Clinical Therapeutics/Volume 37, Number 8, 2015
Commentary
Accelerating Regulatory Science Initiatives for the Development
of Drugs for Alzheimer’s Disease in Japan
Takashi Moritoyo, MD, PhD1,2
1
Unit for Early and Exploratory Clinical Development, The University of Tokyo Hospital, Tokyo, Japan; and
2
Office of New Drug II, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
ABSTRACT
Purpose: The Ministry of Health, Labour and
Welfare (MHLW) of Japan launched a regulatory
science research project in which the aim is to promote
the establishment of guidelines for the development of
innovative drugs thorough interactions between aca-
demia and Japan’s regulatory agency, the Pharma-
ceuticals and Medical Devices Agency (PMDA).
In this project, a research system with the aim of deve-
loping a guideline for the clinical evaluation of drugs
intended for the treatment of Alzheimer’s disease (AD)
was established.
Methods: Two research groups were set up: (1) the
Biomarker and Clinical Evaluation Group to establish
biomarker-based criteria for the clinical evaluation of
drugs for AD, and (2) the Modeling and Simulation
(M&S) Group to create a disease model of AD using
M&S techniques based on data from the Alzheimer’s
Disease Neuroimaging Initiative (ADNI). Furthermore, a
human resource exchange between the University of
Tokyo Hospital and the PMDA is conducted to establish
a guideline that is suitable for regulatory use.
Findings: As an interim report of this project, issues
that require consideration for the clinical evaluation
and development were summarized, including topics
such as the use of biomarkers in the inclusion criteria,
the efficacy endpoint, and the clinical data package
required for application in Japan.
Implications: As the result of collaboration between
the University of Tokyo Hospital and PMDA, this
document is the first to summarize perspectives on the
Accepted for publication April 24, 2015.
http://dx.doi.org/10.1016/j.clinthera.2015.04.014
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.
1622
development of drugs for AD in Japan. (Clin Ther.
2015;37:1622–1626) & 2015 Elsevier HS Journals,
Inc. All rights reserved.
Key words: Alzheimer’s disease, regulatory science,
biomarker, clinical evaluation.
INTRODUCTION
Alzheimer’s disease (AD) is the most common disease of
dementia and is characterized by a gradual progression
of cognitive impairment that interferes with the patient’s
independent activities of daily living. AD has severe
effects not only on patients but also on their caregivers.
Japan is now an aging society, and AD is one of the
most worrisome and urgent matters of concern from a
socioeconomic point of view. In 1999, donepezil was the
first drug approved for the treatment of AD in Japan. In
2011, 2 cholinesterase inhibitors (galantamine and
rivastigmine) and an N-methyl-D-aspartate receptor in-
hibitor (memantine) were approved as symptomatic
drugs, and the prescription of 3 drugs to patients with
AD thus became clinically possible, thereby overcoming
the “drug lag for AD” issue.1
The Japan Health Sciences Foundation has surveyed,
on a periodic basis since 1994, the satisfaction of
physicians with treatment outcomes and the degree to
which individual drugs contribute to treatments.
According to their reports, AD has received the lowest
ranking in terms of both treatment satisfaction and
relevant drug contribution.1 Thus, medications that can
inhibit the progression of clinical symptoms are urgently
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Volume 37 Number 8
 T. Moritoyo

Human resource development

by personal exchange
Pharmaceuticals and Medical
Devices Agency Dispatch reviewers

Accept researchers
National Institute of Health Sciences Academia Medical Institute

Learn innovative technologies

Rearch results Develop regulatory science experts

Accelerated, higher quality review Promote proper R & D

Early development of standards

and/or guidelines

Promote implementation of
innovative technologies
(eliminate drug lag and device lag)

Figure 1. Accelerating regulatory science initiatives in Japan. R & D ¼ Research & Development.

