Correspondence

Decisions about Voriconazole versus Liposomal Amphotericin B

N Engl J Med 2002; 346:1499May 9, 2002

Article

To the Editor:

The letter from Powers et al. (Jan. 24 issue)1 challenged our use of the unstratified analysis in evaluating the overall response to empirical antifungal therapy and stated that a Bonferroni correction for multiple testing is required for the comparison of treatment groups with respect to the frequency of breakthrough fungal infections. The basis for our analyses2 is the protocol document that was approved before the study by the data safety and monitoring board of the National Institute of Allergy and Infectious Diseases Mycoses Study Group. The plan in the protocol is for an unstratified analysis of the primary end point, which was the overall response to empirical therapy. Among the elements of the composite end point, only the difference between treatment groups in the frequency of breakthrough fungal infections was specified in the protocol. Consequently, a Bonferroni correction for multiple comparisons was not necessary. The analyses presented in the article followed the prespecified plan.

The vote by the Antiviral Drug Products Advisory Committee of the Food and Drug Administration was not unanimous against the broad approval of voriconazole for the indication of empirical antifungal therapy in patients with neutropenia. Two members voted yes, two were equivocal, and six voted no for the broad indication.3 This vote then prompted further discussion concerning voriconazole for empirical antifungal therapy in high-risk patients with neutropenia. Goldberger also requested that the committee provide guidance in developing language for this possible indication. Five additional members indicated support for an indication of empirical antifungal therapy restricted to high-risk patients with neutropenia.4 Hence, the majority of the advisory committee members affirmed support for an indication of empirical antifungal therapy with voriconazole, particularly in high-risk patients with neutropenia.

Thomas J. Walsh, M.D.
National Cancer Institute, Bethesda, MD 20892
walsht@mail.nih.gov

Jeannette Lee, Ph.D.
William E. Dismukes, M.D.
University of Alabama at Birmingham, Birmingham, AL 35294-0111

4 References

1. 1

   Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever. N Engl J Med 2002;346:289-290
   Full Text | Web of Science | Medline

2. 2

   Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225-234
   Full Text | Web of Science | Medline

3. 3

   Dockets. Rockville, Md.: FDA Dockets Management Branch, 2001:124. (Accessed April 19, 2002, at http://www.fda.gov/ohrms/dockets/ac/cder01.htm#Anti-Viral.)
   

4. 4

   Dockets. Rockville, Md.: FDA Dockets Management Branch, 2001:124-30. (Accessed April 19, 2002, at http://www.fda.gov/ohrms/dockets/ac/cder01.htm#Anti-Viral.)
   

Author/Editor Response

The authors reply:

To the Editor: Voriconazole fails to meet the statistical definition of noninferiority in both the stratified and unstratified analyses of the overall response in the clinical trial that compared voriconazole with liposomal amphotericin B as empirical antifungal therapy in febrile patients with neutropenia.1 In certain disease states, failing to meet the noninferiority margin in a clinical trial could mean that the drug not only may not be equivalent to the control regimen but also may have no efficacy as compared with no treatment.2 As Marr states in the accompanying editorial,3 the previous trials of empirical antifungal therapy in patients with neutropenia that compared amphotericin B deoxycholate with no treatment had insufficient power to determine a difference in the rate of breakthrough fungal infections. Although this does not mean that empirical antifungal therapy is not beneficial in febrile patients with neutropenia, these trials do not give a clear estimate of the magnitude of such a benefit. Given these uncertainties, one could view failing to meet the noninferiority margin of –10 percent as demonstrating that voriconazole may not be equivalent to the control regimen and, in the worst case, may not have a benefit over no treatment.

