A Comprehensive Analysis of Factors That Contribute to Conditional Approval and All-Case Surveillance Designations That Subsequently Lead to Shortening of Review Times in Japan

Shoyo Shibata, Ryotaro Uemura, Koji Chiba, Takeshi Suzuki


We examined conditional approval and all-case surveillance designations for new molecular entities investigated between 2000 and 2014 in Japan. Using univariate or multivariate logistic-regression analysis, this study attempted to clarify profiles that affect the receipt of these designations, and to provide guidance for effectively using conditional approval and all-case surveillance designations. Analysis showed that the highest number of drugs to which these systems were applied was category L (“Antineoplastic and immunomodulating agents”) of the Anatomical Therapeutic Chemical Classification System. Orphan drug designation (ODD) and L drugs were significantly correlated with the receipt of both conditional approval and all-case surveillance. These designations shortened the review time. Positive factors that shortened the period of review included ODD, using global data, and joining a global study. Bridging strategy was the only negative factor. Utilization of this Japan-specific PMS system can shorten drug lag, thereby securing the safety of Japanese subjects.


drug development; all-case surveillance; conditional approval; regulatory review time; drug lag; PMDA

Full Text:



G. Sinha, Japan works to shorten “drug lag,” boost trials of new drugs, J. Natl. Cancer Inst. 102 (2010) 148–151.

K. Tsuji, K. Tsutani, Approval of new biopharmaceuticals 1999–2006: comparison of the US, EU and Japan situations, Eur. J. Pharm. Biopharm. 68 (2008) 496–502.

T. Ishibashi, K. Yasuda, M. Kusama, Y. Sugiyama, S. Ono, Clinical development and review times for new drugs in Japan: associated factors, Clin. Pharmacol. Ther. 88 (2010) 487-491.

K. Ichimaru, S. Toyoshima, Y. Uyama, PMDA’s challenge to accelerate clinical development and review of new drugs in Japan, Clin. Pharmacol. Ther. 88 (2010) 454-457.

FA. Thiers, AJ. Sinskey, ER. Berndt, Trends in the globalization of clinical trials, Nat. Rev. Drug Discov. 7 (2008) 13-14.

SW. Glickman, et al, Ethical and scientific implications of the globalization of clinical research, N. Engl. J. Med. 360 (2009) 816-823.

Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour, and Welfare. Basic Principles on Global Clinical Trials. Notification no. 0928010. http://www.pmda.go.jp/files/000153265.pdf. Accessed 14 August, 2015.

Concept paper on the development of a CHMP guideline on extrapolation results in clinical studies to the EU-population. London, 24 January 2007. Doc. Ref. EMEA/CHMP/EWP/7799/2007.

Reflection paper on the extrapolation of results from clinical studies conducted outside Europe to the EU-population. London, 19 February 2007. Doc. Ref. EMEA/CHMP/EWP/692702/2008

H. Uesaka, Sample size allocation to regions in a multiregional trial, J. Biopharm. Stat. 19 (2009) 580-594.

SJ. Wang, Multi-regional clinical trials--what are the challenges? Pharm. Stat. 9 (2010) 171-172.

SW. Glickman, et al, Ethical and scientific implications of the globalization of clinical research, N. Engl. J. Med. 360 (2009) 816-823.

K. Mori, Recent approaches by the PMDA to promoting new drug development: change in the status of the PMDA in relation to new drug development over the last five years, Ther. Innov. Regul. Sci. 43 (2009) 47-55.

M. Narukawa, Research on the situation and implications of the post-marketing all-case surveillance study in Japan — considerations based on a questionnaire survey, Regulatory Science of Medical Products. 4 (2014) 199-206.

E. Mori, M. Kaneko, M. Narukawa, The current status of all-case surveillance study in Japan and factors influencing the judgement of its necessity, Jpn. J. Clin. Pharmacol. Ther. 46 (2015) 185-189.

C. Kurosawa, C. Uchiyama, T. Sakurada, E. Kobayashi, N. Satoh, Problems of prescription drug labeling: on conditions for approval, Jpn. J. Clin. Pharmacol Ther. 43 (2012) 381-386.

WM. Wardell, Introduction of new therapeutic drugs in the United States and Great Britain: an international comparison, Clin. Pharmacol. Ther. 14 (1973) 773-790.

K. Yonemori, et al, The notorious “drug lag” for oncology drugs in Japan, Invest. New Drugs. 29 (2011) 706-712.

R. Shimazawa, I. Kusumi, M. Ikeda, Delays in psychiatric drug development in Japan, J. Clin. Pharm. Ther. 37 (2012) 348-351.

R. Shimazawa, M. Ikeda, Delays in neurological drug development in Japan, Intern. Med. 50 (2011) 1565-1568.

R. Shimazawa, M. Ikeda, Japan lags behind the UK in neurological drug approvals, Br. J. Clin. Pharmacol. 71 (2011) 473-475.

M. Orfali, et al, Raising orphans: how clinical development programs of drugs for rare and common diseases are different, Clin. Pharmacol. Ther. 92 (2012) 262-264.

E. Kawabata–Shoda, S. Masuda, H. Kimura, 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 (2012) 547-552.

H. Maeda, T. Kurokawa, Regulatory review time for approval of oncology drugs in Japan between 2001 and 2014. Considerations of changes, factors that affect review time, and difference with the United States, J. Clin. Pharmacol. 55 (2015) 481-489.

Y. Hirai, H. Kinoshita, M. Kusama, K. Yasuda, Y. Sugiyama, S. Ono, Delays in new drug applications in Japan and industrial R&D strategies, Clin. Pharmacol. Ther. 87 (2010) 212-218.

I. Melnikova, Rare diseases and orphan drugs. Nat. Rev. Drug Discov. 11 (2012) 267-268.

ME. Haffner, J. Whitley, M. Moses, Two decades of orphan product development, Nat. Rev. Drug Discov. 1 (2002) 821-825.

T. Ueno, Y. Asahina, A. Tanaka, H. Yamada, M. Nakamura, Y. Uyama, Significant differences in drug lag in clinical development among various strategies used for regulatory submissions in Japan, Clin. Pharmacol. Ther. 95 (2014) 533-541.

BL. Strom, How the US drug safety system should be changed, JAMA. 295 (2006) 2072-2075.

WA. Ray, CM. Stein, Reform of drug regulation--beyond an independent drug-safety board, N. Engl. J. Med. 354 (2006) 194-201.

HJ. Malinowski, A. Westelinck, T. Sato J Ong, Same drug, different dosing: differences in dosing for drugs approved in the United States, Europe, and Japan, J. Clin. Pharmacol. 48 (2008) 900-908.

FL. Arnold, M. Kusama, S. Ono, Exploring differences in drug doses between Japan and Western countries, Clin. Pharmacol. Ther. 87 (2010) 714-720.

J. Cross, H. Lee, A. Westelinck, J. Nelson, C. Grudzinskas, C. Peck, Postmarketing drug dosage changes of 499 FDA‐approved new molecular entities, 1980–1999, Pharmacoepidemiol. Drug Saf. 11 (2002) 439-446.

ER. Heerdink, J. Urquhart, HG. Leufkens, Changes in prescribed drug doses after market introduction, Pharmacoepidemiol. Drug Saf. 11 (2002) 447-453.