title: Acceptance of surrogate end points in clinical trials supporting approval of drugs for cancer treatment by the Japanese regulatory agency.
abstract: BACKGROUND
  This study investigated the historic use of different end points to support approval of drugs for cancer treatment in Japan.
  
  
  METHODS
  Anticancer drugs approved between April 2001 and April 2014 were comprehensively investigated using publicly available information.
  
  
  RESULTS
  Before the revision of the guideline for oncology drugs in April 2006 in Japan, >80% of end points supporting approval were response rate and overall survival (OS) was not frequent. After the revision of the guideline in Japan, using OS in pivotal clinical trials applied for approval increased to more than approximately one-third of oncology drugs, although trials with an end point of response rate decreased. Regarding drugs for major cancers including non-small-cell lung cancer, gastric cancer, colorectal cancer, and breast cancer, survival was used as an end point in 44.0%, whereas surrogate end points were used in 56.0%. Exploration of potential factors for using surrogate end points other than survival carried out through determinations of odds ratios and 95% confidence intervals identified 'orphan drug designation in Japan' and 'accelerated approval by the U.S. Food and Drug Administration' as significant factors.
  
  
  CONCLUSIONS
  The revised guideline for oncology drugs in Japan requires the results of phase 3 studies with survival as an end point at the time of new drug application at least for major cancers. The regulatory agency in Japan also accepts surrogate end points as end points supporting approval besides survival; however, the number of surrogate end points has decreased after the revision of the guideline. We consider that accepting surrogate end points in the Japanese regulatory systems is important to approve oncology drugs quickly in Japan.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, Tokyo; Astellas Pharma, Inc., Tokyo, Japan. Electronic address: hideki.maeda@astellas.com.
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Kurokawa
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D017277:Drug Approval; D004341:Drug Evaluation; D006801:Humans; D007564:Japan; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers
keywords: Japan; PMDA; drugs for cancer treatment; oncology drugs; surrogate end point; survival