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LETTERS: James R Smith and Regina Dutkowski Stockpiling oseltamivir: Roche clarifies data for improved mortality with oseltamivir BMJ 2005; 331: 1203-b [Full text]

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Stockpiling oseltamivir: not the NNT

Robin Esmond Ferner   (24 November 2005)

NNT for oseltamivir

Matthew L Grove   (24 November 2005)

Limited benefit and potential harm of oseltamivir including sudden death and death from abnormal behavior

Rokuro Hama   (26 November 2005)

Tamiflu: NNT to prevent a pandemic flu death may be a million

A Rouse   (28 November 2005)

Re: Tamiflu: NNT to prevent a pandemic flu death may be a million

Maarten J Postma   (7 December 2005)

Stockpiling oseltamivir: not the NNT 24 November 2005
Robin Esmond Ferner, Director West Midlands Centre for Adverse Drug Reaction Reporting Send response to journal: Re: Stockpiling oseltamivir: not the NNT	My colleague Andrew Rouse asks what the Number-needed-to-treat (NNT) might be for oseltamivir. Smith & Dutkowski 'clarify' the data on improved mortality by quoting relative risk reductions. The web- site (www.eswi.org) they reference does not give the data needed to calculate NNTs, either. It is co-sponsored by Roche. Is there something to hide? Competing interests: REF provides advice on Therapeutics to Public Health Physicians in Birmingham.
NNT for oseltamivir 24 November 2005
Matthew L Grove, Consultant Rheumatologist NTGH, NE29 8NH Send response to journal: Re: NNT for oseltamivir	Although, as Robin Ferner points out, Smith & Dutkowski are unable to tell the difference between absolute and relative risks, the papers they reference are available via the internet and do give raw data, enabling calculation of NNTs. For example, the Hayden paper (1) Looks at the efficacy of providing influenza contacts with a 10/7 course of post-exposure prophylaxis with oseltamivir, compared to just managing the index case with a 5/7 treatment course of the drug. 62% of index cases had laboratory proven influenza. Working from their published ITT figures, 40/392 contacts of treated influenza cases devloped influenza themselves, compared to 11/400 contacts provided with 10/7 post-exposure prophylaxis - RR 0.27 (95%ci 0.14-0.52), ARR 0.075 (95%ci 0.04-0.11), NNT of 13.4 (95% ci 9-25). The abstract of the Kaiser paper (2) gives sufficient detail for NNT calulations. We are told that 9/1350 oseltamivir-treated influenza patients were hospitalised compared to 18/1063 placebo patients - an impressive RR of 0.39 (95% ci 0.18-0.87)... but a not-so impressive NNT of 97 (95%ci 52-726). Then again, at £16 or so for a course of treatment £1600 to prevent a hospital admission is probably cost-saving. However, the really interesting thing would be the raw data from the large American cohort study of 176001 people - an NNT to prevent death is a really hard outcome. And I can't find that on the Roche-backed website, either... (1) Hayden FG, Belshe R, Villanueva C, Lanno R, Hughes C, Small I, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004;189: 440-9.[CrossRef][ISI][Medline] (2) Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003;163: 1667- 72.[Abstract/Free Full Text] Competing interests: None declared
Limited benefit and potential harm of oseltamivir including sudden death and death from abnormal behavior 26 November 2005
Rokuro Hama, Chairman of Japan Institute of Pharmacovigilance, Editor of Kusuri-no-Check (a drug bulletin) #402 Osaka 2-3-2, Tennoji-ku Osaka, Japan 543-0062�@ Send response to journal: Re: Limited benefit and potential harm of oseltamivir including sudden death and death from abnormal behavior	EDITOR- In response to experts' question, Roche [1] showed very rough data which, they claimed, supports an improvement in mortality with oseltamivir. Although I could not have access to the datasets at <www.eswi.org>, data they showed (32 % and 90 % risk reduction of pneumonia and death respectively) may not be easily believed by those who know the limited benefits shown in the randomized controlled trials (RCTs), potentially harmful effects of the drug shown below and that flu is a self-limiting disease for previously healthy people. In the RCT for treatment of adult flu in Japan [2], Kaplan-Meier curves for proportion of patients without freedom from illness of both groups were almost completely the same in patients with H3N2 influenza A, although oseltamivir improved the symptoms of those with H1N1 influenza A significantly faster than placebo. In the RCT [3] in which chronic asthma children with influenza were tested, oseltamivir did not improve symptoms significantly (average duration of illness is rather 14.7 hours less in placebo