06/17/2014
Tetsuya Teramoto, President
Japan Association of Clinical ReagentsIndustries (JACRI)
MakotoTamura,Chairman,

IVD

Committee, American Medical Devices
andDiagnostics

Manufacturers’

Association (AMDD)
ShuichiHayashi,Diagnostics

Chairman,Committee,

MedicalEuropeanBusiness Council in Japan (EBC)

Proposals on the Appropriate Provision of In-vitro Diagnostics―In consideration of diversifying healthcare needs―
The Japan Association of Clinical Reagents Industries (JACRI), the IVD Committee ofthe American Medical Devices and Diagnostics Manufacturers’ Association (AMDD), andthe Medical Diagnostics Committee of the European Business Council (EBC) would like toprovide the following proposals for appropriate provision of in-vitro diagnostics (IVD) for
use in medical diagnostics in Japan.
Background
Clinical diagnostics are indispensable for medical practice, such as disease prevention,
diagnosis, selection of treatment, and prognosis and monitoring progress in recovery.
Clinical diagnostics include laboratory tests such as blood and urine specimen tests taken
at medical checkups or visits to a hospital, as well as biometric tests such as ultrasoundand electrocardiographic examinations. Among clinical reagents used in clinical diagnostics,
clinical reagents that have been approved and licensed by the Japanese government (e.g.,marketing authorization) are known as “in-vitro diagnostics” (IVDs). Use of IVDs in clinicaldiagnostics enables appropriate provision of highly accurate and quality-assured clinicaldiagnostics to the general public in Japan. Accurate test results through appropriate
clinical diagnostics, for example, enable doctors to obtain data to use as the basis of1diagnosis of life-threatening diseases, such as HIV infection and Hepatitis B and C, andassist diabetic patients with their disease management by enabling them to measure theirblood sugar (glucose) levels by themselves. In such ways, IVDs play an important role inmaintaining health and managing disease among the general public in Japan.
With recent developments in science and technology, IVDs have started playing animportant role not only in diagnosing diseases and monitoring progress as before but also
aiding selection of treatments (companion diagnostics) in personalized medicine where
treatments specifically customized for individual patients are provided. Furthermore,
further contributions to disease prevention and maintenance of the health of the generalpublic in Japan are expected, as it becomes possible to detect abnormalities in body before
they develop into a disease and to predict the degree of risk presented by the disease.
In the report published on August 6, 2013 by the National Council on Social Security
System Reform, as policy directions for reform of the healthcare and nursing care fields, the“Functional differentiation and building network” and “Health maintenance and promotion,etc.” were advocated, and the need for promotion of a community healthcare systemthrough measures, such as incorporating local healthcare providers into networks,
measures for the enhancement of home healthcare and nursing care and the maintenanceand promotion of the health of the general public in Japan, and prevention, early detection,etc. of disease, was mentioned.1 We believe that through appropriate provision andutilization of over-the-counter (OTC) reagents which can be used for Point of Care Testing(POCT: clinical testing near the site of patient care such as a patient’s bedside to obtainquick results) and self-checking purposes, we can contribute to the enhancement of homehealthcare and nursing care.
We have an important role to play in appropriately providing the healthcare and medical
checkup / examination facilities with clinical diagnostics related products that are useful in
conducting highly accurate and efficient diagnosis, preventing disease, and maintaining
and promoting health among the general public in Japan. Toward this end, we are actively
addressing the many various challenges we face. Up to now, through our proposals on thehandling of IVDs2 and the establishment of infrastructure for companion diagnostics,3 wehave engaged in extensive consultations with the Japanese government and relatedorganizations. As a result, improvements in the IVD review and licensing system andestablishment of a system for companion diagnostics have been realized, and several other2

challenges are being addressed.
However, there are still many challenges remaining in healthcare in Japan today;sometests, even tests that can have a significant impact to individual’s live, such as prenatal
diagnosis and breast cancer risk screening, are provided to the general public in Japan
without marketing authorization or clearance by the government to assure their quality,
performance or accuracy. We believe that it is critical for us to build a system that enable us
to provide the general public in Japan with clinical diagnostics, that can affect their healthand lives, in a safe and speedy manner..

