Approval of new drugs 1999-2007: comparison of the US, the EU and Japan situations.

BACKGROUND AND OBJECTIVE: 'Drug lag' was a much-debated issue around the world during the 1970s and 1980s. Because public recognition of drug lag is recent in Japan, the issue has not been studied extensively. Therefore, we created a database of new drug approvals in the US, the European Union (EU) and Japan between 1999 and 2007 and examined the drug lag situation in these three major pharmaceutical markets. METHODS: New drugs approved in the US, the EU and Japan between 1999 and 2007 were identified by their International Non-proprietary Names (INN), and information was gathered primarily from the websites of regulatory agencies of said regions and 'IMS R&D Focus'. In assessing absolute drug lag, we used as variables the number and the percentage of approved drugs in each region out of a total of new drugs approved either in the three regions in the study period. In assessing relative drug lag, two variables were used; one variable was the number and percentage of first approvals in the regions, and the other variable was the approval lag against the first approval granted to each drug in the three regions. Sub-group analyses were conducted according to the originator's nationality, the origin of the substance (biopharmaceuticals and non-biopharmaceuticals) and the therapeutic group. RESULTS AND DISCUSSION: Of the 398 new drugs, 325 (81.7%) were approved in the US, 314 (78.9%) in the EU and 220 (55.3%) in Japan. The median approval lag for the US, the EU and Japan was 0 months, 2.7 months and 41.0 months, respectively. Although the US was ahead of the other two regions, the difference between the US and the EU was small. On the contrary, a striking drug lag was observed for Japan. The approval rate in Japan was low for both the drugs of US origin (43.6%) and EU origin (56.1%). Meanwhile, the drugs of Japanese origin were approved at a high rate in Japan (94.5%). It was surmised that the delay in filing new drug applications for drugs of non-Japanese origin was the main reason for the drug lag in Japan. However, the percentage of approval of new drugs varied according to the therapeutic group, implying that there were different reasons for the drug lag in each group. CONCLUSION: This report provides a comprehensive view of drug lag in the three regions. More detailed analyses are necessary in order for a more in-depth discussion of the background factors, impacts and measures for the drug lag,which is especially noticeable in Japan.

Cost-effectiveness analysis of XELOX for metastatic colorectal cancer based on the NO16966 and NO16967 trials.

BACKGROUND: The purpose of the study was to evaluate the cost-effectiveness of capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX4) as first-line or second-line chemotherapy in patients with metastatic colorectal cancer. METHODS: On the basis of NO16966 and NO16967 trials, mean costs and effectiveness were calculated from patient-level data. Until the disease progressed, the mean costs were calculated from the perspective of health-care payers in Japan. We estimated mean quality-adjusted progression-free survival days (QAPFSD), considering adverse events and patient preference for chemotherapy regimens. Utility scores were obtained by a web-based survey from general people, randomly sampled from a large panel adjusted for sex and age. RESULTS: Incremental effectiveness of XELOX as first-line and second-line chemotherapy for colorectal cancer patients was significantly greater. By use of XELOX, patients gained 10.5 QAPFSD from first-line treatment or 11.3 QAPFSD from second-line treatment. Capecitabine plus oxaliplatin (XELOX) was also proven to significantly reduce treatment costs by 3000 euro (JPY 360,000) and 2300 euro (JPY 270,000) for first-line and second-line treatment, respectively. In health-care settings in the United Kingdom, XELOX decreased medical costs for National Health Service by 7600 pound and 3900 pound for patients who received first-line and second-line treatment, respectively. CONCLUSION: Capecitabine plus oxaliplatin (XELOX) as first-line and second-line chemotherapy was 'dominant'. In terms of effectiveness and cost, XELOX was superior to FOLFOX4.

Personal imports of drugs to Japan in 2005--an analysis of import certificates.

BACKGROUND: Personal imports of unapproved drugs are made by physicians and patients in Japan. Such imports require submission of a request for an import certificate from the Regional Bureau of Health and Welfare (RBHW). So far, there have been few reports on personal imports of drugs in Japan. OBJECTIVE: To assess the extent and nature of personal imports of drugs in Japan. METHODS: The date, product name and amount of drug imported were provided by RBHW for each personal import made by physicians in 2005. All imports were classified into several groups including whether they were for 'prescription drugs for non-cosmetic use (PDNC)' or 'prescription drugs for cosmetic use (PDC)'. Identification of PDNC was made by International Non-proprietary Name (INN). All drugs were classified under therapeutic groups. For the most frequently imported unapproved drugs, the approval year in the US/EU and development status in Japan were recorded. RESULTS: A total of 12 196 personal imports were initiated by physicians in 2005. 5428 were for PDNCs corresponding to 242 drugs by INN. 55 PDNCs were each the subject of 10 or more imports. 11 drugs (252 imports) out of the top 55 PDNCs were available on the Japanese market during 2005 and 44 (4713 imports) were not approved. Of the 44 unapproved drugs, 11 (1019 imports) had been approved and 10 (2785 imports) were in the pre-registration phase as of December 31, 2006. Of the 44 unapproved drugs, 12 (1213 imports) were approved during 2000-2004, and 17 (3138 imports), during 1995-1999 in the US or EU. While the majority of imported drugs were antineoplastic drugs, drugs for various kinds of non-serious diseases were also imported. CONCLUSIONS: A substantial number of unapproved drugs were being imported to Japan. A formal system for monitoring the use of those drugs should be established.

