Government Publications
Registration Number (GPRN)
11-1471057-000647-01

MFDS NAMs Report:
Regulatory Acceptance andResearch Outcomes■ 상하조합

MFDS NAMs Report: Regulatory Acceptance andResearch Outcomes|Ⅰ| KoCVAM and R&D in NAMs ··································································5
1. KoCVAM: past, present and future ·················································································7
2. Regulatory acceptance of NAMs ·····················································································8
3. MFDS R&D budget relating to NAMs ···········································································10|Ⅱ| Development and validation of internationally harmonizedalternative test methods recognized by the OECD ···················15
1. The first domestically-developed skin sensitisation test method adopted in OECD TG 18
2. Development of an alternative eye irritation test method adopted fourth in theOECD Test Guideline 492 ·····························································································24
3. Development and OECD adoption of androgen receptor screening assay ················34
4. Development and OECD adoption of an alternative skin irritation test method ·······40|Ⅲ| Development and validation of NAMs based on advanced
technologies ····························································································47
1. Development and standardization of organoid platform for toxicity assessment ·····50
2. Development of next-generation toxicity prediction and evaluation method ···········59
3. Study on creation of basis for next-generation toxicologic pathology diagnosis ······72
4. Survey on the latest technology trends of stem cells and organoid ·······················82
5. Study on next-generation safety pharmacology evaluation of cardiovascular effects ··84
6. Study on next-generation neurotoxicity evaluation method ······································90
7. Study on development of a method for evaluation of (new) narcotics pharmacology
and toxicity in central nervous system ··································································95|Ⅳ| Latest studies on NAMs and their regulatory acceptance ····111
1. Study on development of OECD skin sensitization test method using nanomaterial ·114
2. Development of mitochondria-targeted toxicity evaluation method ·························130
3. Development of alternative developmental neurotoxicity evaluation technology using
stem cells ·····················································································································140
4. Study on evaluation of drug interaction using big data and machine learning ·······148
5. Study on establishment of big data-based model for prediction of drug
cardiovascular safety ··································································································155

Ⅰ. KoCVAM and R&D in NAMs

Ⅰ KoCVAM and R&D in NAMs
1●

KoCVAM: past, present and future
Korean Center for the Validation of Alternative Methods (KoCVAM) has been operated
within the Ministry of Food and Drug Safety (MFDS) since 2009 in order to introduce
alternative test methods or new approach methodologies (NAMs) in safety assessment,
which conventionally relies on animal testing, and to support the promotion andutilization of NAMs.

●

MFDS has provided support for the promotion of NAMs since when they were notmuch popular and nor studied by, for example, conducting research and providing
education on the methods. MFDS is the only government agency in Korea that hasdeveloped NAMs adopted in OECD Test Guidelines. As a member of the OECD, Korea
has adhered to the Mutual Acceptance of Data (MAD), a multilateral agreement onrecognition of the safety assessment data of chemicals including cosmetics, and mutuallyaccepts the safety assessment data with other participating countries. According thethe OECD, the MAD saves around 300 million euros (300M €) of testing cost and sacrificesof over 10,000 laboratory animals each year. MFDS has helped the national industry
and GLP facilities to increase their competitiveness in the world by helping domestic
technologies to be adopted by the OECD, which the MAD system is based on.

●

This is attributed to over 14 years of KoCVAM’s commitment to international cooperation
with the OECD and the International Cooperation on Alternative Test Methods (ICATM).

●

KoCVAM signed the Memorandum of Cooperation (MOC) to join the ICATM in 2011and has participated in the development and validation of over 30 NAMs led by the
ICATM member countries.

7

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes●

MFDS has focused on regulatory acceptance and development of NAMs for evaluationof medical products including medical devices as well as cosmetics ingredients. In
particular, an in vitro skin irritation test for evaluation of medical devices developedby MFDS has been approved unanimously as an internationally standardized test method
at the ISO/TC194* Meeting held in October 2023. This is the first and the only
accomplishment made by a national organization relating to ISO 10993-23** skin irritationtest.
* Technical Committee of ISO (International Organization for Standardization) dealing withbiological and clinical evaluation of medical devices** International standard ISO 10993-23:2021 (Biological evaluation of medical devices-Part 23:
Tests for irritation)●

Also, KoCVAM has provided full support for distribution of NAMs in Korea to promote
the use of the methods by organizing workshops and training programs (including
video training) for academia and industry including non-clinical research institutions
as well as co-organizing international symposium each year since 2013●

KoCVAM has been committed to supporting the development of NAMs and promoting
practical use and regulatory acceptance of advanced new methods through active
international cooperation.

2●

Regulatory acceptance of NAMs
The world has tightened ban on animal testing for safety assessment of chemicals
including cosmetic ingredients and medical devices, and the ban has increasingly spreadto medical products. Therefore, it is imperative to develop and accept internationallyharmonized NAMs.

8

Ⅰ. KoCVAM and R&D in NAMs●

Since the EU’s complete ban on animal testing for cosmetics, more and more countries
have also prohibited animal testing. With the revision of Cosmetics Act in 2016, Korea
has also banned sales and marketing of cosmetics and their ingredients tested on animals.

●

The domestic companies exporting cosmetics and medical devices need NAMs for safetyassessment, and failing to perform one will make them experience a huge financial
loss. The current Korean laws relating to NAMs are; Laboratory Animal Act; Cosmetics

Act; Regulation on Evaluation of Functional Cosmetics; and Standards for Biological
Safety Evaluation of Medical Devices. Pursuant to the Laboratory Animal Act. MFDS
is responsible to establish and implement the policy to support development andacceptance of NAMs able to replace animal testing. Accordingly, the Minister has
established KoCVAM that carries out tasks related to development, validation, anddissemination of NAMs. Reticently, “the draft bill for promotion of development,

dissemination and utilization of alternative test method (proposed by law maker In-soon
Nam, Dec. 2020)” and “the draft bill for encouraging development, distribution anduse of alternative test methods (proposed by law maker Jung-ae Han, Dec. 2022)” havebeen submitted to the national assembly in order to strengthen the role of KoCVAM
and to promote the use of NAMs in Korea.
●

In 2023, MFDS revised the Korean Pharmacopoeia to accept NAMs for quality controlof pharmaceutical products. With the revision, the test methods using recombinantfactor C have newly been included to replace the use of horseshoe crab blood todetect endotoxins in pharmaceutical products.

●

With the establishment of the FDA Modernization Act 2.0 in December 2022, FDA
allows the use of NAMs in new drugs and biologics application. In other words, thelaw concerning foods, drugs and cosmetics has permitted the use of the data generatedusing NAMs as non-clinical test data.

●

To keep up with the change in the U.S., MFDS has made an administrative noticeon implementation of the revised “Regulation on Pharmaceuticals Approval, Notification

and Review”. The revised regulation allows submission of data from non-animal methods
or human biology-based tests (cell-based test, MPS, bioprinting, computaional model,etc.) that are produced in accordance with the Good Laboratory Practice.
●

To proactively respond to the changes in the world where NAMs are expanding theirrealm from cosmetics including cosmetic ingredients and medical devices topharmaceuticals, MFDS has worked hard to promote NAMs in Korea for the last 14
years. With the knowledge and know-hows accumulated in KoCVAM, MFDS will beable to take lead nationally and internationally in the field of NAMs.
9

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

3●

MFDS R&D budget relating to NAMs
The Toxicological Evaluation and Research Department at the National Institute ofFood and Drug Safety Evaluation (NIFDS), an affiliation of MFDS, has conducted researches
on development of advanced safety assessment methods since 1998 as part of MFDS
research and development project for food and drug safety.

●

The project is intended to establish base technologies for safety prediction and evaluation
including development of toxicological, pharmacological and clinical tests, advanced
analytic methods, laboratory animals and alternative test methods, which can serve
as a scientific basis for the policies relating to safety management of foods, drugs,
etc. As a part of the project for development of safety assessment methods, theToxicological Evaluation and Research Department has developed and validated NAMs
and developed novel toxicity assessment and narcotics analysis methods.

●

KoCVAM and Toxicological Screening and Testing Division of the Department hasdeveloped and validated NAMs for safety assessment of cosmetics, medical devices,
etc. in the project.

Table 1. R&D project for development of NAMs for safety assessment conducted by Toxicological Screening
and Testing Division
Title

Main topic

Establishment of foundation
ㅇ Development of internationally harmonized test guidelines for NAMs
for development andreflecting animal welfare and their acceptance in Korea
validation of NAMs●

Scientific outcome of the project- The R&D project for development of NAMs for safety assessment is divided into 8
studies, which are carried out by each division in Toxicological Evaluation andResearch Department.
- Many remarkable papers have been able to be published from the project, leading toestablishment of scientific basis for the regulations on safety management of foods and drugs.
* 139 SCI(E)-grade papers were published through this project for the past 3 years (2020 to 2023),
exhibiting average Impact Factor of 4.17●

Social outcome of the project- Establishment of the system to control new narcotics and to prevent their introductionin Korea by rapidly responding to them.
* Selected as one of the 100 best national R&D projects in 2020

10

Ⅰ. KoCVAM and R&D in NAMs

- Reduction of public fear over hazardous chemicals by performing toxicity evaluationon consumer chemical products and medicinal substances and establishingregulations on hazardous ingredients that might threaten public health.
- Protection of public health from corona virus by preparing the draft guideline for
efficacy evaluation of drug candidates and by providing information on clinical trials
in order to facilitate rapid development of COVID-19 treatments●

Technical outcome of the project- Development of internationally harmonized alternative test methods adopted inOECD Test Guidelines- Application of 14 patents in Korea and in other countries for the technologies
developed by internal R&D project* Out of the 14 patents applied for the past 3 years (2020 to 2023) through the project, 3applications have been filed in other countries* A qualitatively remarkable outcome with 5.00 of patent rating in SMART

Budget for R&D on Establishing foundation
for Development & validation of NAMs●

Unit: 1 million won

The project for research and development of safety assessment technology will continue
to serve as a platform for strengthening the country’s global profile and competitivenessby developing safety assessment technology meeting international standards. ➊ In orderto actively respond to global bans on animal testing, research for development of NAMs
using advanced technologies will be performed to obtain original technology for next
11

MFDS NAMs Report: Regulatory Acceptance and Research Outcomesgeneration safety assessment method and to enhance economic feasibility of the domestic
industry by using the technologies and products produced within the country.
➋

Confidence in the policy for safe management of narcotics and safe use of foods

and drugs will be maintained by preemtively responding to new narcotics, foods anddrugs. ➌ The public will continue to trust MFDS as it is able to rapidly execute politicalcountermeasures to any issues relating to toxic substances in foods and drugs.
●

Research project: establishment of foundation for advanced toxicity evaluation
technology (2022~2025)- Toxicological Research Division of NIFDS has conducted the study aiming to establish
foundation for regulatory science by preemtively obtaining advanced toxicity
evaluation technologies developed in Industry 4.0 (budget: 8.38 billion won).
- The Division has been working to propose a toxicity evaluation platform using liverorganoid as an international standard and to create new bioindustry by performing
an independent validation study and peer-review.

●

New research project: standardization of NAMs for practical implementation (2024~2028)- Toxicological Research Division of NIFDS will launch 5 year project in 2024 budgetedat 47.5 billion. The project aims to improve coherence of regulatory science andto encourage practical use of NAMs by developing, optimizing and standardizing
NAMs for safety, efficacy and quality evaluation of drugs.
- The project consists of research on development of alternatives to animal testing
especially for safety evaluation and for specification testing of drugs. It will focus
on standardization of toxicity and efficacy evaluation technologies includingorganoid, organ-on-chips and 3D tissue models and fostering their regulatory
acceptance.
* ➊ heart ➋ kidney ➌ nerve system ➍ respiratory system ❺ skin ❻ digestive system- MFDS will build intergovernmental cooperation system to facilitate development of
toxicity and safety evaluation methods based on standardized organoids andorgan-on-chips and to propose the methods as OECD Test Guidelines with support
from KoCVAM.

12

Ⅰ. KoCVAM and R&D in NAMs

Table 2. Main topics of the research project “standardization of alternative test methods for practicalimplementation”
Main Topics
Project Title Development of alternatives to animal testing for safety evaluation of drugs
Detailed subject

Timelinebudget① International harmonization and standardization of alternative
test methods② International harmonization and standardization of safety
and efficacy evaluation technologies based on heart organoidand (or) tissue chip
③ Optimization and standardization of safety and efficacy
evaluation technologies based on nerve system organoidand (or) tissue chip
Project A④ Optimization and standardization of safety and efficacy
evaluation technologies based on skin organoid and (or)tissue chip
5 years⑤ Optimization and standardization of safety and efficacy
evaluation technologies based on respiratory systemorganoid and (or) tissue chip

30.875 billionwon⑥ Optimization and standardization of safety and efficacy
evaluation technologies based on kidney organoid and(or) tissue chip
⑦ Optimization and standardization of safety and efficacy
evaluation technologies based on digestive systemorganoid and (or) tissue chip
⑧ Development of AI-based alternative test methods
Project title Development of alternative test methods for specification testing of drugs
Detailed subject

timelinebudget① Development of alternative test methods for quality
evaluation of plasma-derived medicinal products
Project B② Development of alternative test methods for evaluationof oral mucosa irritation potential of medical devices 5 years③ Development and optimization of alternative test methods
using zebrafish and C. elegans

16.625 billion
won④ Establishment of biological resource bank13Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

Development and validation of internationally harmonized

Ⅱ alternative test methods recognized by the OECD
□ Development and validation of alternative test methods●

Test Guidelines (TGs) issues by the OECD are adopted by governments, industries andresearch institutions in the world for hazard and safety evaluation of chemicals including
cosmetic ingredients. Use of the Test Guidelines that are based on validated test methods
help obtain reliable safety assessment data for protection of human and animal health.

●

Most NAMs for evaluation of hazardous substances should be validated by nationaland (or) international organizations. The size of validation studies can range from small
to large, international scale.

●

Validation of a test method (or an approach) is a research process that is based on
scientific principles to establish reliability and relevance.
- Reliability refers to measures of the extent that a test method can be performed
reproducibility within and between laboratories over time, when performed using
the same protocol.
- Relevance refers to description of relationship of the test to the effect of interest
and whether it is meaningful and useful for a particular purpose. It is the extent
to which a test correctly measures or predicts the biological effect of interest.

●

KoCVAM has supported the OECD adoption of the NAMs developed by NIFDS’ R&D
projects in Test Guidelines. The test methods in OECD TGs are regulatorily acceptedin Korea under Cosmetics Act, Regulation on Evaluation of Functional Cosmetics, andStandards for Biological Safety Evaluation of Medical Devices and utilized in safetyassessment of not only drugs that MFDS is concerned but also chemicals and pesticides.

17

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes1

The first domestically developed skin sensitisation test method adopted
in OECD TG

Supervising
division

Toxicological Screening and Testing Division of NIFDS

type

Internal project

title

Study on international harmonization for development of test guidelines based onalternative test methods (I)(17181MFDS486)□ Background for the study●

Since the 3R principles (reduction, refinement and replacement) suggesting ethicaluse of animals in science were proposed, demand for NAMs for safety assessment has
been increased.

●

There should be an alternative to the existing Local Lymph Node Assay (LLNA) (OECDTG 429) that uses lab animals and radioisotope.
- A KoCVAM-developed “me-too” method to TG 442B (alternative to TG 429) is able
to overcome some of the limitations of LLNA. The method was included in the OECD
workplan in April 2016 and adopted in the TG 429 in June 2018 following a successful
validation study and an independent peer-review.

●

There has been an increasing demand on alternatives to animal testing in biologicalsafety assessment of medical devices. An alternative skin sensitisation test method forsafety assessment of medical devices should be developed.

□ Study in brief●

The objectives of the research were to propose the revised OECD TG 442B including
LLNA: BrdU-FCM developed in Korea; to conduct follow-up study based on the commentsfrom the OECD expert group; and to perform research on the skin sensitisation test
method for safety assessment of medical devices.

