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What is necessary for industrialization of regenerative medicine? (1) -All 2 episodes-

Dr. Ken-ichiro Hata

Photo:J-TEC (Gamagori City, Aichi Prefecture)

J-TEC (Gamagori City, Aichi Prefecture)

This time we visited Dr. Hata Ken-ichiro, Oral Surgeon and Managing Director, R&D Department, Japan Tissue Engineering Co., LTD (J-TEC). The company has an objective of "industrializing regenerative medicine", and is promoting R&D activities. J-TEC, established in February 1999, developed a Green-type cultured epidermis as the first regenerative medicine product using human cells in Japan and, in October 2007, obtained approval for manufacture and sale of "JACE", an autologous cultured epidermis, from the Ministry of Health, Labour and Welfare. iPS research is now one of J-TEC's activities, and we ask Dr. Hata to tell us what experiences J-TEC have had in its medical business using human living cells, as well as what problems it will have to solve.

Interviewer :
We have a website on iPS cells where we publish interviews with experts involved in this area. This time we would like to ask Dr. Hata about what J-TEC will need to do in order to industrialize iPS cells. The company has experiences in cultured skin business and has recently launched a joint research project on iPS cells with RIKEN (the Institute of Physical and Chemical Research).

Hata :
There are many applications of iPS cells that may be industrialized, for example, for drug discovery, but here I would like to talk only about regenerative medicine. In fact, there is no company in Japan who is running a business as a development activity for regenerative medicine. We have a product of cultured skin called JACE, but can hardly call it business. It is something at a handicraft level rather than at an industrial level.

Interviewer :
Why does it remain at a handicraft level?

Hata :
To industrialize pharmaceutical products and medical devices, it is necessary to accumulate experiences with these products or devices.
Chinese herbal medicines are now sold everywhere. Imagine that, if these are something that did not exist and have been just developed, we do not know yet exactly what components in what ratios they contain, and in this case, it would be difficult for us to accept these as pharmaceutical products. I can say that we accept Chinese herbal medicines because we have an enormous accumulation of experimental data on these products in China.

The accumulation of experience is necessary for the industrialization

Photo:Dr. Ken-ichiro Hata

Dr. Ken-ichiro Hata

Interviewer :
Why does it remain at a handicraft level?

Hata :
To industrialize pharmaceutical products and medical devices, it is necessary to accumulate experiences with these products or devices.
Chinese herbal medicines are now sold everywhere. Imagine that, if these are something that did not exist and have been just developed, we do not know yet exactly what components in what ratios they contain, and in this case, it would be difficult for us to accept these as pharmaceutical products. I can say that we accept Chinese herbal medicines because we have an enormous accumulation of experimental data on these products in China.

Interviewer :
I understand that it is necessary to accumulate experiences on cells used for regenerative medicine, if we want to industrialize the cells.

Hata :
I have served as an oral surgeon at Nagoya University. I resigned the post at the university on a certain occasion to move to the current position. At that time (in the beginning of the 1990s), there was an atmosphere in which clinicians were allowed to make experiences in clinical research more freely than now.
Between the 90s and 2000, however, there was a growing trend toward questioning the safety. Consequently, we were not allowed any more to deal with anything fuzzy as it was. Pharmaceutical administration requires objective data on the safety and efficacy. As regards cells used for regenerative medicine, there are not many clinicians who are studying these cells and we have not enough experiences and data.

Interviewer :
Are severe conditions imposed in Japan?

Hata :
The system itself does not impose very severe conditions, and the problem is that it has no rules where rules are required.

People tend to adhere too strongly to stated principles in Japan

Dr. Ken-ichiro Hata(Sketch by Sato Katsuaki)

Dr. Ken-ichiro Hata
(Sketch by Sato Katsuaki)

Interviewer :
Does it mean that things are left to your discretion?

Hata :
Yes. Private companies make decisions at their own discretion. In the USA, FDA examiners make judgment at their own discretion, while in Japan it is more difficult for their counterparts to do it because people tend to adhere strongly to right arguments (stated principles). It is necessary for us to have accumulated experiences in order to raise arguments more persuasive than these stated principles It is a matter of culture.

Interviewer :
Then, what is needed is a social setting in which something with risk is accepted.

Hata :
For our cultured skin, its first clinical use was reported in 1981, and since then experiences in its clinical use have been accumulated. In 1984, 97% of patients with burns were treated successfully with cultured skin. However, when it was used for the first time for treatment of burns, it was not supposed to be a "non-risk" treatment. Pharmaceutical administration has a stated principle of "non-risk use", and it seems that this has hindered advancement of regenerative medicine.

Evaluation of safety and efficacy of cultured cells

Interviewer :
What was the most important point that favored the approval of the cultured skin of J-TEC for clinical use?

