EC Report Analyzes Regulatory Frameworks for Advanced Therapies in US, Canada, Japan and Korea

Regulatory NewsRegulatory News | 06 July 2016 |  By 

The European Commission report released Wednesday dissects the similarities in how gene-, cell- and tissue-based advanced therapies are regulated across the four different geographic regions, though ongoing research projects in such therapies are heavily concentrated in the US and Japan.

The 327-page report highlights the “high degree of convergence” in the regulation of advanced therapies across the US, Canada, South Korea and Japan, noting that only Japan has enacted (in 2014) a specific framework for approving advanced therapies, while the other regions regulate the products mostly as biologics.

“In Japan, advanced therapies that are developed for the purposes of marketing are regulated under the medicines framework (Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act, or PMD Act), which is also comparable to the frameworks that exist in Canada, US and South Korea,” according to the report, written by experts from Ecorys Nederland and University Utrecht and commissioned by the EC’s Consumers, Health, Agriculture and Food Executive Agency. “However, this [Japanese] framework has a new time limited conditional approval pathway specifically for advanced therapies. Japan also enforces specific manufacturing and quality requirements for advanced therapies, which are known as Good, gene, Cellular and Tissue-based product manufacturing Practice (GCTP).”


To date, six advanced therapies have been granted marketing authorization in the EU, though the report notes that the actual number of patients treated with advanced therapies and the number of advanced therapies on the market are limited.

“This has led to the perception that the regulatory procedures to develop and authorise advanced therapies is less fit-for-purpose in the EU than in other jurisdictions, such as US, Canada, Japan and South Korea,” the report notes.

In 2008, the European Medicines Agency and US Food and Drug Administration (FDA) set up a platform to share experiences and discuss regulatory approaches for advanced therapies, and in 2012 Health Canada joined the sharing of information.

The report notes a number of advanced therapies that are unique to each region, including:

  • US: TheraCys (biologic response modifier), this is the only approved biologic response modifier; Provenge (autologous cellular immune-therapy).
  • Canada: Prochymal (allogeneic bone marrow) is the only product approved (Prochymal of Mesoblast/Osiris and TEMCELL of JCR Pharmaceuticals is exactly the same product. Prochymal is used in Canada and TEMCELL in Japan).
  • Japan: JACC (autologous cultured cartilage, tissue based), one of two products developed by J-TEC, both products are autologous and tissue based; HeartSheet (autologous skeletal myoblast sheet).
  • South Korea: Cupistem (autologous adipose derived mesenchymal stem cells) and Kaloderm (allogeneic keratinocytes) are the only two allogeneic products with approval in Korea.

  • Research

    In the US, the researchers identified 132 ongoing research projects on advanced therapies (10.6% of Phase II-III or III trials) and five available advanced therapies. Similarly, in Japan, 131 research projects on advanced therapies were conducted (2.3% phase II-III or III trials) and two advanced therapies were available.

    In Canada, however, 39 research projects were identified as ongoing (15.4% Phase II-III or III trials) and one advanced therapy is approved.

    And in South Korea, 43 ongoing research projects on advanced therapies (14% Phase II-III or III trials) were listed, though there are 18 approved advanced therapies.

    The majority of the developers involved in the research are for non-profit organizations or academia (US: 74.2%, Japan: 92.4% and South Korea: 74.4%), the report notes, though in Canada the involvement of for-profit and nonprofit/academic organizations is more balanced (51.3% and 48.7%, respectively).

    “With regard to the late phase trials, we found that in the US and Canada, the majority of all late phase trials are done by for profit organisations (respectively 71.4% and 83.3%). In Japan and South Korea, however, we found that for profit organisations appear not to be involved in late phase trials,” the report says.


    In general, US developers and associations told the authors of the report that they “perceived the regulatory process as challenging given the absence of general standards for clinical trial design and manufacturing and quality. This was perceived to be particularly the case when advanced therapies were developed for rare indications for which no precedents had been established. If there is no standard or comparable treatment available, developers have to engage in partnerships with physicians to develop appropriate outcome measures.”

    Health Canada also acknowledged that “not all regulations for biologic drugs may be applicable to advanced therapies” and its regulatory decisions are based on a risk-benefit assessment on a case-by-case basis with a flexible approach.

    “Overall, Canadian developers were positive about the interactions with Health Canada and the support they received in interpreting the prevalent standards,” the report says. “Some developers were uncertain about the standards they needed to adhere to and mentioned some barriers in product development. Some of the issues should be understood in light of the specifics of the advanced therapies sector in Canada, which is mainly populated by academic centres and less by pharmaceutical companies who are generally more used to work with regulatory frameworks. Importantly, two developers also mentioned that the biggest barrier for development of advanced therapies in Canada is not the regulatory framework, but gaps in funding in academic research, a lack of financial incentives for industrial developers and scientific challenges.”

    For Japan, overall, an unidentified association “indicated that many aspects of the new regulatory framework are not yet set-in-stone. Hence, flexibility of regulators in implementing the framework was deemed essential for success.”

    Among advanced therapy developers in Japan, the report notes there is a general expectation that the time to market for regenerative medicine products will “substantially decrease with the introduction of the conditional approval scheme. However, given that no product has received authorisation through the scheme so far it is difficult to substantiate this claim. A Japanese developer recently received approval of the PMDA for a product that consists of myoblast sheets, based on safety and feasibility data originating from earlier stage clinical development only (phase I and IIa). Clinical efficacy data remains to be proven in larger clinical trials after conditional marketing authorisation.”

    And in Korea, the government has stimulated the development of advanced therapies by providing funds for public-private partnerships, with milestones directly linked to regulatory moves, such as filing an IND, which has led the country’s regulator, known as the Ministry of Food and Drug Safety (MFDS), to provide more guidance to industry.

    On the negative side, a Korean developer told the report’s authors “that it was difficult to market a cell therapy product, because of the lack of clear standards. Obtaining a marketing authorisation required a lot of communication between the developer and the MFDS.”

    IP Landscapes

    The intellectual property (IP) laws in the various regions also vary considerably. In the US, substantially manipulated cells “are patentable as long as a claim is not encompassing a human being.

    “Whether substantially manipulated cells are patentable in Canada is dependent on the origin and the features of the substantially manipulated cell(s). In Japan it is only possible to receive a patent when a product is material based (i.e. not for a method). In South Korea substantially manipulated cells are patentable according to the statutory requirements that apply to all types of patents,” the report says.

    However, not all advanced therapies that have been granted marketing authorization are also reimbursed in the regions.

    In the US, only three out of five advanced therapies are reimbursed, while in Canada, the approved product is not reimbursed, though in Japan all approved products are reimbursed and in South Korea, four products are reimbursed, nine are not reimbursed for, and the reimbursement status of the other products (5) is not known.

    “The reasons for these divergent practices have not been assessed as part of this study, but may be due to differences in pricing and reimbursement systems, as this is a competency of each jurisdiction. This claim, however, would need to be further investigated,” the report adds.

    Study on the Regulation of Advanced Therapies in Selected Jurisdictions



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