●

LLNA:BrdU-FCM- LLNA:BrdU-FCM, a “me-too” method to OECD TG 429, has advantages over OECD
TG406 that requires use of guinea pigs. The method is able to detect skin sensitisation
potential without using radioisotope, to reduce the number of animals used, andto alleviate pain in animals as it does not require the use of an adjuvant.

18

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD●

Principle of the method: A local lymph node assay is able to detect skin sensitisation
potential of test substances according to the UN GHS1) by evaluating T-cell activationand proliferation, the fourth key event of skin sensitisation Adverse Outcome Pathway(AOP).
- The method is able to evaluate skin sensitisation potential of test substances using
a flow cytometry that measures proliferation of auricular lymph node cells during
the induction phase of skin sensitisation.

□ Overview of the Research Outcome●

Major accomplishment: LLNA:BrdU-FCM developed by NIFDS has become the first
domestically-developed toxicity test method adopted in OECD Test Guideline (OECDTG 442B)- Validation study: KoCVAM worked with international stakeholders and operated avalidation management team to coordinate the validation study in accordance withthe guidance suggested by the OECD, and prepared the validation study report.
- OECD recognition: The scientific rationale of the method was proved during the peer
review, and the method was officially included in OECD TG 442B in June 2018
following the OECD WNT approval in April 2018.
* WNT: OECD Working Group of National Co-ordinators of the TGs programme who takedecisions on TGs (approve and update of TGs) and decide on project proposals to include in
the work plan. The group consists of representative from the member countries that adhere
to MAD and meets annually.

●

Academic accomplishment- Awarded as one of the best MFDS R&D projects in 2017
- Publication: 1 paper in a SCI-grade journal** Regulatory Toxicology and Pharmacology□ Excellence and advantages●

Excellence: LLNA: BrdU-FCM developed in Korea has been recognized as a reliable
and relevant alternative to OECD TG 442B and a “me-too” method to OECD TG 442B
during the KoCVAM-coordinated international peer review consisting of experts fromthe U.S., Switzerland and Japan.

1) UN GHS: United Nations Globally Harmonized System of classification and labelling of chemicals
19

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes●

Advantages: Compared to Local Lymph Node Assay (LLNA) that often faces issues relating
to radiation exposure or disposal of radioactive waste due to use of radioisotope,
LLNA:BrdU-FCM is able to evaluate skin sensitisation potential without using radioisotope
and to perform mechanistic research including B-cell and T-cell.

□ Utilization of the Outcome and Its Impact●

The outcome has proven that KoCVAM plays a leading role in the field of alternative
test methods in Korea.
* Countries developed test methods recognized in OECD TGs: the U.S., 5 European Countries(Germany, Italy, Netherlands, Belgium, and France), Japan, Canada and Korea.

●

International relation: International exchange and cooperation has been promoted (e.g.
participation and presentation in the general meeting of ISO/TC194, Biological andclinical evaluation of medical devices).
* Countries joining in the ISO/TC194 general meeting: 29 participating countries including
Germany (host), Australia, Austria, Belgium, Canada, the U.S. Japan Brazil and 19 observing
countries●

The related industry has grown thanks to introduction and dissemination of a newalternative test method, which has helped nurture professional personnel, and technicalsupport provided by the government.
- Guidance on the use of LLNA:BrdU-FCM, has been published, education workshops
have been organized; and training programs have been run to transfer the techniques
required to use the method to those working in the domestic GLP facilities and related
academic area.

□ Performance of the research
Title
1

MFDS performance evaluation standard
type

performance indicators

Proposal to add a method in the OECD Encouragement of practical use Number of TG proposals
Test Guideline (OECD TG442B)
by policy improvement, etc.
submitted

Press release: Alternative test method
Number of the education or
Education and promotion of
2 developed in Korea soon to be added inpromotion materials about
the research outcome
OECD TG
the outcome

3

20

Publication: Evaluation of skinsensitization potential of chemicals by
local lymph node assay using
5-bromo-2-deoxyuridine with flow
cytometry

Building on expertisethrough academic
accomplishment

Number of papers publishedin SCI-grade journal

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

Title

MFDS performance evaluation standard
type

performance indicators

Publication: Development of the LLNA:
BrdU-FCM for Skin Sensitization
Evaluation

Building on expertisethrough academic
accomplishment

Number of presentations
and publications ininternational workshops

Publication in academic journal:
Evaluation of Skin Sensitization Potency
5
Using the LLNA: BrdU-FCM and the Ex
vivo Cytokine Assay

Building on expertisethrough academic
accomplishment

Number of presentations
and publications in national
workshops

Publication: Evaluation of Skin
6 Sensitization Potential of Chemicals Using
the LLNA: BrdU-FCM

Building on expertisethrough academic
accomplishment

Number of presentations
and publications in national
workshops

Publication: Predictive Possibility of the
7 Ex vivo Cytokine Assay in LNCs on Skin
Sensitization Potency

Building on expertisethrough academic
accomplishment

Number of presentations
and publications ininternational workshops

48

Addition in OECD Test Guideline(OECD TG 442B)

Encouragement of practical
Number of TG proposals
use by policy improvement,
submitted
etc.

9Awarded as an excellent R&D project

Number of the education or
Utilization and dissemination
promotion materials aboutof research outcome
the outcome

10

Press release: MFDS-developed skin
Number of the education or
Utilization and dissemination
sensitisation test method adopted inpromotion materials aboutof research outcome
OECD TG
the outcome

11

Making presentation in 2018 Education Utilization and dissemination
Workshop on Alternative Test Mehtodof research outcome

Level of mutual exchange of
information fordissemination of technology

12

Hosting 2019 Training Workshop on
Alternative Test method

Utilization and disseminationof research outcome

Level of mutual exchange of
information fordissemination of technology

13

SOP-sensitisation-19: Local Lymph
Node Assay Using Medical Devices

Improvement of ability in
Total count of test methods
testing, research anddeveloped
experiment

14

Making oral presentation in the 29th
ISO/TC194 general meeting

Improving national
competitiveness

Performance in international
exchange(e.g. signing MOU etc.)

Publication: Evaluation of the Local Lymph Encouragement of practical Number of presentations
15 Node Assay: BrdU-FCM to investigate use by policy improvement,
and publications in
Skin Sensitizers
etc.
international workshops
Publication: Utilization of the LLNAL:
BrdU-FCM and the Ex vivo Cytokine Assay16
to evaluation of Skin Sensitization
Potency.

Building on expertisethrough academic
accomplishment

Number of presentations
and publications in national
workshops

21

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major accomplishment
1. Adoption in OECD Test Guideline (OECD TG442B)

22

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

3. Publication: Evaluation of skin sensitization potential of chemicals by local lymph node assay using
5-bromo-2-deoxyuridine with flow cytometry23

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes2

Development of an alternative eye irritation test method adopted
fourth in the OECD Test Guideline 492

Supervising
division

Toxicological screening and testing division of NIFDS

Project type Entrusted project (prof. Kyung-min Lim, Ewha Womans University)
Title

Validation study on the eye irritation test method using RhCE (16182MFDS522)□ Background for the study●

Local toxicity tests are an integral part of cosmetics safety assessment. In particular,
an eye irritation test requires use of animals (rabbits) and includes procedures causing
pain to the animals, and thus should be replaced by an alternative method.

●

With the global ban in European countries on animal testing for cosmetics and theiringredients, Korea has revised the Cosmetics Act. In this sense, development of a newalternative test method that can be utilized by national industry and non-clinical test
facilities was considered necessary.

□ Study in brief●

The study aimed to develop an in vitro eye irritation test method using RhCE (reconstructed
human cornea-like epidermis), MCTT HCETM, as an alternative to Rabbit Eye Draize
Test (OECD TG405) that uses rabbits.

●

An in vitro eye irritation test method using MCTT HCETM developed in Korea was studied
further, and an international validation study was performed to verify the feasibilityof the method as an internationally harmonized one accepted by the OECD.

●

MCTT HCETM is a 3D human cornea model that is manufactured with primary cultured
cornea epithelium using residual skin tissues from cornea transplant. Since humanprimary cornea cells are used, its morphological microstructure and biomarker
expressions are similar to those of human epithelium.

●

Principle of the method: This method evaluates an eye irritation potential of a test
chemical by measuring reduction in cell viability of MCTT HCETM following local exposure
to the test chemical using WST-1 assay.

24

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

- Serious eye damage and (or) eye irritation (corneal opacity, iritis, conjunctival redness
and/or conjunctical chemosis) are the results of the responses initiated by penetrationof a test chemical through cornea and/or conjunctiva and following cell damage.
●Development and validation of the test method: A validation study on the eye irritation
test method using MCTT HCETM was conducted in accordance with OECD guidance.
KoCVAM led the validation study in cooperation with the method developer.

□ Overview of the study outcome●

Major accomplishment: An eye irritation test method using the model developed in
Korea, MCTT HCETM EIT, has become the fourth test method adopted in the OECD
TG 492 as one of the internationally harmonized methods.
* MCTT HCE™ is the only model in the world that is manufactured with human primary cultured
epithelium.

- Validation study: KoCVAM was in charge of assuring that the validation study fulfilledOECD guidance by cooperating with international partners including OECD
Secretariat and operating a validation management team.
- OECD recognition: The method was approved to be included in the OECD Test
Guideline 492 at the WNT Meeting in April 2019 and the revised TG was officially
issued in June 2019.
* WNT: OECD Working Group of National Co-ordinators of the TGs programme who takedecisions on TGs (approve and update of TGs) and decide on project proposals to include in
the work plan. The group consists of representative from the member countries that adhere
to MAD and meets annually.
●

Major accomplishment- Academic accomplishment: publication of 4 papers in SCI and non-SCI grade journals* Food and Chemical Toxicology, Toxicology in vitro and Toxicological Research□ Excellence and advantages●

Excellence: Compared to the other OECD-adopted models that are manufactured withhuman keratinocytes (EpiOcularTM) or corneal epithelial cell line (SkinEthic HCE), MCTTHCETM used in this test method is manufactured with human primary cultured corneal
cells and thus able to effectively mimic human corneal responses.

25

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes●

Advantages: Other methods using EpiOcularTM or SkinEthicTM HCE use separate protocols
for liquids and solids and require a lot of models because each protocol requires inclusionof both positive and negative controls. In this regard, the test method using MCTTHCETM has advantages over the two methods.

●

Economic advantage: Foreign Models including EpiOcularTM and SkinEthicTM HCE are
unlikely to be shipped directly to the Korean users. Further, shipment takes a longtime due to shipping or customs process. Since MCTT HCETM is domestically-developedmodel, it does not require long shipment period and tends to cost less compared to
the foreign models.

□ Utilization of the outcome and its impact●

The outcome has proven that KoCVAM plays a leading role in the field of alternative
test methods in Korea.
* Countries having test methods recognized in OECD TGs: the U.S., 5 European Countries(Germany, Italy, Netherlands, Belgium, and France), Japan, Canada and Korea.

●

Increasing export: MCTT HCETM is the first domestically-developed and manufactured
ocular model that has been internationally recognized and can be exported to overseas
test facilities conducting eye irritation testing.

●

Development of related industry: Eye irritation test was highly dependent on foreignmodels in the past. However, the development of MCTT HCETM), will help increase
the sales of the domestic manufacturer.

●

Introduction and dissemination of the alternative test method helps train professional
personnel and transfer necessary techniques and thus promote the related industry.
- Following development of MCTT HCETM eye irritation test method, standard operatingprocedure and guideline have been prepared and the method have been transferredto the people at the national GLP test facilities and academia in education workshops,
etc.

26

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

□ Performance of the study
Title
Presentation: Identification of ezrin
expression as a possible biomarker of in-vitro
1 eye irritation using a 3D reconstructed humancorneal model MCTT HCE™ and immortalized
human corneal cells

MFDS performance evaluation standard
type

performance indicators

Building on expertisethrough academic
accomplishment

Number of presentations
and publications in national
workshops

Presentation at the industry, academia andgovernment workshop for promotion of
Number of education or
Utilization andalternative test methods development and2dissemination of research promotion materials about
advancement of validation management:
outcomethe outcome
Global trends in development of alternative
test methods and future demandPresentation at the 1st Cosmetics forum
Utilization andNumber of education or
3 organized by Cosmetics ICC: Overview of dissemination of research promotion materials about
current research on alternative test methods
outcomethe outcome
4

Intensive course in non-clinical education
Utilization andNumber of education or
program hosted by KOHI: International dissemination of research promotion materials about
validation study and global trends
outcomethe outcome

Presentation: A new 3D reconstructed humancornea-like epithelium, MCTT HCETM and its
5application for alternative to draize rabbit eye
irritation test

Building on expertisethrough academic
accomplishment

Number of presentations
and publications in national
workshops

Presentation: Development of 3D
reconstructed human cornea-like epithelium,
6
MCTT HCETM from primary limbal cells, andits application for alternative to animal test

Building on expertisethrough academic
accomplishment

Number of presentations
and publications ininternational workshops

7 Producing specialists with a master’s degree

Nurturing professional
personnel

Manpower training
performance

8 Producing specialists with a master’s degree

Nurturing professional
personnel

Manpower training
performance

9 Producing specialists with a master’s degree

Nurturing professional
personnel

Manpower training
performance

10

Improvement of ability in
Number of test methods
testing, research anddevelopment
experiment

Digital PCR assay

SOP: Ezrin reporter assay-based eye toxicity Improvement of ability in
Number of test methods
11 evaluation method using immortalized corneal testing, research anddevelopment
cells
experiment
Presentation: Assessment of the Availabilityof Ezrin Expression in 3D Reconstructed
12 Human Cornea Models (MCTT HCE™)and
Immortalized Human Corneal Cell Lines as
Biomarkers of In Vitro Eye Stimulation Tests

Building on expertisethough academic
accomplishment

Number of presentations
and publications in national
workshops

27

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS performance evaluation standard
type

performance indicators

Presentation: An in-vitro test to indentify eye
irritants using a stable human corneal
epithelial-derived EZR reporter cell line

Building on expertisethough academic
accomplishment

Number of presentations
and publications in national
workshops

Presentation: Application of the EZR repoter
14
assay as an in vitro test

Building on expertisethough academic
accomplishment

Number of presentations
and publications in national
workshops

Presentation: Investigation of ezrin
expression as a potential biomarkers for
15 in-vitro eye irritation using a 3D reconstructed
human corneal model MCTT HCE™ andimmortalized human corneal cells

Building on expertisethough academic
accomplishment

Number of presentations
and publications in national
workshops

Presentation: Development of the EZR luc
assay as an in vitro test

Building on expertisethough academic
accomplishment

Number of presentations
and publications ininternational workshops

13

16

Utilization andNumber of education or
17 Press release: 2017 Rush Prize Awarded dissemination of research promotion materials aboutoutcomethe outcome
Publication: Evaluation of ocular irritancy ofcoal-tar dyes used in cosmetics employing
18
reconstructed human cornea-like epitheliumand short time exposure tests

Building on expertisethough academic
accomplishment

Number of papers
published in SCI-grade
journalPublication: Nervonoylceramide (C24:1Cer),a lipid biomarker for ocular irritants released
19from the 3D reconstructed human cornea-likeepithelium, MCTT HCE™

Building on expertisethough academic
accomplishment

Number of papers
published in SCI-grade
journalPublication: Prevalidation trial for a novel invitro eye irritation test using the reconstructed20
human cornea-like epithelial model, MCTT
HCE™

Building on expertisethough academic
accomplishment

Number of papers
published in SCI-grade
journalPublication: Alternatives to In Vivo Draize
Rabbit Eye and Skin Irritation Tests with a
Focus on 3D Reconstructed Human
21
Cornea-Like Epithelium and Epidermis
Models.

Building on expertisethough academic
accomplishment

Number of papers
published in
non-SCI-grade journal

Presentation: OECD TG492 Performancestandard based multi-laboratory validation
22 study for a new in vitro eye irritation test using
the reconstructed human corneal epithelial
model, MCTT HCE™.

