保健医療科学

2019Vol.68 No.1 p.45−54

Topics: Recent topics in public health in Japan 2019

＜ Review ＞
Research and development on intractable & rare diseases in Japan:
Contribution of the National Institute of Public Health to research
program management
Shinji Takemura 1,3), Tomofumi Sone 2,4)
1) Department of Health Policy and Technology Assessment, National Institute of Public Health2) Vice President, National Institute of Public Health3) Program Officer, Research program on rare and intractable diseases, Health, Labour and Welfare Sciences
Research Grants
4) Program Director, Research program on rare and intractable diseases, Health, Labour and Welfare Sciences
Research Grants
Abstract
This paper outlines the history of research and development (R&D) for intractable & rare diseases in Japan, and describes how the National Institute of Public Health (NIPH) has been involved in and contributed
to R&D and how the NIPH will address it.
Since 1972, R&D for intractable & rare diseases had been implemented in accordance with the “Outline of Intractable Disease Measures”, which was a policy guideline for implementing national measures
for addressing intractable & rare diseases. Because the outline listed “promotion of survey/research” ashigh priority measure, a wide range of research, including basic, clinical, and epidemiological research, waspromoted for years. However, the goal of the research was not so clear, and on the other hand, it was not
focused on development of orphan drugs, unlike in other countries. The R&D projects on intractable diseases were mainly implemented in the Research Program for Overcoming Intractable Diseases, funded by
the Ministry of Health, Labour and Welfare. After the budget for the program was increased substantially,
to 10 billion yen in 2009, the R&D was divided in two directions: “Expansion of target diseases for survey/
research”, and “Development and clinical application of innovative medical technology such as pharmaceuticals”. Then, the NIPH became the Funding Agency for the program in 2010, and addressed clarificationof the goal of research projects and development of the management system of the research program. As aresult, disease concepts and diagnostic criteria were established for many diseases for which surveys andresearch had scarcely been conducted. Moreover, clinical trials and regulatory approvals were completed forseveral drugs and medical devices.
Since the enactment of the Act on Medical Care and Social Supports for Patients with Intractable/Rare
Diseases in 2014, and the foundation of the Japan Agency for Medical Research and Development in 2015,
the framework of R&D for intractable & rare diseases has changed significantly. Research programs had
been divided into two programs: the Research Program on Policy of Measures for Intractable/Rare Diseases, and the Research Program on Practical Application of Measures for Intractable/Rare Diseases. The
NIPH had the role of the funding agency for the former research program, and had the responsibility forproviding a scientific basis for supporting the medical cost subsidy system and the medical services delivery system under the act, which meant establishing diagnostic criteria, disease severity classifications, andclinical practice guidelines.

Corresponding author: Shinji Takemura
2-3-6 Minami, Wako, Saitama 351-0197, Japan.
E-mail: takemura.s.aa@niph.go.jp

J. Natl. Inst. Public Health, 68 (1) : 201945

Shinji Takemura, Tomofumi Sone
Since 2014, the NIPH has established a new research program management system as follows: (a) The
goal of the research program was set as maximizing the number of diseases for which diagnostic criteria,
disease severity classifications, and clinical practice guidelines were developed or revised by the research
projects, and were approved by the relevant academic societies; (b) It was required for each research project to set the goals for each disease to be studied, such as development of diagnostic criteria and disease
severity classifications, revision of clinical practice guidelines, approval for the clinical practice guidelines
by academic societies, etc.; (c) Annual submission of the research outcome report was made mandatory foreach project in order to implement progress management and evaluate the research outcome. As a result,diagnostic criteria and disease severity classifications were developed or revised for many intractable &rare diseases at the end of 2017 (85% and 78% of 582 target diseases, respectively). On the other hand, thenumber of cases of development or revision of clinical practice guidelines remained at one half, and therefore, it is necessary to have projects set an appropriate goal in accordance with the program policy.
In the future, the NIPH is willing to continue to proactively conduct the management of the Research
Program on Policy of Measures for Intractable/Rare Diseases in order to achieve many research outcomesthat contribute to intractable & rare disease policy.
keywords: intractable & rare diseases, research and development (R&D), program management, project
management, research management(accepted for publication, 21st December 2018)

