Telithromycin and Acute Liver Failure
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In their study of the efficacy of telithromycin in patients with acute asthma exacerbations, Johnston et al. (April 13 issue)1 discount the risk of acute liver failure. They do not mention that in 2001 an advisory committee of the Food and Drug Administration (FDA) voted against approval of telithromycin primarily because of concern about hepatotoxicity.2 In response, the drug's manufacturer conducted a trial involving 24,000 patients that was plagued by issues of fraud and data integrity of such magnitude that the FDA could not use the results to support approval.2
Lacking reliable data to counter the advisory committee's concern, the FDA took the unprecedented step of requesting post-marketing data from voluntary case reports from Germany and France as proof of the drug's safety, rather than requiring another clinical trial.2 Data on the extent of overseas use of telithromycin were redacted from the FDA's official review2 but were reported elsewhere.3 With the use of additional data on international reporting of adverse drug reactions4 and national population estimates,5 the information value and credibility of the overseas post-marketing data relied on by the FDA can be estimated.
The overseas data were equivalent to 7.6 to 11.9% of the information subsequently required by the FDA to signal an increased risk of acute liver failure with telithromycin (Figure 1). Although it took the FDA about 700 days from the start of marketing to identify this signal, the overseas data used for approval were equivalent to the signaling capacity of the FDA's database after only 50 to 80 days of marketing. The FDA interpreted the absence of a signal of acute liver failure in the overseas data as confirmation of telithromycin's safety6 when the data could not be used to identify the problem. In effect, the FDA's decision in 2004 to approve the use of telithromycin for acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, and community-acquired pneumonia was made in the absence of reliable data disproving the concern expressed in 2001 by the advisory committee.
Figure 1. U.S. Signaling Threshold and Relative Amount of Data from Voluntary Case Reports of Adverse Drug Reactions in France and Germany Analyzed to Evaluate the Risk of Acute Liver Failure with Telithromycin.
The signaling threshold of 1.0 represents the extent of telithromycin use in the United States that was required to generate a signal suggesting an increased risk of acute liver failure with the drug. Data from France and Germany accounted for an estimated 50 to 75% of telithromycin use overseas and were the focus of the FDA's analysis.2
A recent analysis of the FDA's post-marketing database showed that the rate of reporting of acute liver failure was 3.5 to 11 times as high for telithromycin as for other antibiotics marketed for similar indications, with a reporting rate of 167 cases of acute liver failure per 1 million person-years of telithromycin use, as compared with the expected rate of 1 case per 1 million person-years.3 Without accounting for underreporting (the actual incidence could be 10 times as high), this reporting rate is greater than that for troglitazone or trovafloxacin and is similar to that for bromfenac — three drugs previously removed from the U.S. market by the FDA because of the increased risk of acute liver failure. Given that telithromycin is neither clinically superior to other drugs prescribed for respiratory tract infections nor uniquely life-saving, physicians, patients, and third-party payers might wish to reconsider their choice of antibiotic for such infections.
David J. Graham, M.D., M.P.H.
Office of Surveillance and Epidemiology, Food and Drug Administration
Silver Spring, MD 20993
david.graham1@fda.hhs.gov
The views expressed are those of the author and do not necessarily reflect those of the FDA.
References
Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600.
Cooper C. Medical officer safety review of NDA 21-144: telithromycin (Ketek), March 31, 2004. (Accessed November 1, 2006, at http://www.fda.gov/cder/foi/nda/2004/21-144_Ketek.htm.)
Mathews AW. FDA panel urges prominent warning label for antibiotic. Wall Street Journal. May 19, 2006:B1.
Lindquist M. Vigibase — a global resource for public safety. Presented at the 42nd Annual Drug Information Association Meeting, Philadelphia, June 18–22, 2006.
Department of Economic and Social Affairs, Population Division. World population prospects: the 2004 revision: highlights. New York: United Nations, February 2005:28-33. (Accessed November 1, 2006, at http://www.un.org/esa/population/publications/WPP2004/2004Highlights_finalrevised.pdf.)