Building on expertisethough academic
accomplishment

Number of presentations
and publications ininternational workshops

Presentation: Validation study of alternativein vitro eye irritation test with
23
3D-reconstructed human cornea epithelium,
MCTT HCE™ for OECD Test guideline

Building on expertisethough academic
accomplishment

Number of presentations
and publications in national
workshops28

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

□ Major accomplishment
1. Adoption in OECD TG492

29

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

4. Publication: Evaluation of ocular irritancy of coal-tar dyes used in cosmetics employing reconstructed
human cornea-like epithelium and short time exposure tests

30

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

5. Publication: Nervonoylceramide (C24:1Cer), a lipid biomarker for ocular irritants released from the
3D reconstructed human cornea-like epithelium, MCTT HCE™

31

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

6. Publication: Pre-validation trial for a novel in vitro eye irritation test using the reconstructed humancornea-like epithelial model, MCTT HCE™

32

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

7. Publication: Alternatives to In Vivo Draize Rabbit Eye and Skin Irritation Tests with a Focus on
3D Reconstructed Human Cornea-Like Epithelium and Epidermis Models.

33

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes3

Development and OECD adoption of androgen disruptor screening assay

Supervising
division

Food Safety Risk Assessment Division of NIFDS

Project typeInternal project

Title

Study I on development of internationally harmonized (OECD) estrogen/androgen receptor
interaction test method using novel technique (18161MFDS108)□ Background for the study●

With increasing development and use of chemicals, potential endocrine disruptor, also
known as environmental hormone, has become a global issue. Therefore, it is necessary
to develop an internationally harmonized test method (OECD Test Guideline) that canbe used to screen existence of substances with potential endocrine disrupting effectthat people consume or are exposed to in daily life.

□ Study in brief●

The study aimed to develop an alternative method to animal testing for evaluationof androgen interaction by endocrine disruptors. The method can reduce sacrificesof lab animals by screening and selecting test chemicals at the cell experiment stage.

●

Principle of the method: This assay can evaluate existence of endocrine disruptors
relating to androgen hormone at a cell-level by qualitatively measuring the expressionof the genes in a cell line that specifically interacts with androgen receptor - test
chemical conjugate in the cell line.

●

Development and validation: The androgen disruptor screening assay was developed
using a prostate cancer cell line, and validated in collaboration with KTR (Korea Testing& Research Institute) and Dongguk University.
- In the study, the existing human prostate cancer cell line (22Rv1/MMTV)* was
optimized by minimizing false positive responses by removing glucocorticoid
receptors that have the same hormone response elements with androgen receptors.
The assay was developed using the optimized cell line (22Rv1/MMTV-GR-KO)**.
* Study on the development of endocrine disruptors screening assay – Androgen receptor andtranscriptional activation assay (11162MFDS728, Prof. Mi-sook Dong, Korea University)** International validation study on development of standardized androgen screening assay using
a cell line (for OECD recognition) (16161MFDS115, Food Safety Risk Assessment Divison)34

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

□ Overview of the study outcome●

Major accomplishment: OECD Recognition of the androgen disruptor screening assay
using human prostate cancer cell line (OECD TG 458).

●

Summary- OECD recognition: Approval of inclusion of the assay in the OECD TG 458 by theOECD WNT in April 2020, and the revised TG was officially issued in June 2020.

□ Excellence and advantages●

Excellence: An androgen transcriptional activation assay using a human prostate caner
cell line for detection of androgen receptors. This is the first national and the second
OECD adopted test method for evaluation of endocrine disruption activation. Thisshows that our domestic technology is recognized internationally as advanced technology.
* Compared to the existing androgen screening test using the cell line that does not include
activated androgen receptors (developed by Japan in 2016), the assay exhibits improved
accuracy and sensitivity.

●

Advantages: This is an alternative method having improved accuracy and sensitivity
for detection of androgenic substances. The method can address ethical issues relating
to use of laboratory animals by reducing their sacrifices. The method brings economic
benefit as well since it can detect a large number of substances with endocrine activation
in a short period (4 days).
* Comparison with the existing technology

Summary

test chemical
number/repetition
Test period(cell line test) Androgen screening assay (animal test) Reproductive and developmental
using a human prostate cancer cell line toxicity screening assay *A screening assay for determination of
An assay for detection of endocrine active
developmental and (or) reproductive toxic
chemicals that can interact with androgendoes. It aims to obtain initial information
receptors using human prostate cancer cell
about the impact of test chemicals online expressing androgen receptors
reproduction and development.
4 test chemicals/96-well plate

1 test chemical

4 daysat least 50 days
at least 40 male mouseat least 48 female mouse (including at least
40 pregnant mouse)

Number ofanimals used

-

Other
experimental
condition

Should be performed in a laboratory withShould be performed in a GLP test facility
Bio safety level 2 (BL2) for 22R1V1 cellfor animal experimentline experiment* Chapter 5 of the Regulation on Testing of Chemicals: tests on health effects, paragraph 16:
reproductive and developmental toxicity screening test
35

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Utilization of the Outcome and Its Impact●

The assay was developed to support the safety management of the chemicals withendocrine disrupting potential and has been recognized as an internationally harmonizedmethod. This shows that MFDS plays a leading role in development of NAMs.

●

Support for industry, academia and research institute: The know-hows accumulated
during the development of the first successful endocrine disruptor assay in Korea is
expected to bring about a leap ahead in a follow-up study aiming international
standardization.
- 22Rv1/MMTV_GR-KO cell line developed with our own technology has been donatedto the KCTC (Korean Collection for Type Cultures) for national and overseas
researchers. The cell line can be obtained with no charge. This will contribute toutilization and development of the related technology and field.
- Access to the information on the assay has been expanded. OECD TG 458 wastranslated in Korean and published in July 2020, uploaded on the NIFDS website
and distributed to related organizations. Also, press release on the publication was sent.
- Minimization of sacrifices of lab animals: Countries in the world have been focusing
on developing alternatives to animal testing in order to reduce use of lab animals.
The assay developed in this study is expected not only to reduce the cost for tests
but also to address ethical issues relating to lab animals by minimizing their sacrifices.

□ Performance of the study
Title

MFDS Performance Evaluation Standard
type

Performance Indicators

1

Adoption in OECD Test Guideline(OECD TG 458)

system improvement and Proposal and inclusion in
utilization of policy
OECD TG

2(Establishment of standardized product)
Development and donation of
22Rv1/MMTV_GR-KO cell line

Number of development
Establishment of basis for(donation) of standardized
standardization
products

3

Guideline on Endocrine disruptor screening system improvement and Publication and revision of
assay (Korean translation of OECD TG 458)
utilization of policy
guidelines

Publication in academic journal: Assessmentof androgen receptor agonistic antagonistic4
effects on 25 chemicals in household
applicants by OECD in vitro stably transfectedtranscriptional activation assays

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journalPublication in academic journal: Enhancementof androgen transcriptional activation assay
5
based on genome edited glucocorticoid knockout human prostate cancer cell line

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journal36

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

□ Major accomplishment
1. Adoption in OECD Test Guideline37

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

4. (Publication in academic journal) Assessment of androgen agonistic/antagonistic effect on 25 chemicals
in household applicants by OECD in vitro stably transfected transcriptional activation assays

38

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

5. (Publication in academic journal) Enhancement of androgen transcriptional activation assay basedon genome edited glucocorticoid knock out human prostate cancer cell line

39

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes4

Development and OECD adoption of an alternative skin irritation test method

Supervising
division

Toxicological screening and testing division of NIFDS

Project type

Entrusted project (prof. Kyung-min Lim, Ewha Womans University)

Title

Pre-validation of an alternative to skin irritation test using RhE tissue model developedin Korea (18182MFDS463)□ Background for the study●

With enforcement of Cosmetics Act in Korea and global bans on animal testing forcosmetics and their ingredient including the EU and other countries, development ofalternatives to animal testing that can be utilized in the national industry and GLP
facilities considers necessary.

●

In particular, an in vitro test method that can replace in vivo Draize rabbit skin irritation
test (OECD TG 404) is needed.

□ Study in brief●

A pre-validation study on KeraSkinTM SIT (skin irritation test), which closely mimics
human skin and generates more precise results while reducing sacrifices of experimental
rabbits, was conducted.
- The pre-validation was performed in collaboration with KoCVAM●

KeraSkinTM: KeraSkinTM is 3D reconstructed human epidermis (RhE) model manufactured
with human-derived keratinocytes isolated from foreskin. It owns biochemically andmorphologically similar features to human skin.

- KeraSkinTM is produced by culturing it until it forms highly differentiated,
multi-layered RhE. It consists of multi-layered stratum corneum composed of basal
layer, spinous layer, and lamellar lipid layer representing main lipid classes analogous
to those found in vivo.
●

Principle of the method: The method evaluates skin irritation potential of test
chemical-induced cell viability of KeraSkinTM using MTT assay following local exposureof the chemical to the RhE model.
- Skin irritants may damage the underlying layers of keratinocytes by penetrating
through stratum corneum. The damaged cells may induce an inflammatory cascade40

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

which also acts on the cells in the dermis, particularly the stromal and endothelial
cells of the blood vessels.
●

Development and validation: Validation study on KeraSkinTM SIT using the domesticallydeveloped RhE model, KeraSkinTM, was set up by KoCVAM and performed in collaboration
with national researchers* Pre-validation study on KeraSkinTM SIT (18182MFDS463, Prof. Kyung-min Lim, Ewha Womans
University)□ Major outcome●

Summary: KeraSkinTM SIT using the domestically developed RhE model was approved
and adopted in OECD Test Guideline (OECD TG 439)
- KeraSkinTM is the world’s first and only model that is manufactured with residual
foreskin separated after circumcision.

●

Overview of the outcome- Validation study: KoCVAM coordinated the validation study and ensured that it
fulfilled the OECD guidance by operating a validation management team andcooperating with the OECD.
- OECD approval: Inclusion of the method to OECD TG 439 was approved by the OECDWNT in April 2021 and the updated TG was officially issued in June 2021.
* WNT: OECD Working Group of National Co-ordinators of the TGs programme who takedecisions on TGs (approve and update of TGs) and decide on project proposals to include in
the work plan. The group consists of representative from the member countries that adhere
to MAD and meets annually.

- Academic accomplishment: Publication of 2 papers in SCI-grade journal* Toxicology in vitro and Regulatory Toxicology and pharmacology□ Excellence and advantages●

Excellence: An international peer-review panel consisting of experts from the U.S.,
Switzerland and Japan organized by KoCVAM concluded that KeraSkinTM SIT isscientifically valid “me-too” method to OECD TG 439.

●

Advantages: KeraSkinTM used in this test method is manufactured in Korea. With OECD
recognition, the data generated using this domestic model can be accepted by regulatory
bodies in the world.
* The RhE-based assays in OECD TG 439 are the only alternatives to in vivo skin irritation test
and are essential in cosmetic toxicity testing.
41

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Utilization of the outcome and its impact●

The outcome has proven that KoCVAM plays a leading role in the field of alternative
test methods in Korea.
* Countries developed test methods recognized in OECD TGs: the U.S., 5 European Countries(Germany, Italy, Netherlands, Belgium, and France), Japan, Canada and Korea.

●

Increasing export: International recognition of the RhE model for evaluation of skinirritation that is developed and produced in Korea enables export of the model toforeign test facilities conducting skin irritation test.

●

Supporting the related industry: Utilization of domestically-developed RhE models inthe skin irritation tests that highly depend on oversea models is expected to promote
the sales of the manufacturer.

●

The related industry is expected to grow thanks to introduction and disseminationof a new alternative test method because it will help nurture professional personnel
and support for new technique will be provided.
- Training on the techniques needed to perform KeraSkinTM SIT has been provided
to the people working in GLP test facilities and the related academic field by
publishing and distributing the guideline on KeraSkinTM SIT; by organizing workshops;
and by servicing the video demonstrating the method.

□ Performance pf the study
Title
1

Adoption in OECD Test Guideline

MFDS Performance Evaluation Standard
Type

Performance Indicators

Encouragement ofpractical use including
policy improvement

Number of TG proposals
approved

Preparation of the draft protocol for in vitro Improvement of ability in
Number of test method
2 skin irritation test with a 3D-reconstructed testing, research anddevelopment
experimenthuman skin model, KeraSkin™.
Publication: Employment of cytology for in
3 vitro skin irritation test using a reconstructed
human epidermis model, Keraskin™.

Encouragement ofpractical use including
policy improvement

Number of publication in
SCI-grade journal

Publication: Me-too validation study for in vitro
skin irritation test with a reconstructed human4epidermis model, KeraSkin™ for OECD test
guideline 439.

Encouragement ofpractical use including
policy improvement

Number of publication in
SCI-grade journal

Presentation: Employment of cytological
5 evaluation of skin irritancy for Keraskin™, 3D
reconstructed human epidermis model.

Encouragement ofpractical use including
policy improvement

Number of presentations(publications) in national
workshops

6

Presentation: Global trends in alternatives toanimal tests and regulatory uptake.

Encouragement ofpractical use including
policy improvement

Number of publications in
national workshops

7

Presentation: In vitro toxicity evaluation of
biocide using RhE models

Encouragement ofpractical use including
policy improvement

Number of publications in
national workshops

42

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

□ Major accomplishment
1-1. OECD Adoption in OECD Test Guideline (OECD TG 439)

43

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

1-2. OECD Adoption in OECD Test Guideline (OECD TG 439)

44

Ⅱ. Development and validation of internationally harmonized alternative test methods recognized by the OECD

3. Publication: Employment of cytology for in vitro skin irritation test using a reconstructed humanepidermis model, Keraskin™.

45

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

4. Publication: Me-too validation study for in vitro skin irritation test with a reconstructed human epidermis
model, KeraSkin™ for OECD test guideline 439.

46

Ⅲ. Development & validation of NAMs based on advanced technologies

Development & validation of NAMs based on advanced

Ⅲ technologies●

Countries around the world have developed alternatives to animal testing or new approach
methodologies (NAMs) in order to address various issues including ethical issues related
to laboratory animals and interspecies differences.

●

The definition of NAMs has evolved from the methods reflecting the 3R principles
to the methods based on advanced technologies.

The methods replace and reduce the use ofanimals or refine the treatment of animals basedon the 3R principles●

Comprehensive term embracing NAMs (New
Aproach Methodologies) using innovative→
non-animal methods (approaches) which can
improve predictivity against human

The U.S. FDA enacted the FDA Modernization ACT 2.0 in December 2022 that allows
the use of NAMs for new drug and biologic applications. The data generated with
NAMs using advanced technologies including MPS and bioprinting are able to be submitted
as non-clinical data.

●Also, MFDS has made administrative notice on the revision of Regulations onpharmaceuticals approval, notification and review, and allows submission of the data
generated with non-animal or human biology based methods (e.g. cell-based assays,
MPS, bioprinting, computational model, etc.) that are conducted in accordance with
the GLP.

●

MFDS and KoCVAM has focused on developing NAMs using advanced technologies
in order to actively respond to such a global change.

●

Different government agencies have conducted research on advanced technologies
including organoid in order to obtain source technology. However, regulatory acceptanceof organoid requires validation of assays using the source technology.
- MFDS, as a regulatory body, has focused on development and international harmonizationof safety assessment methods using organoid.

49

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes1

Development and standardization of organoid platform for toxicity
assessment

Supervising
division
Type

Title

Toxicological Research Division of NIFDS
Entrusted project
Development of an organoid platform for toxicity assessment(22213MFDS386, Myung-Jin Son, KRIBB)Validation study on an organoid platform for toxicity assessment(23213MFDS489, Gun-Hwa Kim, NST)

□ Background for the study●

There has been an urgent need to develop an toxicity evaluation model able to makean accurate toxicity prediction and support rapid decision-making during new drug
development that require enormous cost and time.
- The toxicity evaluation model will help prevent waste of money incurred fromwithdrawal of drug candidates from the market by supporting rapid and accurate
selection of the candidates passing non-clinical stage.

●

For the last decade, a lot of money has been invested into R&D led by different government
agencies and some achievements have been made. However, none of them has feasibility
in actual utilization for evaluation.

●

With development of advanced technologies, countries are competing harshly witheach other to hold a lead in the competition concerning the technologies. However,such advanced technologies are rarely accepted by regulatory bodies. Stakeholders
from industry, academia and research institutes have urged the regulatory authorities
to accept the technologies.
- Since it was demonstrated that Korea has technological prowess in organoid, MFDS
has determined to take the lead to develop and propose an international standard
for organoid.