I．Introduction
In Japan, the national program for addressing intractable& rare diseases was implemented in accordance with the“Outline of Intractable Disease Measures[1]” compiled in
1972[2]. It was one of the oldest programs on disease control. However, the outline was not an act but a guideline;
therefore, the measures were implemented based on anannual budget request. The Act on Medical Care and Social
Supports for Patients with Intractable/Rare Diseases[3](hereinafter called the Intractable/Rare Diseases Act) was
then enacted in 2014, and the legal grounds for the measures were established for the first time in more than 40
years.
From 1972, a wide range of research on intractable &rare diseases, which included basic research, clinical research, development research, public health research, andso on, were promoted for the purpose of overcoming them.
However, the goal of each research project was not clear
because a research management system did not exist. In
2010, the National Institute of Public Health (NIPH) had therole as the Funding Agency (FA) for the national research
program on intractable & rare diseases, and the clarificationof the goal of research projects, development of the management system of the research program, and efficiency of
the research fund were addressed. Moreover, the restructuring of the research and development (R&D) management system and the establishment of new goals for R&D
have been progressing since the enactment of Intractable/
Rare Diseases Act in 2014 and establishment of the Japan
Agency for Medical Research and Development (AMED) in

46

2015.
This paper outlines the history of R&D for intractable& rare diseases in Japan, and describes how the NIPH wasinvolved in and contributed to the R&D and how the NIPH
will address it.

II．History of Intractable & Rare Disease
Measures in Japan
Intractable & rare diseases are called nambyo in Japanese. However, as the Japanese characters do not themselves contain the meaning “rare,” the meaning is limited
to “intractable disease.” This characterized Japan’s R&D
with respect to intractable & rare diseases, which took apathway that differed from that of other countries.
1. Initial Intractable Disease Measures
It was the occurrence of subacute myelo-optic neuropathy (SMON) during the 1960s that triggered efforts toaddress intractable diseases. In response to SMON, forwhich the cause was unknown, in 1969 a large-scale study
group was formed in collaboration with the then Ministryof Health and Welfare and the then Science and Technology
Agency, which conducted a multidirectional and intensive
survey and research, including nationwide epidemiological studies. As a result, Kinoholm (Clioquinol, Chinoform,or Quinoform), an antidiarrheal drug, was revealed to be
the cause of SMON in 1972, which was only three years
later[4,5]. The ministry then banned the sales of the drug,
and the incidence of SMON decreased drastically. A lesson
learned from this experience was that even in cases involv-

J. Natl. Inst. Public Health, 68 (1) : 2019

Research and development on intractable & rare diseases in Japan: Contribution of the National Institute of Public Health to research program management
ing an intractable disease with unknown cause, it is possible
to reduce the occurrence of diseases by promoting a survey
and research. Therefore, “promotion of survey/research”
became the first measure listed in the Outline of Intractable
Disease Measures that was established in 1972. (Table 1)
There is no policy for diseases that R&D is given priority
over elsewhere (e.g., “promotion of research & development” is specified under Article 19 of the Cancer Control
Act[6]).
Another characteristic of the Outline of Intractable Disease Measures is that the definition of intractable disease
does not include “rarity”. In other countries, survey andresearch is being conducted with the concept of a rare disease, with the central aim of the development and dissemination of orphan drugs (i.e., drugs that would not be developed by sponsors under the usual market mechanism dueto the small number of patients). For example, in the UnitedStates, the Rare Diseases Act[7] was enacted in 2002, following the enactment of the Orphan Drug Act[8] in 1983,
indicating that drug development has priority. In contrast,
in Japan, the survey and research specified in the Outline
of Intractable Disease Measures was widely conducted toobtain an understanding of patient status such as in an epidemiological study, basic research such as an elucidationof pathogenesis and pathophysiology, and clinical researchsuch as an evaluation of treatment method, but was notnecessarily focused on development research for drugs andmedical devices.
2. Progress of Intractable Disease Measures and the
Involvement of the NIPH
The major national measures that have been undertaken
for the survey/research of intractable diseases were the
Research Program for Overcoming Intractable Diseases andthe Research Project on Treatment for Specified Diseases.
The former is one of the research programs operated byHealth, Labour and Welfare Sciences Research Grants,
a competitive research fund provided by the Ministry of
Health, Labour and Welfare (MHLW), aiming for the promotion of the survey/research specified in the Outline ofIntractable Disease Measures. On the other hand, regarding
the latter, although it was named a research project, its main
objective was medical cost subsidy for patients (i.e., thereduction of copayment of medical fees). At the same time,
many epidemiological studies have been conducted utilizing
patient data from medical expense subsidy applications[9].
The number of target diseases has increased yearly, andin 2009 the number of target diseases for the Research
Program for Overcoming Intractable Diseases reached 130,
while that for the Research Project on Treatment for Specified Diseases reached 56. In addition, the budget for the

