- Email: [email protected]
Telithromycin and the FDA: implications for the future
Reflection and Reaction
The study of the infected vaccinees could provide relevant information for testing vector-mediated activation and the following issues should be investigated: (1) analysis of CD4 T-cell activation both in blood and mucosal tissues; (2) vector-specific CD4 T-cell responses; (3) expansion of the pre-existing vaccine-induced T-cell response during primary infection; (4) kinetics of the de novo HIV-specific T-cell responses (were these responses delayed?); and (5) magnitude and functional profile of de novo HIV-specific T-cell responses. It is clear from the STEP trial that the clinical development of the homologous Ad5 prime/boost regimen should be halted. We should, however, continue the clinical development of heterologous prime/boost, such as DNA plus adenovirus or DNA plus poxvirus strategies. Nevertheless, the results from the STEP trials have shown the potential association between pre-existing immunity to the vector and enhanced susceptibility to HIV infection. In light of these results, regimens including Ad5 vector-based vaccines should not be tested in patients with pre-existing immunity to Ad5 vector. Since the smallpox vaccination programme was stopped in 1980, pre-existing immunity may be much less of a problem for poxvirus vector-based vaccines. Last but not least, Merck, HVTN, and NIAID investigators should be praised for their outstanding work in conducting the trial, for the transparency in the communication of the STEP results to the public domain, and for their commitment to the development of an HIV vaccine.
Giuseppe Pantaleo Service of Immunology and Allergy, Centre Hospitaliere Universitaire Vaudois, University of Lausanne, Rue Bugnon, 1011 Lausanne, Switzerland [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
7
8
9
10
Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: what we know, what we don’t know, what we should know. Nat Med 2004; 10: 806–10. Pantaleo G, Demarest JF, Soudeyns H, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994; 370: 463–67. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary immunodeficiency virus type 1 infection. J Virol 1994; 68: 6103–10. Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68: 4650–55. Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283: 857–60. Migueles SA, Laborico AC, Shupert WL, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3: 1061–68. McDermott AB, O’Connor DH, Fuenger S, et al. Cytotoxic T-lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01-positive rhesus macaques. J Virol 2005; 79: 15556–66. Casimiro DR, Wang F, Schleif WA, et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with DNA and recombinant adenoviral vaccine vectors expressing Gag. J Virol 2005; 79: 15547–55. Wilson NA, Reed J, Napoe GS, et al. Vaccine-induced cellular immune responses reduce plasma viral load after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J Virol 2006; 80: 5875–85. Stanley SK, Ostrowski MA, Justement JS, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996; 334: 1222–30.
Telithromycin and the FDA: implications for the future The recent evaluation of telithromycin, an antibiotic active against resistant respiratory pathogens, by the Anti-Infectives Advisory Committee (AIDAC) of the Food and Drug Administration (FDA),1 demonstrates once again that the FDA has an impossible job. The FDA is responsible for ensuring that products are safe and efficacious for the indication for which they are marketed in the USA. At the same time, the FDA must deal with the desire to provide antibiotics active against resistant microorganisms in an environment where many sponsors have abandoned antibacterial research altogether. At the AIDAC meeting, held in Silver Spring, MD, USA, on Dec 14–15, 2006, the FDA positioned telithromycin as an antibiotic of questionable efficacy http://infection.thelancet.com Vol 8 February 2008
for the treatment of acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, since approval was granted based on non-inferiority rather than placebo-controlled superiority trials. The FDA described rare but serious side-effects including three cases of severe hepatotoxicity attributed to telithromycin.2 In this context, the FDA asked the advisory committee to weigh the risk-to-benefit ratio of telithromycin in acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. Telithromycin was approved in 20043 after a long regulatory history where several toxicity signals were seen in the phase III trials. However, post-marketing surveillance, mainly in Europe, but also in countries 83
Syncope
4·2
2·0
1·6
Hepatic failure
3·7
2·5
1·8
Hepatitis
5·8
4·2
3·2
1·0
1·3
2·0
0·3
1·1
0·9
1·2
0·6
0·7
1·4
3·1
4·8
1·3
1·1
2·8
1·2
1·2
1·1
1·0
Paracetamol
3·9
2·9
Nitrofurantoin
1·1
1·4
Trovafloxacin
2·1
1·4
Moxifloxacin
8·9
0·8
