LECTURE

Why Do Japan’s Advanced Medical Treatments
Never Get Ahead?
Nobuyo Hatanaka,1 Shinichi Matsumoto,1, 2 Yuji Tanaka1 and Masahiro Kami1

Division of Social Communication System for Advanced Clinical Research,
the Institute of Medical Science, the University of Tokyo, Tokyo, Japan
2
Baylor Research Institute Fort Worth Campus, Texas, USA

1(Received for publication on September 2, 2009)(Revised for publication on November, 4, 2009)(Accepted for publication on November 19, 2009)

Islet cell transplantation is a minimally invasive procedure which effectively controls blood
glucose level for diabetic patients but is considered as experimental. After islet transplantation, type 1 diabetic patients could become insulin free with stable glycemic control. But forlong term effects, only stable glycemic control was maintained and not insulin free status. In
2004 Kyoto University performed the first Japanese islet cell transplant using non-heart beating donor. Of note, due to the lack of cadaveric donors in Japan, the same group performed theworld’s first successful case of living donor islet transplantation in 2005. Both patientsachieved transit insulin-independence; however excellent glycemic control was able to be
maintained for a prolonged period. Even though the series of islet transplants at Kyoto University showed promising results, the leading scientist did not continue his research in Japan.
This was because it is extremely difficult to implement newly developed treatment as a standard therapy in Japan. (Keio J Med 59 (2) : 46－51, June 2010)

Keywords: islet transplantation, type 1 diabetes, bio-artificial islet
Introduction

techniques, it was rendered possible. These islet isolation techniques have been highly acclaimed all over theworld, and the success of islet cell transplantation using
NHBDs became a leading achievement in terms of thesuccess rate of pancreatic islet isolation.2 These islet isolation techniques also enabled to perform “living donor
islet cell transplantation”, whose validity for islet isolation needed confirmation for the first time in theworld.3, 4 Even though they possessed high-level technology which has earned evaluations all over the world,
Japanese researchers did not adopt it as standard treatment, despite the fact that patients were in need of new
medical treatments. In this article, we describe the reasons why re-importation from the United States is needed to be done.

In Japan, in order for new medical technology to beapproved by the Drugs, Cosmetics and Medical Instruments Act (DCMIA) to obtain approval as standard
treatment, the Highly Advanced Medical Treatment System (HAMTS) has been widely used by medical doctors.
However, in September 2006, the HAMTS was abolished resulting in closing the way for new technologies
to become standard treatments for medical doctors in Japan. The new technology for islet cell transplantation,
which is aimed at treating type 1 diabetes mellitus, wasaffected also.
Due to the fact that organs from brain-dead donors are
not available for islet cell transplantation in Japan, organs from non-heart-beating donors (NHBDs) wereused.1 Islet cell transplantation from NHBDs is extremely difficult, but with excellent pancreatic islet isolation

Presented at the 1631st meeting of The Keio Medical Society in Tokyo, July 10, 2009.
Reprint requests to: Shinichi Matsumoto, MD, PhD, Baylor Research Institute Fort Worth Campus, 1400 8 th avenue Fort Worth, Texas 76104, USA, E-mail:shinichm@baylorhealth.edu
46Keio J Med 2010; 59 (2): 46－51

Transplantation for
Insulin Dependent Diabetic Patients
Insulin-dependent diabetes mellitus such as type 1 diabetes is a condition in which the insulin-producing cells(beta cells) are lacking, and supply of insulin from outside the body is necessary to maintain life. Unlike noninsulin-dependent diabetic conditions such as type 2 diabetes, in type 1, improvement of symptoms cannot be
achieved by changing lifestyle habits alone. For insulindependent diabetes, controlling the blood glucose levelis sometimes difficult even with intensive insulin therapy. The disease often takes on the form of hypoglycemia
unawareness or severe hypoglycemia in which patientscannot detect the low blood glucose levels that could result in dangerous coma and seizure. Hypoglycemia unawareness and severe hypoglycemia are not the types ofhypoglycemia that can be prevented by patients themselves. Hypoglycemia unawareness is also one of thefactors which limit the patients from going out alone. As
a result, the patient’s quality of life (QOL) will severely
decline. Under such circumstances, transplantation ofbeta cells will be considered as the next step of treatment. There are two ways of possible transplantation ofbeta cells. One is pancreas transplantation which can beprovided as a standard treatment covered by medical insurance. The other is islet cell transplantation which is at
the level of experimental treatment, and is provided at
the patient’s own expense or at the cost of researchfunds. In either case, the purpose of the treatment is tostabilize the blood glucose levels and to improve the
QOL of the patients.
There are risks involved in pancreas transplantation
performed under general anesthesia as major abdominal
surgery. Therefore, pancreas transplants have predominantly been performed simultaneously with kidneytransplants for which the advantages outweigh the risks.
If this simultaneous pancreas and kidney transplant is
successful, then unstable blood glucose level and dialysis can be solved with a single surgery. Many diabetic
patients also suffer from vascular complications. Whenpatients are anxious about their physical conditions, inorder to choose pancreas transplantation, they should bewell informed and prepared. If the patient’s body rejects
the newly transplanted organ, the patient must undergo
another surgery to remove the transplanted pancreas.
In contrast, in the case of islet cell transplantation, theprocedure can be more easily performed by packing islet
cells into transfusion bags and performing transplantation through an intravenous route. A catheter is inserted
percutaneously into the portal vein under local anesthesia, and transplantation is performed through the catheter
while paying attention to the portal blood pressure. 5
Transplantation itself is very simple and safe. In addition, only islet cells will be spontaneously eliminatedwhen they are rejected. For these reasons, when patients47