Research Program for Overcoming Intractable Diseases,
which had been kept at around 2 billion yen since 1998, wasincreased substantially to 10 billion yen in 2009, in accordance with the intention of the then Minister of Health,Labour and Welfare. In response, the survey/research was
extended and promoted in two directions: “Expansion oftarget diseases for survey/research” and “Development andclinical application of innovative medical technology such as
pharmaceuticals.” In addition, in order to efficiently manage
the research program in accordance with these directions,
the NIPH became the FA for the Research Program forOvercoming Intractable Diseases, replacing the MHLW in2010.
With regard to “Expansion of target diseases for survey/
research,” “Encouraged Research Projects” were newly
launched in order to establish disease concepts, elucidate
pathogenesis and pathophysiology, and develop diagnostic
criteria for rare diseases, for which survey and research had
scarcely been conducted, excluding the 130 diseases covered in the Research Program for Overcoming Intractable
Diseases. By 2012, a total of 234 diseases were studied, anddisease concepts and diagnostic criteria had become established for them.
With regard to “Development and clinical application of
innovative medical technology such as pharmaceuticals,”
although research projects had been conducted focusing on
innovative diagnostic and treatment methods since 1996,
from 2012 onward research projects were conducted withregulatory approval as the eventual goal of them. Specifically, “Step 1” research projects, in which good laboratory
practice (GLP) studies preparing for clinical trial and protocol development for clinical trial were performed to shift toinvestigator-initiated clinical trials, as well as “Step 2” research projects, in which investigator-initiated clinical trials
were performed, including the submission of investigational
new drug (IND), Phase I, Phase II, and obtaining proof ofconcept (POC), were conducted. In this research area, thecompletion of clinical trials and regulatory approvals wereachieved for some drugs and medical devices, by clearly
indicating the expected outcome (such as the report of
GLP studies, reports of clinical trials, and an Investigator’sBrochure) under funding opportunity announcements ofresearch projects and strictly conducting the progress management of each research project (such as hearings withprincipal investigators and site visits to research institutes)[10,11].
Meanwhile, regarding medical cost subsidy, not only the
number of target diseases but also the number of target
patients has increased, reaching 780,000 by the end of fiscal
year 2011. Subsequently, the annual budget for the Research Project on Treatment for Specified Diseases reached

J. Natl. Inst. Public Health, 68 (1) : 201947

Shinji Takemura, Tomofumi Sone
more than 40 billion yen, which made the project difficult tomanage smoothly. In addition, for medical cost subsidy, due
to an increasing number of opinions requesting the expansion and revision of target diseases, it was becoming necessary to reexamine the methodologies for selecting target
diseases and recognizing target patients.
3. Enactment of Intractable/Rare Diseases Act andthe Subsequent Promotion of Intractable & Rare
Disease Measures
Discussions on what measures for intractable & rare diseases should be taken began around 2011 at the Committee
on Disease Control of the Health Science Council of MHLW,
and a few reports were presented. In addition, it was stipulated in the “Outline of the Comprehensive Reform of theSocial Security and Tax Systems[12]” in 2012 that a fairer
and more stable support system was to be established forsubsidizing the medical expenses of patients with intractable & rare diseases, including legislation and expansion of
the range of eligible intractable & rare diseases.
Then, the Act on Medical Care and Social Supports forPatients with Intractable/Rare Diseases[3] was enacted
on May 23, 2014, and came into effect on January 1, 2015.

