Investigational New Drugs

, Volume 37, Issue 5, pp 1086–1093 | Cite as

The drug lag and associated factors for orphan anticancer drugs in Japan compared to the United States

  • Hiroki NakayamaEmail author
  • Naoki Matsumaru
  • Katsura Tsukamoto
Phase III Studies


The approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orphan anticancer drugs in 2016–2017 was 727.0 days (interquartile range, IQR, 310.0–1054.3). The approval lag was significantly correlated with the submission lag (correlation coefficient = 1.00, P < 0.001) but not with the review-time lag (correlation coefficient = −0.16, P = 0.22). The submission lag was significantly longer for orphan anticancer drugs than non-orphan drugs (median, 712.5 days [IQR, 186.0–1448.3] vs. 387.0 days [92.8–1096.0], P = 0.023). External collaboration in drug development was associated with a longer submission lag (coefficient = 762.1, P = 0.017), while breakthrough therapy designation in the US was associated with a shorter submission lag (coefficient = −832.8, P = 0.035). In conclusion, we revealed that an approval lag for orphan anticancer drugs still existed in 2016–2017. A submission lag for orphan anticancer drugs was the main component affecting the approval lag, and was longer than that for non-orphan drugs. External collaboration in drug development may be a potential factor in reducing the submission lag for orphan anticancer drugs.


Cancer Orphan drug Drug lag Japan External collaboration Breakthrough therapy designation 



The authors express their gratitude to Katsuya Nakano for his review of the study from a regulatory affairs viewpoint and to Makoto Tanaka for his useful suggestions.

Compliance with Ethical Standards

Conflict of Interest

Hiroki Nakayama is an employee of Astellas Pharma Inc. Naoki Matsumaru declares that he has no conflict of interest. Katsura Tsukamoto declares that he has no conflict of interest. The Global Regulatory Science laboratory is financially maintained by donations from Otsuka Pharmaceuticals Co., Ltd.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10637_2018_612_MOESM1_ESM.pdf (147 kb)
Table S1 (PDF 146 kb)


  1. 1.
    Blay JY, Coindre JM, Ducimetiere F, Ray-Coquard I (2016) The value of research collaborations and consortia in rare cancers. Lancet Oncol 17(2):e62–e69. CrossRefGoogle Scholar
  2. 2.
    Gatta G, van der Zwan JM, Casali PG, Siesling S, Dei Tos AP, Kunkler I, Otter R, Licitra L, Mallone S, Tavilla A, Trama A, Capocaccia R (2011) Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer 47(17):2493–2511. CrossRefGoogle Scholar
  3. 3.
    Heemstra HE, van Weely S, Buller HA, Leufkens HG, de Vrueh RL (2009) Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today 14(23–24):1166–1173. CrossRefGoogle Scholar
  4. 4.
    Ministry of Health, Labour and Welfare (2015) Overview of orphan drug/medical device designation system. (in Japanese) Accessed 06 Feb 2018
  5. 5.
    Maeda K, Kaneko M, Narukawa M, Arato T (2017) Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs. Orphanet J Rare Dis 12(1):143. CrossRefGoogle Scholar
  6. 6.
    Ueno T, Asahina Y, Tanaka A, Yamada H, Nakamura M, Uyama Y (2014) Significant differences in drug lag in clinical development among various strategies used for regulatory submissions in Japan. Clin Pharmacol Ther 95(5):533–541. CrossRefGoogle Scholar
  7. 7.
    Yonemori K, Hirakawa A, Ando M, Hirata T, Yunokawa M, Shimizu C, Katsumata N, Tamura K, Fujiwara Y (2011) The notorious "drug lag" for oncology drugs in Japan. Investig New Drugs 29(4):706–712. CrossRefGoogle Scholar
  8. 8.
    Kawabata-Shoda E, Masuda S, Kimura H (2012) Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan. J Clin Pharm Ther 37(5):547–552. CrossRefGoogle Scholar
  9. 9.
    Maeda H, Kurokawa T (2015) Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan? Int J Clin Oncol 20(6):1072–1080. CrossRefGoogle Scholar
  10. 10.
    Nakayama H, Tsukamoto K (2018) Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan. Investig New Drugs.
  11. 11.
    Tsuji K, Tsutani K (2010) Approval of new drugs 1999-2007: comparison of the US, the EU and Japan situations. J Clin Pharm Ther 35(3):289–301. CrossRefGoogle Scholar
  12. 12.
    Hirai Y, Kinoshita H, Kusama M, Yasuda K, Sugiyama Y, Ono S (2010) Delays in new drug applications in Japan and industrial R&D strategies. Clin Pharmacol Ther 87(2):212–218. CrossRefGoogle Scholar
  13. 13.
    Ito Y, Narimatsu H, Fukui T, Fukao A, Yoshioka T (2013) Critical review of 'Public domain application': a flexible drug approval system in Japan. Ann Oncol 24(5):1297–1305. CrossRefGoogle Scholar
  14. 14.
    Maeda H, Kurokawa T (2014) Differences in maximum tolerated doses and approval doses of molecularly targeted oncology drug between Japan and Western countries. Investig New Drugs 32(4):661–669. CrossRefGoogle Scholar
  15. 15.
    Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452–458. CrossRefGoogle Scholar
  16. 16.
    U.S. Food and Drug Administration (2014) Guidance for industry expedited programs for serious conditions – drugs and biologics. Accessed 06 Feb 2018
  17. 17.
    Ministry of Health, Labour and Welfare (2015) On the revision of the standard review timeline for new drug applications. (in Japanese) Accessed 06 Feb 2018
  18. 18.
    Pharmaceuticals and Medical Devices Agency (2017) Review report for pralatrexate. (in Japanese) Accessed 06 Feb 2018
  19. 19.
    Mundipharma K.K. (2017) Common technical document for pralatrexate. (in Japanese) Accessed 06 Feb 2018
  20. 20.
    U.S. Food and Drug Administration (2009) Approval letter for pralatrexate. https://www.accessdatafdagov/drugsatfda_docs/appletter/2009/022468s000ltr.pdf Accessed 06 Feb 2018
  21. 21.
    Jones A (2007) Minimizing leakage of value from R&D alliances. Nat Rev Drug Discov 6(9):711–719. CrossRefGoogle Scholar
  22. 22.
    Tanaka M, Matsumaru N, Tsukamoto K (2018) Influence of expedited programs in the United States on oncology drug development in Japan. Ther Innov Regul Sci.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Healthcare Policy & CSRAstellas Pharma Inc.TokyoJapan
  2. 2.Global Regulatory ScienceGifu Pharmaceutical UniversityGifuJapan

Personalised recommendations