are anxious about their physical conditions, they havethe option to choose islet transplantation over the highlyinvasive surgical procedure.
Current major issues of islet transplantation are, 1) low
success rate of islet isolation, 2) requirement of multiple
donors for achieving insulin-free status, and 3) difficulty
to maintain long term insulin independence. If we areable to overcome these major issues, islet transplantation
could become the standard therapy. However, even if islet transplantation becomes the standard therapy, there is
still the major issue of organ donor shortages.
Islet Cell Transplantation in Japan
Japan’s first clinical islet cell transplant was performedat Kyoto University in 2004. 1 All over the world islet
cell transplantation is performed by transplanting islet
cells from the pancreas of brain-dead donors.5 In Japan
however, islet cell transplantation is performed by using
the pancreas of non-heart-beating donors (NHBD).
Compared to that provided by brain-dead donors, pancreata from NHBDs are in marginal condition, making
islet isolation from NHBDs difficult. However, theKyoto University group demonstrated that their islet
transplant results with NHBDs were almost comparable
to the results with brain-dead donors.2
The process of islet cell isolation is the keystone of islet cell transplantation. Islet transplantation is consistedof four following processes; 1) retrieval of the pancreas,
2) preservation of the pancreas, 3) isolation of the pancreatic islets, and 4) purification of the pancreatic islets.6
Many researchers are examining the pancreatic islet isolation process. However, the Kyoto University group
added modifications to these processes. The technique
including these processes was later called the Kyoto
Method. The Kyoto Method became the leading methodin the world in terms of islet cell transplantation due tothe high success rate of islet isolation.
Islet cell transplantation was at the level of experimental treatment not only in Japan but in the United States
also, and is aimed to become the standard of medicalcare worldwide. Japan’s data on the success rate of islet
isolation for islet cell transplantation showed highest results in the world, and was praised as the birth of new
medical technology.
Japanese Patients’ Perspective of
Islet Cell Transplantation
Pancreas transplantation and islet cell transplantation
are both beta cell replacement therapies for type 1 diabetes mellitus, and knowing the patients’ actual expectations for the treatment is important in conducting future
research. For this reason we conducted a survey to understand patients’ expectations.7
From May to September of 2008 in a survey involving

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Hatanaka N, et al: Why Does Japan’s Advanced Medicine Never Get Ahead?

105 type 1 diabetes patients, we conducted an investigation on the patients’ inclination in terms of treatment of
the disease. For each question, we prepared five choices:“strongly agree”, “agree”, “somewhat agree”, “disagree”,
and “strongly disagree.”First, we asked which of the new treatments the patients wanted to undergo in order to be freed from thedisease and what they expected from it. Among the newtreatments were transplantation and bio-artificial endocrine pancreatic islet transplantation.
To the question “Would you want to receive a newtreatment if it frees you from the disease?” 41% responded “strongly agree”, 25% responded “agree”, 27%
responded “somewhat agree”, 4% answered “disagree”,
and 3% answered “strongly disagree”. From these answers, negative answers regarding new treatments
amounted to 7%, while positive answers were as manyas 93% (Fig. 1A). Next, to the question “Do you thinkthat transplantation is the alternative treatment to insulin
therapy?” 22% responded “strongly agree”, 24% responded “agree”, 25% responded “somewhat agree”,
19% answered “disagree”, 5% answered “strongly disagree”, and 5% did not give any answer. From these results, 71% were positive opinions in favor of medicaltransplantation (Fig. 1B). Finally, to the question“Would you want to be treated with a preparation using
swine cells if it is effective?” 14% responded “strongly
agree”, 23% responded “agree”, 24% responded “somewhat agree”, 19% answered “disagree”, 16% answered“strongly disagree”, and 4% did not give any answer.
From these results, 61% of the subjects gave positive answers to new treatments if the treatments are effective(Fig. 1C). Due to the limited number of organ donors,
allogenic islet cell transplantation cannot be made available to all type 1 diabetic patients. Therefore, it is necessary to seek different sources, and the most promisingones are swine pancreatic islets. Nowadays, research on
the use of bio-artificial islet transplantation with swine
pancreatic islets is being conducted worldwide, and theiruse in clinical applications is already underway.8 However, for the future encouragement of bio-artificial islet
transplantation, it is important to know the percentage oftransplant recipient patients who would actually accept
cells from a different species. From the results of thissurvey, the fact that “the majority of the patients thought
positively about accepting” is worth mentioning. These
results can also suggest that type 1 diabetic patients havehigh expectations regarding new treatments.
When type 1 diabetic patients come to the hospital at
the onset of the disease for the first time, it is explainedthat insulin therapy must be continued for a lifetime. In
other words, type 1 diabetic patients live their entire
lives with the disease, which may bring an enormous
mental burden to the patients. Therefore, we analyzed
the patients’ anxiety and fear of diabetes. As a result tothe question “Do you feel anxiety and fear for complica-