Proposal 1: Appropriate category of clinical reagents and clarification of regulatory
requirements in each category by taking advancement of testing technologies
and diversification of clinical needs into account.
In recent years, as progress has been made in molecular biological elucidation of disease
and disease pathology, gene and protein-based biomarkers, etc. that are useful in diagnosis
of diseases, disease risk determination and prediction of treatment effects/risk of side
effects of drugs, have emerged, the importance of clinical diagnostics in diagnosis isincreasing, and the purposes for their use are diversifying. In addition, in the cancer
treatment, demand is increasing for tests that can simultaneously measure multiple
biomarkers to select therapeutic drugs, and tests themselves becoming more advanced andcomplex, as represented by the case of genome testing that applies sequencing technology.
At present, it is necessary to clarify the clinical utility, as well as the analytic validity of aclinical reagent in order to obtain a marketing authorization as an IVD. Due to increasingly
advanced and complex testing technologies and the increased diversification of clinicalpurpose of use, evaluations and epidemiologic studies are required for diseases with alimited target patient population to provide evidence of clinical utility, causing concerns
about the risk of prolonged and increasingly large scale clinical studies. Moreover, some of
newly developed clinical reagents, such as sequencing reagents used as a common reagent
for multiple assays, cannot independently demonstrate their clinical utility, and they needdisease specifc database and an algorithm for analysis to demonstrate their clinical utility.
For this reason, it takes an extremely long time for these types of clinical reagents to obtainmarketing authorization as an IVD, or else obtaining of marketing authorization must be
abandoned altogether, and as a result, it causes delays in provision of clinical reagents3

using the latest technology to clinical medicine.
Therefore, to make the speedy and appropriate provision of clinical reagents using thelatest technology to clinical medicine possible, we propose to build a system to enable theirphasing introduction to clinical medicine by recategorizing clinical reagents into more
appropriate categories and clarifying the regulatory requirements for each category. In
other words, we believe that in a case where clinical utility remains unproven but analytic
validity is recognized, it is appropriate to temporarily make the clinical reagent available toclinical medicine by granting marketing authorization as “Investigational Use Only” (IUO;
as a provisional name) and subsequently grant marketing authorization and apply
insurance coverage to them as “in-vitro diagnostics” (IVDs), once their clinical utility has
been demonstrated. More specifically, the categories and their regulatory requirements anda comparison with the current situation are as shown below.
Current Categories
Main requirements for regulatory

Category

review

Insurancecoveragerequest bycompany

In-vitro diagnostics (IVDs)

Proof of analytic validity andclinical usefulness

Possible

Other than IVD(In general referred
research reagents)

Not
subject
tomarketingauthorization review
Use possible only for research
purposes

Not possible

toasAppropriate Categories
Categories

Main requirements for regulatory
review

Insurancecoveragerequest bycompany

In-vitro diagnostics (IVDs)

Proof of analytic validity andclinical utility

Investigational Use Only (IUO)

Proof of analytic validity

Not possible

Other than IVDs and IUO

Not
subject
tomarketingauthorization review
Use possible only for research
purposes

Not possible

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PossibleAs the roles demanded of clinical diagnostics continue to diversify, we propose theadoption of a new system that enables their more flexible and appropriate use in clinicalmedicine.

Proposal 2: Establishment of a system relating to clinical research with the aim
toward the promotion and acceleration of IVD development.
In order to manufacture, import and sell IVDs, it is necessary to undergo a review, as
required by Pharmaceutical Affairs Law (Pharmaceutical and Medical Device Law), andshortening the period required for both development and review is an important task toenable the early provision of new IVDs to clinical medicine. In recent years various
measures for improvements have been made to reduce the review period, such as the “Planfor Collaboration to Accelerate IVD Evaluation (Fiscal Year 2014 to 2018)”4 formulated by
the Ministry of Health, Labour and Welfare. Further significant reductions in the review
period can be expected if the review process is further streamlined under the “Least
Burdensome Approach.”
Meanwhile, other remaining challenges include the reduction of the development period
for new IVDs. In IVD development, it is necessary to conduct clinical performance testingon numerous clinical specimens, including specimens from patients and healthy subjects, toprove clinical utility of the IVD. However, ethical and other guidelines relating toconducting clinical research have become stricter in recent years, and companies whodevelop clinical reagents are required to invest considerable time and financial resources to
conduct clinical performance studies. Furthermore, since no guidelines have been
established on clinical performance studies for IVDs, there are no clear rules to protect thehuman rights of subjects participating in the studies or to ensure appropriate study design,and there is also an issue that the system for accepting clinical performance study varies
among medical institutions. This situation causes prolonged development periods andbecomes an obstacle to IVD development itself. Therefore, we believe that theestablishment of clinical performance study guidelines that take the characteristics of IVDs
into account is essential for the appropriate and speedy implementation of clinicalperformance testing.
Moreover, we also believe that, since it is possible to use residual specimen or saved5