Gemifloxacin
33·3
1·2
Amoxicillin-clavulanate
Myasthenia
0·4
Cefuroxime
2·3
Ceftibuten
2·3
Cefpodoxime
Erythromycin
1·7
Cefixime
Clarithromycin
100·8
Cefditoren
Azithromycin
Eye
All reports
Dirithromycin
Telithromycin
Reflection and Reaction
0·3
2·5
1·8
1·4
1·0
3·3
1·7
2·2
0·6
2·8
1·4
1·1
4·8
3·2
1·5
1·6
1·0
3·8
0·5
1·4
5·4
4·8
33·1
1·5
6·3
0·3
1·7
6·3
5·8
5·4
Cholestasis
1·9
4·7
8·4
1·6
15·2
1·2
2·6
2·0
1·8
2·2
28·7
0·6
1·1
3·6
3·5
2·1
Drug interaction
3·4
4·5
5·9
1·0
6·3
0·7
0·9
1·2
0·8
1·4
1·4
0·8
1·6
1·8
1·1
4·3
Drug ineffective
0·8
19·1
0·5
0·8
0·5
72·2
1·6
0·9
2·4
0·5
0·5
0·5
0·3
0·6
0·3
2·5
Clostridium infection
1·1
3·8
3·0
2·6
66·2
38·4
42·0
23·5
43·4
24·2
4·5
7·3
3·1
0·9
0·4
Toxic skin
2·2
5·5
2·7
3·5
12·5
3·2
15·4
2·3
5·5
24·1
1·8
2·9
1·2
2·5
5·2
Hypersensitivity
3·0
5·6
3·0
2·9
2·3
28·6
2·4
4·3
3·4
17·1
7·1
2·1
10·6
4·6
4·7
1·7
Min.
≤1·5
≤2
≤4
>4
EBGM 0
1·5
2
4
Figure: Empirical Bayes Geometric Mean (EGBM) for various adverse events as scored from the Adverse Event Reporting System by the Food and Drug Administration
outside the USA and EU, showed no substantial safety problems after a review of data on almost 4 million courses of therapy.4 Thus, the agency approved telithromycin for the treatment of community-acquired pneumonia, acute bacterial sinusitis, and acute bacterial exacerbations of chronic bronchitis. Since approval of telithromycin in the USA, the FDA has concluded that non-inferiority trials (used for approval of every antibiotic in history for every bacterial respiratory infection studied to date) are not sufficient to prove efficacy for acute bacterial sinusitis and possibly not for acute bacterial exacerbations of chronic bronchitis as well. Placebo-controlled trials will be required as noted for gemifloxacin and faropenem.5,6 Thus, since telithromycin had not demonstrated efficacy in acute bacterial sinusitis or acute bacterial exacerbations of chronic bronchitis, the FDA asked advisors to help determine if the risk-to-benefit ratio for telithromycin justified continued marketing for its approved indications. An analysis by the FDA of the risk of hepatotoxicity caused by telithromycin as determined by data mining of the self-reported Adverse Event Reporting System database (figure) suggested that the compound was 84
associated with no more risk than other antibiotics (including amoxicillin-clavulanate) or paracetamol.7 The incidence of severe hepatotoxicity was in the order of 1 in 100 000 to 1 in 200 000 patients treated. Visual disturbances for telithromycin were much more common—perhaps up to 1 in 100 patients—but only one or two cases resulted in motor vehicle accidents where there was death or injury. The FDA safety group used a risk calculation based on lifetimes of use as one might use for drugs given for chronic diseases.8 Fatal anaphylactic reactions from the penicillins occur with a frequency of 1 in 50 000 to 1 in 67 000, and serious immediate hypersensitivity reactions occur as often as 1 in 7000 courses of therapy.9 The figure suggests that the risk ratio for hypersentivity reactions to amoxicillin-clavulanate, in particular, is higher than the hepatotoxicity attributed to telithromycin. Amoxicillin-clavulanate, amoxicillin, and even oral penicillin are all used for treatment of acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. To be consistent, the FDA might be obliged to withdraw approval for all antibiotics for use in acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis where there is any safety risk. http://infection.thelancet.com Vol 8 February 2008
Reflection and Reaction
The advisory committee voted 17 to two in favour of withdrawing approval for telithromycin for acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, and the FDA has followed this advice. These indications comprise some of the largest opportunities in the anti-infectives marketplace. Now, even if one were able to show efficacy in a placebo-controlled trial, since acute bacterial sinusitis and possibly acute bacterial exacerbations of chronic bronchitis are, primarily, self-limited, any safety risks, even at levels below those currently accepted for the penicillins, might lead to withdrawal of approval post-launch. From the viewpoint of many in the industry, the risks of developing antibiotics are increasing substantially while the market potential for these products continues to fall. Will industry take the risks necessary, including the required placebo-controlled trials, to bring new products to market for acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis? Some companies have embarked on these trials and many are awaiting the outcome of their efforts. Clearly the entire situation remains a difficult one not only for the FDA but also for all of the potential developers of new antimicrobials, for patients, and for physicians desiring optimum therapy for their patients.