tions?” 37% responded “strongly agree”, 29% responded“agree”, and 28% responded “somewhat agree”. Therefore, those who felt fear and anxiety of complications
accounted for 94% (Fig. 2A). To the question “Doestype 1 diabetes mellitus cause difficulties in everyday
life?” 28% responded “strongly agree”, 29% responded“agree”, and 24% responded “somewhat agree”. Therefore, 81% of the respondents experienced some impairment (Fig. 2B). In the long-term fight against this illness, patients have a very strong fear of developing complications and want to recover completely if possible.
Therefore, we can assume that their expectations regarding new treatments are high.
From Experimental Medicines toStandard Medical Care
In Japan, several systems are offered as a way for experimental treatments to become standard medical care.
F i r s t , H i g h l y A d v a n c e d M e d i c a l Te c h n o l o g y(HAMTS) had been widely used by medical doctors.
Doctors in Japan can initiate new medical treatments under approval of the Institutional Review Board. Aftercompleting cases which could confirm the usefulness
and safety of a new treatment, doctors could submit theirapplications through HAMTS. Subsequently, a review
will be conducted by the Central Social Insurance Medical Council (CSIMC) of the Ministry of Health, Labour,and Welfare (MHLW) through an extensive medical audit meeting to examine the technology. When safety andefficacy are confirmed, subsequently, suitability for insurance coverage is discussed at a meeting specializing
in advanced medical care that examines insurance at the
CSIMC. When the treatment is recognized as HAMT,
then the treatment can be provided to patients fromhealth insurance combined with a co-payment by the patients. Further research is conducted and data aiming at
approval as standard medical care can be collected.
However, in accordance with the partial revision of the
Health Insurance Act on October 1, 2006, the HAMTS
and the Leading Edge Health Care System (LEHCS)
were merged, and the advanced health care system wasreorganized into a new system.
The second system is the Advanced Medical System(AMS). Unlike the HAMTS, the condition for submission of notification is that the medical technology uses
medical supplies and medical equipment which have received approval from the DCMIA, or that the medical
technology is being examined for introduction into theinsurance system. A notification is sent to the MHLW
where it is received by internal subdivisions in charge ofthe insurance department, where its adaptation for combination with insurance is judged by a conference of experts on advanced medical care. Subsequently, the effectuation (establishment criteria) of advanced medical care
will be set, and its combination as healthcare services

Keio J Med 2010; 59 (2): 46－51

A

49

4％ 3％

C

4％

n=105

16％

27％

41％

23％

19％

25％

B

5％ 5％

24％

n=105
22％

19％

24％

25％

n=105

14％

Strongly agree
AgreeSome what agree
DisagreeStrongly disagree
Unanswered

Fig. 1 Patients’ opinions of new treatment (A), transplantation (B), and xeno-transplantation (C) for the treatment of diabetes.

A

4％ 2％
n=105
37％

28％

29％

B

2％

9％

8％

n=105

28％

24％
29％

Strongly agree
Agree
Somewhat agree
DisagreeStrongly disagree
Unanswered

Fig. 2 Patients’ opinions about anxiety and fear (A) and difficulties (B) related to diabetes.

Hatanaka N, et al: Why Does Japan’s Advanced Medicine Never Get Ahead?

