Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
A $1900 worth monthly pill for lung cancer?
- Zubair Kabir (11 May 2003)
-
Did FDA overlook real toxicity of gefitinib in Japan?
- Rokuro Hama (13 May 2003)
|
|
|||
|
Zubair Kabir, Research Fellow CResT Directorate, St. James's Hospital, Dublin 8.
Send response to journal:
|
Sir, Cancer is not only a concern for the developed nations, but would also be a huge burden in the developing countries over the next two decades (1). In 2000, there were more new cancer cases (53%) and deaths (57%) occurring in developing countries than in developed countries (2). I always have this gut feeling that researchers (ironically the vast majority are from the developed nations!) fail to have a bigger picture of any disease burden, cancer in particular. Paradoxically, health-policy bodies in the developing countries would follow suit any new developments in the developed countries. I understand research in general and cancer research in particular, has never been a priority in most of the developing nations. Not even primary prevention has been conceived as an option, particularly for cancer prevention. Secondary prevention, such as screening may also overwhelm the Western industry (3). I am a public-health doctor from India, but ironically, at all levels of our health care system and right up to the policy-making body, curative management (tertiary level of prevention) has always been a priority. Who is to blame for this paradigm shift? Even at the undergraduate medical training, research in general and public-health research in particular, is completely written off! Overall lung cancer incidence, as well as mortality across both sexes is tending to decline in the majority of the developed nations, but they are on the rise in all the developing nations (2). The impact of smoking cessation programmes seems to have reached a plateau. Contemporaneously, weak carcinogens are emerging as important risk factors in the causal pathway of lung cancer. Much attention is being paid to risk factors, such as environmental tobacco smoke (4) and obesity (5). These observations certainly rekindle our hope and faith in primary prevention, particularly from a global perspective. I wonder if $1900 worth a monthly pill is the right decision for reducing global burden despite its apparent side- effects, or is it Astra-Zeneca sitting at the driving seat? 1. World Health Organization. World Cancer Report. Lyon: International Agency for Research on Cancer Press, 2003. 2. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533-43. 3. Smith R. The screening industry. BMJ 2003; 26 April. 4. Kreuzer M, Krauss M, Kreienbrock L, Jockel K-H, Wichmann H-E. Environmental tobacco smoke and lung cancer: a case-control study in Germany. Am J Epidemiol 2000; 151: 241-50. 5. Calle EE, Rodriguez C, Thurmond KW, Thun MJ. Overweight, obesity and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003; 348: 1625-38. Competing interests: ZK is a Research Fellow in Lung Cancer Epidemiology at the University of Dublin (Trinity College) |
|||
|
|
|||
|
Rokuro Hama, Chairman, NPOJIP: Non-Profit Organization "Japan Institute of Pharmacovigilance" #502 Ohsaka 2-3-1, Tennouji-ku, Osaka, Japan 543-0062
Send response to journal:
|
Did FDA overlook real toxicity of gefitinib in Japan? Sir: According to AstraZeneca (1), FDA approval is based upon data from trial #39. Analyzing 142 of the 216 patients, in the 250 mg/day group, 13.6% (95% CI: 6.4-24.3) of the patients partially responded. But according to the FDA's briefing documents (2), the response rate in the 250 mg/day group was 11.8 % (95%CI: 5.5-18.0) and overall response rate (RR) was 10.2% (95%CI: 6.5%, 15%). By the FDA's analysis, 139 of the 216 patients were actually refractory/intolerant to both a platinum drug and to docetaxel. And after exclusion of additional 32 ineligible patients, eligible patients would be 107. Exclusion of ineligible patients does not change the overall RR. The lengthening of the median duration of response among responders may be the only change in the re-analysis of trial #39. AstraZeneca mentioned that most of the frequent adverse reactions (ARs) were usually mild to moderate. 2% of patients stopped taking it due to ARs. About 1% of interstitial lung disease (ILD) has been observed and approximately 1/3 of them were fatal. The reported incidences of ILD in the 23,000 patient US expanded access program was about 0.3%. In Japanese PMS the reported rate of ILD was about 2%. But the fact is as follows: The mortality rates due to ARs by the intensive surveillance at 4 oncology hospitals in Japan were 11.1% (2/18) (3), 0.7% (1/149), 3.6% (4/112) and 4.8% (5/102) (the latter three data are based on the documents prepared by safety division of MHLW). The overall rate was 3.2 % (12/381: 95%CI; 1.4-4.9) which is significantly higher than the overall mortality rate in phase I and phase II clinical trials (0.3%=2/677) (odds ratio 42.2; 95%CI; 5.6, 319, p<0.001) and almost the same level as that due to adverse event (AEs) in the clinical trials other than in Japan which range 3.1 to 13 % (overall 6.1%=33/544). These facts mean that most of the death due to AEs were decided as non-related by investigators in the clinical trials. After marketing Iressa in Japan, many fatal cases (more than 246 fatal cases up to April 22, 2003) were reported. Thus, most of the death considered as non-related in the clinical trials should have been classified as related. Japanese health ministry has said that the benefits of gefitinib continue to outweigh the dangers, because they consider that the rate of adverse reactions fell dramatically this year after new guidelines for use were introduced (4). But this statement is misleading. One of the reasons is that as you mention (4) decrease of the sales of gefitinib by less than a half. And the other is because the number of deaths is increasing in a particular period as time passed (5). For example total number of deaths due to ILD at the last two month of 2002 was 31 at the end of 2002 which increased to 62 at the end of January 2003 and increased to 107 at the end of April 2003. So the number of death in this year (after new guidelines for use were introduced) will surely increase by two to three times of that at this moment. So I estimate that the mortality rate among gefitinib users might not substantially decreased at all (5). According to the disclosed data of INTACT-1, death rate due to AEs seems higher in the Iressa 250mg group than in the placebo group, although it is not significant strictly speaking (p: about 0.07). However, if one died less in the control group or if one died more in the Iressa group, it might significantly different (5). Most cells have EGFRs and gefitinib not only inhibits the growth of cancer cells but also inhibits physiological replacement of normal cells, particularly of recovering tissues require more epidermal growth factor. This effect has been demonstrated in animal models including injured corneal and bleomycin-induced alveolar damage. Six month toxicity study with clinical dose (oral 5mg/kg) suggests lung toxicity with one fatal dog among 8. Further information can be browsed in our two articles with references (6). References (1) http://www.astrazeneca-us.com/news/article.asp?file=2003050501.htm [accessed May 6, 2003] (2) http://www.fda.gov/ohrms/dockets/ac/02/briefing/3894B1_03_FDA- Medical Officer Review.doc [Accessed May 6, 2003] (3) Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361(9352): 137-9. (4) Dyer O. FDA announces fast track approval of new drug for lung cancer. BMJ 2003;326:1004 http://bmj.com/cgi/content/full/326/7397/1004/d [accessed May 9, 2003] (5) Hama, R. Gefitinib: death due to adverse reaction may be more than a thousand (in Japanese). Web-Kusuri-no-Check May 5, 2003: Available from: http://www.npojip.org/iressa/iressa13.html [accessed May 6, 2003] (6) Hama, R. and Sakaguchi K. gGefitinib Story.h ISDB Newsletter 2003 (Mar): 17 (1): 6-9 available from http://www.npojip.org/english/The- gefitinib-story.pdf [accessed May 6, 2003] Hama, Rokuro MD
Competing interests: None declared |
|||