specimen to evaluate the performance of IVDs, the establishment of a specimen bank, inwhich specimen from patients and healthy subjects could be collected and saved inadvance for use when needed, would be effective in reducing IVD development periods. Byutilizing a specimen bank that stores appropriately collected, in compliance with ethicaland other guidelines, residual specimens from clinical diagnostic tests conducted inregular medical check-ups and medical examinations, it would be possible for us to use thevaluable clinical specimens efficiently and thoroughly in the development of advanced
IVDs. Specimen banks have already been launched in some medical institutions, but since
the types of diseases and the number of specimens, etc. are limited, and methodologies foruse of specimen banks have not been established, in reality, they have not been used in
IVD development. We strongly desire the establishment of a specimen bank in which
patient specimens encompassing various diseases and specimens from healthy persons ofa wide range of ages are appropriately collected and stored for use in the development ofIVDs, as well as the establishment of rules for its use, to enable earlier provision of IVDs
using the latest technologies to clinical medicine.

Proposal 3: Promotion of use of IVDs in home healthcare, nursing care, community
healthcare, and self-care.
(1) Promotion of use of POCT in home healthcare, nursing care and community healthcare
In recent years, use of POCT (Point of Care Testing: on-the-spot tests in clinicalmedicine/bedside testing) has drawn attentions as clinical diagnostics that can be
implemented outside of the laboratory in clinical medicine. POCT can contribute to theprovision of high quality healthcare based on a quick diagnosis and treatment, since highly
accurate results can be obtained as necessary by performing testing while at the side of thepatient. POCT makes it possible for testing to be provided at the site of various medical
service provision, without being limited to medical institutions alone, and in particular, we
expect that through active use of POCT during home visits, at visiting nursing stations,and on similar occasions, it can become an essential tool for the promotion of community
healthcare, enabling the transition from in-hospital to home healthcare.
As described previously, making POCT widely available is desirable, but there areseveral challenges that need to be addressed in order to realize it. Firstly, the quality of6tests must be secured. While POCT enables us to obtain results conveniently, routine
accuracy management, maintenance of devices, etc., and expert knowledge and skills
relating to the operation and interpretation of measurement results are required for highly
accurate and appropriate test report. We believe that it is essential to designate POCT
specific coordinators and develop human resource for the appropriate provision of POCT.
The second challenge is to realize appropriate insurance reimbursement coverage for
POCT. Based on the need in clinical medicine to perform convenient and appropriate
testing at a patient’s side, various technological developments are in progress to make
POCT devices smaller and to improve operation. We strongly desire the introduction of a
new insurance reimbursement scheme for promoting and making POCT widely available torealize the patient side testing, a separate system from the reimbursement system for thetests conducted in laboratories at medical institutions.
By promoting availability of POCT needed for developing community healthcare andenhancing home nursing and healthcare, and building a collaborative system where
necessary tests can be performed not only by physicians but also by nurses, pharmacists,
medical technicians, public healthcare workers, etc. and appropriate information can beprovided to a physician, we will continue to develop this field as one that is useful forcommunity healthcare and healthcare collaborations.
(2) Promotion of use of IVDs in Self-care
Awareness on Self-care, take care of one’s health oneself, is growing, due to rising
healthcare costs caused by aging society and the increase in psychological illness andage-related, lifestyle-related, or social-environment-related illnesses. In this context,
self-checks, whereby people review their health status themselves, are also increasingly
attracting attention from the perspective of preventive medicine, such as personal healthmanagement and early detection and diagnosis of diseases. However, the current
environment is not sufficient for conducting self-checks, and we believe it is important toestablish a system and regime utilizing IVDs for enabling the provision of appropriate
self-checks.
(i)Provision of appropriate testing in clinical test facilities