□ Study in brief●

Development of organoid models (liver and intestine) for toxicity assessment and selectionof test methods●
50

Pre-validation and transfer of the organoid-based toxicity assessment methods

Ⅲ. Development & validation of NAMs based on advanced technologies●

Optimization of the toxicity assessment methods based on the organoids (liver andintestine) through pre-validation●

Proposal of an international standardization through establishment of theorganoid-based toxicity assessment method and a between-laboratory validation study(using liver organoid, proposal of an OECD SPSF)●

Final goal: Development of a toxicity assessment method using the standardized organoid* Study on the development of an organoid platform for toxicity assessment (22213MFDS386,
Myung-Jin Son, KRIBB) Validation study on an organoid platform for toxicity assessment(23213MFDS489, Gun-Hwa Kim, NST)

□ Overview of the study outcome●

Major accomplishment: Development of organoid models (liver and intestine) for toxicity
assessment and standardized organoid through between-laboratory validation andestablishment of assessment the method.

●

Main outcome- Development of organoid models for toxicity assessment using human-derived stem cells* A standard organoid pool categorized by races, genders and ages has been established.

- Establishment of the organoid models for toxicity assessment: A Quality Control (QC) method
for standard organoids have been established. Following selection of a toxicity assessment
method (evaluation of within-laboratory reproducibility and accuracy) and reference
substances, the method has been validated by confirming reproducibility and accuracy.
- Standardization of the organoid model

1) Reliability and relevance of the toxicity assessment method has been demonstrated
by performing within-laboratory pre-validation and between-laboratory validation.
The standardized method has been established by transferring it to other laboratories.
2) Proposal of the standardized organoid model to the OECD for international
standardization* MFDS presented the toxicity assessment method using the organoid model at the WNT 35(April 2023). Many countries made positive response and offered joint research.
* MFDS presented the toxicity assessment method using the organoid model at the OECD ESCA
meeting in June 2023 and received positive response. With guidance by the OECD secretariat,
MFDS has been focusing on standardization of the method for international acceptance.

51

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Excellence and advantages●

Excellence- The organoid-based toxicity assessment method has been developed with our own
technology- The model owns various advantages* that can compensate some of the limitationsof the existing models and able to produce more accurate results in a short period.
* The model is able to be customized for each patient, passaged over 90 times, and be frozen
and thawed repeatedly. Further, it enables toxicity evaluation based on mechanism andproduces more accurate results compared to animal testing.

- Drugs that passed non-clinical and clinical studies but were withdrawn from themarket due to hepatotoxicity have been tested with our organoid model. The model
exhibited over 80% of accuracy, which is higher than the accuracy from thenon-clinical trials using animals.
●

Advantages- This toxicity assessment method is not a “me-too” method that is developed bymodifying exiting method. Rather, it is developed using our original technology basedon the organoid developed in Korea- Among many nations researching organoids, Korea is the first to announce
international standardization of organoids and presented study outcome. Now, MFDSof Korea is leading the international standardization of organoid.
* MFDS presented the toxicity assessment method using the organoid model at the WNT 35(April 2023). Many countries made positive response and offered joint research.
* MFDS presented the toxicity assessment method using the organoid model at the OECD ESCA
meeting in June 2023 and received positive response. With guidance by the OECD secretariat,
MFDS has been focusing on standardization of the method for international acceptance.

□ Utilization of the outcome and its impact●

Development of national industry: Development of OECD Test Guideline fororganoid-based toxicity assessment method accepted internationally is expected tohelp create a new bio-industry relating to organoid.

●

Contribution to new drugs development: With increased accuracy in replicating human
response, the toxicity evaluation model is expected to reduce time and cost for drug
development.

52

Ⅲ. Development & validation of NAMs based on advanced technologies□ Performance of the research
Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Promotion andNumber of evaluation anddissemination of research promotion materials aboutoutcomethe outcome

1

MFDS researching toxicity assessment
method using organoid

2

Publication: Advances in liver organoids: Modelsystems for liver disease

Academic outcome

Number of papers
published in SCI-grade
journals

Publication: Limosilactobacillus reuteri
DS0384 promotes intestinal epithelial
3
maturation via the postbiotic effect in humanintestinal organoids and infant miceAcademic outcome

Number of papers
published in SCI-grade
journals

4

Publication: Advanced human liver models forassessment of drug-induced liver injury

Academic outcome

Number of papers
published in
non-SCI-grade journals

5

Publication: Recent advancements ofmulticellular human liver models

Academic outcome

Number of papers
published in
non-SCI-grade journals

6

Presentation: 2022 International Conference:
Korean Society for Molecular and Cellular
Biology

Academic outcome

Number of presentations(publications) inworkshops

7

Encouragement of
Preparation of draft: Draft SOP on liver organoid
Number of TG proposals
practical use by policy
passagingsubmitted
improvement, etc.

Encouragement of
Number of TG proposals
Preparation of draft: Draft SOP on liver organoid
practical use by policy
8
Indocyanine Green absoption and release test
submitted
improvement, etc.
9

Encouragement of
Number of TG proposals
Preparation of draft: Draft SOP on liver organoid
practical use by policy
freezing
submitted
improvement, etc.

Encouragement of
Preparation of draft: Draft SOP on orgaonid
Number of TG proposals
10practical use by policy
differentiation induction
submitted
improvement, etc.
1112Preparation of draft: Draft SOP on
measurement of cell count on orgaonid

Encouragement of
Number of TG proposals
practical use by policy
submitted
improvement, etc.

Encouragement of
Preparation of draft: Draft SOP on organoid
Number of TG proposals
practical use by policy
thawing
submitted
improvement, etc.

Preparation of draft: Draft SOP on
Encouragement of
Number of TG proposals
13 measurement of organoid CYP3A4 activation practical use by policy
submitted
level
improvement, etc.

53

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

14

Preparation of draft: Draft SOP on
measurement of bile acid pool size on
oraganoid

Encouragement of
Number of TG proposals
practical use by policy
submitted
improvement, etc.

15

Preparation of draft: Draft SOP on
determination of liver function marker
expression on organoid using IF staining

Encouragement of
Number of TG proposals
practical use by policy
submitted
improvement, etc.

Encouragement of
Preparation of draft: Draft SOP on quantitative
Number of TG proposals
16
practical use by policy
analysis of albumin secretion on organoid
submitted
improvement, etc.
17

Encouragement of
Preparation of draft: Draft SOP on quantitative
Number of TG proposals
practical use by policy
analysis of alpha-1-antitrypsin on organoid
submitted
improvement, etc.

18

Encouragement of
Preparation of draft: Draft SOP on mycoplasma
Number of TG proposals
practical use by policy
test method
submitted
improvement, etc.

Organization of industry, academia andPromotion andNumber of education and
19 research institutes meeting for standardization dissemination of research promotion materials aboutof organoid
outcomethe outcome
20

Promotion and
Attending and making presentation at thedissemination of researchOECD WNT35
outcome

Performance ininternational exchange

21

Promotion and
Attending and making presentation at thedissemination of researchOECD ESCA
outcome

Performance ininternational exchange54

Ⅲ. Development & validation of NAMs based on advanced technologies□ Major accomplishment
2. Publication: Advances in liver organoids: Model systems for liver disease55

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

3. Publication: Limosilactobacillus reuteri DS0384 promotes intestinal epithelial maturation via the
postbiotic effect in human intestinal organoids and infant mice56

Ⅲ. Development & validation of NAMs based on advanced technologies

4. Publication: Advanced human liver models for assessment of drug-induced liver injury

57

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

5. Publication: Recent advancements of multicellular human liver models

58

Ⅲ. Development & validation of NAMs based on advanced technologies

2

Development of next-generation toxicity prediction and evaluation method

Supervising
division

Toxicological Research Division of NIFDS

Type

Entrusted project

Title

Study on the development of next-generation toxicity prediction and evaluation method
using advanced technologies□ Background for the study●

Every year, thousands of new chemicals are introduced and used as ingredients infoods and drugs, cosmetics, medical devices, etc. Humans are exposed many new alienchemicals as well as known existing chemicals that are flown into air and water.

●

It is a universal task for countries around the world to evaluate the effects of thechemicals on humans, diagnose their risks and introduce necessary regulations. However,the current approaches (or methodologies) are unlikely to rapidly investigate theirmechanism and their interaction with humans or environment.

●

In particular, the existing toxicity test methods relied on laboratory animals tend tohave issues concerning energy consumption and environmental pollution. Also, theexisting methods have limitations including differences incurring during interspecies
extrapolation and dose extrapolation that evaluates biological toxicity of chemicals
based on the results following high-volume exposure of the chemicals to parenchyma
cells in a single organ.

●

This increases the need for use of laboratory animals. Further, for lots of chemicals
that are used nowadays, it is difficult to obtain their safety data in a rapid and efficientmanner.

59

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Study in brief●

Goal: Development of an intelligent toxicity prediction and evaluation model basedon Industry 4.0. technologies●

Big data were collected to support the development of a toxicity prediction model●

A plan for development and utilization of an intelligent toxicity prediction model was proposed●

Hepatotoxicity prediction system was developed based on deep-learning techniquewith the big data related to toxicology●

A two-stage* deep learning model for toxicity prediction was built based on the big data
* Deep learning algorithm for toxicity prediction based on chemical structure, physical andchemical properties, and atomic information* Deep learning algorithm for toxicity network prediction based on integrated data oftranscriptome and bionetwork.

●

Confirming and validating feasibility of the toxicity prediction model□ Overview of the study outcome●

Major accomplishment: Development of a hepatotoxicity prediction system using a
deep learning technique by creating hepatotoxicity big data.

●

Main outcome(1) Collecting data on compounds and creating big data related to hepatotoxicity- Data on compounds including their hepatotoxicity potential were collected fromTox-21 (EPA), LTKB (FDA) and LiverTox- Structure and physical and chemical property of the compounds were collected from
PubChem, ChEMBL and ZINC, and atomic information from RDKit.
- Information on the transcriptome before and after application of the compounds
were collected from cMAP, LINCS (Human) and Drug Matrix (Mouse/Rat).

(2) Development of a deep learning model for the big data
- A positive and negative compound set for heapatotoxicity was defined.
- A positive and negative compound set was defined using compound structure,physical and chemical properties and atomic information- A deep learning model for toxicity prediction was created based on transcriptome60

Ⅲ. Development & validation of NAMs based on advanced technologies(3) Validation of the performance of the deep learning model for hepatotoxicity prediction- The deep learning model was applied to the compounds with no toxicity information
to identify the compounds with hepatotoxic potential.
- A toxicity evaluation platform applied with the toxicity prediction model wasestablished and 17 reference substances were evaluated with the platform.
- Producing real cases of toxicity prediction based on the developed model: The
toxicity prediction model was validated with substances selected specifically for thevalidation using in vivo and in vitro toxicity test platform.

□ Excellence and Advantages●

Excellence- Development of AI-based deep learning algorithm for toxicity prediction using ourown technology- Laying the foundation for the development of an alternative to animal testing bybuilding a database containing information on over 5000 chemicals and developinga hepatotoxicity prediction model* An evidence-based hepatotoxicity prediction model developed based on the database appliedwith AI technology- The AI-based toxicity prediction model is able to identify chemicals with hepatotoxic
potential, which is expected to help reduce time and cost of drug development.
- With the development of the toxicity prediction model, hepatotoxicity predictionof newly developed chemicals* used in consumer chemical products is possible, andbase technology for risk and toxicity prediction of chemicals that humans are exposed
to is obtained.
* Perfluorinated compounds (e.g. PFOS, PFAS, PFOA, F53B, etc.) and Bisphenol are reported
to induce hepatotoxicity●

Advantages- Development of the nation’s first AI-based toxicity prediction model and chemical
database- Risk and (or) toxicity information on over 5000 chemicals scattered across various
national or foreign databases have been collected and standardized to create big
data for development of a two-stage toxicity prediction model.

61

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- The database* has been developed based on the standardized big data and thetwo-stage prediction model, which is expected to support the new drug developmentand (or) chemical developers by providing information on toxicity prediction.
* HepatoToxicity portal based on AI and applied with hepatotoxicity prediction technology□ Utilization of the outcome and its impact●

Safety assessment: In the non-clinical study of compounds, the model can be utilized
as a hepatotoxicity screening system before performing animal experiment- The model can provide basis for a next-generation safety assessment technology
adhering to the 3R principles●

Mechanism prediction: toxicity mechanism can be predicted by generating transcriptome
data on compounds□ Performance of the Study
Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Publication: A review on compound-protein
1 interaction prediction methods: Data, format,
representation and model

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

2

Publication: On modeling and utilizing chemicalcompound information with deep learningtechnologies; A task-oriented approach

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals3

Publication: Drug-likeness scoring based on
unsupervised learning

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Publication: Subnetwork representation
learning for discovering network biomarkers
4
in predicting lymph node metastasis in early
oral cancer

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Publication: Risk stratification for breast cancer
patient by simultaneous learning of molecular5
subtype and survival outcome using genetic
algorithm-based gene set selection

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Publication: Improved drug response
6 prediction by drug target data integration via
network-based profiling

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Publication: Supervised chemical graph mining
improves drug-induced liver injury prediction

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

762

Ⅲ. Development & validation of NAMs based on advanced technologies

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Publication: DRPreter: interpretable anticancer
drug response prediction using
8
knowledge-guided graph neural networks andtransformer

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Presentation: A Supervised Markovian
Random Walk Model for Investigating
9
Hepatotoxicity Signatures of Chemical Drugs
with Structural Alerts

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Presentation: Identification of toxic signaturein transcriptomic space

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Presentation: Integrating Drug Target
11 Information via Network Propagation for Drug
Response Prediction

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Presentation: Leveraging biologicalknowledge as guide for random walk on
12biomedical heterogeneous network for drug
repurposing

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Presentation: Leveraging hierarchical tree data
13 as guide for random walk on heterogeneous
network for drug repurposing

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Presentation: 1H NMR-based metabolomicsof brain, urine and serum in rat model of
14
valproic acid-induced autism spectrum
disorders (ASD)

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

Creation of website(database)

Number of DB creation or
updates

1015

DB creation: HepatoToxicity Portal
https://www.kobic.re.kr/htp/

63

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major outcome
1. Publication: A review on compound-protein interaction prediction methods: Data, format, representationand model

64

Ⅲ. Development & validation of NAMs based on advanced technologies

2. Publication: On modeling and utilizing chemical compound information with deep learningtechnologies; A task-oriented approach

65

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

3. Publication: Drug-likeness scoring based on unsupervised learning66

Ⅲ. Development & validation of NAMs based on advanced technologies

4. Publication: Subnetwork representation learning for discovering network biomarkers in predicting
lymph node metastasis in early oral cancer

67

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

5. Publication: Risk stratification for breast cancer patient by simultaneous learning of molecular subtype
and survival outcome using genetic algorithm-based gene set selection

68

Ⅲ. Development & validation of NAMs based on advanced technologies

6. Publication: Improved drug response prediction by drug target data integration via network-based profiling

69

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

6. Publication: Improved drug response prediction by drug target data integration via network-based profiling70

Ⅲ. Development & validation of NAMs based on advanced technologies

8. Publication: DRPreter: interpretable anticancer drug response prediction using knowledge-guided
graph neural networks and transformer

71

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes3

Study on creation of basis for next-generation toxicologic pathology diagnosis

Supervising
division

Toxicological Research Division of NIFDS

Type

Entrusted project lead by Jae-Wooo Cho, KIT

Title

Creation of basis for next-generation toxicologic pathology diagnosis (20183MFDS411)□ Background for the study●

As new types of cancers are introduced to human body, AI-based pathology systemthat can rapidly and accurately diagnoses cancers have emerged.
- With adoption of a digital pathology software, rapid and accurate diagnosis of humanpathology data become possible.

●

In toxicologic pathology that is used to make comprehensive toxicological decisionin the non-clinical safety assessment, a standardized program for toxicologic pathology
diagnosis using big data and AI is necessary.
- With the emergence of the Industry 4.0, demand from research institute and industry for
digital pathology technologies in non-clincal safety assessment has increased, and the needto build a digital system for pathology diagnosis led by the government has been increasing.