Table 1The purposes of this act were: (1) to establish a fairer andmore stable system by enabling the allocation of consumption tax revenues to the subsidy of medical cost expenses
for patients with intractable/rare diseases, as a measure
based on the law related to promoting the reform in orderto establish a sustainable social security system; and, (2) totake measures such as the development of basic policy, promotion of research on medical care for intractable/rare diseases, and the implementation of community-based health/
medical care and welfare services. In this manner, a stable
medical cost subsidy system was established for even morepatients with intractable/rare diseases than so far.
The definition of intractable/rare diseases and themeasures for intractable/rare diseases stipulated in the
Intractable/Rare Diseases Act are shown in Table 1. While
intractable/rare diseases are clearly defined by four requirements, “Designated Intractable/Rare Diseases” are definedas those that also meet the following two additional requirements: (5) the number of patients in Japan is less than aspecified level (approximately 0.1% of the population); and,(6) objective diagnostic criteria (or the equivalent) havebeen established, and they have become a target disease for
medical cost subsidy. The accreditation criteria for medical

Comparison between Outline of Intractable Disease Measures and the Intractable/Rare Diseases Act
Outline of Intractable Disease Measures[1]Year of the establishment

1972

Definitions of diseases ad- (1) A disease which cause has not yet been
dresseddetected and for which there is no established therapy, and which may likely leave
an aftereffect

Implementation Methods

2014(1) The cause of the disease is not clear.
(2) The treatment method of the disease is not established.
(3) The occurrence of the disease is rare.
(4) A long-term cure for the disease is needed.

(2) A disease which is chronic and poses not
only financial problems, but a heavy burden
on the patientʼs family due to the great dealof effort required in caring for the patients,
including potential psychological burdens

Requirements for Designated Intractable/Rare Diseases, in addition to the above:(5) The number of patients in Japan is less than a certain level(approximately 0.1% of the population).
(6) Objective diagnostic criteria (or the equivalent) have been
established.

(1) Promotion of survey/research(1) Development of basic policy(2) Development of a new, fair, and stable system for the subsidization of specific medical expenses related to intractable/rare diseases• Provide subsidies for medical costs to patients with intractable/rare diseases targeted by medical cost subsidies (designated intractable/rare diseases)• Appointment of medical institutions that implement medicalcare for designated intractable/rare diseases• The certificates to be attached to a subsidy application are to
be prepared by a designated doctor(3) Promotion of research on medical care for intractable/rare
diseases(4) Implementation of community-based health/medical careand welfare services(Intractable/rare disease consultation/support center service,home-visit nursing care)(2) Establishment of medical institutions(3) Reduction of copayment of medical fees48