group than that in oseltamivir group: p value was not stated). Oseltamivir did not significantly decrease the proportion of patients with flu-like symptoms based on data from an RCT for prevention of flu in Japan (proportion of patients with symptom was 21.9 % in the oseltamivir group and 23.5 % in the placebo group), although the proportion of patients both with symptoms and test-proven flu virus was significantly reduced in the oseltamivir group than in the placebo group[4,5]. Additionally, I have reported three death cases closely related to the use of oseltamivir recently at a scientific meeting in Japan [6]. One of the leading Newspaper reported my presentation [7]. Of these only one case (a 14-year-old male) is included in the 12 pediatric death cases all from Japan that FDA reported in November 18 [8]. It was concluded that co- morbidity and confounding factors in many of the cases, limited and missing data in majority of cases makes it difficult to establish a direct causal relationship between the use of oseltamivir and the reported deaths [8]. However, according to my history taking that I presented in Japanese [6], neither fever nor other drugs could be the causes of his abnormal behavior and death of a 14-year-old boy. He was one of the two boys reported by the newspaper [7]. Japanese MHLW (Ministry of Health, Labour, and Welfare) reported a case of teenage girl as a warning that oseltamivir could cause hallucination and abnormal behavior [8]. She tried to rush out of the window as soon as her body temperature went down. Fever was not the cause of the strange behavior in this case either. This case was not mentioned in the reports by FDA. I also reported a previously healthy 2-year-old boy who became breathless suddenly during afternoon nap and had very low body temperature [6]. Another 2-year-old boy whose parents noticed his abnormal breathing and took him to a hospital by their car, stopped breathing in the car before he arrived at the hospital [10]. This case is not included in the 12 Japanese pediatric death cases reported by FDA [8]. These cases strongly suggest that the infants died from respiratory suppression. As I mentioned [11], four other sudden infant deaths during sleep were reported [12]. In total, six infants of sudden death during sleep or death from abnormal breath were previously healthy and did not take antipyretics. Causality to such sudden death was considered as follows in the memorandum of FDA-CDER [13]: "the contribution of the drug to the death of these patients, especially with the case of sudden death and cardio-pulmonary arrest, cannot be excluded based upon the information available." Previously reported cases of influenza-related encephalopathy (IRE), especially fatal cases, were closely related to non-steroidal anti- inflammatory drug (NSAIDs) antipyretics such as diclofenac and/or mefenamic acid, and the incidence of the fatal cases has decreased since warnings about NSAIDs antipyretics for flu children were issued in 2000. Even fatal cases of classical type of IRE did not cause death so suddenly as the six cases above. So Shiomi called his cases as a new type of IRE [12]. The new type of IRE cases have started to be reported in the winter season just after marketing of oseltamivir for children had begun in July 2002. It should be stressed that the mechanism of sudden death from respiratory suppression in human infants is confirmed by at least three animal toxicity studies conducted by Roche [2-4]. Ten minutes to seven hours (mainly 2 to 3 hours) after the first dose of Tamiflu, many 7-day old rats died from respiratory suppression, exhibiting spontaneously decreased movement, weakened respiration which subsequently became irregular [2-4]. Considering the similarity between the signs and symptoms in human infants and the juvenile rats, and rather low safety index; only 26 to 40 times based on the peak plasma concentration, close causal relationship should be suspected between oseltamivir and the infant sudden death from respiratory suppression during sleep. Central nervous system suppressants including sedatives, hypnotics and anesthetics may induce death from respiratory suppression at high dose, and may induce hallucination, delirium and abnormal behavior by disinhibition or dyscontrol of the central nervous system at a certain dose. They are well-known adverse reactions to barbiturate and benzodiazepins and so on. It should be noted that FDA did not discuss the animal toxicity studies indicating suppressive effects of oseltamivir on central nervous system, the similarity of clinical course of human and animal, and disinhibition or dyscontrol action of oseltamivir as a central nervous system suppressant at all. Number