50

provided by health insurance is made possible. Until October 2006 this AMS was called the “Leading Edge
Health Care System,” and after October 2006 it was integrated with the HAMTS, and its name has alsochanged. This system could not be applied for islet transplantation because islet transplantation uses unapproved
drugs.
The third system is the Evaluation of Advanced
Healthcare System (EAHS). This system was founded in
April 2008 and had contents similar to the HAMTS
which had been abolished. It deals with medical technologies using medical supplies/medical equipment not yet
approved and indicated by the DCMIA, for which applications are sent to the MHLW as high level healthcare.
Safety and efficacy are confirmed by a conference within the EAHS at the Health Policy Bureau within the internal subdivisions of the MHLW, and then the adequacyof its combination with insurance is determined by theconference of experts on advanced medical care. As a result, extensive medical care is determined as advanced
medical care, and the combination as healthcare services
provided by health insurance is made possible. This system is available for islet transplantation nowadays.
The Researchers’ Dilemma
after the Abolition of the HAMTS
With the abolition of the HAMTS in 2006, medical
doctors lost the way to implement innovative treatments
as standard medical care, and subsequent plans had to beestablished. Other than the HAMTS, clinical trials sponsored by medical doctors have been under consideration.
For most clinical trials conducted by pharmaceuticalcompanies, research funds are calculated and spent only
if sufficient amount of profits can be expected in the future. For this reason, Japanese pharmaceutical companies rarely spend research funds for treatments like islet
cell transplantation in which the number of targeted patients is small. Although islet cell transplantation developed in Japan was a leading medical technology in theworld, there was hardly a way to make it standard treatment in Japan.
Until recently, Japan has been promoting healthcare in
the form of medical care imported from Western countries. For this reason, only certain exceptional new medical treatments were implemented into standard medicalcare. Living donor liver transplantation was one such exception. And it was through the HAMTS that it was able
to become standard healthcare. In order to establish islet
cell transplantation as standard medical care, establishment as medical care in the United States was aimed as ashortcut to re-import it later. There were no considerations to conduct clinical trials which would have required a new medical system and financial support.

Do New Technologies in Japan
Come Through the United States?
The low success rate of islet isolation, the necessity ofmultiple donors for achieving insulin-independence, andthe difficulty of long-term insulin-free independence arethree major issues for islet transplantation.
In the United States, data regarding islet cell transplantation have improved after introduction of the Kyoto
Method. Success rate in isolating transplantable islets
from a donor’s pancreas has increased to approximately
100%,9 while with the University of Alberta,1 0 the University of Miami,11 and the University of Minnesota,1 2
known leaders in terms of islet cell transplantation, therates were reported to be about 40%.
The number of pancreatic islets in a healthy human being is approximately 1 million. It has been reported thatusing the current standard method of islet isolation, an
average number of 300,000 pancreatic islets can be isolated from one pancreas. With the Kyoto Method, an average of 700,000 pancreatic islets can be isolated. 1 3Therefore, insulin-independence may be gained throughtransplantation of islet cells isolated from one pancreas.
In fact, with the latest islet cell transplantation protocol
implemented by Baylor Regional Transplant Institute,
blood glucose level stabilization and withdrawal frominsulin injections were achieved after a single donor islet
transplant.14
Our first islet cell transplant in the United States was
conducted in February of 2007. We were able to provide
high quality and quantity of islets to the patient, and todate the patients remain insulin-free, and was able tomaintain excellent glycemic for more than two years.1 5
These are promising results for the maintenance of longterm insulin-free independence.
With the introduction of new islet isolation technologies, the once major issues of islet transplantation seemto be resolved. We are currently preparing to apply for
FDA approval to promote our islet transplantation as thestandard therapy in the United States. Once this standardof therapy is approved, we should be ready for re-importation of islet transplantation into Japan.
Conclusion
Japan has a history of introducing new medical carefrom foreign countries because its national system forthe establishment of standard treatments is weak. Furthermore, since the HAMTS has been abolished, it has
become difficult for new medical treatments to become
standard treatments. Re-importation from Europe andthe United States has been considered to be a shortcut
for the development of new medical care, and even pharmaceutical companies perform clinical trials in Europe
and the United States. As globalization progresses, researchers look for places to exercise the maximum of

Keio J Med 2010; 59 (2): 46－51

their own capabilities, and aim to establish new medical
care.
Ironically, Japan has been conducting research in orderto develop technologies that can be attainable worldwide, yet has abandoned their establishment in the final
stages.
Is there a way to improve the current situation inwhich we are forced to aim establishing technologies in
the Western countries? The earnest desire of Japanesepatients waiting for new medical care is for Japanese researchers to aim at the establishment of medical care in
Japan without having to go overseas.
We hope that the EAHS will be a shortcut for the establishment of new medical care. For this, we should
continuously improve the EAHS system to make it more
effective. Medical doctors and Japanese government
should work together to improve this system.
Additionally, Japan should also consider building anenvironment in which researchers can devote themselvesto their research without losing motivation for establishing new medical care.
Acknowledgements
This study was supported in part by a grant from the
Health Labour Sciences Research Grant for Research on
Basic Researches from the Japanese Ministry of Health,Labour and Welfare (H19-Trans-General-004: Establishment of islet cell transplantation as the result of translational research).
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