needed. Although disease-modifying drugs have under-
gone extensive development over the last decade, their
clinical efficacy has not yet been successfully demon-
strated.2 Under these circumstances, University of Tokyo
Hospital and the Pharmaceuticals and Medical Devices
Agency (PMDA) started a novel regulatory science
research project for the development of drugs for AD.
The objective was to describe the current status of this
regulatory science research for the development of drugs
for Alzheimerʼs disease in Japan.
ACCELERATING REGULATORY SCIENCE
INITIATIVES IN JAPAN
In 2012, the Ministry of Health, Labour, and Welfare of
Japan launched a novel project entitled “Accelerating
Regulatory Science Initiatives” to facilitate the develop-
ment of innovative drugs and medical devices, as well as
to facilitate its approval review (Figure 1). One of the
aims of this project was to develop a guideline for inn-
ovative drugs and medical devices. The other aim was to
promote the exchange of human resources between the
PMDA (or else the National Institute of Health Sciences
[NIHS]) and academic research institutions. In this
project, PMDA (or NIHS) members, mainly reviewers
or pharmacists, work at academic research institutions
(eg, universities) and study the latest advances in science
and technology, thereby enabling the introduction of
accelerated, higher quality reviews for innovative drugs
and medical devices. Academic researchers, mainly
physicians, may also work at the PMDA (or NIHS),
where they learn about regulatory issues and thus are able
to address such issues when working to translate their
product into practical use. This exchange will enable the
development of regulatory experts and will promote
proper research and development at academic research
institutions.
These interactions in human resources are expected
to lead to the early development of standards and/or
guidelines and to promote the implementation of in-
novative technologies. In 2012, 70 research institutions
applied for the program, and 21 institutes (8 related to
pharmaceuticals, 7 related to medical devices, and 6
related to regenerative medicine) were selected. Then 18
researchers were accepted as specially appointed experts
in PMDA (or NIHS), while 30 reviewers were dis-
patched to research institutions. From 8 institutions of
application, 3 more institutions (2 for the field of
pharmaceuticals and 1 for the field of regenerative
medicine) joined in 2013. For projects concerning AD,
University of Tokyo Hospital was selected to study
clinical issues and Kyoto University Graduate School of
Medicine was selected to study preclinical issues.
NOVEL REGULATORY RESEARCH FOR THE
DEVELOPMENT OF DRUGS FOR AD IN JAPAN
The University of Tokyo Hospital, in cooperation with
the PMDA, performed a novel regulatory science re-
search project to establish a guideline for the clinical

August 2015 1623

 Clinical Therapeutics

Human resources
Collaboration The University of Tokyo Hospital exchange

Academic societies Project team for establishment of

Japan Society for Dementia
Research
Societas Neurologica Japonica
The Japanese Society of
Psychiatry and Neurology
The Japan Geriatrics Society
Japanese Socirty of
Neurological Therapeutics
Japanese Psychogeriatric
Society
Using open-label data
ADNI clinical trials, etc
Establish the clinical evaluation guideline
Neuroimaging (PET, MRI)
Biomarkers
Cognitive function test
standards for clinical evaluation of
anti-AD drugs
Biomarker and Office of New Drugs II
Clinical Evaluation
Group Office of Regulatory Science
Unit for early/exploratory
clinical development
Omics Project Group
Clinical research support center
New Statistics Project Group
Modeling and Simulation
Group
Collaboration
Pharmaceutical department
EMA
FDA
Support development of new AD drugs

Figure 2. Structure of regulatory science research between University of Tokyo Hospital and the Pharmaceu-
ticals and Medical Devices Agency (PMDA). AD ¼ Alzheimer’s disease; EMA ¼ European Medicines
Agency; FDA ¼ US Food and Drug Administration; ADNI ¼ Alzheimer’s Disease Neuroimaging
Initiative; PET ¼ positron emission tomography; MRI ¼ magnetic resonance imaging.

evaluation of drugs for AD. In this project, a research
system aimed at developing a guideline for the clinical
evaluation of drugs for AD was established (Figure 2).
Two research groups were created: (1) the Biomarker
and Clinical Evaluation Group, to establish biomarker-
based criteria for the clinical evaluation of drugs for AD;
and (2) the Modeling and Simulation Group, to create a
disease model of AD using these techniques. Basic and
clinical research and medical practices for AD are
extensively performed at University of Tokyo Hospital,
and the hospital is recognized as the center of excellence
for this field in Japan. The researchers in the hospital
joined the discussion on this research project. Further-
more, a human resource exchange between the Univer-
sity of Tokyo Hospital and the PMDA was conducted to
establish guidelines that are suitable for regulatory use.
Research issues will also be discussed with Japanese
academic societies, and the PMDA has begun contacting
other regulatory agencies for the global development of
drugs for AD. Based on this research structure, a
guideline for the clinical evaluation of drugs for AD will
be created to support the development of new AD drugs.
In the Biomarker and Clinical Evaluation Group,
an interim report on this project was released in
Japanese in 2013, and the process of translating this
report into English is underway. Because the patho-
physiologic changes associated with AD begin years
before the onset of dementia, many disease-modifying
drugs failed to show any efficacy when patients with
AD were targeted and the early intervention before the
onset of dementia was considered. To conduct a
clinical study in such patients, it is essential to use
appropriate end points as well as inclusion criteria
suitable for the selection of eligible patients at a target
disease stage. It is particularly difficult to select
patients at an early stage of disease, as well as to
evaluate the efficacy of a drug based only on clinical
symptoms. Therefore, the use of biomarkers reflecting
pathophysiologic changes associated with AD is in-
creasingly needed in this field. With a growing number
of global clinical studies reflecting the increase in
large-scale and long-term studies, the establishment
of adequate biomarker-based criteria for clinical
development is warranted for AD drugs.
In this interim report, the issues to be considered
for clinical evaluation and development were sum-
marized; these issues included the use of biomarkers in
inclusion criteria, the efficacy end point, and the