Under the Ministry of Health, Labour and Welfare Notification of March 31, 2014, thelegal status of clinical test facilities has been established,5 and it has become possible for7pharmacists and other healthcare providers to perform simple test procedures, such as
obtaining blood specimen from fingertip with a lancet. Testing at clinical test facilities
such as pharmacies will create further opportunities of self-checks for the population who
previously lacked opportunities to undergo medical checkups, including people who are
not employed, such as young people, housewives, and the elderly. Also it is considered that
self-checks can be effective in early detection and prevention of lifestyle-related illnesses,
etc. through collaboration with community healthcare institutions, etc. On the other hand,
as is shown in the Guidelines on Clinical Test Facilities,6 their safe and appropriate
operation is also important, and we believe the following challenges exist relating to theappropriate conduct and making testing available at clinical test facilities.


Improve availability of POCT compatible reagents and instruments whose
maintenance and accuracy management are simple to perform and require small
amount of blood from a finger-prick for measurement.



Build an infrastructure to provide appropriate tests with sufficient accuracy andprecision at clinical test facilities, including systems for the maintenance andaccuracy management of testing instruments and reagents. In other words, a systemshould be built to provide systematic education and training on specialist knowledge
and skills, such as methodologies for measurement and accuracy management, topharmacists and other healthcare professionals responsible for testing.

In order to provide correct test results at clinical testing facilities which would become
more popular in coming years, we believe that a system should be established, as a matterof urgency, to provide appropriate tests at clinical test facilities by addressing challenges inboth operation and infrastructure aspects.
(ii)

Appropriate use of over-the-counter (OTC) reagentsThe scope of OTC reagents that can be used for self-checks has not increased in over 20
years since the tests for glycosuria, proteinuria, and pregnancy were approved as OTC
reagents in 1990 and 1991. One of the reasons why OTC reagent tests have not become
widely available is that rules for switching professional-use IVDs to OTC reagents have notbeen established. However, in response to the proposal from the Cabinet Office’s Council for
Regulatory Reform, which supports building a system and rules at the earliest opportunity,
measures have now been launched aiming at a system to be operational during fiscal 2014,8and it is highly likely to promote the approval of professional-use clinical reagents as OTC
reagents
One remaining issue to be addressed in near future is to expand the scope of test items
for which OTC reagents can be used. Regarding this question, in “Basic Thinking on
Introduction to the Field of Self-care” (First phase report by the Year 1990 Study Group),
the conditions for use of OTC reagents were given that OTC reagents can only be used for
qualitative and semi-quantitative tests which can be performed with specimens obtained ina non-invasive manner. Tests meeting these conditions include tests for fecal occult blood,
ovulation period, urine occult blood, and influenza. However,technological advancement

in recent years has made possible safe blood specimen collection by using a lancet on
fingertips and easy-to-use medical devices have been developed, we believe that thequantitative tests using combination of the blood specimen collected with a lancet in a
low-invasive way and easy-to-use medical devices should be considered as a candidate test
item for the use of OTC reagents, in addition to the tests recognized in 1990. OTC reagentsshould be used not only for the purpose of diagnosis of diseases but also for encouraging
people to consult a medical institution if an anomaly was found. Or else they should be used
under regular health management for lifestyle-related illnesses which often lack subjective
symptoms. For this reason, we believe that tests which is useful for self-checks to review
one’s own health status oneself, such as blood glucose, HbA1c, lipid tests for cholesterol, etc.,
and hepatic function tests, should be considered as candidate tests for which OTC reagentsshould be available.
In order to widely utilize OTC reagents that would benefit preventive medicine, such as
health management and early detection and diagnosis of diseases by the general public in
Japan, establishing a system that accommodate broad range of OTC reagents andeducation for promoting appropriate use of self-checks is urgently needed.
End.