needed to Harm (NNH) of vomiting at the first day of oseltamivir commencement in the RCT for treatment of children is 15 [3,6]. NNH of headache, nausea and vomiting in the RCT of preventative use of oseltamivir for adults is 25, 24 and 55 respectively [4,6]. These results and the evidence of bulged fontanel in the 5 month-old baby adminidtered oseltamivir for flu prevention [13] indicate that unchanged oseltamivir alone could increase intracranial pressure even in adults. If we take into account of these well-known pharmacological actions of central nervous system suppressants and the effect on intracranial pressure, full spectrum of psychiatric and neurological adverse effects of oseltamivir could be well understood. We should not overlook these potentially harmful effects in addition to the limited benefit of oseltamivir not only in daily practice but also in stockpiling oseltamivir. References 1. James R Smith and Regina Dutkowski Stockpiling oseltamivir: Roche clarifies data for improved mortality with oseltamivir BMJ, Nov 2005; 331: 1203 2. New drug approval package (NAP) of oseltmivir (in Japanese); Tamiflu capsule (2000): http://211.132.8.246/shinyaku/g0012/07/53039900_21200AMY00238.html 3. NAP of oseltmivir (in Japanese); Tamiflu dry syrup (2002): http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html? 4. NAP of oseltmivir (in Japanese); Tamiflu capsule for prevention (2004) : http://211.132.8.246/shinyaku/g0407/g040703/index.html 5. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis against influenza- -placebo-controlled double-blind multicenter phase III trial. Kansenshogaku Zasshi (J Infection). 2000 Dec; 74(12): 1062-76 (in Japanese). 6. Hama R. Discussion of the causal relationship between Oseltamivir phosphate (Tamiflu), and sudden death and death from abnormal behavior(presentation at a session of Japanese Society for Pediatric Infectious Diseases in Tsu, Mie Prefecture November 12 2005) available at: http://www.npojip.org/sokuho/051112.html (in Japanese) and http://www.npojip.org/english/no59.html (in English) 7.Mainichi Daily News: Abnormal reaction to Tamiflu medicine tied to deaths of two boys; http://mdn.mainichi- msn.co.jp/national/news/20051112p2a00m0na030000c.html 8. Truffa MM. One Year Post-Exclusivity Adverse Event Review forTamiflu® (oseltamivir) http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4180s_03_truffa.ppt#17 9. Japanese FDA MHLW. Pharmaceuticals and Medical Devices Safety Information No.202 (June 2004; in Japanese ) http://www.mhlw.go.jp/houdou/2004/06/h0624-2/index.html#gai2 10. Fujii F et al. A death case of influenza-related encephalopathy without showing neurological signs and symptoms. Infection and Immunity in childhood (2004) 16(2) : 231-232 (in Japanese) 11. Hama R. New type of influenza-related encephalopathy or new adverse drug reaction? BMJ Rapid Response, 28 February 2005. http://bmj.bmjjournals.com/cgi/eletters/328/7433/227#98374 12. Shiomi S. Clinical spectrum of influenza-related encephalopathy. Pediatric internal medicine (in Japanese). 2003: 34(10); 1676-1681. 13. Memorandum of FDA CDER: Tamiflu AE �EReviewed. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005- 4180b_06_01_Tamiflu%20AE_reviewed.pdf Competing interests: None declared
Tamiflu: NNT to prevent a pandemic flu death may be a million 28 November 2005
A Rouse, Consultant Heart of Birmingham PCT B16 9PA Send response to journal: Re: Tamiflu: NNT to prevent a pandemic flu death may be a million	My original submission asked who had briefed Mrs Hewitt on a major medical issues? 1). I asked because I have to advise a PCT on its ability to respond to flu pandemic. Having reviewed much of the relevant evidence, I concluded that: a) If given within 48 hours of onset of symptoms (as proposed by the Department of Health) Tamiflu marginally reduces duration of illness. b) Many patients will feel that this small benefit will offset the side effects and possible serious harm associated with Tamiflu’s use. As such when given to a fully consenting patient under “normal” doctor patient conditions Tamiflu’s use is acceptable c) Under the Government’s flu pandemic plans, Tamiflu will probably be distributed- en mass – sometimes from mass distribution centres – in circumstances, which will make “informed consent” impossible. d) When public policy expects a citizen to take a medication on faith, (because it is impractical to obtain informed consent) it is axiomatic that the benefit to harm ratio must be much higher than in the normal “doctor-patient” situation. To my knowledge no such evaluation has been undertaken. I concluded that there was no place for “mass population Tamiflu” in our flu pandemic plan. I also believe that until a credible benefit to