|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.20.3307 on November 10 2008 © 2008 American Society of Clinical Oncology.
Cooperative Relationship Between Pharmaceutical Companies, Academia, and Media Explains Sharp Decrease in Frequency of Pulmonary Complications After Bortezomib in Japan
Division of Strategic Outcome Research Program for Cancer Control, Ministry of Health, Labor and Welfare Commission, Japan Cancer Society, Tokyo, Japan; Division of Exploratory Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan
Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
Division of Exploratory Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan
Third Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
Division of Exploratory Research, the Institute of Medical Science, University of Tokyo, Tokyo, Japan To the Editor: Bortezomib (Velcade; Millenium Pharmaceuticals, Cambridge, MA) is a promising new drug for multiple myeloma that was approved by the US Food and Drug Administration in May 2003. Japan lags behind Europe and the United States in the release of new drugs. There, unapproved, privately imported bortezomib was administrated without clinical trials until December 2006, when it was approved and released.1,2 In October 2005, it became clear that patients who were administered bortezomib before approval in Japan had fatal pulmonary complications.3 This was 14 months before bortezomib received approval from the Ministry of Health, Labor and Welfare and appeared on the open market in Japan. At that time, there were few reports about severe pulmonary complications with bortezomib in Europe and the United States.4,5 Medical staff did not recognize that bortezomib might be causing severe pulmonary complications in some patients. By reading reports, medical staff involved in caring for these patients realized the reason for these complications and took measures to reduce the adverse effects. In consequence, it became clear that the frequency of pulmonary complications that occurred before bortezomib became commercially available was dramatically decreased when these adverse effects were reported in the interim report of the postmarketing clinical trial that had been recently disclosed publicly. Information about how the adverse effects of bortezomib were overcome in a short period will prove to be useful in assessing adverse effects of other new drugs. But in the case in question, additional details about the process are still not known. To investigate the frequency of and reasons for pulmonary complications, we reviewed scientific articlespapers, Web-based information from societies and pharmaceutical companies, newspaper reports, and assessment reports from the Pharmaceuticals and Medical Devices Agency (PMDA). We examined information dating from October 2003, when pulmonary complications were first discovered, to December 2007, when the intermediate results of postmarketing clinical tests were reported. We also interviewed the concerned parties (Fig 1).
Clinical trials of bortezomib as the sole treatment for multiple myeloma patients were started in Japan by Janssen Pharmaceutical Corp in May 2004. Registration of patients was stopped because one patient died as a result of pulmonary complications after bortezomib administration. As a result of meetings held by a third-party evaluation committee, patients with lung problems seen on imaging tests such as a computed tomography were excluded from the clinical trial. Registration of patients was then resumed.6 Finally, thirty-four patients were registered at the clinical trial; only one (3%) had pulmonary complications. Corticosteroids were not administered in combination with bortezomib to any of the patients. Almost all the patients whose Karnofsky performance status was > 80% were in better health7 compared with patients who received privately imported bortezomib (Table 1). This information had not been reported by the media until it was made available on Janssen's Web site in October 2005.
In October 2005, Miyakoshi et al suspected that bortezomib was the cause of the pulmonary complications because of their experience administering bortezomib to patients who later suffered from pulmonary complications. Miyakoshi contacted colleagues and researchers and learned that similar cases often occurred (S. Miyakoshi, personal communication, June 2008). Miyakoshi's research group investigated medical records from 13 patients who were administered bortezomib that was imported between January 2004 and September 2005.3 Four patients (31%) had severe pulmonary complications and two of them (14%) died (Table 1). Four patients who had pulmonary complications were not given corticosteroids at the same time. Performance status (PS; Eastern Cooperative Oncology Group) in these four patients and clinical information for nine patients who had no pulmonary complications were not available. In October 2005, Miyakoshi et al sent the first report about the possibility of pulmonary complications with bortezomib to PMDA, Janssen, and a company that imports bortezomib (RHC USA Corp, Honolulu, HI). PMDA asked Jansses to issue announcements to patients who took part in the clinical trial and to medical staff about the severe pulmonary complications