Medicinal herbs for hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is a serious health problem world-wide. Medicinal herbs are increasingly being used for hepatitis C. OBJECTIVES: To assess the efficacy and safety of medicinal herbs for hepatitis C virus infection. SEARCH STRATEGY: Searches were applied to The Controlled Trial Registers of The Cochrane Hepato-Biliary Group, The Cochrane Complementary Medicine Field, and The Cochrane Library as well as MEDLINE, EMBASE, BIOSIS, Chinese and Japanese databases. Five Chinese journals and one Japanese journal were handsearched. No language restriction was used. SELECTION CRITERIA: Randomised clinical trials comparing medicinal herbs (single herb or compound of herbs) versus placebo, no intervention, general non-specific treatment, other herbal medicine, or interferon and/or ribavirin treatment. Trials of medicinal herbs plus interferon and/or ribavirin versus interferon and/or ribavirin alone were also included. Trials could be double-blind, single-blind, or unblinded. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. The methodological quality of the trials was evaluated using the generation of allocation sequence, allocation concealment, double blinding, and the Jadad-scale. The outcomes were presented as relative risk or weighted mean difference, both with 95% confidence interval. MAIN RESULTS: Ten randomised trials, including 517 patients with mainly chronic hepatitis C, evaluated ten different medicinal herbs versus various control interventions (four placebo, four interferon, two other herbs). The methodological quality was considered adequate in four trials and inadequate in six trials. Compared with placebo in four trials, none of the medicinal herbs showed positive effects on clearance of serum HCV RNA or anti-HCV antibody or on serum liver enzymes, except one short-term trial in which a silybin preparation showed a significant effect on reducing serum aspartate aminotransferase and gamma-glutamyltranspeptidase activities. The herbal compound Bing Gan Tang combined with interferon-alpha showed significantly better effects on clearance of serum HCV RNA (relative risk 2.54; 95% confidence interval 1.43 to 4.49) and on normalisation of serum alanine aminotransferase activity (relative risk 2.54; 95% confidence interval 1.43 to 4.49) than interferon-alpha monotherapy. The herbal compound Yi Zhu decoction showed a significant effect on clearance of serum HCV RNA and normalisation of ALT levels compared to glycyrrhizin plus ribavirin. Yi Er Gan Tang showed a significant effect on normalising serum alanine aminotransferase compared to silymarin plus glucurolactone. There was no significant efficacy of the other examined herbs. The herbs were associated with adverse events. REVIEWER'S CONCLUSIONS: There is no firm evidence of efficacy of any medicinal herbs for HCV infection. Medicinal herbs for HCV infection should not be used outside randomised clinical trials.

[The Cochrane Collaboration: the present and the future].

The Cochrane Collaboration has developed in response to the call for systematic, up-to-date reviews of all relevant randomized controlled trials (RCTs) of health care. Both evidence-based medicine (EBM) and the Cochrane Collaboration have been gaining attention of healthcare professionals in Japan recently. Ways for Japanese people to contribute to the Cochrane Collaboration are as follows: participating in a collaborative review group as a reviewer; increasing registry number of Japanese RCT articles; and Japanese translation of their outputs and its dissemination. Establishment of Japan Cochrane Center will integrate and promote the related activities. Furthermore, the positive recognitions for the Cochrane Collaboration and EBM among Japanese people can improve environments for conducting clinical trials and epidemiological studies in Japan.

Discriminant analysis in renal histological diagnosis of primary glomerular diseases.

Differences in clinical and laboratory findings between different renal histological lesions were examined in 138 patients with primary glomerular diseases, and discriminant analysis was carried out in 72 patients to determine whether each histological type could be distinguished by the linear combination of these findings. The histological types were classified into 7 groups: minimal change nephrotic syndrome (MCNS); focal glomerular sclerosis (FGS); membranous nephropathy (MN); membranoproliferative GN (MPGN); proliferative GN (PGN); PGN with focal crescents (P X fc); and minor glomerular lesions (MGL). Ten variantes were selected from the clinical and laboratory findings in the early stage of the disease: sex, age of onset, acute onset, oliguria, urine protein, RBC in urinary sediment, serum albumin, serum total cholesterol, serum creatinine, and systolic blood pressure. In the discriminant analysis made regarding all these items collectively as continuous variantes, there was a significant difference (p less than 0.001) in the combination patterns of the variantes among histological types. Therefore, further analysis was performed using canonical axes and a multi-stage discriminant method. The canonical score and data obtained by a multi-stage discriminant method demonstrated that MCNS, MN, MPGN, and the group of PGN, P X fc and MGL could be distinguished from each other well, but that the degree of proliferation or the presence of focal lesions could not be predicted. As a result of these studies, we obtained a discriminant formula with which we could predict, with fairly high accuracy, some histological types on the basis of data on the 10 items mentioned.