Articles

Newsletter Summer 2018 - Rob Claar on Fast-Track Opportunities in Japan for Regenerative Medical Products


 

Kyoto University professor Shinya Yamanaka co-won the 2012 Nobel Prize in physiology or medicine for his 2006 discovery that mature cells in mice could be reprogrammed and induced to become immature and pluripotent stem cells (iPS cells). This dramatically accelerated what was already a nascent revolution in Japan for regenerative medicine. New legislation was created, government and private funds became available, new companies and industry associations sprung up and old companies entered this new field.

Human iPS cells were first implanted for the treatment of age-related macular degeneration (autologous implant in September of 2014 and allogeneic transplant in March of 2017). Additional iPS cell clinical trials were approved in Japan for Parkinson’s disease in 2017 and severe ischemic cardiomyopathy in 2018, with more programs under development, including for thrombocytopenia and spinal cord injury.

Breakthrough research in iPS cells is what got this started, but that is not the whole story. This article explores the current status of regulations and opportunities in Japan. The environment has now been established for fast-tracked clinical research and approvals in the regenerative medical field. What does that mean for companies in Japan and companies interested in coming here to accelerate their development programs?

In November of 2013, Japan announced new regulations which became law in November of 2014. The new Act on Pharmaceuticals and Medical Devices (PMD Act) established regenerative medical products (RMPs) as a distinct third category, after drugs and devices. A new office was established for the review and regulation of this new category in the Pharmaceuticals and Medical Devices Agency (PMDA): the Office of Cellular and Tissue-based Products.

 

RMPs are defined as processed (more than minimal manipulation) live human or animal cells that are intended to be used for the reconstruction, repair, or formation of structures or functions of the human body, the treatment or prevention of human diseases or for gene therapy.

 

The goal of the RMP inclusion in the PMD Act was specifically to enable early conditional approvals. Now, conditional approval is possible based on a limited number of cases to ‘demonstrate safety and anticipate efficacy’, while ongoing evidence can be studied in post-marketing registration studies within 7 years from conditional approval.

 

The stated goal is to enable treatment access for patients with unmet medical needs. Certainly, the government of Japan was also very keen to trigger economic growth based on the Yamanaka effect, and wanted to create a framework that enabled speedy but safe development for RMPs.

 

At the same time as the PMD Act, Japan created the Act on the Safety of Regenerative Medicine (Safety Act) under regulation by the Ministry of Health, Labour and Welfare (MHLW). The goal of the Safety Act is also very clear. Japan needed to rein in potentially unsafe practices at cosmetic and other clinics where doctors were administering to patients willing to pay for expensive, unproven stem cell therapies and cancer vaccines, etc. The Safety Act doesn’t outlaw these practices, but requires that all facilities and programs be properly registered.

 

The Safety Act categorizes RMP programs into 3 classes by risk level, which in turn determines the level of certification and oversight required:

 

-          Class I: iPS cells, ES cells, other allogeneic cells, gene therapy, other engineered cells and high risk programs

-          Class II: Autologous cell therapies

-          Class III: Autologous cell therapies without transdifferentiation

 

Programs are further categorized as Medical Care, which are patient pay commercial programs, and Clinical Research. As of this writing, the current total number of RMP programs in Japan is 3,704. Of these, there are 144 registered Clinical Research Programs nationwide.

 

 

Medical Care Programs

Clinical Research Programs

Class I

0

18

Class II

141

66

Class III

3,419

60

 

The requirements before initiating first-in-human clinical studies include product, CMC and non-clinical study factors. In terms of product factors, the applicant must investigate the main and secondary pharmacological actions in vitro and in vivo and confirm the mechanism of action of the therapy, the characteristics of source cells and the rationale for animal models to be used in non-clinical studies.

 

CMC requirements include an explanation of the structure and other product characteristics, process for the management of impurities and an explanation of the method of ensuring quality consistency of the investigational product.

 

Required non-clinical study results include pharmacodynamics, immunological cross-reaction data, in vitro safety pharmacology and toxicity. The minimum anticipated biological effect level (MABEL) needs to be defined based on the results of these non-clinical studies in the most appropriate animal models.