The Food and Drug Administration has approved liposomal amphotericin B and itraconazole for empirical antifungal therapy in febrile patients with neutropenia on the basis of trials with a design similar to that of the voriconazole trial. Although there were important differences in patient demographics and end-point definitions between these trials, both drugs were within a –10 percent margin of noninferiority as compared with the control regimen.4

We still believe that one should use caution in interpreting the results of subgroup analyses when there is no statistically significant evidence of efficacy in the primary end point of the trial. The demonstrated efficacy of voriconazole in invasive aspergillosis4 and the subgroup analysis in high-risk patients from the empirical-therapy trial generate hypotheses that voriconazole may have a benefit in empirical therapy of febrile patients with neutropenia, but it is not possible to determine this conclusively from the study by Walsh et al. We hope there will be interest in conducting further studies of voriconazole and other antifungal drugs as empirical antifungal therapy in febrile patients with neutropenia, including the high-risk subgroup of patients, in order to answer these important questions.

John H. Powers, M.D.
Cheryl A. Dixon, Ph.D.
Mark Goldberger, M.D., M.P.H.
Food and Drug Administration, Rockville, MD 20850
powersjoh@cder.fda.gov

4 References

1. 1

   Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225-234
   Full Text | Web of Science | Medline

2. 2

   Powers JH, Ross DB, Brittain E, Albrecht R, Goldberger MJ. The United States Food and Drug Administration and noninferiority margins in clinical trials of antimicrobial agents. Clin Infect Dis 2002;34:879-881
   CrossRef | Web of Science | Medline

3. 3

   Marr KA. Empirical antifungal therapy -- new options, new tradeoffs. N Engl J Med 2002;346:278-280
   Full Text | Web of Science | Medline

4. 4

   NDA 21-266, Vfend (voriconazole) tablets: NDA 21-267, Vfend I.V. (voriconazole) for injection. Washington, D.C.: Food and Drug Administration Antiviral Drugs Advisory Committee, October 4, 2001. (Accessed April 19, 2002, at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3792t2.htm.)
   

Citing Articles (9)

Citing Articles

1. 1

   Jane A Cecil, Richard P Wenzel. (2009) Voriconazole: a broad-spectrum triazole for the treatment of invasive fungal infections. Expert Review of Hematology 2:3, 237-254
   CrossRef

2. 2

   Marit D. Moen, Katherine A. Lyseng-Williamson, Lesley J. Scott. (2009) Liposomal Amphotericin B. Drugs 69:3, 361-392
   CrossRef

3. 3

   Jutta Auberger, Cornelia Lass-Flörl, Hanno Ulmer, Elisabeth Nogler-Semenitz, Johannes Clausen, Eberhard Gunsilius, Hermann Einsele, Günther Gastl, David Nachbaur. (2008) Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. International Journal of Hematology 88:5, 508-515
   CrossRef

4. 4

   L. Senn, J. O. Robinson, S. Schmidt, M. Knaup, N. Asahi, S. Satomura, S. Matsuura, B. Duvoisin, J. Bille, T. Calandra, O. Marchetti. (2008) 1,3- -D-Glucan Antigenemia for Early Diagnosis of Invasive Fungal Infections in Neutropenic Patients with Acute Leukemia. Clinical Infectious Diseases 46:6, 878-885
   CrossRef

5. 5

   Suganthini Krishnan-Natesan, Pranatharthi H Chandrasekar. (2008) Current and Future Therapeutic Options in the Management of Invasive Aspergillosis. Drugs 68:3, 265-282
   CrossRef

6. 6

   Jean Klastersky, Marianne Paesmans. (2007) Antifungal therapy in febrile neutropenic patients: review of treatment choices and strategies for aspergillar infection. Supportive Care in Cancer 15:2, 137-141
   CrossRef

7. 7

   George Aperis, Eleftherios Mylonakis. (2006) Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations. Expert Opinion on Investigational Drugs 15:6, 579-602
   CrossRef

8. 8

   Peter G. Pappas, John H. Rex, Jack D. Sobel, Scott G. Filler, William E. Dismukes, Thomas J. Walsh, John E. Edwards. (2004) Guidelines for Treatment of Candidiasis. Clinical Infectious Diseases 38:2, 161-189
   CrossRef

9. 9

   Leonard B. Johnson, Carol A. Kauffman. (2003) Voriconazole: A New Triazole Antifungal Agent. Clinical Infectious Diseases 36:5, 630-637
   CrossRef