Hata :
There were two things. One is that we could reach some degree of agreement on endpoints for evaluation of safety and efficacy of the cells. The other is that we limited the indications to cases of patients with severe burns who would die if we did not use the cultured skin and whom we could salvage from possible adverse events.
For new drugs, we follow a procedure of applying them to mild cases, and then to severer cases. For cultured skin cells, we started with applying them to severe cases, and we had many difficulties.
For approval for iPS cells, it seems that we will have to follow the same procedure as that for cultured skin.
If we have no experience, the product is not approved, and if the product is not approved, we are not able to make experience. How we break this paradoxical cycle?

Interviewer :
Dr. Kishimoto Tadamitsu, professor emeritus and former president of Osaka University, said that, as it is difficult to perform clinical trials in Japan, a Japanese company may adopt a way in which it accumulates experiences in clinical trials in other countries and with these experiences obtains approval in Japan.

Photo:A cultured epidermal sheet (provided by J-TEC)

A cultured epidermal sheet (provided by J-TEC)

Hata :
For companies, there is no border between Japan and other countries.
There are also university professors who find it better to take actions and accumulate experiences in other countries than to spend too much time in Japan for approval.
We are not allowed to go forward step by step. There are no rules. Such is the current situation in Japan. This is a life-and-death matter for companies rather than for universities.

Interviewer :
Isn't it that the administration has to be cautious because there have been many cases of drug- or chemical-induced sufferings caused by companies.

Hata :
Japan's medical care is faced with problems including a large excess of import and overwork of physicians, and the government seems to have an understanding that it will dysfunction if things will not change.
What is important is how to persuade public opinion including the media. In Japan, the position of companies is low, and this may have originated from an old hierarchy of samurai, farmers, artisans and merchants in Edo society. For many Japanese medical doctors, companies are only "suppliers of products or services" and not partners for R&D activities.
Therefore, it is difficult for companies to get involved in medical care. In contrast, in other countries, large pharmaceutical companies are highly ranked at scientific meetings. It seems necessary that the government take the initiative in Japan.

Interviewer :
Recently, The Japan Science and Technology Agency (JST) held an event called Science Agora (an event aimed to create communication between science and society), and it included a public consultation event on the theme "innovation and regulations". On this occasion an example of Suica (Super Urban Intelligent Card), a rechargeable contactless smart card used as a fare card on train lines in Japan was presented. In the case of Suica, the problem was that this card was regarded as wireless communication equipment and each ticket gate with the Suica system was regarded as a wireless station to seek approval.
Then the manufacturing company negotiated with the authorities and reached an agreement that the company applies for approval for each train station.

Hata :
The obstacle for Suica and home delivery services was approval. In contrast, it is a mass of right arguments (stated principles) or public feeling that constitutes an obstacle and it is not easy to deal with.

Interviewer :
Now, let us return to our subject. What will we have to do when we will use iPS cells in regenerative medicine?

Hata :
I try to answer from our experiences in cultured skin business.
For applying the cultured skin cells to regenerative medicine, we had two problems, "identity" and "impurities". In the case of pharmaceutical products, we are able to identify a product based on the identity of its active ingredient. In the case of cells, cells are collected from individuals and it is difficult to set criteria for "identity".
For example, in the case of JACE, cultured skin cells derived from babies and those from aged persons show different patterns of cell growth, but we have to use the same "release-specifications".
For instance, if we have same cells cultured in different culture media, can these cells be considered identical or not? For the moment, J-TEC is working at its own discretion.
For the problem of "impurities", a pharmaceutical product of 95% purity means it is contaminated with 5% of impurities, and we have to give a proof that these impurities are harmless.
In the case of cultured skin cells, they are contaminated with a small number of non-skin cells, and we have to deal with these non-skin cells as impurities. The state of these impurities may vary with patients and how to deal with the differences?
How we establish specifications for impurities is a problem. It will be more difficult to establish specifications for iPS cells.


Interviewed by Sato Katsuaki, Watanabe Mio(Japan Science Technology Agency)
Published on 24 December, 2009

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Dr. Ken-ichiro Hata

Dr. Hata Ken-ichiro is Doctor of Medicine, dentist, and Managing Director, R&D Department, Japan Tissue Engineering Co., Ltd. (J-TEC).

He graduated from the Dental department at Hiroshima University in 1991, and received his Ph.D. from the Graduate School of Medicine, Nagoya University. After positions of physician working for the Department of Dental and Oral Surgery at Meijo Hospital (Nagoya City), research associate at the Graduate School of Medicine, Nagoya University, associate professor for endowed courses of tissue engineering in the Faculty of Medicine, Nagoya University, and associate professor in the Center for Genetic and Regenerative Medicine, Nagoya University Hospital, he has been holding the present post since 2004.

The research theme is regenerative medicine in general (e.g., skin, cartilage, cornea, peripheral nerves, cardiac valves and bones).

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