□ Study in brief●

Collecting toxicologic pathology data relating to a digital pathology technology andcreating big data●

Standardizing toxicologic pathology diagnosis on main organs- Diagnostic terminology of lesions in main organs (standardization of INHAND-based
diagnostic terminologies and KNTP toxicologic pathology terminologies) werestandardized.
- Intensity of toxicologic pathology diagnosis was standardized.

●

Developing and validating toxicologic pathology diagnosis technology based on digitalpathology technology- Database for learning lesions in main organs was created and learning algorithm was created.
- Learning algorithm for intensity of lesions was generated using AI: Toxicologic
pathology diagnosis technology was developed.

72

Ⅲ. Development & validation of NAMs based on advanced technologies●

Final Goal

□ Overview of the study outcome●

Major accomplishment: Establishment of basis for next-generation toxicologic pathology
diagnosis by converging big data containing large image files of toxicologic pathology
slides and AI.

●

Summary of the outcome(1) Creation of toxicologic pathology big data for digital pathology technology- Existing pathology diagnosis models and technologies in Korea and in the world were
investigated.
- Toxicologic pathology data were obtained and WSI (Whole Slide Image) archive wasconstructed.
· data includes multi-site slides. The WSI archive is accessible on-line and utilized as
education material for researchers in the related field.
- Data set for AI diagnosis was created.
· Images of over 20 multi-site lesions in liver, kidney and lung have been obtained andover 10,000 data set has been created for each organ.

(2) Standardization of terminologies and intensity of toxicologic pathology diagnosis- Terminologies for toxicologic pathology diagnosis were standardized.
73

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes· Terminologies for diagnosing lesions in main organs has been standardized based on
INHAND· Consultation group consisting of pathologists from GLP facilities was organized tocreate the system for validation of standard terminologies for diagnosis· The standard terms has been disseminated and an education system created.
· The terms are available on KNTP as standard terminologies for toxicologic pathology· Standardized terminologies for AI-based diagnosis system and the guideline for readingwere provided.

(3) Development of toxicologic pathology diagnosis program- Based on the database for learning lesions in liver, kidney and lung, the algorithms
for learning the lesions and the intensity of the lesions by using AI were created
and toxicologic pathology diagnosis program was developed.
- Toxicologic pathology viewer was developed: The viewer that supports management oftissue reading history was created and linked to auto-documentation of reading results
and diagnosis standardization files. All these greatly enhance convenience of pathologists□ Excellence and advantage●

Excellence- The AI-based system and toxicologic pathology diagnosis has been developed with
our own technology.
- The AI model selected is appropriate for toxicologic pathology and exhibits over
90% of average accuracy.
* Digital slide images can be analyzed by developing a program viewer equipped with AI technology- Time and accuracy of diagnosis by pathologists have greatly improved thanks toautomation using AI●

Advantages- The nation’s first AI-based toxicologic diagnosis (reading) program- By upgrading the learning contents on the program format, the program can be
expanded and customized program for individual research can be supplied.
- AI accuracy is expected to be improved by giving access of the toxicologic pathology
data sets to the AI model researchers74

Ⅲ. Development & validation of NAMs based on advanced technologies□ Utilization of the outcome and its impact●

Development of the nation’s first AI-based toxicologic pathology diagnosis program
will lead to development of the overall domestic industry.

●

Enhanced diagnostic speed and accuracy of toxicologic pathology, an essential partof non-clinical study, will eventually improve the speed and accuracy of drug
development.

□ Performance of the study
Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Promotion andNumber of education andParticipated in 2023 KALAS winter symposium
1
dissemination of research promotion materials about
as an exhibitor
outcomethe outcome
2

Presentation: Possibility and reality of
toxicologic pathology evaluation through AI
model

Academicaccomplishment

Number of presentations(publications) in national
symposium3

Toxicologic pathology diagnosis terminology
explanation programIntellectual property

Number of patentapplications(In Korea)

4Authomatic pathology screening programIntellectual property

Number of patentapplications(In Korea)

5

Region extraction method of medical image
data

Intellectual property

Number of patentapplications(In Korea)

6

Promotion andMeeting to report research the outcome of
Number of education andthe project on establishing basis for next dissemination of research promotion materials about
generation toxicologic pathology diagnosis
outcomethe outcome

Publication: A comparative study for the
7 implementation of deep learning algorithms
to analyze hepatic necrosis in toxicity studies.

Academicaccomplishment

Number of papers
published in SCI-grade
journals

Presentation: A comparative study of artificial
intelligence analysis for diagnosis of liver
fibrosis in rats

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Artificial
Intelligence(AI)-assisted Histopathology
9
Analysis of Acetaminophen-induced Rat Liver
Injury in Preclinical Study

Academicaccomplishment

Number of presentations(publications) in national
symposium

Publication: Artificial intelligence-assisted
10 image analysis of acetaminophen-induced
acute hepatic injury in Sprague-Dawley rats

Academicaccomplishment

Number of papers
published in SCI-grade
journals

Presentation: Evaluation on seatosis using AI
11model learning steatosis in digital slide image

Academicaccomplishment

Number of presentations(publications) in national
symposium

875

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Presentation: Hepatic steatosis screening
12 analysis study applying artificial intelligence
to rats

Academicaccomplishment

Number of presentations(publications) in national
symposium

Publication: Image analysis for acetaminophen
13 (APAP)-induced liver necrosis in SD rat usingclassification algorithm

Academicaccomplishment

Number of presentations(publications) in national
symposium

Publication: Preparing pathological data to
14 develop an artificial intelligence model in the
nonclinical study

Academicaccomplishment

Number of papers
published in SCI-grade
journals

15

Presentation: Segmentation algorithm can beused for detecting hepatic fibrosis in SD rat

Academicaccomplishment

Number of presentations(publications) in national
symposium

16

Presentation: Study on effect of staining
condition in H&E slide on prediction
performance of AI model

Academicaccomplishment

Number of presentations(publications) in national
symposium

17

Presentation: How to create lesion image data
set for AI-based tissue slide reading

Academicaccomplishment

Number of presentations(publications) in national
symposium

18

Database for toxicologic pathology diagnosis Creation and utilization of Creation of information
terminologyDBbasis (e.g. database)

19

Patent application:
10-2021-0072051_extraction method of
medical image data

Intellectual property

Number of patentapplications(In Korea)

Patent application: 10-2022-0049876_
20 region extraction method of medical image
data

Intellectual property

Number of patentapplications(In Korea)

21

Patent registration: 10-2383495_ extraction
method of medical image data

Intellectual property

Number of patentapplications(In Korea)

22

TPX 2022 Series EP2

Promotion andNumber of education anddissemination of research promotion materials aboutoutcomethe outcome

Publication: Implementation and Practice ofDeep Learning-Based Instance Segmentation
23
Algorithm for Quantification of Hepatic Fibrosis
at Whole Slide Level in Sprague-Dawley Rats

Academicaccomplishment

Number of papers
published in SCI-grade
journals

Presentation: Application of object detection
deep learning algorithms for automated24
detection of infiltration of mononuclear cell in
SD rat liver

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Artificial intelligence-assisted
25 histopathology analysis of APAP-induced rat
liver injury in preclinical study

Academicaccomplishment

Number of presentations(publications) in national
symposium76

Ⅲ. Development & validation of NAMs based on advanced technologies

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Presentation: Automated detection using the
26 deep-learning method of liver lesions inducedby acetaminophen in Sprague-Dawley rats

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Preliminary study for developing
27 renal injury diagnosis system in SD rat using
deep learning method

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Quantification of hepatic fibrosis
in SD rats using deep learning instance28
segmentation focused on H&E staining wholeslide level

Academicaccomplishment

Number of presentations(publications) ininternational symposium

Presentation: Segmentation of histology
29 images of mononuclear cell infiltration in liverof SD rat through deep learning algorithms

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Segmentation of histology
30 images of the portal triad in liver of SD rat
through deep learning algorithms

Academicaccomplishment

Number of presentations(publications) in national
symposium

31

Presentation: Deep Learning and theApplication Trend in Veterinary Medicine
Research

Academicaccomplishment

Number of presentations(publications) in national
symposium

32

Patent application:
10-2021-0072051_extraction method of
medical image data

Academicaccomplishment

Number of patentapplications(In Korea)

33

Promotion andNumber of education and
Press release: Developing AI-based toxicity
dissemination of research promotion materials about
prediction technology
outcomethe outcome

Presentation: Current status and practice of
34 toxicologic pathology evaluation using andartificial intelligence model.

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Pixel level detection of rat liver
fibrosis using Mask R-CNN

Academicaccomplishment

Number of presentations(publications) in national
symposium

Presentation: Research on a Proper Deep
36 Learning Algorithm for Automated Detectionof Coagulative Necrosis in SD Rat

Academicaccomplishment

Number of presentations(publications) in national
symposium

35

77

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major outcome
7. Publication: A comparative study for the implementation of deep learning algorithms to analyze
hepatic necrosis in toxicity studies.

78

Ⅲ. Development & validation of NAMs based on advanced technologies

10. Publication: Artificial intelligence-assisted image analysis of acetaminophen-induced acute hepatic
injury in Sprague-Dawley rats

79

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

14. Publication: Preparing pathological data to develop an artificial intelligence model in the nonclinical
study

80

Ⅲ. Development & validation of NAMs based on advanced technologies

23. Publication: Implementation and Practice of Deep Learning-Based Instance Segmentation
Algorithm for Quantification of Hepatic Fibrosis at Whole Slide Level in Sprague-Dawley Rats

81

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

4

Survey on the latest technology trends of stem cells and organoidSupervising
division

Clinical Research Division of NIFDS

Type

Entrusted project (led by Prof. Si-woon Kim, Konkuk University)

Title

Study on utilization of stem cell-based translational medicine – focusing on stem cells
and organoid (21182MFDS293)□ Background for the study●

Research on translational technology has been actively performed globally in order
to better predict the reactions of human body to drugs in the process of drug development.
- In order to address limitations of in vivo animal models and ethical issues related
to animal experiment, many are attempt to assess pharmaceuticals’s efficacy andsafety using induced pluripotent stem cells (iPSCs) or organoid including 3D culture
mimicking the structure and function of human organs and tissues.

□ Study in brief●○ Survey and analysis of research trends of pharmaceutical evaluation using stem
cells and organoid (translational technology)- Changes in national and international environment and megatrend (of R&D andindustry) were analyzed.
- Studies published in national and international academic journals were surveyed.

●

Mid to long-term study plan on pharmaceutical evaluation technology using stem cells
and organoid (translational technology) was established.
- Based on analysis of SWOT and GAP, key strategies, mid to long-term researchroad-map and new projects were proposed.

□ Overview of the study outcome●

Major accomplishment: Providing information on the most updated technology trends
on the use of stem cells and organoid82

Ⅲ. Development & validation of NAMs based on advanced technologies●

Main outcome- Publication: Providing the most updated information on the market trend of theadvanced assessment technology including organoid, research and development, andrelated patent status in collaboration with KRIBB.
- Publication and promotion of casebook: Providing the most updated information
including the cases creating organoid specific to an organ/cancer type and andefficacy evaluation models using the organoid.
- Presentation in workshops: Promoting and disseminating the research outcome bypresenting in professional workshops.

□ Excellence and advantage●

Excellence: Establishment of mid to long term research plan on pharmaceuticals efficacy
and safety evaluation technology using advanced technologies.

●

Advantage: Providing R&D strategy of an assessment system using organoid and the direction
for future research (multi-site validation, need for establishment of technology infra
structure including exper training, etc.)from the perspective of regulatory organization□ Utilization of the outcome and its impact●

The publications prepared in the study can be referred by drug developers and researchers
when establishing a research plan and strategy for safety and efficacy evaluation of drugs.

●

Also, it provides basis for developing and utilizing NAMs using iPSCs and organoid.

□ Performance of the study
Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

1

BioINdustry No. 160(2021-06)
Promotion and dissemination- Global market status and prospect of organoidsof research outcome

publications

2

Publication of casebook of creation andPromotion and dissemination
utilization of organ-specific organoids andof research outcome
upload on the official website

publications

3

Presentation: Establishment of advanced
multi-organoid model based on functional
characteristics

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops

4

Presentation: Generation of Human iPSCs
Derived Heart Organoids Structurally andFunctionally Similar to Heart

Building on expertisethrough academic
accomplishment

Number of presentations(publications) in national
workshops
83

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes5

Study on next-generation safety pharmacology evaluation of cardiovasculareffects

Supervising
division

Pharmacological Research Division of NIFDS

Type

Internal project

Title

Study on next-generation safety pharmacology evaluation of cardiovascular effects(21181MFDS276)□ Background for the study●

The paradigm of regulatory science of safety pharmacology evaluation has shifted todevelopment of human-relevant models and the ICH (International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) also
is adapting to the shift.

●

Since inclusion of a new test method using a stem cell line in ICH S7B, a guideline
for cardicovascular safety pharmacology, is currently being discussed, it is necessary
to establish in Korea a next generation safety pharmacology technology for evaluationof cardiovascular effects.

●

Therefore, the goal of this study was to establish next generation safety pharmacology
technology for evaluation of cardiovascular effects using human hiPSC and to understandelectrophygiology of cardiotoxicity.

□ Study in brief●

Development of cardiotoxicity evaluation models for drugs causing deep vein thrombosis- Drugs causing deep vein thrombosis (high/intermediate/low risk) were selected.
- Sensitivity of each drug in cells with cardiac ion channel expression and hiPSC-CMs
ion channels was compared.

●

Mechanism study on cardiotoxicity induction of durgs (test drugs) causing cardiotoxicity- Mechanism inhibiting cardiac ion channel was investigated.
- Pathway effects related to cardiovascular system caused by test drugs were compared
and analyzed.

84

Ⅲ. Development & validation of NAMs based on advanced technologies□ Overview of the study outcome●

In vitro safety pharmacology test methods for high/intermediate/low TdP-risk drugs
on cardiovascular system- Development of a multiple cardiac ion channel test method using CiPA-based cell line
- Development of a test method for repolarization delay using CiPA-based hiPSC-CMs- Development of a test method for cardiac action potential measurement using stem cells●

Study on a next-generation multiple cardiac ion channel test method using
commercialized national hiPSC-CMs- Development of test methods for cardiac action potential and multiple cardiac ionchannel using hiPSC-CMs- Similarity was observed from the test results using cell lines and hiPSC-CMs●

Cardiovascular safety pharmacology assay- Development of a test method for prediction of TdP risks based on the results fromthe test method for cardiac repolization delay□ Excellence and advantage●

Overcoming current limitations of cardiovascular safety pharmacology methods- It was demonstrated that the existing methods have limitations of low specificity inprediction of TdP induction risks due to their dependency on hERG channel.
- In this study, a cardiovascular safety pharmacology method for high/intermediate/low
TbP risk drugs was developed, which would help overcome some of the limitationsof the existing methods with higher accuracy and reliability.

●

Proposal of the need for multiple cardiac ion channel evaluation- This study has proposed the need for novel methods for multiple cardiac ion channelevaluation to assess the effects of drugs.

●

Utilization of an hiPSC-CMs model- This study demonstrated the possibility of various applications of hiPSC-CMs ashuman-relevant models and reliability and accuracy compared to existing in vitro
cell culture models

85

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Utilization of the outcome and its impact●

Responding to the updated ICH (S7B) that can replace hERG assay and telemetry- This study has contributed to the revision of ICH (S7B) by developing and proposing
novel methods for cardiovascular safety pharmacology that are able to replace hERG
assay and telemetry.

●

Inclusion of various ion channel evaluation- While the existing method rely on hERG channel, the methods developed in this study
are able to conduct more sophisticated evaluation by including various ion channels
including action potential measurement of calcium and sodium channel as well as
potassium channel (hERG).

●

Utilization of hiPSC-derived cardiomyocytes- This study demonstrated the reliability and usefulness of the new method bydeveloping human-relevant cardiovascular model using hiPSC-derived cardiomyocyte
models●Provision of scientific basis for prediction of adverse drug reaction- This study has contributed to pharmaceutical development and safety evaluation by
providing scientific basis for prediction of adverse drug reaction using a new
cardiovascular safety pharmacology method.

