Comparison of Regulations for the Development of Oncolytic Virus Therapy in the United States, the European Union, and Japan.

Takuma Matsuda, Atsushi Aruga


Oncolytic Viral Therapy (OVT) is one of the novel approaches for treating cancer and has a preferable safety profile. If a response to the therapy can been demonstrated, it can become one of the main therapies for cancer. We conducted a comprehensive comparative analysis of regulations for OVT development in the United States (US), the Europe Union (EU) and Japan to confirm a perceived lag in OVT development activities in Japan and explore its regulatory basis.

Clinical development of OVT has begun all over the world. However, most of the development has been conducted outside of Japan. The lack of OVT development was not caused by scientific reasons but rather regulatory reasons. In this context, this article focuses on the regulatory dierences surrounding OVT throughout the developed world. In Japan, unlike the US, data from clinical development are required to obtain regulatory approval from Pharmaceuticals and Medical Devices Agency (PMDA); in other words, data from clinical research are not enough. However, in the US, data from either clinical development or clinical research can be utilized for new drug applications. In addition, Japan ratified the Cartagena Protocol, which demands special procedures for the use of viruses, which are key to OVT; the US need not follow these procedures as it did not ratify the Protocol. In short, in order to stimulate the development of OVT in Japan, we should harmonize our regulations on OVT
with those of the US and EU.


drug development, oncolytic virus therapy, oncology, drug lag, regulatory science

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K. M. Wong, A. Capasso, S. G. Eckhardt, The changing landscape of phase I trials in oncology, Nat. Rev. Clin. Oncol. 13 (2016) 106.

H. Ledford, Cancer-fighting viruses near market, Nature 526 (2015) 622.

S. J. Russell, K.W. Peng, Viruses as anticancer drugs, Trends Pharmacol. Sci. 28 (2007) 326.

E. A. Chiocca, S. D. Rabkin, Oncolytic viruses and their application to cancer immunotherapy, Cancer Immunol. Res. 2 (2014) 295.

H. L. Kaufman, F. J. Kohlhapp, A. Zloza, Oncolytic viruses: a new class of immunotherapy drugs, Nat. Rev. Drug Discov. 14 (2015) 642.

K. Garber, China approves world’s first oncolytic virus therapy for cancer treatment, J. Natl. Cancer Inst. 98 (2006) 298.

H. Ledford, Cancer-fighting viruses win approval, Nature 526 (2015) 622.

E. Dolgin, Oncolytic viruses get a boost with first FDA-approval recommendation, Nat. Rev. Drug Discov. 14 (2015) 369.

M. Nakamori, H. Yamaue, Current state of oncolytic virotherapy in Japan, Gan To Kagaku Ryoho 40 (2013) 553. Phase I/II Study to Evaluate the Safety and Efficacy of Telomelysin (OBP-301) in Patients With Hepatocellular Carcinoma.

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

Y. Fujita, A. Kawamoto, Regenerative medicine legislation in Japan for fast provision of cell therapy products, Clin. Pharmacol. Ther. 99 (2016) 26.

S. Hacein-Bey-Abina, C. von Kalle, M. Schmidt, et al., A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency, N. Engl. J. Med. 348 (2003) 255.

A. L. Pecora, N. Rizvi, G. I. Cohen, et al., Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers, J. Clin. Onco. 20 (2002) 2251.

B. Park, T. Hwang, T. C. Liu, et al., Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial, Lancet Oncol. 9 (2008) 533.

E. J. Small, M. A. Carducci, J. M. Burke, et al., A Phase I Trial of Intravenous CG7870, a Replication-Selective, Prostate-Specific AntigenTargeted Oncolytic Adenovirus, for the Treatment of Hormone-Refractory, Metastatic Prostate Cancer, Mol. Ther. 14 (2006) 107.

I. R. Edwards, J. K. Aronson, Adverse drug reactions: definitions, diagnosis, and management, The Lancet 356 (2000) 1255.

S. Shibata, R. Uemura, K. Chiba, et al., 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, Journal of Regulatory Science 4 (2016) 1.

P. Hagen, J. B. Weiner, Cartagena Protocol on Biosafety: New Rules for International Trade in Living Modified Organisms, Geo. Int’l Envtl. L. Rev. 12 (1999) 697.

S. Oberthr, T. Gehring, Institutional interaction in global environmental governance: The case of the Cartagena protocol and the world trade organization, Global Environmental Politics 6 (2006) 1.

A. Gupta, Governing trade in genetically modified organisms: The Cartagena Protocol on Biosafety. Environment: Science and Policy for Sustainable Development, Lancet Oncol. 42 (2000) 22.

T. A. Cheema, H. Wakimoto, P. E. Fecci, et al., Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model, Proc. Natl. Acad. Sci. 110 (2013) 12006.

R. Pazdur, Endpoints for assessing drug activity in clinical trials, Oncologist 13 (2008) 19.

M. B. Shea, S. A. Roberts, J. C. Walrath, et al., Use of multiple endpoints and approval paths depicts a decade of FDA oncology drug approvals, Clin. Cancer Res. 10 (2013) 3722.

A. Ocana, I. F. Tannock, When are ’Positive’ clinical trials in oncology truly positive?, J. Natl. Cancer Inst. 103 (2011) 16.

J. S. Brown, B. B. Tadmor, L. Lasagna, Availability of anticancer drugs in the United States, Europe and Japan from 1960 through 1991, Clin. Pharmacol. Ther. 58 (1995) 243.