*David M Shlaes, Robert C Moellering Anti-Infectives Consulting, LLC, Stonington, CT 06378, USA (DMS); and Department of Medicine, Harvard Medical School, Boston, MA, USA (RCM) [email protected] DMS consults for several small pharmaceutical companies working in the area of antibacterial discovery and development, but does not have any direct relationship with, nor owns stock in, Sanofi-Aventis. RMC also consults for a number of companies including Sanofi-Aventis. 1
2
3 4
5
6
7
8 9
Food and Drug Administration Center for Drug Evaluation and Research (CDER). Anti-Infective Drugs Advisory Committee in joint session with the Drug Safety and Risk Management Advisory Committee; Silver Spring, MD, USA; Dec 14–15, 2006. Agenda. http://www.fda.gov/ ohrms/dockets/ac/06/agenda/2006-4266a1-Final.pdf (accessed Dec 20, 2007). Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP, Banks PM. Severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006; 144: 415–20. Food and Drug Administration. NDA 21-144 approval letter. http://www. fda.gov/cder/foi/appletter/2004/21144ltr.pdf (accessed Dec 20, 2007). Soreth J. Ketek (telithromycin) regulatory history. http://www.fda.gov/ ohrms/dockets/ac/06/slides/2006-4266s1-01-03-FDA-Soreth.ppt (accessed Jan 3, 2008). Food and Drug Administration Center for Drug Evaluation and Research Summary minutes of the Anti-Infective Drugs Advisory Committee September 12, 2006. http://www.fda.gov/ohrms/dockets/ac/06/ minutes/2006-4232m1.pdf (accessed Dec 20, 2007). Replidyne. Replidyne announces third quarter results, Oct 26, 2006. http://www.secinfo.com/dsvrp.vJ98.d.htm#1stPage (accessed Dec 20, 2007). Levine JG, Szarfman A. Data mining analysis of multiple antibiotics in AERS. http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06FDA-Levine.ppt (accessed Jan 3, 2008). Graham DJ. Telithromycin and acute liver failure. New Engl J Med 2006; 355: 2260–61. Idsoe O, Guthe T, Sillcox RR, de Weck AL. Nature and extent of penicillin side-reactions with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968; 38: 159–88.
Universal hepatitis B vaccination Jane Zuckerman and colleagues1 recently made the case for universal childhood hepatitis B vaccination in low-prevalence countries that currently only vaccinate high-risk groups. Figure 2 in their Review compares the effects of various vaccination strategies in the Netherlands; however, this figure wrongly gives the impression that vaccination of high-risk groups has no effect on hepatitis B incidence. We would like to take the opportunity to correct this and explain in more detail our evaluation of different vaccination strategies in the Netherlands using a mathematical model in combination with cost-effectiveness analysis. In the Netherlands, routine screening of pregnant women for hepatitis B surface antigen has been done since 1989, with a coverage of about 90%. On the basis of a cost-effectiveness analysis, the Health Council of the Netherlands decided in 2001 that children of http://infection.thelancet.com Vol 8 February 2008
whom at least one parent was born in a medium or high-endemicity country should be offered a free hepatitis B vaccination.2 Since 2003, about 15% of all newborn babies have been vaccinated against hepatitis B.3 At the same time, to increase the coverage of hepatitis B vaccination in high-risk groups, an intensive vaccination programme was started in 2002, in which hepatitis B vaccination was offered to men who have sex with men, heterosexual people with high rates of partner change, sex workers, and hard drug users. During the 4 years the programme was running, about 64 000 people were vaccinated against hepatitis B. We have evaluated the effectiveness of vaccination of high-risk groups by further development of a previously published dynamic mathematical model4 in combination with cost-effectiveness analysis. The (cost)-effectiveness of vaccinating high-risk groups was also compared with 85
The study of the infected vaccinees could provide relevant information for testing vector-mediated activation and the following issues should be investigated: (1) analysis of CD4 T-cell activation both in blood and mucosal tissues; (2) vector-specific CD4 T-cell responses; (3) expansion of the pre-existing vaccine-induced T-cell response during primary infection; (4) kinetics of the de novo HIV-specific T-cell responses (were these responses delayed?); and (5) magnitude and functional profile of de novo HIV-specific T-cell responses. It is clear from the STEP trial that the clinical development of the homologous Ad5 prime/boost regimen should be halted. We should, however, continue the clinical development of heterologous prime/boost, such as DNA plus adenovirus or DNA plus poxvirus strategies. Nevertheless, the results from the STEP trials have shown the potential association between pre-existing immunity to the vector and enhanced susceptibility to HIV infection. In light of these results, regimens including Ad5 vector-based vaccines should not be tested in patients with pre-existing immunity to Ad5 vector. Since the smallpox vaccination programme was stopped in 1980, pre-existing immunity may be much less of a problem for poxvirus vector-based vaccines. Last but not least, Merck, HVTN, and NIAID investigators should be praised for their outstanding work in conducting the trial, for the transparency in the communication of the STEP results to the public domain, and for their commitment to the development of an HIV vaccine.