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Research and development on intractable & rare diseases in Japan: Contribution of the National Institute of Public Health to research program management
cost subsidy are stipulated as “patients with a certain levelof severity, as defined by the disease severity classification,
and who have difficulty in their daily or social lives.” With
regard to Designated Intractable/Rare Diseases, 110 diseases were designated in January 2015, with 196 diseases designated in July 2015, then 24 diseases designated in April
2017, and one disease designated in April 2018, reaching acurrent total of 331 diseases.
On the other hand, survey and research has changed
significantly due to reform of the research and development
framework in the medical field. In April 2015, the Japan
Agency for Medical Research and Development (AMED)
was founded. It promotes top-down research by unifying
the management of the research and development budget
in the medical field, which had previously been under thejurisdiction of multiple ministries, based on the “Healthcare
Policy[13]” in 2014.
In response, Health, Labour and Welfare Sciences Research was categorized into “policy research” and “practicalresearch,” with the former falling under the jurisdiction of
the MHLW and the latter under the AMED. With regard to
intractable & rare diseases, while basic research, clinicalresearch, development research, and public health research
had previously been conducted in a comprehensive manner
under the Research Program for Overcoming Intractable
Diseases, since 2014 it has been conducted under two research programs: (1) the Research Program on Policy of
Measures for Intractable/Rare Diseases, funded by MHLW,
which aims to understand the current status of patients
based on epidemiological studies, establish diagnostic
criteria and disease severity classifications, and establish
and widely disseminate evidence-based clinical practiceguidelines; and, (2) the Research Program on Practical Application of Measures for Intractable/Rare Diseases, fundedby the AMED, which aims to elucidate pathogenesis andpathophysiology as well as develop innovative diagnostic
and treatment methods. In particular, the latter is positioned as the Rare/Intractable Disease Project of Japan,
which is one of the AMED’s nine main projects, and it isbeing conducted intensively with a budget of approximately 10 billion yen, aiming to achieve at least 11 regulatory
approvals or indication expansion of drugs and medical devices for intractable & rare diseases by 2020. Moreover, thepolicy research program and the practical research program
are conducted systematically, in joint cooperation.

III．The NIPHʼs Approach to Intractable &Rare Disease Research
1. Outline of the Funding Agency at the NIPH
The FA at the NIPH is responsible for assessing research

proposals to be applied, selecting research projects to bevalued, and allocating research funds for the projects. It also
supports the appropriate implementation of the projects ofresearch programs[14]. In the FA, Program Directors (PD)and Program Officers (PO) have also been instituted. They
are responsible for the following operations:(1) Assessment of research proposals, including selectionof assessment committee members, conduct of themeetings of the committee, provision of information andreports to the committee, and summarization of the results of assessment and the comments from committee
members, etc.;(2) Progress management of research projects, including attendance at project meetings and consultation about the
research plan, hearings, site visits, etc.
In addition, they identify research areas and research
projects that should be the focus of promotion by taking into
consideration trends in related research and developments
and make proposals for the funding opportunity announcement.
2. The Past Contributions of the NIPH
In the past, the NIPH has contributed greatly to the development of measures for intractable & rare diseases. In
2011 serious discussion began regarding the Intractable/
Rare Diseases Act, which was supported by the substantially increased research budget from 2009, as well as progressin intractable & rare disease research resulting from theactivities of the FA at the NIPH. Specifically, the diagnostic criteria for rare diseases established by “Encouraged
Research Projects” were used as the basic reference whenselecting Designated Intractable/Rare Diseases. In addition,
the framework for the R&D established by the NIPH is stillused at the AMED.
On the other hand, through the enactment of the Intractable/Rare Diseases Act, the positioning of intractable &rare disease research has changed greatly. While researchitself was the main purpose of the Outline of Intractable
Disease Measures, in the Intractable/Rare Diseases Act,it was positioned as a scientific basis for supporting boththe medical cost subsidy system and the medical services
delivery system for intractable & rare diseases. Therefore,
under the Act, a research program should be conducted forthe purpose of developing: (1) “diagnostic criteria” contributing to the selection of Designated Intractable/Rare Diseases; (2) “disease severity classifications” contributing tofair and appropriate certification of patients with DesignatedIntractable/Rare Diseases; (3) “clinical practice guidelines”
contributing to improvement of the quality of medical care