with bortezomib. In the past, information about adverse effects in patients who took part in clinical trials had not been made available except to the hospital that took part in the clinical trial. This time, Jansses showed this information on its Web site on October 24th, 2007, in compliance with PMDA's request. RHC USA Corp wrote letters to doctors on October 25th, 2005, providing them with the information. Miyakoshi et al. submitted this result to Blood on November 16th, 2005, and posted it online on January 12th, 2006.3 Miyakoshi pointed out the problem of information disclosure related to private medicine importing during an online interview.8 In August and November 2006, American hospitals reported that African Americans had the same severe pulmonary complications with bortezomib.9,10 The Japanese Society of Hematology and the Japanese Society of Clinical Hematology together surveyed self-reported pulmonary complications on a nationwide scale in November 2005. They showed the results on their Web sites on December 6th, 2005. The results were reported in the Asahi Shimbun newspaper on December 11th, and in Nikkei Biotech on December 19th. Final results of the investigation were shown on both societies’ Web sites on March 20th, 2006, and were also shown in both societies’ academic journals.1,2 A total of 46 patients were administered imported bortezomib from January 2003 to July 2005. Their median Karnofsky PS was 70% (range, 20% to 100%).11 Seven (15%) had pulmonary complications, and three (6.5%) died. Twenty-five (54%) were administered corticosteroids with bortezomib and experienced significantly decreased frequency of pulmonary complications.1 Bortezomib was approved by the Ministry of Health, Labor and Welfare on October 2006, and sales began on the open market in December 2006. After being requested to investigate usage results for all patients, Janssen set a proper usage criterion and recommended that doctors withhold administration of bortezomib from patients whose Karnofsky PS was < 60 and who had interstitial lesions on their chest radiographs. It came to light in January 2007 that two patients with PS 4 who were administered bortezomib had died of pulmonary complications.12 This was discussed at a third-party evaluation committee headed by Jansses, after which the corporation strongly recommended that doctors not use bortezomib for PS 3 or PS 4 patients. Intermediate results of postmarketing clinical tests performed in 666 patients who were administered bortezomib after it came to market in November 2007 were reported on Janssen's Web site in December 2007. Twenty-four (3.6%) had pulmonary complications, and three (0.5%) died (Table 1).13 Information about PS has not been made available to the public. It came into the open in a May 2008 Janssen lecture delivered in Tokyo to commemorate the sale of Velcade that corticosteroids were administered with bortezomib to almost 70% of patients. The drug manufacturer in the United States showed pulmonary complications for Asians in the product document of bortezomib in May 2006.14 Compared with the period when bortezomib was being imported by doctors, the frequency and lethality rate of pulmonary complications at the postmarketing clinical trial decreased. We think some possible causes for this are as follows: first, combined administration with corticosteroids became popular. Fifty-four percent of patients who were administered imported bortezomib were also administered a steroid in combination.3,6 This frequency increased to 70% at the postmarketing clinical trial. The steroid has an antitumor effect on multiple myeloma and is used with many kinds of medicine. Gotoh et al1,2 showed that the risk of pulmonary complications decreased with a combination of bortezomib and the steroid. As a result of this study, some doctors might begin using bortezomib in combination with the steroid for preventing pulmonary complications. Second, as reports of pulmonary complications with bortezomib increased, some doctors began to choose patients carefully. During the clinical trial, Miyakoshi et al found that pulmonary complications occurred in succession with patients in poor general condition who were administered an unapproved drug. After bortezomib went on the market, Janssen set a proper usage criterion that included lung disease history and Karnofsky PS, and the company thoroughly educated doctors. This probably contributed widely to the decrease in adverse events in postmarketing clinical trials. In this case, the period between the discovery of pulmonary complications with bortezomib and the adoption of countermeasures was short. It took only 14 months from the discovery of possible pulmonary complications with bortezomib by Miyakoshi et al to the start of the postmarketing clinical test. During this period, strong measures to reduce the pulmonary complications were taken in clinical practice, as presented in this article. The case highlights some interesting points regarding the communication of medical information. Miyakoshi, who first realized the complications, called and sent e-mails directly to neighborhood hospitals to inquire about this. This shows that doctors can exchange information easily because of the widespread use of