Giuseppe Pantaleo Service of Immunology and Allergy, Centre Hospitaliere Universitaire Vaudois, University of Lausanne, Rue Bugnon, 1011 Lausanne, Switzerland [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
7
8
9
10
Pantaleo G, Koup RA. Correlates of immune protection in HIV-1 infection: what we know, what we don’t know, what we should know. Nat Med 2004; 10: 806–10. Pantaleo G, Demarest JF, Soudeyns H, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994; 370: 463–67. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary immunodeficiency virus type 1 infection. J Virol 1994; 68: 6103–10. Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68: 4650–55. Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283: 857–60. Migueles SA, Laborico AC, Shupert WL, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3: 1061–68. McDermott AB, O’Connor DH, Fuenger S, et al. Cytotoxic T-lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01-positive rhesus macaques. J Virol 2005; 79: 15556–66. Casimiro DR, Wang F, Schleif WA, et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with DNA and recombinant adenoviral vaccine vectors expressing Gag. J Virol 2005; 79: 15547–55. Wilson NA, Reed J, Napoe GS, et al. Vaccine-induced cellular immune responses reduce plasma viral load after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J Virol 2006; 80: 5875–85. Stanley SK, Ostrowski MA, Justement JS, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996; 334: 1222–30.
Telithromycin and the FDA: implications for the future The recent evaluation of telithromycin, an antibiotic active against resistant respiratory pathogens, by the Anti-Infectives Advisory Committee (AIDAC) of the Food and Drug Administration (FDA),1 demonstrates once again that the FDA has an impossible job. The FDA is responsible for ensuring that products are safe and efficacious for the indication for which they are marketed in the USA. At the same time, the FDA must deal with the desire to provide antibiotics active against resistant microorganisms in an environment where many sponsors have abandoned antibacterial research altogether. At the AIDAC meeting, held in Silver Spring, MD, USA, on Dec 14–15, 2006, the FDA positioned telithromycin as an antibiotic of questionable efficacy http://infection.thelancet.com Vol 8 February 2008
for the treatment of acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, since approval was granted based on non-inferiority rather than placebo-controlled superiority trials. The FDA described rare but serious side-effects including three cases of severe hepatotoxicity attributed to telithromycin.2 In this context, the FDA asked the advisory committee to weigh the risk-to-benefit ratio of telithromycin in acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. Telithromycin was approved in 20043 after a long regulatory history where several toxicity signals were seen in the phase III trials. However, post-marketing surveillance, mainly in Europe, but also in countries 83
Syncope
4·2
2·0
1·6
Hepatic failure
3·7
2·5
1·8
Hepatitis
5·8
4·2
3·2
1·0
1·3
2·0
0·3
1·1
0·9
1·2
0·6
0·7
1·4
3·1
4·8
1·3
1·1
2·8
1·2
1·2
1·1
1·0
Paracetamol
3·9
2·9
Nitrofurantoin
1·1
1·4
Trovafloxacin
2·1
1·4
Moxifloxacin
8·9
0·8
Gemifloxacin
33·3
1·2
Amoxicillin-clavulanate
Myasthenia
0·4
Cefuroxime
2·3
Ceftibuten
2·3
Cefpodoxime
Erythromycin
1·7
Cefixime
Clarithromycin
100·8
Cefditoren
Azithromycin
Eye
All reports
Dirithromycin
Telithromycin
Reflection and Reaction
0·3
2·5
1·8
1·4
1·0
3·3
1·7
2·2
0·6
2·8
1·4
1·1
4·8
3·2
1·5
1·6
1·0
3·8
0·5
1·4
5·4
4·8
33·1
1·5
6·3
0·3
1·7
6·3
5·8
5·4
Cholestasis
1·9
4·7
8·4
1·6
15·2
1·2
2·6
2·0
1·8
2·2
28·7
0·6
1·1
3·6
3·5
2·1
Drug interaction
3·4
4·5
5·9
1·0
6·3
0·7
0·9
1·2
0·8
1·4
1·4
0·8
1·6
1·8
1·1
4·3
Drug ineffective
0·8
19·1
0·5
0·8
0·5
72·2
1·6
0·9
2·4
0·5
0·5
0·5
0·3
0·6
0·3
2·5
Clostridium infection
1·1
3·8
3·0
2·6
66·2
38·4
42·0
23·5
43·4
24·2
4·5
7·3
3·1
0·9
0·4
Toxic skin
2·2
5·5
2·7
3·5
12·5
3·2
15·4
2·3
5·5
24·1
1·8
2·9
1·2
2·5
5·2
Hypersensitivity
3·0
5·6
3·0
2·9
2·3
28·6
2·4
4·3