 

Besides certification and oversight, the Safety Act also includes one accelerating aspect. It enables medical institutions to outsource cell culturing and processing activities to certified companies. This was seen as time consuming and a development bottleneck for some medical facilities.

The current number of approved cell culturing and processing facilities, including medical institutions and companies in Japan is 62 for Class I programs and an enormous 2,510 facilities for Class II and III programs. In addition, the MHLW has approved 5 companies from Korea and 1 company from Taiwan. There is an opportunity for more overseas CDMOs to obtain MHLW certifications under this regulation.

 

The sheer number of facilities requiring materials, media, systems support and logistics must represent a significant business opportunity, if one is to believe the gold rush adage of profits being made by those supplying the miners.

 

We see that five years after the new regulations, many companies and medical facilities are active in cell processing and clinical studies, and a robust ecosystem has grown around this clinical and research activity. The initiation of studies has become easier and the possibility for early conditional approval makes Japan particularly attractive.

 

However, the fact remains that Japan still has only 4 RMP approvals: JACE and JACC from J-TEC (a FujiFilm subsidiary), HeartSheet from Terumo and TEMCELL from JCR Pharma.

 

So, what does the future hold? It is helpful to look at the IND / Clinical Trial Notification submissions to see what approvals are likely to come soon. It’s also interesting to note the following 3 foreign capital firms with ongoing clinical trials in Japan: Novartis Pharma, Janssen Pharmaceutical and Caladrius Biosciences.

 

 

Cell Therapy

Gene Therapy

Total

Sponsor Submissions

27

9

36

Investigator Submissions

19

6

25

Total

46

15

61

 

Our view is that Japan is an attractive market with many ongoing clinical programs and a significant number of new approvals coming in the near future. Information from the PMDA showing an increase in the number of development consultations for RMPs indicate that the number of clinical research programs and clinical trials will continue to grow.

 

We are on the cusp of regenerative medicine breakthroughs in Japan, and five years into the new regulatory regime, in many ways it still feels like we are at the starting gate.

 

Japan enables early initiation of development programs based on supportive regulations, highly motivated researcher physicians and an advanced ecosystem of medical facilities and companies. Japan also offers the possibility for approval based on limited data which can come from physician-initiated studies.

 

It’s true that there are only 4 approvals so far, and it’s also true that not every RMP program in Japan will utilize the conditional approval pathway available for regenerative medicine. While this pathway enables a quicker route to patient access and commercialization, some companies feel there are drawbacks versus a traditional development path. Those include all-case post-marketing surveillance and limited ability for commercial rollout to a broad number of medical facilities until the full approval is obtained.

Another interesting factor is that Japanese regenerative medicine companies with global reach are not starting all their programs in Japan first as a matter of course. They are certainly focused on Japan development but are choosing their first region for each of their programs based on epidemiology and market needs. Fujifilm and Healios are examples of Japanese companies with overseas RMP programs.

 

For an overseas company looking at coming to Japan, regardless of whether you intend to develop your asset yourself or license to a Japanese company, and whether you plan to develop based on the conditional approval or traditional pathway or decide along the way, two factors will be absolutely critical to your success. First is selecting and partnering with KOL doctors. Second is collaboration with the PMDA.

 

Doctor relationships at important facilities are necessary for generating medical society support, political support and validation for your program. Onboarding your investigator team early with a full understanding of their motivations, personal and facility capabilities, relationships and network is of great and lasting importance. Their involvement in Japan can also support your ex-Japan activities and networks.

 

Positive PMDA collaboration is also necessary for success. Ensuring your Japan-based investigators are fully supportive and willing to advocate in front of regulators is one factor. Another is to remember that RMPs are hard to regulate, and every program is new and unique. Despite the PMDA’s good intentions, they will struggle to regulate and approve new and unfamiliar programs.

 

Sponsor companies should think of the PMDA as a partner that requires support in order to move programs forward. Partnership and collaboration among the sponsor company, KOL doctors, the PMDA and experienced consultants is necessary for success.

 

Japan is open for RMP business, and I hope we can help more overseas companies launch their programs here.