J. Natl. Inst. Public Health, 68 (1) : 201949

Shinji Takemura, Tomofumi Sonefor patients with intractable & rare diseases; and, (4) innovative diagnostic and treatment methods (drugs and medical devices) contributing to overcoming intractable & rarediseases.
3. A New Challenge in Research Program Management at the NIPH
From 2010, the NIPH was responsible as the FA for all
intractable & rare disease research. However, in 2014 it
became responsible as the FA for the Research Programon Policy of Measures for Intractable/Rare Diseases, whichprimarily aims to develop diagnostic criteria, disease severity classifications, and clinical practice guidelines. This
resulted in a need to revisit research program management.
As little research[15-17] had been performed on the management of research programs or projects, it was necessary
for the NIPH to develop a methodology on its own.
In the process of implementing program management,
the first effort was to establish the goals of the program, as
well as the indices enabling a clear understanding of progress toward and achievement of the goals. As the purposeof the Research Program on Policy of Measures for Intractable/Rare Diseases is “to improve the standards of medicalcare for intractable & rare diseases by understanding thecurrent status of patients based on epidemiological studies,
establishing diagnostic criteria and disease severity classifications, and establishing, disseminating, and revising evidence-based clinical practice guidelines of intractable & rarediseases[18]”, the indices of program management was set
as (a) the number of diseases developed or revised throughdiagnostic criteria, disease severity classifications, andclinical practice guidelines, and (b) the number of diseasesof which diagnostic criteria, disease severity classifications,and clinical practice guidelines developed or revised wereapproved by the academic societies related to them, while
the goal of the research program was to maximize (a) and (b).
Approval by academic societies is considered as one of theeffective measures to “disseminate” research outcomes.
Secondly, in order to achieve the program goal, it wasnecessary to set goals for the research projects funded by
the program. At the time of invitation of public subscriptions, it was required to select one or more intractable &rare diseases to be studied and to set one or more goals foreach disease among the following:(1) Development or revision of diagnostic criteria(2) Development or revision of disease severity classifications(3) Development or revision of clinical practice guidelines(4) Approval by academic societies for diagnostic criteria(5) Approval by academic societies for disease severity classifications

50(6) Approval by academic societies for clinical practiceguidelines
In this manner, we tried to establish the R&D management system to achieve the goal of the program effectively
and efficiently by setting attainable goals for each project.
Lastly, it was necessary for the status of achievement
to be “reported” for the goals of each project, in order toimplement progress management to achieve the goal of theentire program. The Research Outcome Report Form wascreated as the common format. Contents of the report to bestated were as follows:- target diseases- goals by each disease (stated above)- deadline- status of achievement of each goal (date of achievement,
expected month and year of achievement, or unachieved)at the end of each year
When the goal has been achieved, documented evidence
to prove the outcome was to be attached to the following
pages (such as developed or revised diagnostic criteria, disease severity classification, and clinical practice guideline).
Annual submission of the outcome report was made mandatory for each project and was used for midterm and/or
final evaluation of the project and progress management. By
this means, the PD and PO were able to monitor the statusof goal achievement for each disease targeted by each project, and the principal investigators of the projects were able
to proceed with their research with an awareness of thestatus of goal achievement.
As of the end of 2017, the total number of ongoing projects stood at 113, targeting a total of 582 diseases. Amongthese diseases, Designated Intractable/Rare Diseases
accounted for 342, while others accounted for 240. Amongthese 331 Designated Intractable/Rare Diseases, some areconsidered to form a “disease group” (e.g., lysosomal storage diseases, congenital anomaly syndrome, and hereditary
autoinflammatory diseases). It should also be noted thatsince there are projects that are addressing multiple diseases that are individually included in a single DesignatedIntractable/Rare Disease, the actual number of target diseases (342) is larger than those of Designated Intractable/
Rare Diseases (331).
Table 2 shows the status of development and revisionof diagnostic criteria, disease severity classifications, andclinical practice guidelines for the target diseases of thisresearch program at the end of 2017 (obtained by tabulating the contents of the research outcome reports of eachresearch project). The number of diseases for which diagnostic criteria, disease severity classifications, and clinicalpractice guidelines were developed was 494 (85%), 456(78%), and 293 (50%), respectively.