3·4
17·1
7·1
2·1
10·6
4·6
4·7
1·7
Min.
≤1·5
≤2
≤4
>4
EBGM 0
1·5
2
4
Figure: Empirical Bayes Geometric Mean (EGBM) for various adverse events as scored from the Adverse Event Reporting System by the Food and Drug Administration
outside the USA and EU, showed no substantial safety problems after a review of data on almost 4 million courses of therapy.4 Thus, the agency approved telithromycin for the treatment of community-acquired pneumonia, acute bacterial sinusitis, and acute bacterial exacerbations of chronic bronchitis. Since approval of telithromycin in the USA, the FDA has concluded that non-inferiority trials (used for approval of every antibiotic in history for every bacterial respiratory infection studied to date) are not sufficient to prove efficacy for acute bacterial sinusitis and possibly not for acute bacterial exacerbations of chronic bronchitis as well. Placebo-controlled trials will be required as noted for gemifloxacin and faropenem.5,6 Thus, since telithromycin had not demonstrated efficacy in acute bacterial sinusitis or acute bacterial exacerbations of chronic bronchitis, the FDA asked advisors to help determine if the risk-to-benefit ratio for telithromycin justified continued marketing for its approved indications. An analysis by the FDA of the risk of hepatotoxicity caused by telithromycin as determined by data mining of the self-reported Adverse Event Reporting System database (figure) suggested that the compound was 84
associated with no more risk than other antibiotics (including amoxicillin-clavulanate) or paracetamol.7 The incidence of severe hepatotoxicity was in the order of 1 in 100 000 to 1 in 200 000 patients treated. Visual disturbances for telithromycin were much more common—perhaps up to 1 in 100 patients—but only one or two cases resulted in motor vehicle accidents where there was death or injury. The FDA safety group used a risk calculation based on lifetimes of use as one might use for drugs given for chronic diseases.8 Fatal anaphylactic reactions from the penicillins occur with a frequency of 1 in 50 000 to 1 in 67 000, and serious immediate hypersensitivity reactions occur as often as 1 in 7000 courses of therapy.9 The figure suggests that the risk ratio for hypersentivity reactions to amoxicillin-clavulanate, in particular, is higher than the hepatotoxicity attributed to telithromycin. Amoxicillin-clavulanate, amoxicillin, and even oral penicillin are all used for treatment of acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. To be consistent, the FDA might be obliged to withdraw approval for all antibiotics for use in acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis where there is any safety risk. http://infection.thelancet.com Vol 8 February 2008
Reflection and Reaction
The advisory committee voted 17 to two in favour of withdrawing approval for telithromycin for acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, and the FDA has followed this advice. These indications comprise some of the largest opportunities in the anti-infectives marketplace. Now, even if one were able to show efficacy in a placebo-controlled trial, since acute bacterial sinusitis and possibly acute bacterial exacerbations of chronic bronchitis are, primarily, self-limited, any safety risks, even at levels below those currently accepted for the penicillins, might lead to withdrawal of approval post-launch. From the viewpoint of many in the industry, the risks of developing antibiotics are increasing substantially while the market potential for these products continues to fall. Will industry take the risks necessary, including the required placebo-controlled trials, to bring new products to market for acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis? Some companies have embarked on these trials and many are awaiting the outcome of their efforts. Clearly the entire situation remains a difficult one not only for the FDA but also for all of the potential developers of new antimicrobials, for patients, and for physicians desiring optimum therapy for their patients.
