Web-Kusuri-no-Check May 14, 2003

Gefitinib Information No4

HAMA's Rapid response to BMJ News
"Did FDA overlook real toxicity of gefitinib in Japan?"

AstraZeneca announced that Gefitinib (IRESSA) was approved by FDA and by the Australian regulatory agency recently.


BMJ also reported this news.

I made a rapid response to the BMJ's news.

Please browse it and the letter to the FDA by Health Research Group of Public Citizen as well at:


Following is the beginning of HAMA's rapid response to BMJ News:

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).

Continued: Please browse the following at:


Further information could be browsed in our two articles with references 5, 6, 7) and the letter to FDA 8) and the press release 9) by Public Citizen's Health Research Group.

13 May 2003
Rokuro Hama,
Chairman, NPOJIP: Non-Profit Organization "Japan Institute of Pharmacovigilance"
#502 Ohsaka 2-3-1, Tennouji-ku, Osaka, Japan 543-0062


  1. http://www.astrazeneca-us.com/news/article.asp?file=2003050501.htm [accessed May 6, 2003]
  2. FDA- Medical Officer Review [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 [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 [accessed May 6, 2003]
  6. Hama, R. and Sakaguchi K. "Gefitinib Story."; ISDB Newsletter 2003 (Mar): 17 (1): 6-9 [accessed May 6, 2003]
  7. Hama, R. "Iressa should have never been approved"
  8. Public Citizen's Health Research Group.
  9. Public Citizen's Health Research Group.