J. Natl. Inst. Public Health, 68 (1) : 2019

Research and development on intractable & rare diseases in Japan: Contribution of the National Institute of Public Health to research program management
Table 2Current status of target diseases
disease severity
classification

diagnostic criteria

clinical practiceguideline

No. ofdiseases%No. ofdiseases%No. ofdiseases

%

494

84.9%

456

78.4%

293

50.3%

29
73
110
130
81
53
18

5.9%
14.8%
22.3%
26.3%
16.4%
10.7%
3.6%

14
33
114
156
83
44
12

3.1%
7.2%
25.0%
34.2%
18.2%
9.6%
2.6%

12
57
40
54
66
61
3

4.1%
19.5%
13.7%
18.4%
22.5%
20.8%
1.0%

341
153

69.0%
31.0%

252
204

55.3%
44.7%

238
55

81.2%
18.8%

Has been developed(Breakdown)Year of development or revision
Before 20082009 to 2013
2014
2015
2016
2017
Unknown
Academic society approval
Yes
No

Among the diseases for which development or revision
was achieved, the proportion of those in and after 2014
was 76% for diagnostic criteria, 87% for disease severity
classifications, and 75% for clinical practice guidelines. The
percentage of diseases approved by the relevant academic
societies was 69% for diagnostic criteria, 55% for disease
severity classifications, and 81% for clinical practice guidelines.
As described above, diagnostic criteria and disease severity classifications were developed or revised for many
intractable & rare diseases under the Research Programon Policy of Measures for Intractable/Rare Diseases implemented since 2014. This suggests that the NIPH’s program
management method on goal and deadline setting, andprogress monitoring has a certain level of effectiveness.
On the other hand, the number of cases of development
or revision of clinical practice guidelines, which plays acrucial role in the standardization of medical care for intractable & rare diseases, remained at one half. In addition,
for roughly one quarter of diseases, diagnostic criteria andclinical practice guidelines have not been revised for morethan five years. Possible reasons for pending development

or revision include, for example, that there is no need forrevision due to a lack of new evidence, or that it is not possible to develop evidence-based clinical practice guidelines
due to extremely limited evidence.
Table 3 shows the current status of designated versus
nondesignated intractable/rare diseases. A higher percentage of Designated Intractable/Rare Diseases have developed diagnostic criteria, disease severity classifications, andclinical practice guidelines. These results suggest that theoutcome of this research program contributed to intractable& rare diseases measures, especially, the standardization of
medical care for Designated Intractable/Rare Diseases. It
has been reported that the utilization of research outcomes
into policy was accelerated by the active involvement of a
PO in the research process of each project[19]. Similarly, inthis research program, the PO’s attendance at project meetings and advice on the implementation of research projects
is considered to have contributed to the improvement of theresearch process of each project.
Since 2017, not only the development and revision ofdiagnostic criteria, disease severity classifications, andclinical practice guidelines, but also public awareness (sup-Table 3 Current status of target diseases for Designated versus Nondesignated Intractable/
Rare Diseases
Designated(342 diseases)

Nondesignated(240 diseases)

Total(582 diseases)

No. ofdiseases%No. ofdiseases%No. ofdiseases%Has diagnostic criteria

318

93.0%

176

73.3%

494

84.9%

Has a disease severity
classification

306

89.5%

150

62.5%

456

78.4%

Has clinical practiceguidelines

203

59.4%

90

37.5%

293

50.3%

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Shinji Takemura, Tomofumi Sone
porting patient advocacy group, holding symposiums, etc.),
operation of a patient registry[9,20], transition from pediatric to adult health care[21], and collaboration with related
research were expected as the goal of the Research Program on Policy of Measures for Intractable/Rare Diseases.
Therefore, it is necessary to conduct progress managementof them by setting appropriate indices (e.g., whether or not
and how often a symposium is held, whether or not and how
many patient registries are available, etc.).
In the near future, the NIPH is willing to continue toproactively conduct object management, progress management, and outcome management of the Research Programon Policy of Measures for Intractable/Rare Diseases in order to achieve many research outcomes that contribute to
intractable & rare disease policy, as the FA of intractable &rare disease research.

Conflicts of Interest
The authors declare that there are no conflicts of interest
regarding the publication of this article.