*David M Shlaes, Robert C Moellering Anti-Infectives Consulting, LLC, Stonington, CT 06378, USA (DMS); and Department of Medicine, Harvard Medical School, Boston, MA, USA (RCM) [email protected] DMS consults for several small pharmaceutical companies working in the area of antibacterial discovery and development, but does not have any direct relationship with, nor owns stock in, Sanofi-Aventis. RMC also consults for a number of companies including Sanofi-Aventis. 1
2
3 4
5
6
7
8 9
Food and Drug Administration Center for Drug Evaluation and Research (CDER). Anti-Infective Drugs Advisory Committee in joint session with the Drug Safety and Risk Management Advisory Committee; Silver Spring, MD, USA; Dec 14–15, 2006. Agenda. http://www.fda.gov/ ohrms/dockets/ac/06/agenda/2006-4266a1-Final.pdf (accessed Dec 20, 2007). Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP, Banks PM. Severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006; 144: 415–20. Food and Drug Administration. NDA 21-144 approval letter. http://www. fda.gov/cder/foi/appletter/2004/21144ltr.pdf (accessed Dec 20, 2007). Soreth J. Ketek (telithromycin) regulatory history. http://www.fda.gov/ ohrms/dockets/ac/06/slides/2006-4266s1-01-03-FDA-Soreth.ppt (accessed Jan 3, 2008). Food and Drug Administration Center for Drug Evaluation and Research Summary minutes of the Anti-Infective Drugs Advisory Committee September 12, 2006. http://www.fda.gov/ohrms/dockets/ac/06/ minutes/2006-4232m1.pdf (accessed Dec 20, 2007). Replidyne. Replidyne announces third quarter results, Oct 26, 2006. http://www.secinfo.com/dsvrp.vJ98.d.htm#1stPage (accessed Dec 20, 2007). Levine JG, Szarfman A. Data mining analysis of multiple antibiotics in AERS. http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06FDA-Levine.ppt (accessed Jan 3, 2008). Graham DJ. Telithromycin and acute liver failure. New Engl J Med 2006; 355: 2260–61. Idsoe O, Guthe T, Sillcox RR, de Weck AL. Nature and extent of penicillin side-reactions with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968; 38: 159–88.
Universal hepatitis B vaccination Jane Zuckerman and colleagues1 recently made the case for universal childhood hepatitis B vaccination in low-prevalence countries that currently only vaccinate high-risk groups. Figure 2 in their Review compares the effects of various vaccination strategies in the Netherlands; however, this figure wrongly gives the impression that vaccination of high-risk groups has no effect on hepatitis B incidence. We would like to take the opportunity to correct this and explain in more detail our evaluation of different vaccination strategies in the Netherlands using a mathematical model in combination with cost-effectiveness analysis. In the Netherlands, routine screening of pregnant women for hepatitis B surface antigen has been done since 1989, with a coverage of about 90%. On the basis of a cost-effectiveness analysis, the Health Council of the Netherlands decided in 2001 that children of http://infection.thelancet.com Vol 8 February 2008
whom at least one parent was born in a medium or high-endemicity country should be offered a free hepatitis B vaccination.2 Since 2003, about 15% of all newborn babies have been vaccinated against hepatitis B.3 At the same time, to increase the coverage of hepatitis B vaccination in high-risk groups, an intensive vaccination programme was started in 2002, in which hepatitis B vaccination was offered to men who have sex with men, heterosexual people with high rates of partner change, sex workers, and hard drug users. During the 4 years the programme was running, about 64 000 people were vaccinated against hepatitis B. We have evaluated the effectiveness of vaccination of high-risk groups by further development of a previously published dynamic mathematical model4 in combination with cost-effectiveness analysis. The (cost)-effectiveness of vaccinating high-risk groups was also compared with 85