information technology. It would have taken much longer for doctors to realize the problem of pulmonary complications with bortezomib without the advantage of information technology. In addition, Miyakoshi et al promptly communicated the risk of adverse effects to the PMDA, Janssen, academic societies, and import agencies. In Japan, a system for collecting information on adverse events related to unapproved drugs has not been established.15 In this case, however, the information was transmitted to doctors comprehensively and promptly because Miyakoshi et al shared their finding of adverse effects related to bortezomib with several organizations, each of which disclosed the information in their own way. Various media reported this problem at an early stage. Mass media such as the Asahi Shinbun newspaper reported that not only medical staff but also patients and their families recognized the adverse effects of bortezomib. When we think about broadcasting information to the nation, it is necessary to work together with the mass media and medical community, and we should consider the special qualities of each form of media in order to provide information effectively and efficiently. It has been shown in previous situations that mass media such as newspapers can distribute information to many people, but there is a possibility that the information may be incomplete or inaccurate.16 However, although they are targeted only at medical professionals, industry publications such as Medical Research Information Center and Nikkei Biotech can provide more accurate and detailed information in a way that cuts across disciplinary divisions in the world of specialized medicine. In this case, different types of media supplied information concerning pulmonary complications with bortezomib through journals and academic societies, and the risk became widely known in a very short time. The information about pulmonary complications with bortezomib was shared with concerned parties in a short time, and administration of bortezomib was optimized. In this process, in addition to academic societies and pharmaceutical companies, the mass media, use of e-mail, and the Internet played a stronger role. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS This study is supported by a grant from Health and Labor Sciences Research Grants, the third-term comprehensive control for cancer (H18-011) from the Ministry of Health, Labor and Welfare, Tokyo, Japan NOTES published online ahead of print at www.jco.org on November 10, 2008. REFERENCES 1. Gotoh A, Ohyashiki K, Oshimi K, et al: Lung injury associated with bortezomib therapy in relapsed/refractory multiple myeloma in Japan: A questionnaire-based report from the "Lung Injury by Bortezomib" joint committee of the Japanese society of hematology and the Japanese society of clinical hematology. Int J Hematol 84:406-412, 2006[CrossRef][Medline] 2. Gotoh A, Ohyashiki K, Oshimi K, et al: Lung injury associated with bortezomib therapy in relapsed/refractory multiple myeloma in Japan: A questionnaire-based report from the "Lung Injury by Bortezomib" Joint Committee of the Japanese Society of Hematology and the Japanese Society of Clinical Hematology [in Japanese]. Rinsho Ketsueki 47:1521-1527, 2006[Medline] 3. Miyakoshi S, Kami M, Yuji K, et al: Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. Blood 107:3492-3494, 2006 4. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 5. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004[CrossRef][Medline] 6. Pharmaceuticals and Medical Devices Agency: Assessment reports of Bortezomib [in Japanese]. http://www.info.pmda.go.jp/shinyaku/g061004/800155000_21800AMX10868000_A100_3.pdf 7. Ogawa Y, Tobinai K, Ogura M, et al: Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Cancer Sci 99:140-144, 2008[Medline] 8. MRIC: MRIC Extraordinary, Vol. 5: Interview with Dr. Miyakoshi [in Japanese]. http://mric.tanaka.md/2006/02/28/2006_mric_vol.html 9. Ohri A, Arena FP: Severe pulmonary complications in African-American patient after bortezomib therapy. Am J Ther 13:553-555, 2006[CrossRef][Medline] 10. Boyer JE, Batra RB, Ascensao JL, et al: Severe pulmonary complication after bortezomib treatment for multiple myeloma. Blood 108:1113, 2006 11. Japanese Society of Hematology: (Home page) [in Japanese]. http://www.jshem.or.jp/en/ 12. Janssen Pharmaceutical Corporation: Report from third-party evaluation committee on pulmonary complication [in Japanese]. http://www.janssen.co.jp/sickness/velcade/pdf/discussion-result_070119.pdf 13. Janssen Pharmaceutical Corporation: Intermediate results of post-marketing clinical tests: Bortezomib (December 2007) [in Japanese].http://www.janssen.co.jp/inforest/portalexternal/diviewitemeventdatafiledownload?paf_gear_id=2200032&cid=cnt45112 14. US Food and Drug Administration: VELCADE (bortezomib) for injection. http://www.fda.gov/medwatch/safety/2006/Dec_PIs/Velcade_PI.pdf 15. Miyakoshi S, Kusumi E, Kodama Y, et al: Adverse events of unapproved drugs in Japan. Lancet Oncol 9:414-415, 2008[CrossRef][Medline] 16. Moynihan R, Bero L, Ross-Degnan D, et al: Coverage by the news media of the benefits and risks of medications. N Engl J Med 342:1645-1650, 2000
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