FDA public health advisory: Ketek (telithromycin) tablets, January 20, 2006. (Accessed November 1, 2006, at http://www.fda.gov/cder/drug/advisory/telithromycin.htm.)
Lacking reliable data to counter the advisory committee's concern, the FDA took the unprecedented step of requesting post-marketing data from voluntary case reports from Germany and France as proof of the drug's safety, rather than requiring another clinical trial.2 Data on the extent of overseas use of telithromycin were redacted from the FDA's official review2 but were reported elsewhere.3 With the use of additional data on international reporting of adverse drug reactions4 and national population estimates,5 the information value and credibility of the overseas post-marketing data relied on by the FDA can be estimated.
The overseas data were equivalent to 7.6 to 11.9% of the information subsequently required by the FDA to signal an increased risk of acute liver failure with telithromycin (Figure 1). Although it took the FDA about 700 days from the start of marketing to identify this signal, the overseas data used for approval were equivalent to the signaling capacity of the FDA's database after only 50 to 80 days of marketing. The FDA interpreted the absence of a signal of acute liver failure in the overseas data as confirmation of telithromycin's safety6 when the data could not be used to identify the problem. In effect, the FDA's decision in 2004 to approve the use of telithromycin for acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, and community-acquired pneumonia was made in the absence of reliable data disproving the concern expressed in 2001 by the advisory committee.
Figure 1. U.S. Signaling Threshold and Relative Amount of Data from Voluntary Case Reports of Adverse Drug Reactions in France and Germany Analyzed to Evaluate the Risk of Acute Liver Failure with Telithromycin.
The signaling threshold of 1.0 represents the extent of telithromycin use in the United States that was required to generate a signal suggesting an increased risk of acute liver failure with the drug. Data from France and Germany accounted for an estimated 50 to 75% of telithromycin use overseas and were the focus of the FDA's analysis.2
A recent analysis of the FDA's post-marketing database showed that the rate of reporting of acute liver failure was 3.5 to 11 times as high for telithromycin as for other antibiotics marketed for similar indications, with a reporting rate of 167 cases of acute liver failure per 1 million person-years of telithromycin use, as compared with the expected rate of 1 case per 1 million person-years.3 Without accounting for underreporting (the actual incidence could be 10 times as high), this reporting rate is greater than that for troglitazone or trovafloxacin and is similar to that for bromfenac — three drugs previously removed from the U.S. market by the FDA because of the increased risk of acute liver failure. Given that telithromycin is neither clinically superior to other drugs prescribed for respiratory tract infections nor uniquely life-saving, physicians, patients, and third-party payers might wish to reconsider their choice of antibiotic for such infections.
David J. Graham, M.D., M.P.H.
Office of Surveillance and Epidemiology, Food and Drug Administration
Silver Spring, MD 20993
david.graham1@fda.hhs.gov
The views expressed are those of the author and do not necessarily reflect those of the FDA.
References
Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600.
Cooper C. Medical officer safety review of NDA 21-144: telithromycin (Ketek), March 31, 2004. (Accessed November 1, 2006, at http://www.fda.gov/cder/foi/nda/2004/21-144_Ketek.htm.)
Mathews AW. FDA panel urges prominent warning label for antibiotic. Wall Street Journal. May 19, 2006:B1.
Lindquist M. Vigibase — a global resource for public safety. Presented at the 42nd Annual Drug Information Association Meeting, Philadelphia, June 18–22, 2006.
Department of Economic and Social Affairs, Population Division. World population prospects: the 2004 revision: highlights. New York: United Nations, February 2005:28-33. (Accessed November 1, 2006, at http://www.un.org/esa/population/publications/WPP2004/2004Highlights_finalrevised.pdf.)
FDA public health advisory: Ketek (telithromycin) tablets, January 20, 2006. (Accessed November 1, 2006, at http://www.fda.gov/cder/drug/advisory/telithromycin.htm.)