which were based on information independently obtained from epoetin manufacturers1 (Table 1). Varying the number of cases of pure red-cell aplasia or of patient exposures for each product did not alter their main findings. Reporting of these estimates allowed health authorities to make timely recommendations about the safety of epoetin products. As outlined in the FDA guidelines, a prospective study is essential. Johnson & Johnson, the manufacturer of Eprex, has initiated a multisite study in Canada in which hemoglobin levels and antiepoetin antibodies will be measured in 20,000 patients with chronic kidney disease, but there is concern that a much larger study is needed, given that the incidence of this phenomenon is probably low.
Table 1. Exposure to Epoetin Products and Incidence of Antibody-Associated Pure Red-Cell Aplasia According to Formulation and Route of Administration.
Charles Bennett, M.D., Ph.D., M.P.P.
Jesse Brown Veterans Affairs Medical Center
Chicago, IL 60611
Nicole Casadevall, M.D.
H?pital H?tel-Dieu
75004 Paris, France
Denis Cournoyer, M.D.
McGill University Health Centre
Montreal, QC H36 IA4, Canada
References
Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-erythropoietin antibody-mediated pure red-cell aplasia after treatment with recombinant erythropoietin products: recommendations for minimization of risk. J Am Soc Nephrol 2004;15:2728-2734.