□ Performance of the research
Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

New in vitro multiple cardiac ion channel
screening system for preclinical Torsades de1
Pointes risk prediction under theComprehensive in vitro Proarrhythmia Assay
concepta

academic outcome

Number of papers
published in SCI-grade
journals

In vitro cardiac safety and pharmacology
2 assessment of the 3 drugs categorized as TdP
low risk, intermediate risk and high risk

academic outcome

Number of papers
published in
non-SCI-grade journals

Assessment of Drug Proarrhythmic Potential
in Human iPSC-Dereived Cardiomyocytes
3
using Microelectrode Arrays (Korean Society
for Stem Cell Research)academic outcome

Number of publications
and presentations in
national workshops

86

Ⅲ. Development & validation of NAMs based on advanced technologies

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

In vitro cardiac safety and pharmacology
assessment of the 3 drugs categorized as TdP
4
low risk, intermediate risk and high risk (Korean
Society for Stem Cell Research)academic outcome

Number of publications
and presentations in
national workshops

In vitro electrophysiological assessment forproarrhythmia risk prediction under CiPA
initiative (Korean Physiological Society)academic outcome

Number of publications
and presentations in
national workshops

Cardiotoxicity Screening for Proarrhythmic
Potential of Drugs in Human iPSC-Dereived
6
Cardiomyocytes using Microelectrode Arrays(Korea Society of Toxicology)

academic outcome

Number of publications
and presentations in
national workshops

A Novel Approach in the Area of Preclinical
7 Cardiac Safety Testing via the CiPA Concept(
Korea Society of Toxicology)

academic outcome

Number of publications
and presentations in
national workshops

social assessment

Number of educational
and promotion materials
about the study outcome(e.g. social assessment,
rewards, etc.)

5

Outstanding poster award: A Novel Approachin the Area of Preclinical Cardiac Safety Testing8
via the CiPA Concept (awarded by Korea
Society of Toxicology)

9

Guidance on cardiovascular safety
pharmacology assessment methods

Promotion andNumber of educational
dissemination of the study and promotion materials
outcomeabout the study outcome

10

Q&A book on comprehensive deep veinthrombosis evaluation

Promotion andNumber of educational
dissemination of the study and promotion materials
outcomeabout the study outcome

87MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major accomplishment
1. Publication: New in vitro multiple cardiac ion channel screening system for preclinical Torsades
de Pointes risk prediction under the Comprehensive in vitro Proarrhythmia Assay concepta

88

Ⅲ. Development & validation of NAMs based on advanced technologies

2. Publication: In vitro cardiac safety and pharmacology assessment of the 3 drugs categorized as
TdP low risk, intermediate risk and high risk

89

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes6

Study on next-generation neurotoxicity evaluation method

Supervising
division

Pharmacology Research Divison of NIFDS

Type

Entrusted project

Title

Study on next-generation neurotixicity evaluation method (Ι) (19182MFDS408)□ Background for the study●

Recently, drug abuse cases are increasing and drug users are becoming younger andmore diverse, which become a serious social issue.
- In addition, drug abuse cases are expected to increase since new narcotics arecontinuously introduced and the society is becoming more complex and diverse.

●

There is no neurotoxicity test method for neuroterapeutic drugs targeting adult nervous
system instead of developmental stage in the world.
- Although a safety pharmacology test of the central nervous system do exist, it remains
at the level of behavioral evaluation analysis using rodents (Functional Observation
Battery: FOD, Modified Irwin’s)□ Study in brief●

Establishment of human-mimicking neuron test system* using hiPSC* neurons, astrocytes, and microglia●

Development and validation of neurotoxicity test method using the establishedneurotoxicity test system.

<Concept mapping of the study on development of next-generation neurotoxicity test method basedon iPSC-derived neurons>90

Ⅲ. Development & validation of NAMs based on advanced technologies- Establishment of neurotoxicity analysis method based on morphology, electrophysiology,
nerve function and apoptosis.
- Development of drug abuse test method for mid to long term exposure to drugs* 30 substances including reference drugs and narcotics were evaluated for toxicity●

Establishment of a platform system that can be used to encourage practical use ofstem cell-based toxicity evalaution methods.

□ Overview of the study outcome●

Establishment of hiPSCs derived from human fibroblast- A differentiation method for stable and homogenous neuronal system has been established.
* neural progenitor cells, glutamatergic neurons, GABAergic neurons, motor, dopaminergic
neurons, and astrocytes

neural progenitor cells produced

glutamatergic neurons produced

GABAergic neurons produced

astrocytes produced- Development of drug abuse evaluation method for middle to long term exposure to drugs* Development and validation of a cell line using for drug evaluation using a multi-electrode assay
91

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes●

Establishment of neurotoxicity analysis method for toxicity evaluation based onmorphology, reactive oxygen, apoptosis, and electrophysiology- 30 substances including reference drugs and narcotics were evaluated for toxicity* Preparation of SOP for toxicity evaluation on central nervous system□ Excellence and advantage●

Utilization of human-mimicking neuron test system established using iSPC-derived stem cells- The differentiation method for iSPC-derived neurons that is highly functional andefficient can be utilized as efficacy evaluation method in drug envelopment.
- The 3D cell culture plaform can be utilized as a new cell culture technology, andin production of medical devices.

□ Utilization of the outcome and its impact●

Publication of guidance on neurotoxicity test method using stem cells- Accurate prediction of human body response to drugs can reduce failure of new drug
development caused by toxicity, and can be used in central nervous system safety
pharmacology which is an integral part in a non-clinical study.
* While existing methods eevaluate toxicity inducing neuronal cell apoptosis, this method
evaluates electrophysiological changes and receptor abnormality of neurons that will be followedby real neurological symptom.

●

Provision of scientific basis for regulation and safety management policy of substancesof abuse risk including narcotic drugs- While there is no reliable evaluation method for drug abuse, this study proposes a
standard for abuse evaluation based on human-mimicking neurons.

□ Performance of the study
Title

MFDS Performance Evaluation Standard
Type

Performance Indicator

Publication: BAPTA, a calcium chelator, neuroprotects Building on expertise Number of papers
1 injured neurons in vitro and promotes motor recovery through academic
published inafter spinal cord transection in vivo
accomplishment
SCI-grade journal
Publication: Development and validation of
Building on expertise Number of papers
dual-cardiotoxicity evaluation method based on analysis
2
through academic
published inof field potential and contractile force of human iPSC-derived
accomplishment
SCI-grade journal
cardiomyocytes/multielectrode assay platform92

Ⅲ. Development & validation of NAMs based on advanced technologies□ Major accomplishment
1. Publication: BAPTA, a calcium chelator, neuroprotects injured neurons in vitro and promotes motor
recovery after spinal cord transection in vivo

93

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

2. Publication: Development and validation of dual-cardiotoxicity evaluation method based on analysis
of field potential and contractile force of human iPSC-derived cardiomyocytes/multielectrode assay
platform94

Ⅲ. Development & validation of NAMs based on advanced technologies

7

Study on development of a method for evaluation of (new) narcotics
pharmacology and toxicity in central nervous system

Supervising
division

Pharmacological Research Division of NIFDS

Type

Entrusted project

Title

Study on development of a method for evaluation of (new) narcotics pharmacology
and toxicity in central nervous system (20182MFDS423)□ Background for the study●

As the number of new narcotics introduced into Korea is increasing, a regular system
for hazard evaluation should be established in Korea. Further, the evaluation system shouldmeet the national regulations (three years of designation period as) temporary narcotics)
and the requirements by the UN and other advanced countries for designation of narcotics.

●

Neurotoxicity or dependency evaluation performed on animals has a limitation ofrequiring a lot of samples, and thus a new assay for evaluation of toxicity andpharmacological mechanism should be developed to overcome the limitation.

□ Study in brief●

Establishment of a new assay for evaluation of new narcotics of central nervous system
actions and dependency/abuse potential- An electrophysiological measurement method using mouse tissues and neurons
derived from human stem cells, and a method for analyzing binding force andfunction of mitochondria to narcotic receptors have been developed.

●

Establishment of new dependency test methods by utilizing various electricalmeasurement methods on the existing neural cells and circuits- An electrical measurement method using rat-derived primitive neurons has been established.
- An electrical measurement method using hippocampal slices and nucleus accumbens
slices has been established.

●

Establishment of stem cell-derived neurons for evaluation central nervous system
reactions to narcotics.
- Human stem cell-based cell lines for evaluation narcotics on central nervous system
actions have been established.
95

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- Human stem cell-based cell lines for evaluation of neurotoxicity/ dependency havebeen established.
●

Establishment of methods for prediction of narcotic receptor binding affinity- Non-radioactive receptor binding assay using Surface Plasmon Resonance (SPR) has
been established.
- Narcotic receptor binding affinity is evaluated using SPR.

●

Development of new test methods using analysis of mitochondria function- The effect of narcotics on central nervous system is evaluated by analyzing
mitochondria function.
- Neurotoixicity and (or) dependency of narcotics are evaluated by analyzing
mitochondria function.

□ Overview of the study outcome●

The following pharmacology and toxicity test method of new narcotics on central nervous
system using neurons have been established: a new narcotics central neurotoxicity
and dependency test method using synapse; a novel test method based on mitochondria
function; and a novel SPR-based test method.
- SPR (surface plasmon resonance) evaluation method for measurement of new narcotics
receptor binding affinity· The method evaluates hazard of new narcotics by assessing their binding affinity to
receptors using SPR.
- Mitochondria function test method neurons derived from human pluripotent stem cells· The method evaluates safety on new narcotics on neurons by assessing their effecton the function of mitochondria in neurons derived from human pluripotent stem cells(Glycolytic ATP production and Mitochondrial ATP production).
- Neuron activation level measurement method· The method analyzes activation level of nuerons by confirming neuron excitation based on
the action potential measured by changes in membrane potential of Na+ and K+ ion channels.
- Method for measuring neurotransmitter release· The method measures neurotransmitter glutamate release by analyzing membranepotential changes of neuron synapse channels (NMDAR, AMPAR, and GABAR)96

Ⅲ. Development & validation of NAMs based on advanced technologies- Method for measuring disruption of dopamine receptor· A sensor (GFAP104-GRABda2m) for measuring dopamine has been introduced toinvestigate changes in GFP (green fluorescent protein) that incur during interaction
between dopamine and dopamin receptor.
- Method for evaluating presynapse release using paired pulsed ratio· The method confirms inhibition of neurotransmitter release by new narcotics byanalyzing paired pulsed ratio- In vitro dependency test method· Dependency of new narcotics is evaluated by observing LTP (long term potentiation)that regulates memory and learning. In addition, existence of dependency is determinedby observing increase in synapse AMPA receptor expression, a major mechanism of LTP.
- New narcotics test method using a synapse channel· The method evaluates the effect of new narcotics on neurons by analyzing disruption
level of synapse channel based on glutamate release measurement.

□ Excellence and advantage●

Academic accomplishment: publication of papaers with 90% mrnIF- The study provides the scientific basis and objectivity of MFDS safety management
skills and standard specifications by publishing high quality papers (2 papers with
94% and 80% mrnIF each)* Digital selective transformation and patterning of highly conductive hydrogel bioelectronics bylaser-induced phase separation. SCIENCE ADVANCES. 2022. 8(23).
* An Octopus-derived pepetide with antidiuretic activity in rats. Marine drugs. 2022. 20.

●

SOP: While there is lack of research on neurotoxicity test methods for new narcotics
and narcotics, this study provides research basis to research institutes or laboratories
that newly perform neurotoxicity studies by establishing related test methods andpreparing SOPs.

●

Action mechanism: This study has become the first in the world to reveal the action
mechanism by which four temporary narcotics (4-EA-NBOMe, LY-2183240, DCMP,
AB-CHGFUPYCA) induce neurotoxicity.

●

For the temporary narcotics that cannot be designated as narcotics based the the resultsfrom the existing test method (rodent behavioral test), their neurotoxicity test results
97

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

obtained in this study has been utilized to prepare technical report that provides scientificbasis for revision of Narcotics Control Act.
- This study provides a neuron-based test method for temporary narcotics that are
difficult to be tested by the traditional dependency test methods focused on
behavioral test including 4-EA-NBOMe, and LY-2183240□ Utilization of the outcome and its impact●

Utilization of the outcome- The data generated in this study is utilized as scientific basis for hazard evaluationof new narcotics for designation of them as (temporary) narcotics.
- The basis that can be used in preparation of technical report for designation of
temporary narcotics (amendment to the enforcement decree of the Narcotics ControlAct) has been obtained.

●

Impact of the outcome- The data generated in this study are utilized as raw data for evaluation ofneurotoxicity and dependency of narcotics. It is used as base data for the Narcotics
Control Act and contributes to public safety management.
- The SOPs on neuron-based toxicity test methods prepared in this study would help
research institutes or laboratories that newly adopt narcotics neurotoxicity test
methods.

●

Demonstration of excellence and reliability of MFDSs safety assessment methods- The influx of new narcotics into Korea has emerged as a serious social problem,
amplifying public anxiety. Against this backdrop, this study provides preemptive
measures to safely and scientifically evaluate the new narcotics, which would respondto the needs of the people and increase the public trust to the government agency.
- Since the 2000s, stem cells have been constantly attracting public attention with newscience and technology. Announcement of practical research using stem cells is
expected to contribute to increasing public trust to the MFDS while promoting theexcellence of the Ministry’s research capabilities.

98

Ⅲ. Development & validation of NAMs based on advanced technologies□ Performance of the study
Title

1

MFDS Performance Evaluation Standard
Type

Performance Indicators

Digital selective transformation and patterning of Building on expertise Number of papered
highly conductive hydrogel bioelectronics bythrough academic
published in SCI-grade
journallaser-induced phase separation.
accomplishment

Establishment of Neurotoxicity Assessment Using
Building on expertise Number of papered
Microelectrode Array (MEA) with hiPSC-Derived
2
through academic
published in SCI-grade
Neurons and Evaluation of New Psychoactive
journalaccomplishment
Substances (NPS).
3

Acute effects of 4-EA-NBOMe, 3, 4-DCMP, Building on expertise Number of papered
LY-2183240 and AB-CHFUPYCA on thethrough academic
published in SCI-grade
excitability of rat cortical primary cultured neurons.
accomplishment
journal4

An Octopus-derived pepetide with antidiuretic
activity in rats

Building on expertise Number of papered
through academic
published in SCI-grade
journalaccomplishment

5 Anti-stress effects of octopus cephalotocin in rats.

Building on expertise Number of papered
through academic
published in SCI-grade
accomplishment
journalClassifcation of advanced methods for evaluatingneurotoxicity

Building on expertise Number of papered
through academic
published in SCI-grade
accomplishment
journal6

BAPTA, a calcium chelator, neuroprotects injured Building on expertise Number of papered
7 neurons in vitro and promotes motor recovery after
through academic
published in SCI-grade
spinal cord transection in vivo
accomplishment
journalDevelopment and validation of dual-cardiotoxicity
evaluation method based on analysis of field Building on expertise Number of papered
8
potential and contractile force of humanthrough academic
published in SCI-grade
iPSC-derived cardiomyocytes / multielectrodeaccomplishment
journalassay platform
4-EA-NBOMe, an amphetamine derivative, alters
glutamatergic synaptic transmission through 5-HT Building on expertise Number of publications
9
receptors on both C57BL/6 mouse andthrough academicor presentations inSprague-Dawley (SD) rats (The Korea Society ofaccomplishment
national workshops
Toxicogenomics and Toxicoproteomics)

In vitro evaluation of new psychoactive substances Building on expertise Number of publications
10 (NPS) by using synaptic channels (Korea Society
or presentations inthrough academicof Toxicogenomics and Toxicoproteomics)
accomplishment
national workshops
In vitro evaluation of new psychoactive substances Building on expertise Number of publications
11 (NPS) by using synaptic channels (Korean Society
or presentations inthrough academicof Toxicology)
accomplishment
national workshops
Establishment of Advanced Multi-organoid Model Building on expertise Number of publications
12 Based on Functional Characteristics (Korea Tissue
through academicor presentations inEngineering and Regenerative Medicine Society)accomplishment
national workshops
99