Reference Materials
1)

Report of the National Council on Social Security System Reform (Overview):
Path to leaving assured social security for future generations (National Council on
Social Security System Reform, Aug. 6, 2013)9http://www.kantei.go.jp/jp/singi/kokuminkaigi/pdf/houkokusyo.pdf
2)

Opinions on the Handling of IVDs
(JACRI, AMDD, and EBC, Aug. 4, 2010)
http://www.jacr.or.jp/osirase/shiryou/doc/100804IVDPositionPaper.pdf

3)

Proposals on the Establishment of Infrastructure for Companion Diagnostics for
Promotion of Individualized Healthcare (JACRI, AMDD, and EBC, Oct. 21, 2011)
http://www.jacr.or.jp/osirase/shiryou/doc/111021teiansyo.pdf

4)Plan for Collaboration to Accelerate IVD Evaluation (Fiscal 2014 to 2018)(Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare,Mar. 31, 2014)
http://www.mhlw.go.jp/file/04-Houdouhappyou-11124500-Iyakushokuhinkyoku-Iryoukikishinsakanrishitsu/taishin.pdf

5)Notification on Partial Revision of Facilities Prescribed by the Minister of Health,Labour and Welfare Based on the Provision of Article 20-3, Paragraph 1 of the Act on
Clinical Laboratory Technicians, etc. (2014 Ministry of Health, Labour and Welfare
Notification No. 156)
http://wwwhourei.mhlw.go.jp/hourei/doc/hourei/H140401G0350.pdf

6)

Guidelines on Clinical Test Facilities (Health Policy Bureau, Ministry of Health,Labour and Welfare, Apr. 9, 2014)
http://wwwhourei.mhlw.go.jp/hourei/doc/tsuchi/T140411G0070.pdf

10Japan Association of Clinical Reagents Industries (JACRI)

Japan Association of Clinical Reagents Industries is an organization composed ofcompanies that contribute to the medical care and welfare of the people of Japan by
manufacturing (or importing) IVDs for sale to medical institutions in Japan, mainly
through pharmaceutical wholesalers, as well as export of IVDs to the world market at large.
The purpose of the Association is to pursue the original mission of IVDs and ensurecompliance with related laws and regulations, as well as to develop and spread high quality
and performance products through the development and introduction of advanced
technology, with response to the demands of the people of Japan as its weighty
responsibility. The Association aims for the healthy development of the industry by further
enhancing its business performance capabilities and organizational foundations as anindustry organization for clinical reagents. See www.jacr.or.jp for details.
American Medical Devices and Diagnostics Manufacturers’ Association (AMDD)

The American Medical Devices and Diagnostics Manufacturers’ Association (AMDD) wasestablished on April 1, 2009, and is an industrial organization composed of 67 Japanesearms of US companies (as of end March 2012) mainly providing advanced medical
technologies, such as medical devices and IVDs. AMDD member companies provide a
broad range of advanced medical technologies, from coronary pace-makers and ICD,
cardiac valve prostheses, catheters such as PCI, stent grafts, surgical apparatus andinstruments including prosthetics, intraocular lenses, large diagnostic imaging devices,
genetic diagnosis, IVDs and system devices. Member companies create a total of approx.
21,000 or more jobs in Japan and are involved in various activities to contribute to theimprovement of healthcare in Japan through the provision of advanced medical
technologies. See http://www.amdd.jp for details.
European Business Council (EBC)

The European Business Council (EBC) is an organization in charge of trade policy for the
17 countries of the European Chamber of Commerce and Business Associations in Japan.
Since its establishment in 1972, the EBC has been working to improve the trade andinvestment environment for European companies located in Japan. At present, we
represent over 2500 corporate and individual members who belong to the European
Chamber of Commerce. Of these, approx. 300 companies participate in the EBC’s 29
industrial committees and are involved in wide-ranging work in their respective economic

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fields. The EBC seeks to closely collaborate with the EC Mission to Japan, the Embassies ofmember countries and other European business associations in Japan, while making
proposals and recommendations to the Japanese government for the establishment of anopen trade and investment environment. See www.ebc-jp.com for details.

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