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Originally published as JCO Early Release 10.1200/JCO.2009.23.9020 on November 2 2009 © 2009 American Society of Clinical Oncology.
Critical Review of the Determination Process by the Japanese Reviewing Authority in Approving the Additional Efficacy of Fludarabine PhosphateDivision of Social Communication System for Advanced Clinical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Cancer Control Programs Administration Division, Center for Cancer, Control and Information Services, National Cancer Center, Tokyo, Japan
Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Division of Social Communication System for Advanced Clinical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan To the Editor: The off-label use of drugs is a common practice among clinicians.1 Use of fludarabine as a part of preparative regimens has increased dramatically with the recent prevalence of reduced-intensity stem-cell transplantation (RIST).2 This drug was approved for chronic lymphocytic leukemia in 1999 in Japan, but off-label use has been performed as a part of preparative regimens for RIST. In December 2004, a petition calling for the approval of the drug as a part of preparative regimens for hematopoietic stem-cell transplantation was submitted by related medical societies to the Ministry of Health, Labour and Welfare. Subsequently, in April 2006, Nihon Schering K.K. (now Bayer Yakuhin Ltd, Osaka, Japan) applied for an expansion of the indications via a so-called public domain application, that is, by showing that the efficacy of the drug relevant to the application is widely acknowledged, and fludarabine was approved as a part of preparative regimens for allogeneic hematopoietic stem-cell transplantation in May 2008. New drugs are approved mainly on the basis of clinical evidence. However, for a new drug for a rare disease, for example, it may be difficult to compile high-quality evidence by means of clinical trials. It is supposed that whether it is actually approved is largely related to the determination of the review authority, which in Japan is the Pharmaceuticals and Medical Devices Agency (PMDA). However, in most cases to date, determination by the reviewing authority has not been examined academically. This is in contrast to the juristic field, in which the judgment by the court is often critically reviewed. Therefore, we herein critically reviewed the determination by the reviewing authority in the process of approving fludarabine. A summary of this public domain application and the determination by the PMDA is shown in Table 1.3 After this regulatory review, it was approved by the Ministry of Health, Labour and Welfare in Japan.
We re-evaluated the data of 98 articles that had been submitted to the PMDA. There were no randomized controlled trials. The engraftment rate was difficult to evaluate because of inconsistent criteria (Table 2).
The data that were submitted for application did not include any studies containing substantial evidence, and fludarabine was not proven to be safe and effective as a part of preparative regimens at the same level as that of a common anticancer drug application. However, these studies and the report by the Japan Society for Hematopoietic Cell Transplantation revealed that fludarabine is widely used both domestically and internationally. This shows that constant consensus regarding the efficacy and safety of fludarabine as a part of preparative regimens has been obtained in clinical practice. As for the postdisease efficacy, it was difficult to determine from the submitted original studies and the studies that were quoted as grounds for the description in the textbooks and guidelines. The review report explained that many of the diseases were included on the basis of whether they were described in the textbooks and guidelines, which indicates that their selection might have been affected by the opinions of a minority of the persons in authority. We revealed that the determination by PMDA was mainly influenced by a consensus opinion in clinical practice. We concluded that this determination by the PMDA is appropriate for the following reason: more than 1,000 cases of usage in clinical practice beyond the coverage for care had been accumulated at the time of the application in Japan. In this situation, participating in a strictly designed clinical trial would result in less merit both for patients and healthcare professionals than using the drug outside clinical trials. Therefore, it would be difficult to conduct such a clinical trial in the future. In fact, a physician-led clinical trial aimed at establishing the additional efficacy of fludarabine was cancelled because the targeted number of patients could not be achieved.4 Therefore, we concluded that it was a practical determination by the PMDA to give approval mainly based on the consensus in clinical practice. The approval was granted with a limitation on the indicated diseases. Because the graft-versus-malignancy effects largely depend on the size of a tumor, the growth rate of a tumor, and the graft-versus-malignancy effect sensitivity of the primary disease, the PMDA determined that it was necessary to individualize the indicated diseases and defined the indication per disease. However, as this opinion was expressed in a special conference in which the PMDA listened to opinions from third-party healthcare professionals in considering the efficacy of this drug as a part of preparative regimens, an evaluation thereof should be made according to graft survival duration. Therefore, there may be a method for establishing the efficacy and effect for allogeneic hematopoietic cell transplantation without determining the indicated disease. Intravenous busulfan,5 which has been recently approved, was given approval as a part of preparative regimens for allogeneic hematopoietic stem-cell transplantation per the following justifications: 1 the efficacy can be evaluated with engraftment as an end point, which can be evaluated separately from the efficacy of transplantation itself, and 2 it is difficult in practice to compile sufficient evidence per individual disease. However, the review report by the PMDA does not contain a sufficient explanation of the difference in determination between intravenous busulfan and the fludarabine. In the case of fludarabine, given that it would be difficult to conduct a new clinical trial, it would be difficult to compile sufficient evidence per disease in the future. For the approval of a public domain application for a new indication, a drug without certain safety and efficacy may be used in clinical practice because no clinical trials were not conducted in Japan. Instead, it is necessary to gather information on the safety and efficacy even after marketing. In fludarabine, a voluntary postmarketing surveillance study will be conducted (Table 3). These responses could be a model case in submitting a public domain application.
In conclusion, we showed that the determination process by the PMDA was both practical and appropriate. The result of this study may not be generalizeable outside of Japan because of the difference in the approving process; however, we believe that critical reviews of the determination process by reviewing authorities would be beneficial for the optimization of approving process of drugs in many countries other than Japan, despite of the differences in the approving system among those countries. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Radley DC, Finkelstein SN, Stafford RS: Off-label prescribing among office-based physicians. Arch Intern Med 166:1021–1026, 2006. 2. Locatelli F: Reduced-intensity regimens in allogeneic hematopoietic stem cell transplantation for hemoglobinopathies. Hematology Am Soc Hematol Educ Program, 398–401, 2006. 3. Pharmaceuticals and Medical Devices Agency. Assessment Reports of Fludarabine From the Pharmaceuticals and Medical Devices Agency (in Japanese). http://www.info.pmda.go.jp/shinyaku/r08/0402/630004000_21700AMY00037000_A100_1.pdf. 4. Saito AM, Kami M, Mori S, et al: Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan. Am J Hematol 82:873–880, 2007.[CrossRef][Medline] 5. Pharmaceuticals and Medical Devices Agency. Assessment Reports of Busulfan Injection From the Pharmaceuticals and Medical Devices Agency (in Japanese). http://www.info.pmda.go.jp/shinyaku/g060704/23014500_21800AMY10108000_A101_3.pdf.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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