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J. Natl. Inst. Public Health, 68 (1) : 201953

Shinji Takemura, Tomofumi Sone

日本の難病に関する研究開発の動向―研究開発管理における国立保健医療科学院の貢献―

武村真治 1,3），曽根智史 2,4）
1）

国立保健医療科学院政策技術評価研究部

2）

国立保健医療科学院次長

3）

厚生労働科学研究費補助金（難治性疾患政策研究事業）研究事業推進官

4）

厚生労働科学研究費補助金（難治性疾患政策研究事業）研究事業企画調整官

抄録
本稿では，日本の難病に関する研究開発の歴史を概観するとともに，国立保健医療科学院のこれま
での難病研究への関与と貢献，そして今後の取り組みについて論述する．
日本の難病に関する研究開発は，1972年から，国の難病施策の指針の「難病対策要綱」にしたがって実施されてきた．この要綱では「調査研究の推進」が難病施策の第一に掲げられており，基礎研究，臨床研究，疫学研究など，幅広い調査研究が推進されてきた．しかし調査研究が広範であるがゆえにその目標は明確ではなく，また諸外国と異なり，必ずしも希少疾病用医薬品（オーファンドラッグ）の開発に重点が置かれたわけではなかった．難病に関する研究課題（研究プロジェクト）は，主に厚生労働省の資金提供による「厚生労働科学研究費補助金（難治性疾患克服研究事業）」で実施されてきた．2009年度に事業予算が100億円に大幅に増額されたことを受けて，調査研究を「研究対象疾患の網羅的な拡大」と「画期的な医薬品等医療技術の開発・実用化の推進」の 2 つの方向性で拡充することとなった．またその方向性にしたがって研究事業を円滑に運営するために，2010年度より国立保健医療科学院が本研究事業に係る研究費配分機関（Funding Agency：FA）となり，研究課題の目標の明確化，研究事業（研究プログラム）の管理システムの構築を行った．その結果，これまでほとんど調査研究が実施されてこなかった多くの難病で疾患概念の確立と診断基準の策定がなされ，また複数の医薬品・医療機器で治験の完了や薬事承認を達成することができた．
2014年の「難病の患者に対する医療等に関する法律（難病法）」の制定，2015年の日本医療研究開発機構（AMED）の設立によって，難病に関する研究開発の枠組みは大きく変化した．つまり，これまでの難治性疾患克服研究事業が「難治性疾患政策研究事業」と「難治性疾患実用化研究事業」に分割され，国立保健医療科学院は前者のFAとして，難病法に基づく医療費助成制度や難病医療提供体制を支える科学的基盤である診断基準，重症度分類，診療ガイドラインの確立を進めることとなった．
国立保健医療科学院は，2014年度から，新たな研究事業の管理システムを構築し，運用している．
具体的には，(a)研究事業の目標を，診断基準，重症度分類，診療ガイドラインが策定・改訂された疾患数，及びそれらが関係学会で承認された疾患数の最大化に設定したこと，(b)各研究課題に，研究対象とする各疾患に関して，「診断基準」，「重症度分類」，「診療ガイドライン」のいずれか，あるいは全てについて，「策定・改訂」，「学会での承認」のいずれか，あるいは両方を目標として設定させたこと，(c)各研究課題に「研究成果申告書」を毎年提出することを義務づけ，進捗管理と研究評
価を徹底したこと，などが推進された．その結果，2017年末までに，多くの難病の診断基準，重症度分類が策定・改訂された（582の対象疾患の85％，78％）．しかし一方で，診療ガイドラインの策定・改訂は半数にとどまり，今後は研究課題が「自ら」目標を設定するだけでなく，「研究事業の方針に従って」適切な目標を設定できるよう支援する必要がある．
国立保健医療科学院は，今後も難病研究のFAとして，難病政策に資する多くの研究成果を上げる
ために，難治性疾患政策研究事業の目標管理，進捗管理，成果管理を積極的に行っていくつもりである．
キーワード：難病・希少疾患，研究開発（R&D），プログラムマネジメント，プロジェクトマネジメ
ント，健康関連研究開発管理

54

J. Natl. Inst. Public Health, 68 (1) : 2019