Investigational New Drugs

, Volume 36, Issue 4, pp 702–708 | Cite as

Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan

  • Hiroki Nakayama
  • Katsura Tsukamoto


The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281.0 days [interquartile range, 263.3–336.0]; 222.5 patients [66.0–454.3]) were significantly lower than those on non-orphan drugs (353.0 days [277.0–535.5]; 521.0 patients [303.5–814.5], respectively) (P < 0.001). Phase II, non-randomized and non-controlled designs were more frequently used in pivotal studies on orphan anticancer drugs (45.9%, 41.9% and 43.2%) than non-orphan drugs (17.2%, 14.1% and 14.1%, respectively). Response rate was more commonly used as a primary endpoint in pivotal studies on orphan anticancer drugs (48.6%) than non-orphan drugs (17.2%). Indications limited by molecular features, second or later treatment line, and accelerated approval in the United States were associated with the use of response rate in orphan anticancer drug studies. In conclusion, we demonstrated that orphan anticancer drugs in Japan have unique characteristics compared to non-orphan drugs: shorter regulatory review and pivotal studies frequently using phase II, non-randomized, or non-controlled designs and response rate as a primary endpoint, with fewer patients.


Cancer Orphan drug Regulatory approval Pivotal study Endpoint Japan 



The authors express gratitude to Katsuya Nakano for his review of the study from a regulatory affairs viewpoint.

Compliance with ethical standards

Conflict of interest

Hiroki Nakayama is an employee of Astellas Pharma Inc. 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.


  1. 1.
    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. CrossRefPubMedGoogle Scholar
  2. 2.
    Bogaerts J, Sydes MR, Keat N, McConnell A, Benson A, Ho A, Roth A, Fortpied C, Eng C, Peckitt C, Coens C, Pettaway C, Arnold D, Hall E, Marshall E, Sclafani F, Hatcher H, Earl H, Ray-Coquard I, Paul J, Blay JY, Whelan J, Panageas K, Wheatley K, Harrington K, Licitra L, Billingham L, Hensley M, McCabe M, Patel PM, Carvajal R, Wilson R, Glynne-Jones R, McWilliams R, Leyvraz S, Rao S, Nicholson S, Filiaci V, Negrouk A, Lacombe D, Dupont E, Pauporte I, Welch JJ, Law K, Trimble T, Seymour M (2015) Clinical trial designs for rare diseases: studies developed and discussed by the international rare cancers initiative. Eur J Cancer 51(3):271–281. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gaddipati H, Liu K, Pariser A, Pazdur R (2012) Rare cancer trial design: lessons from FDA approvals. Clin Cancer Res 18(19):5172–5178. CrossRefPubMedGoogle Scholar
  4. 4.
    Billingham L, Malottki K, Steven N (2016) Research methods to change clinical practice for patients with rare cancers. Lancet Oncol 17(2):e70–e80. CrossRefPubMedGoogle Scholar
  5. 5.
    Boyd N, Dancey JE, Gilks CB, Huntsman DG (2016) Rare cancers: a sea of opportunity. Lancet Oncol 17(2):e52–e61. CrossRefPubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Kumar Kakkar A, Dahiya N (2014) The evolving drug development landscape: from blockbusters to niche busters in the orphan drug space. Drug Dev Res 75(4):231–234. CrossRefPubMedGoogle Scholar
  8. 8.
    Kesselheim AS, Myers JA, Avorn J (2011) Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA 305(22):2320–2326. CrossRefPubMedGoogle Scholar
  9. 9.
    Ministry of Health, Labour and Welfare, (2015) Overview of orphan drug/medical device designation system. (in Japanese) Accessed 18 Jan 2018
  10. 10.
    Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452–458. CrossRefPubMedGoogle Scholar
  11. 11.
    Ministry of Health, Labour and Welfare, (2012) On the standard review timeline for new drug applications. (in Japanese) Accessed 18 Jan 2018
  12. 12.
    Ministry of Health, Labour and Welfare, (2006) Q&a of the revision of the guideline for clinical evaluation methods of anticancer drugs. (In Japanese) Accessed 18 Jan 2018
  13. 13.
    U.S. Food and Drug Administration (2015) Rare diseases: common issues in drug development guidance for industry. https://www.fdagov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485pdf Accessed 18 Jan 2018
  14. 14.
    European Medicines Agency (2006) Guideline on clinical trials in small populations. Accessed 18 Jan 2018
  15. 15.
    U.S. Food and Drug Administration (2014) Guidance for industry expedited programs for serious conditions – drugs and biologics. Accessed 18 Jan 2018
  16. 16.
    Ministry of Health, Labour and Welfare, (2005) On the revision of the guideline for clinical evaluation methods of anticancer drugs. (in Japanese) Accessed 18 Jan 2018
  17. 17.
    Maeda H, Kurokawa T (2015) Acceptance of surrogate end points in clinical trials supporting approval of drugs for cancer treatment by the Japanese regulatory agency. Ann Oncol 26(1):211–216. CrossRefPubMedGoogle Scholar
  18. 18.
    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. CrossRefPubMedGoogle Scholar
  19. 19.
    Menis J, Hasan B, Besse B (2014) New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev 23(133):367–378. CrossRefPubMedGoogle Scholar

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

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