2024.12.9

Technology Focus Series: Regenerative Medicine & Cellular Therapy Market Access in Japan

In 2014, Japan implemented two new laws that effectively established regenerative medicines and cellular therapies as a separate regulatory category in Japan - the Act on the Safety of Regenerative Medicine and the Pharmaceuticals, Medical Devices, and other Therapeutic Products Act. More specifically, the following kinds of products (A or B) are reviewed by the regulatory bodies in Japan as regenerative medicines or cellular therapies:

A. Products that involve processes such as the culturing of human or animal cells and that (1) allow for the regeneration, restoration, and/or reformation of the structure or functionality of the body and (2) are meant to be used for prevention or treatment of a condition

B. Products that introduce human cells to the body as gene therapy

As of December 2024, at least 20 regenerative medicine products had been approved for marketing and 19 had been listed for reimbursement in Japan. Moreover, nearly 20 other regenerative medicine and cellular therapy products have received orphan designation and/or Sakigake (breakthrough) designation - meaning that they have a relatively high chance of development success and receiving regulatory approval in the not-too-distant future.

The reimbursement of regenerative medicines in Japan is determined based on whether the product is considered closer to a drug agent or a medical device. JCR’s Temcell HS mesenchymal stem cells and Novartis’s Kymriah (tisagenlecleucel), for example, were reimbursed using the drug reimbursement process. However, Terumo's HeartSheet autologous skeletal myoblast-derived cell sheet and, more recently, Aurion Biotech’s Vyznova (nelependocel), for example, were reimbursed as a medical device. The table below provides a list of the regenerative medicine and cellular therapies that were reimbursed in Japan as of December 2024 – as well as the approach to reimbursement that was used and their reimbursement outcome.

Out of the 20 regenerative medicine and cellular therapy products that are currently listed, 9 products were reimbursed using the medical device reimbursement pathway. That typically includes products that are cellular therapies applied to the body like J-TEC’s autologous epitheleal and joint treamtents (JACE, JACC, Nepic, etc.) and, more recently, Aurion Biotech’s in vitro corneal endothelial cells treatment, Vyznova (nelependocel), for bullous keratopathy. Note that as of December 2024, Janssen’s Carvykti (ciltacabtagene autoleucel) and SanBio’s Akuugo (vandefitemcel) have also received marketing approval in Japan, but have not yet been listed for reimbursement.

It is also common for regenerative medicine and cellular therapies to be reimbursed using a cost-based approach – likely because they tend to be quite novel in terms of their mechanism of action and molecular structure. On the other hand, in the case of CAR T treatments, the first CAR T therapy, Kymriah (tisagenlecleucel), was reimbursed using the cost-based approach, but subsequent CAR T therapies (Yescarta, Breyanzi, Abecma) have all been reimbursed in comparison to Kymriah with no premiums allowed – even though some of those newer treatments have shown different outcomes and/or target different conditions. This issue has, in part, driven some discussion about the establishment of a separate reimbursement process for regenerative medicines and cellular therapies which is apparently still underway.

Several products had received orphan designation and/or Sakigake (breakthrough) designation. Please see the updates below for an overview of those designation and their potential impact on reimbursement.

Two products, Terumo’s HeartSheet and AnGes’s Collategene, have recently discontinued sales due to inability to meet requirements of their conditional approval (i.e., inability to shown efficacy based on post-marketing surveillance). Two other products, Nipro’s Stemirac autologous mesenchymal stem cells and Daiicihi-Sankyo’s Delytact (teserpaturev), also received conditional approval and will have to submit for formal approval when their review period are completed. Both products received a review period of 7 years, so by our calculations Stemirac’s should be up for review later this year and Delytact will be up for review in 2028. SanBio’s Akugo (vandefitemcel) also received conditional approval earlier this year, but it has yet to be listed in Japan.

Another important point is that Optimal Clinical Use Guidelines (hereafter “optimal use guidelines”) have been established for some regenerative medicine and cellular therapy products – namely all of the CAR T therapies (Kymriah, Yescarta, Breyanzi, and Abecma), Stemirac, and Delytact (teserpaturev). These guidelines are developed by medical societies in Japan at the request of the reimbursement authorities, and they further limit the reimbursement of products by specifying the kinds of patients that can receive them (in even more detail than label itself) and the hospital settings that they can be administered in. Optimal use guidelines are issued to ensure that innovative drugs and regenerative medicines are provided to the most appropriate patients. Elsewhere it has been stated that they are meant to help address the increasing number of expensive drugs in Japan. Notably, however, optimal use guidelines have not been requested for many other regenerative medicine and cellular therapy products, some of which are even more expensive those mentioned above, including Zolgensma (onasemnogene abeparvovec), which is currently Japan’s most expensive treatment at 167,077,222 JPY (or about 1.1 million USD) per administration. This may be because those products do not involve as detailed of a delivery process or that their risk of over-usage and/or extended indications is not as high. Nevertheless, new regenerative medicine and cellular therapy products could be asked to prepare optimal use guidelines in the future at the time of listing.

Closing thoughts:

Since Dr. Shinya Yamanake received the Nobel Prize for his work on induced pluripotent stem (iPS) cells in 2021, Japan has been a leader in the development of regenerative medicine and cellular therapy products. Moreover, to our knowledge, Japan is one of the first countries to establish a somewhat transparent reimbursement pathway for those products. However, the ability for Japan to reimburse novel new regenerative medicine and cellular therapy products may come into crisis as the availability of those treatments increase. The listing of new gene therapies to treat hemophilia conditions such as Biomarin’s valoctocogene roxaparvovec, CSL Behring’s etranacogene dezaparvovec, and Pfizer giroctocogene fitelparvovec, will probably “stir the coals” of that debate further over the next couple of years. In other countries, novel risk-sharing agreements such as pay-for-performance agreements and capitation-based agreements have become more prevelanet with the emergence of regenerative medicine and cellular therapy products. However, those kinds of agreements currently do not exist in Japan. This is primarily due to the fact that current reimbursement system in Japan does not really allow for retrospective settling of payments between patients, insurers, and providers. Another consideration, however, is HTA review. One of the key selection criteria for an HTA review in Japan is that the new treatment has “a remarkably high reimbursement price”. While the formal threshold for “a remarkably high reimbursement price” has not been defined, many regenerative medicine and cellular therapy products are likely to meet this criterion. Products selectedf for HTA review are asked to submit a cost-effectiveness analysis (CEA) following intiial listing and their reimbursement may be reduced by a small, but non-trivial amount if they are unable to show cost-effectiveness. Since the start of the HTA system in Japan in April 2019, all the CAR T treatments have been selected for HTA review as well as Zolgensma (onasemnogene abeparvovec). The CAR T review led to about a 4% reduction in the reimbursement rate of those products. However, the review for Zolgensma has been postponed until more data can be collected to allow for a CEA to be conducted. Regardless, it is important to think ahead concernig the potential challenges of obtaining and defending the approval and reimbursement status of regenerative medicine and cellular therapy products in Japan through well-designed and well-managed post-marketing surveillance studies and health economic studies following listing. GinePro can assist with these aspects, if needed, so please drop us a line if you need support.

New Regenerative Medicine and Cellular Therapy Product Approvals and Listings for Japan (As of December 2024)

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