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

Establishment of advanced multi-organoid model Building on expertise Number of publications
through academic
13 based on functional characteristics (Korean Society
or presentations infor Stem Cell Research)accomplishment
national workshops
Establishment of next-generation
Building on expertise Number of publications
pharmacotocixity using iPS- derived neuron and
14through academicor presentations in
cardiomyocyte (Korean Society of Toxicologic
accomplishment
national workshops
Pathology)
Establishment of next-generation
Building on expertise Number of publications
15 pharmacotocixity using iPS- derived neuron andthrough academicor presentations in
cardiomyocyte (The Organoid Society)accomplishment
national workshops
Evaluation of neurotoxicity and efficacy using in
Building on expertise Number of publications
vitro alternative model: hiPSC-derived mini brain
16
through academicor presentations inwith multi-electrode array(Korean Society foraccomplishment
national workshops
Alternative to Animal Experiments)
Generation of Human iPSCs Derived Heart
Building on expertise Number of publications
17 Organoids Structurally and Functionally Similar tothrough academicor presentations inHeart (The Organoid Society)accomplishment
national workshops
Novel reversible effect of
N-(ortho-methoxybenzyl)-4-Ethylamphetamine(4-EA-NBOMe) on the frequency of excitatory Building on expertise Number of publications
18 postsynaptic currents from rat primary corticalthrough academicor presentations inneurons and mouse medial prefrontal
accomplishment
national workshops
cortex(Korean Society of Toxicology/Korean
Environmental Mutagen Society)
Reversible effect of
N-(ortho-methoxybenzyl)-4-Ethylamphetamine Building on expertise Number of publications
19 (4-EA-NBOMe) on the frequency of excitatory
through academicor presentations inpostsynaptic currents in vitro and ex vivo (Korea
accomplishment
national workshops
Society of Toxicogenomics and Toxicoproteomics)
Special features of
N-(ortho-methoxybenzyl)-4-Ethylamphetamine Building on expertise Number of publications
20 (4-EA-NBOMe) on excitatory postsynaptic current
through academicor presentations infrom rat primary cortical neurons (Korean Society
accomplishment
national workshops
for Brain and Neural Sciences)
SPR (surface plasmon resonance) evaluation
21 method for measuring new narcotics receptor
binding affinity

Improving testing,investigation andresearch capabilities

Number of test method
development

22

iPSC-based method for measuring mitochondria
function

Improving testing,investigation andresearch capabilities

Number of test method
development

23

Method for measuring neuron activation

Improving testing,investigation andresearch capabilities

Number of test method
development

100

Ⅲ. Development & validation of NAMs based on advanced technologies

Title

MFDS Performance Evaluation Standard
Type

Performance Indicators

24 Method for measuring Neurotransmitter release

Improving testing,investigation andresearch capabilities

Number of test method
development

25

Dopamin receptor disruption level measurement
methodImproving testing,investigation andresearch capabilities

Number of test method
development

26

Pre-synapse release evaluation method using
paired pulsed ratio

Improving testing,investigation andresearch capabilities

Number of test method
development

In vitro dependency test method

Improving testing,investigation andresearch capabilities

Number of test method
development

Improving testing,investigation andresearch capabilities

Number of test method
development

27

28 New narcotics test method using synapse channel

101

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major accomplishment
1. Publication: Digital selective transformation and patterning of highly conductive hydrogel
bioelectronics by laser-induced phase separation102

Ⅲ. Development & validation of NAMs based on advanced technologies

2. Publication: Establishment of Neurotoxicity Assessment Using Microelectrode Array (MEA) with
hiPSC-Derived Neurons and Evaluation of New Psychoactive Substances (NPS).

103

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

3. Publication: Acute effects of 4-EA-NBOMe, 3, 4-DCMP, LY-2183240 and AB-CHFUPYCA on the
excitability of rat cortical primary cultured neurons

104

Ⅲ. Development & validation of NAMs based on advanced technologies

4. Publication: An Octopus-derived pepetide with antidiuretic activity in rats

105

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

5. Publication: Anti-stress effects of octopus cephalotocin in rats.

106

Ⅲ. Development & validation of NAMs based on advanced technologies

6. Publication: Classifcation of advanced methods for evaluating neurotoxicity

107

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

7. Publication: BAPTA, a calcium chelator, neuroprotects injured neurons in vitro and promotes motor
recovery after spinal cord transection in vivo108

Ⅲ. Development & validation of NAMs based on advanced technologies

8. Publication: Development and validation of dual-cardiotoxicity evaluation method based on analysis
of field potential and contractile force of human iPSC-derived cardiomyocytes / multielectrode assay
platform

109

Ⅳ. Latest studies on NAMs and their regulatory acceptanceⅣ Latest studies on NAMs and their regulatory acceptance●

The Ministry of Food and Drug Safety (MFDS) has put effort into regulatory acceptanceof NAMs by participating in the development of OECD Test Guidelines and working
groups including OECD Expert Groups, Working Party on Manufactured Nanomaterials(WPMN) and Advisory Group on Emerging Science in Chemical Assessment (AG ESCA).

●

In particular, as the use of nanomaterials with advancement of nanotechnology as
well as the used of chemicals including cosmetic ingredients and medical devices havebeen increasing, MFDS has been working with overseas organizations to perform joint
study on nanomaterials and to revise related test guidelines.

●

MFDS has developed NAMs applicable to medical devices as well as conducted studies
on new methods for regulatory implantation.

●

MFDS has been committed to reducing the use of laboratory animals and increasing
predictivity by, for example, building a system for prediction of the results of druginteraction using bid data in order to reduce adverse effect caused by pharmaceuticals.

113

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes1

Study on development of OECD skin sensitization test method using
nanomaterials

Supervising
division

Toxicological Research Division of NIFDS

Type

Internal Project

Title

Study on enhancing international cooperation and infrastructure for development of toxicity
test methods□ Background for the study●

The OECD constantly publishes and revises Test Guidelines and Guidance Documentsthat reflect advanced technologies and animal welfare to support the mutual acceptanceof data (MAD). Korea has participated in the meetings of OECD expert groups and
WNT to provide inputs for publication and revision of the documents.

●

As the use of nanomaterials is increasing with the development of nanotechnology, a study
that informs the revision of toxicity test methods for evaluation of nanomaterials is necessary.

●

MFDS has performed research on safety assessment of nanomaterials since the late
1990s and produced sufficient toxicity data on nanomaterials by performing target
organ toxicity tests. The paradigm of nanotoxicity research has shifted to developmentof evaluation method using nanomaterials since the mid 2010s, and research keeping
pace with the change is necessary.

●

MFDS has conducted a joint study with the Swiss Federal Office of Public Health (FOPH)
on the properties of nanomaterials in order to revise Test guideline 442D (in vitro
skin sensitization test). The SPSF (Standard Project Submission Form) on the revision
was adopted by the OECD in April, 2019.

●

International joint study on incorporation of nanomaterials properties to skinsensitization test methods was conducted and the draft updated Test Guideline wasprepared to include considerations for toxicity test methods using nanomaterials basedon the study outcome.

□ Study in brief●

Demonstration of scientific basis to update OECD Test Guideline to incorporate testingof nanomaterials.

114

Ⅳ. Latest studies on NAMs and their regulatory acceptance- The draft OECD Test Report (project number 4.133 led by Switzerland) was acceptedby the OECD WNT in April 2023.
- The results we presented was accepted as the scientific basis for the OECD Study Report.

□ Overview of the study outcome●

Major accomplishment: Presenting scientific basis to incorporate testing of manufactured
nanomaterials into OECD Test Guideline and enhancing Korea’s profile in the world
by carrying out international joint study.

●

Main outcome- OECD acceptance: OECD WNT acceptance of the OECD Test Report in April 2023.
- Scientific outcome: Publication of 7 papers in SCI-grade journals and presentationsof 5 posters (awarded as outstanding poster)- Social outcome: Participation in various international conference including OECD
WNT, WPMN, etc.
- Technocal outcome: Monitoring of the skin sensitization tests (OECD TG 442) using
nanomaterials□ Excellence and Advantage●

Exellcence: Establishment of skin sensitization test method for nanomateiral skin
exposure- Risk assessment tests have been conducted using the clinical route of nanomaterial
exposure, but few research has addressed toxicity caused by nanomaterial skin
exposure.
- The international joint study with Swiss FOPH helped establish scientific basis forthe revision of OECD TG to incorporate nanomaterials properties to the skinsensitization test methods in the TG and risk assessment methods for nanomaterial
skin exposure.

●

Advantage: Establishment of scientific basis for acceptance of OECD Test Report- Since the mid 2010s, global paradigm of nanotoxicity research has moved towards
development of nanomaterial assessment methods and many related studies havebeen performed.
115

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- In particular, various studies to develop or revise test methods for nanomaterials
that can by accepted in globally harmonized test guidelines have performed. We
carries out an international joint study with Swiss FOPH to update OECD TG to extend
the applicability of the skin sensitization test methods to nanomaterials.
- The data generated in this study has provided the scientific basis for the approvalof OECD Test Report.

□ Utilization of the outcome and its impact●

Establishment of the major scientific basis for preparation of the Test Report for OECDskin sensitization test methods incorporating nanomaterials properties.
- The international joint study produced scientific and professional data to support
nanomaterials toxicity (skin sensitization) assessment. Based on the data, Test Reportof OECD skin sensitization test methods extending the applicability to nanomaterials
has been prepared. The study outcome is expected to enhance practical use of themethods and have influence related national and global industry and academia.

●

Improvement of the national profile through international cooperation andreinforcement of the infrastructure for toxicity tests- Exchange of regulations and research trend related to safety of nanomaterials, etc.
at international meetings including OECD WNT and WPMN strengthened national
competitiveness in development of nanomaterials safety evaluation methods andinternational standards and improved national profile.

116

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Performance of the study
Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

1

Draft updated TG442D-KeratinoSensTM

Encouragement ofpractical use by policy
improvement, etc.

TG proposal

2

Draft updated TG442Eh-cLAT

Encouragement ofpractical use by policy
improvement, etc.

TG proposal

3

Encouragement ofDraft updated TG442B-LLNA:BrdU-FCM
practical use by policy(skin sensitisation testing of nanomaterials)
improvement, etc.

TG proposal

4

Promotion and35th Annual Meeting of KSOP/KEMS best
Education and promotion
dissemination of researchworkshop posterof research outcome
outcomePromotion and
Education and promotion
5 2020 MFDS best R&D project-1st prize winner dissemination of researchof research outcome
outcome6

7

8

KSOP best workshop poster

Promotion and
Education and promotion
dissemination of researchof research outcome
outcomePromotion and
KSTP best workshop poster-The research of
Education and promotion
toxicity and sensitization potential of
dissemination of researchof research outcome
PEGylated Silver and Gold Nanomaterials
outcome
KSTP best workshop poster

Promotion and
Education and promotion
dissemination of researchof research outcome
outcomePromotion and
Education and promotion
9 2021 MFDS best R&D project-1st prize winner dissemination of researchof research outcome
outcomeSkin sensitisation testing of metal
Building on expertise in
10 nanoparticles (3 test areas, 7 items, and 21 testing, research andcases)
investigation

Monitoring

11

Skin sensitisation testing of nanomaterials (2test areas, 6 items and 19 cases)

Building on expertise intesting, research andinvestigation

Monitoring

12

Skin sensitisation testing of nanomaterials Building on expertise in(OECD TG442D)(1 test areas, 13
testing, research anditems and 13 cases)
investigation

Monitoring

13

Skin sensitisation testing of nanomaterials Building on expertise in(OECD TG442E)(1 test areas, 5testing, research anditems and 5 cases)
investigation

Monitoring

Skin sensitisation testing of nanomaterials Building on expertise in
14(OECD TG442B)(1 test areas, 10
testing, research anditems and 10 cases)
investigation

Monitoring117

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

15

Participation in the 11th OECD EAGMST
Meeting

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

16Participation in the 18th OECD WPMN Meetingand Seminar

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

17Participation in the OECD WNT30 and review
of draft TGs

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

18

Participation in the 14th OECD EAGMST
Meeting

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

19

Participation in the 21st OECD WPMN

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

20

Participation in the OECD WNT33 and review
of draft TGs

Improvement ofinternational
competitivenessInternational exchange
and cooperation (e.g.
signing of MOU, etc.)

Copper and Cobalt Ions Released from Metal
21
Oxide Nanoparticles Trigger Skin Sensitization

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Effect of Pulmonary Inflammation by Surface
Functionalization of Zinc Oxide Nanoparticles

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Evaluation of the Skin Sensitization Potential
23 of Carbon Nanotubes Using Alternative In Vitro
and In Vivo Assays

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Evaluation of the skin sensitization potentialof metal oxide nanoparticles using the
ARE-Nrf2 Luciferase KeratinoSensTM assay

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Flow cytometric evaluation of the potential of
25 metal oxide nanoparticles for skin sensitization
using 5-Bromo-2-deoxyuridine

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

26

Colony-Forming Efficiency Assay to Assess
Nanotoxicity of Graphene Nanomaterials

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

27

Skin Sensitization Evaluation of
Carbon­Based Graphene Nanoplatelets

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

22

24

Six-well plate-based colony-forming efficacy
28 assay and Co-Culture application to assess
toxicity of metal oxide nanoparticles
118

Ⅳ. Latest studies on NAMs and their regulatory acceptance

Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

The Research of Toxicity and Sensitization
Potential of PEGylated Silver and Gold30
Nanomaterials

Building on expertisethrough academic
accomplishment

Publication of papers in
SCO-grade journals

Evaluation of metal nanoparticles on skinsensitization using OECD TG442B

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

Evaluation of the skin sensitisation potential
32 of TiO2 and ZnO nanoparticles using the OECDskin sensitization test guideline

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

Evaluation of nanomaterials by shape
33 difference on skin sensitization using OECD
TG 442B

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

Evaluation of the skin sensitization &34 histopathological analysis by titanium oxide
nanoparticles

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

35

Evaluation of the skin sensitization potential
of Carbon Nanotubes using alternative
methods

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

36

Overview of skin sensitization AOP for titaniumoxide (TiO2) nanoparticles

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

37

Comparison of skin sensitization potential of
metal nanoparticles and metal ions using
OECD TG442B (LLNA: BrdU-FCM)

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

Copper and Cobalt Ions Released from Metal
38
Oxide Nanoparticles Trigger Skin Sensitization

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

Evaluation of the Skin Sensitization Potential
39 of Silica nanoparticles using in vitro and in vivo
assay

Building on expertisethrough academic
accomplishment

Publication orpresentation ininternational workshops

Building on expertisethrough academic
accomplishment

Publication orpresentation in national
workshops

29

31

40

Skin Sensitization Potential and Cellular
ROS-Induced Cytotoxicity of Silica
Nanoparticles

Skin Sensitization Potential and Cellular
ROS-Induced Cytotoxicity of Silica
Nanoparticles

119MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Major accomplishment
21. Publication: Copper and Cobalt Ions Released from Metal Oxide Nanoparticles Trigger Skin Sensitization120

Ⅳ. Latest studies on NAMs and their regulatory acceptance

22. Publication: Effect of Pulmonary Inflammation by Surface Functionalization of Zinc Oxide Nanoparticles

121

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

23. Publication: Evaluation of the Skin Sensitization Potential of Carbon Nanotubes Using Alternative
In Vitro and In Vivo Assays

122

Ⅳ. Latest studies on NAMs and their regulatory acceptance

24. Publication: Evaluation of the skin sensitization potential of metal oxide nanoparticles using the
ARE-Nrf2 Luciferase KeratinoSensTM assay

123MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

25. Publication: Flow cytometric evaluation of the potential of metal oxide nanoparticles for skin sensitization
using 5-Bromo-2-deoxyuridine

124

Ⅳ. Latest studies on NAMs and their regulatory acceptance

26. Publication: Colony-Forming Efficiency Assay to Assess Nanotoxicity of Graphene Nanomaterials

125

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

27. Publication: Skin Sensitization Evaluation of Carbon­Based Graphene Nanoplatelets

126

Ⅳ. Latest studies on NAMs and their regulatory acceptance

28. Publication: Six-well plate-based colony-forming efficacy assay and Co-Culture application toassess toxicity of metal oxide nanoparticles

127

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

29. Publication: Skin Sensitization Potential and Cellular ROS-Induced Cytotoxicity of Silica Nanoparticles

128

Ⅳ. Latest studies on NAMs and their regulatory acceptance

30. Publication: The Research of Toxicity and Sensitization Potential of PEGylated Silver and Gold
Nanomaterials

129

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes2

Development of mitochondria-targeted toxicity evaluation method

Supervising
division

Toxicological Screening and Testing Division of NIFDS

Type

Entrusted project (led by Prof. Kyung-cheol Choi, Chungbuk National University)

Title

Development of mitochondria-targeted toxicity evaluation method (20183MFDS525)□ Background for the study●

Mitochondrial damage causes damages to tissues including cardiac and (or) muscle
tissues that consume a lot of energy or liver tissues that are often exposed topharmaceuticals. In fact, several drugs have been reported to cause adverse effects
on liver, heart and muscle due to mitochondrial toxicity. In this sense, it is necessary
to perform mitochondrial toxicity assay as a screening method in order to assure thesafety of drugs.

