Reference products and toxicity studies for biosimilars in Japan

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In his presentation, at the 14th Annual Biosimilars Group Conference, Dr Daisaku Sato, Director, Office of Cellular and Tissue-based Products at the Pharmaceutical and Medical Devices Agency (PMDA), discussed what reference products are acceptable and whether repeat-dose toxicity studies are required for marketing applications for biosimilars in Japan [1].

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Japan’s regulatory body for the approval of medicines, the Ministry for Health Labour and Welfare (MHLW) released its first guideline for biosimilars in March 2009 [2]. According to this guideline, the reference product should be already approved in Japan.

The PMDA’s position is that the sponsor should confirm the comparability to a reference product, which is approved (and used by healthcare providers and patients) in Japan. If a sponsor needs to use a non-Japan-sourced reference product (RP) in their comparability exercise, they should demonstrate that the non-Japan-sourced reference product is representative of the Japan-sourced RP in terms of analytical assays and publicly available information.

The Japanese position on reference products is in line with the European Medicines Agency (EMA). In its revised overarching biosimilars guideline, which was released in October 2014, EMA also allows for the possibility for biosimilars developers to use a reference product authorized outside its own area of jurisdiction [i.e. the European Economic Area (EEA)] [3].

With respect to the question of whether a toxicity study (repeat-dose toxicity study) is required for biosimilar development, the PMDA has the following opinion:
• A sponsor should evaluate the non-clinical safety of their biosimilar candidate prior to entering into clinical studies, in accordance with ICH S6
• However, in cases where there are no concerns about non-clinical safety based on characterization studies and comparison of the physicochemical and pharmacological properties, in vivo toxicity studies may be not required
• This approach should be evaluated on a case-by-case basis

Finally, in the case of whether toxicity studies are required or not, the PMDA recommends that biosimilars makers use its consultation service.

Editor’s comment
Readers interested to learn more about how biosimilars regulations in Japan compare to other countries/regions are invited to visit to view the following manuscript published in GaBI Journal:

Comparison of biosimilars guidelines

GaBI Journal is indexed in Embase, Scopus, Thomson Reuters’ ESCI, and more.

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

If you would like to receive a PDF copy* of the Daisaku presentation [1], please send us an email.

*For profit organizations subjected to a fee

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1. Daisaku S. Surfing the wave in Japan for Regulatory Convergence of Biosimilar. 14th Annual Biosimilar Medicines Group Conference; 28–29 April 2016; London.
2. GaBI Online - Generics and Biosimilars Initiative. Japanese guidelines for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 30]. Available from:
3. GaBI Online - Generics and Biosimilars Initiative. EMA issues revised version of overarching biosimilars guideline []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 30]. Available from:

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