harm risk analysis of mass Tamiflu provision has been published, the medical fraternity should not support such provision. However, if as Mrs Hewitt stated in October, “Tamiflu will save lives (during a pandemic)”, then this view may be dangerously wrong and I may need to reverse it. This is why we all need to know the veracity of Mrs Hewitt’s statement and the answer to the question, “Who gave her this advice?” My second question related to the NNT to avert a flu pandemic death. Smith and Dutkowski do not answer this(2). I calculate that during a pandemic, in Birmingham, this NNT probably approaches a million. Therefore, if each course of Tamiflu costs about £16, the drug cost alone of each life saved will be about £16 million! Who has advised Mrs Hewitt that this is a sensible use of NHS money? 1. Stockpiling oseltamivir: What is the number needed to treat with oseltamivir to prevent one flu death? A Rouse BMJ 2005;331:1203, doi:10.1136/bmj.331.7526.1203-a 2. Stockpiling oseltamivir: Roche clarifies data for improved mortality with oseltamivir. James R Smith, Regina Dutkowski BMJ 2005;331:1203, doi:10.1136/bmj.331.7526.1203-b Competing interests: None declared
Re: Tamiflu: NNT to prevent a pandemic flu death may be a million 7 December 2005
Maarten J Postma, Associate Professor University of Groningen (Netherlands) Send response to journal: Re: Re: Tamiflu: NNT to prevent a pandemic flu death may be a million	Recent discussions in his journals relating to the stockpiling of oseltamivir for pandemic influenza have focussed on number needed to treat (NNT) to avert one fatal case of influenza (1,2). Notwithstanding the relevance of this parameter, from an economic point of view NNT to avert one hospitalisation should also be considered. Severe influenza-related disease leading to hospitalisations has various economic impacts within an already disruptive society suffering from pandemic influenza. In particular, hospitalisations will further strain an already overburdened health-care system during pandemic situations and severe disease involves production losses in various economic sectors, inclusive crucial civil services and the health-care system itself. Whereas NNT to avert one death may be 1800-3200 (3,4) depending on the exact assumptions, pooled clinical trials (5) show that NNT to avert one hospitalisation are 97 (all-cause mortality) or 142 (more stringent influenza-related mortality only). These NNTs for hospitalisations were derived from pooling 10 randomised clinical trials among patients presenting to the GP within 36 hours of first ILI-symptom onset (also influenza infection was confirmed afterwards). As indicated previously (1), such NNTs probably result in cost savings for oseltamivir treatment of persons presenting with influenza-like illness at the GP’s office. Next to these potential cost savings, reductions in hospitalisations and severe diseases may be crucial in pandemic situations to alleviate the already overburdened health-care system and avert further breakdown of vital civil services due to large-scale sickness absence. In particular, it can easily be derived from the pooled trials that potentially the number of hospitalisations can be reduced by more than 50% through large-scale oseltamivir treatment. Furthermore, we note that additionally indirect effects of oseltamivir treatment during pandemic situations may occur. In particular, the probability that an infected person will transmit influenza to others may be reduced by as much as 80% through antiviral treatment (6). Consequently, instead of causing 2 new infections on average in a susceptible population (the so-called R0), less than 1 new infection will only be caused by an influenza-infected person on oseltamivir treatment. Next to the direct effect of oseltamivir on hospitalisations outlined above, also this indirect effect on transmission may prove to be of crucial importance during an influenza pandemic. 1. Grove ML. NNT for oseltamivir. BMJ.com November 24th 2. Rouse A. Tamiflu: NNT to prevent a pandemic flu death may be a million. BMJ.com November 28th 3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality Associated With Influenza and Respiratory Syncytial Virus in the United States. J Am Med Assoc 2003;289:179-86 4. Nordstrom et al at www.eswi.org 5. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of Oseltamivir Treatment on Influenza-Related Lower Respiratory Tract Complications and Hospitalizations. Arch Intern Med 2003;163:1667-72 6. Longini IM, Halloran ME, Nizam A, Yang Y. Containing Pandemic Influenza with Antiviral Agents. Am J Epidemiol 2004;159:623-33 Competing interests: Dr MJ Postma received research grants from Roche to study the pharmacoeconomics of oseltamivir