1624 Volume 37 Number 8


clinical data package required for application in
Japan. As the result of collaboration between Univer-
sity of Tokyo Hospital and PMDA, this document
was the first to summarize the perspectives regarding
the development of AD drugs in Japan. At present,
many issues remain to be addressed regarding the
conduct of clinical studies. Further investigation and
accumulation of evidence are necessary to resolve the
issues presented in this report and to establish optimal
clinical evaluation methods for these agents.3
In the modeling and simulation group, a novel
mathematical model has been developed that quantita-
tively describes changes in various biomarkers. To
evaluate the pathology of AD, several biomarkers (in-
cluding amyloid-beta peptide, tau protein, and phos-
phorylated tau protein in the cerebrospinal fluid), as
well as the volume of the hippocampus and cerebral
fluorodeoxyglucose positron emission tomography find-
ings, have been widely used, in addition to a score of
neuropsychiatry tests, including the Alzheimer’s Disease
Assessment Scale–Cognitive. In the Alzheimer’s Disease
Neuroimaging Initiative,4 extensive information reg-
arding these biomarkers was collected to define the
progression of AD. However, the information available
regarding biomarkers is fragmented because of practical
restrictions in terms of the observation period, which is
typically 1 to 4 years. In contrast, in most patients, 10 to
20 years elapse during the progression from normal
status to AD. For this reason, the relationships among
the chronological changes in biomarkers and their
significance to the disease state are not yet fully under-
stood. To overcome this situation, a new mathematical
method has been established by this project to estimate
the overall chronological changes of multiple biomarkers
over the course of several decades by compiling short-
term data in the mathematical model.
DISCUSSION
After several candidate agents failed to demonstrate any
efficacy in large, well-designed, Phase III clinical trials for
late-stage disease, the US Food and Drug Administration
(FDA) released “Guidance for Industry, Alzheimer’s
Disease: Developing Drugs for the Treatment of Early
Stage Disease, Draft Guidance, February 2013.”5 This
guidance assists pharmaceutical companies in developing
new drugs for patients who are in the early stages of AD.
The proposed recommendations address patient selection
and the end points for clinical trials, as well as the manner
in which disease modification may be demonstrated.6
August 2015
T. Moritoyo
The FDA has maintained that claims of improved
cognition should be accompanied by evidence of
improvement in function in reviewing New Drug
Applications for the treatment of AD.7 In 2014, the
European Medicines Agency released a paper entitled
“Discussion Paper on the Clinical Investigation of
Medicines for the Treatment of Alzheimer’s Disease
and Other Dementias” (EMA/CHMP/539931/2014
Corr.).8 It discussed the following points: (1) the
impact of new diagnostic criteria for AD (including
early and even asymptomatic disease stages) on clinical
trial design; (2) the choice of outcome parameters and
the need for distinct assessment tools regarding the
various disease stages in AD (eg, different signs and
symptoms, differences in change over time, severity);
(3) the potential use of biomarkers and their temporal
relationship with the various phases of AD in different
stages of drug development (eg, mechanism of action,
target engagement, use as diagnostic tests, enrichment
of study populations, stratification for subgroups,
safety and efficacy markers); (4) the design of long-
term efficacy (maintenance of effect) and safety studies;
(5) the usefulness of combination therapy and corre-
sponding study designs; and (6) stand-alone symptoms
(eg, neuropsychiatric symptoms including agitation,
aggression, depression, sleep–wake cycle disturbances).
The Workshop on Alzheimer’s Disease was held on
November 24 and 25, 2014, and members of the
FDA, the European Medicines Agency, and the
PMDA discussed several issues to be resolved. Interna-
tional harmonization of regulatory requirements for
approval of AD drugs is important and necessary for
promoting drug development. These attempts will
help in global efforts to develop new drugs for AD
and should be continued.
Our project will last until 2016. Until then, this
new approach is expected to propose reasonable
standards for the clinical evaluation of new anti-AD
drugs worldwide and to establish the finalized Japa-
nese guidelines and facilitate development of anti-
AD drugs.
ACKNOWLEDGMENTS
This work was supported by a grant from the
Ministry of Health, Labour and Welfare of Japan
(Accelerating Regulatory Science Initiative). The views
and opinions expressed in this article are those of the
author and should not be attributed PMDA. This is
not an official PMDA guidance or policy statement.
1625
 Clinical Therapeutics

CONFLICTS OF INTEREST 5. U.S. Department of Health and Human Service. Guidance

The author has indicated that he has no conflicts of
interest regarding the content of this article.
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Address correspondence to: Takashi Moritoyo, MD, PhD, Unit for Early and
Exploratory Clinical Development, University of Tokyo Hospital, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: moritoyo-tky@umin.ac.jp

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