□ Study in brief●

Usefulness of mitochondria in development of an alternative model to animal toxicity
testing- Mitochondria are organelles surrounded by double membrane that contain different
kinds of protein and mitochondrial DNA (mtDNA) and play critical role in life anddeath of cells.

●

Development of mitochondria-targeted toxicity assay using cardiac muscle cell line,
mouse embryonic stem cells and kidney cell line
- Test substances that affect cardiac muscle cells, liver and mitochondria were selected.
Then, the substances were applied on cardiac muscle cell line and kidney cell line
to determine mitochondrial toxicity potential by evaluating cell proliferation, active
oxygen generation rate, mitochondrial toxicity and oxygen consumption rate.
- MitoSOXTM dye that enables analysis of mitochondrial peroxide volume and oxidative
stress in cardiac muscle cell line was used to develop and evaluate reproducibilityof the assay.
- Test substances were applied on mouse kidney stem cells and changes inmitochondrial DNA copy number was measured.

130

Ⅳ. Latest studies on NAMs and their regulatory acceptance●Study on mitochondrial-targeted toxicity evaluation method using liver cells and animalmodels- Following application of toxic substances on liver cell line, protein expression of
mitochondrial electron transport chain and oxidative stress were evaluated. The
model cells for evaluation of mitochondrial reactive oxygen species were establishedusing the cell line showing high reproducibility.
- Toxic substances were applied to mouse and liver toxicity index, mitochondrial
membrane potential, reactive oxygen species, protein expression of electrontransport chain and oxidative stress were evaluated.

●

Study on mitochondrial toxicity evaluation using clinical specimen- Non-invasive biomarker for determination of mitochondrial toxicity was identified
using clinical specimen of 17 patients with mitochondrial disease.
- When normal control group and non-alcoholic fatty liver disease patients weredivided by simple steatosis and NASH and compared, reduction in mtDNA copy
number based on occurrence of ALT and diabetes was confirmed.

□ Overview of study outcome●

Major accomplishment: Five mitochondrial toxicity assays for prediction of adverse
effects by chemicals or drugs have been developed, and the study results were publishedand (or) presented in 5 SCI-grade journals and national international workshops.

●

Main outcome- Academic outcome: publication of 5 papers in SCI-grade journals* 「Toxicology in vitro」, 「Toxicologycal Research」, 「Life Sciences」, 「BBA-Molecular Basis of 」
및 「Frantiers in Endocrinology」□ Excellence and advantage●

Excellence: Oxygen consumption rate analysis method was established by evaluating
reactive oxygen generation rate based on mitochondrial activation in target organ cells,
and high reproducibility of the method was confirmed. Correlation between applicationof chemicals and anticancer drugs and mitochondrial toxicity reaction was identified
in in vivo animal models and clinical models.

131

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- There has been no other study that established a Developmental neurotoxicity study
method using embryonic body and analyzed accuracy and transferability of themethod with varioud neurotoxic substances.
●

Advantage: Biomarker was identified from clinical specimen of the patients withmitochondrial diseases□ Utilization of the outcome and its impact●

Technical: The study help improve public health by evaluating mitochondrial toxicity
in chronic disease related to kidney using mouse embryonic stem cell-induced kidneycells, and by establishing mitochondrial-targeted toxicity assay and its scientific basis.

●

Economic and industrial: It is assumed that diabetes and cardiovascular diseases are
induced by mitochondrial damage. Introduction of mitochondrial toxicity assay in drug
development will help reduce social and economic loss.

132

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Performance of the study
Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Publication: Peripheral blood mononuclear cell
Number of papers
1 mitochondrial copy number and adenosine Acamedic accomplisment published in SCI-grade
triphosphate inhibition test in NAFLD
journalPresentation: Peripheral blood mononuclear
cells mitochondrial copy number and2adenosine triphosphate inhibition test in
non-alcoholic fatty liver disease

Building on expertisethrough academic
accomplishment

Publication andpresentation ininternational workshop

Presentation: Peripheral blood mononuclear
cells mitochondrial copy number and3adenosine triphosphate inhibition test in
non-alcoholic fatty liver disease

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshop4

Mitochondrial DNA copy number
measurement method

Establishment of scientific Number of test methodbasis for regulation
development

Publication: Mitoregulin controls
Number of papers
mitochondrial function and stress-adaptation
5
Acamedic accomplisment published in SCI-grade
response during early phase of endoplasmic
journalreticulum stress in breast cancer cells
Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshop

6

Presentation: Monocarboxylate transporter 1
targeting strategy in tamoxifen-resistantbreast cancer cells

7

Mitochondrial membrane potential
Establishment of scientific Number of test methodmeasurement method using human liver
basis for regulation
development
cancer cell line

8

Draft Guideline on mitochondrial-targeted Improvement of regulation
Number of TG proposals
toxicity assay
and utilization in policy

Publication: Effects of anticancer drugs on
Number of papers
the cardiac mitochondrial toxicity and their
9
Acamedic accomplisment published in SCI-grade
underlying mechanisms for novel cardiac
journalprotective strategies
Publication: Establishment of a platform for
Number of papers
measuring mitochondrial oxygen
10
Acamedic accomplisment published in SCI-grade
consumption rate for cardiac mitochondrial
journaltoxicity
Publication: Evaluation of mitochondrial
oxidative toxicity in mammalian
Number of papers
cardiomyocytes by determining the highly
11
Acamedic accomplisment published in SCI-grade
reproducible and reliable increase injournalmitochondrial superoxides after exposure totherapeutic durgs
Presentation: An increase in MitoSOX by
Utilization andLevel of mutual
therapeutic drugs was highly reproducible and12dissemination of the study information exchange forreliable to measure mitochondrial toxicity inoutcometechnology dissemination
mammalian cardiomyocytes
133

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Presentation: Analytical method to assess the
13 oxidative stress in mouse renal stem cell
mitochondria by anticancer chemicals

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshopPresentation: Establishment of evaluation
14 platform for cardiac mitochondrial toxicity
using three cardiomyocyte cell lines

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshopPresentation: Establishment of oxygen
consumption rate as an evaluation platform
15
for mitochondrial toxicity in diverse
cardiomyocytes

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshopPresentation: In vitro oxidative stressmeasuring methods to investigate the16
relationship between mitochondrial toxicity
and kidney injury

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshopPresentation: Methods to measure the17 oxidative stress in mouse kidney stem cell
mitochondria by toxicant

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshop18

Presentation: Novel toxicological method toinvestigate the increased ROS in mouse
kidney stem cell mitochondria by doxorubicin

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshop19

Presentation: Screening for mitochondrial
toxicity in mouse kidney stem cell bymeasuring oxidative stress

Building on expertisethrough academic
accomplishment

Publication andpresentation in national
workshop

Mitochondrial reactive oxygen species
Establishment of scientific Number of test method
20 measurement method using human cardiac
basis for regulation
development
muscle cell line
Mitochondrial reactive oxygen species
Establishment of scientific Number of test method
21 measurement method using mouse kidneybasis for regulation
development
cell line
Mitochondrial oxygen consumption rate
Establishment of scientific Number of test method
22 measurement method using human cardiac
basis for regulation
development
muscle cell line134

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Major accomplishment
1. Publication: Peripheral blood mononuclear cell mitochondrial copy number and adenosine triphosphateinhibition test in NAFLD

135

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

5. Publication: Mitoregulin controls mitochondrial function and stress-adaptation response during earlyphase of endoplasmic reticulum stress in breast cancer cells136

Ⅳ. Latest studies on NAMs and their regulatory acceptance

9. Publication: Effects of anticancer drugs on the cardiac mitochondrial toxicity and their underlying
mechanisms for novel cardiac protective strategies

137

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

10. Publication: Establishment of a platform for measuring mitochondrial oxygen consumption rate
for cardiac mitochondrial toxicity

138

Ⅳ. Latest studies on NAMs and their regulatory acceptance

10. Publication: Establishment of a platform for measuring mitochondrial oxygen consumption rate
for cardiac mitochondrial toxicity

139

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes3

Development of alternative developmental neurotoxicity evaluation technology
using stem cells

Supervising
division

Toxicological Testing and Screening Division of NIFDS

Type

Entrusted Project (led by Prof. Ui-Bae Jung, Chungbuk National University)

Title

Development of alternative developmental neurotoxicity evaluation technology using
stem cells (20183MFDS522)□ Background for the study●

With increasing global interest in animal welfare including OECD, Europe, the U.S.,
etc., test methods that are able to rapidly evaluate toxicity using stem cell gene expression
based on key events of adverse outcome pathway (AOP) have been developed asalternatives to animal testing.

●In order to replace OECD TG426 that requires many laboratory animals, time andcost alternatives that are based on the AOP have been developed and it is considerednecessary to establish technological basis for safety evaluation of developmental
neurotoxicity in Korea.

□ Study in brief●

In this study, an alternative method to animal testing was proposed by investigating
and developing developmental neurotoxicity alternative test method using stem cells(Sox1-GFP) for safety evaluation of pharmaceuticals.

●

Usefulness of stem cells in development of alternatives to animal testing for toxicity
evaluation- Using totipotency stem cells, unlimited number of cells with the identical genetic
background can be obtained, and thus toxicity comparison between similar drugs
or cell reaction comparison under the identical condition and development of highly
efficient screening method are possible.

●

Sox1-GFP stem cell: Sox1 is a gene that plays a critical role in development of central
nerveous system. When Sox1 is expressed, embryonic stem cells are induced toneuroectoderm. Sox1 was used as a marker of neural precursor cell.
- Sox1-GFP stem cells have been derived from Sox1-GFP knock-in reporter mouse140

Ⅳ. Latest studies on NAMs and their regulatory acceptancein which Sox1 genes were replaced by enhanced green fluorescent protein (EGFP).
The cells are characterized by their self-expression of GFP only in the neuroglial
stage.
●

Principle of the method: Developmental neurotoxicity potential is evaluated by measuring
inhibition of differentiation to nerve cells and cell viability following application oftest substances to Sox1-GFP stem cells.

□ Overview of the study outcome●

Major accomplishment: This study produced social and scientific accomplishment.
Development of developmental neurotoxicity assay using stem cells was selected as
one of the best MFDSR&D projects and multiple papers based on the study were publishedin SCI-grade journals.

●

Main outcome- Academic outcome: Publication of 3 papers in SCI-grade journals* 「International Journal of Molecular Sciences」, 「Reproductive Toxicology」, and 「Food andChemical Toxicology」- Award· 2021 MFDS best R&D project· 2020 KSVS Autumn Workshop – best poster award· 2021 KALAS Winter Symposium – best poster award- Development of developmental neurotoxicity assay using Sox1-GFP stem cells□ Excellence and advantage●

Excellence: Development of a method for screening developmental neurotoxic substances
using Sox1-GFP cells that were established by promoting differentiation of mouseembryonic stem cells into neurons- There has been no other study that established developmental neurotoxicity study
method using embryonic body and used difference neurotoxic substances to confirm
accuracy and transferability of the method.

●

Advantage: Developmental neurotoxicity assay using Sox1-GFP can be used tosimultaneously evaluate both neurotoxicity and developmental toxicity.

141

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- Developmental toxicity alternative method in other countries: Embryonic Stem Cell
Test of EURLECVAM and Hand1-Luc EST of JaCVAM- Neurotoxicity alternative methods in other countries: Neurotoxicity assay using
ReNCell CX of EPA●

Public interest: Reduction in use of laboratory animal leads to improvement in animal
welfare- The existing developmental neurotoxicity assay (OECD TG 426) is a large scale animal
experiment that requires use of many laboratory animals. However, developmental
neurotoxicity assay using Sox1-GFP does not use laboratory animals nor involve inbioethical issues.

●

Utilization of the outcome and its impact: Development of developmental neurotoxicity
assay that can replace animal testing- To keep pace with the international changes that pose ban on animal testing, analternative developmental neurotoxicity assay that uses stem cells instead oflaboratory animals has been developed.
- The developed assay can be used in safety evaluation of the pharmaceuticals thathave been unclassified yet.

142

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Performance of the study
Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Presentation: Alternative Developmental
1 neurotoxicity test Based on Sox1-GFP mouseembryonic stem cells

Building on expertisethrough academic
accomplishment

Number of publication andpresentation in national
workshopPresentation: Establishment of a
2 developmental neurotoxicant screening using
Sox1-GFP mouse embyronic stem cells

Building on expertisethrough academic
accomplishment

Number of publication andpresentation in national
workshopPresentation: Establishment of a
3 developmental neurotoxicity test (DNT) using
Sox1-GFP mouse embryonic stem cells

Building on expertisethrough academic
accomplishment

Number of publication andpresentation in national
workshopPresentation: Establishment of a
4 developmental neurotoxicity test using 46C
cells

Building on expertisethrough academic
accomplishment

Number of publication andpresentation in national
workshop5

Presentation: Screening for developmental
neurotoxicity test using 46C cells

Building on expertisethrough academic
accomplishment

Number of publication andpresentation ininternational workshop

6

urturing professional personnel with master’s
Human resource training Human resource training
degree7

Nurturing professional personnel withmaster’s degree

Human resource training Human resource training

8

Nurturing professional personnel withmaster’s degree

Human resource training Human resource training

9

Nurturing professional personnel withmaster’s degree

Human resource training Human resource training

10

MFDS best R&D award

social evaluation

Education and promotion
material about the study
outcome

Publication: Combined Exposure to Diazinon
and Nicotine Exerts a Synergistic Adverse
11
Effect In Vitro and Disrupts Brain Development
and Behaviors In Vivo

Academicaccomplishment

Number of papers
published in SCI-grade
journalPublication: Establishment of a developmental
neurotoxicity test by Sox1-GFP mouseembryonic stem cells

Academicaccomplishment

Number of papers
published in SCI-grade
journalPublication: Pre-validation of an alternative
13 test method for prediction of developmental
neurotoxicity

Academicaccomplishment

Number of papers
published in SCI-grade
journal12143

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Presentation: Development neurotoxicant test
in mouse Sox1-GFP cell

Academicaccomplishment

Number of publication andpresentation in national
workshopPresentation: Establishment of a
15 developmental neurotoxicant screening using
SOX1-GFP mouse embryonic stem cells

Academicaccomplishment

Number of publication andpresentation ininternational workshop

Presentation: Establishment of a
16 developmental neurotoxicant screening using
46C cells

Academicaccomplishment

Number of publication andpresentation in national
workshopPresentation: Perinatal
Octamethylcyclotetrasiloxane exposure to17
maternal mice disrupts brain development andbehavior in offspring miceAcademicaccomplishment

Number of publication andpresentation in national
workshopPresentation: Pre-validation study of
18 alternative developmental neurotoxicity test
using Sox1-GFP cell.

Academicaccomplishment

Number of publication andpresentation ininternational workshop

Presentation: Study for the pre-validation of
19 alternative development neurotoxicity test
using Sox1-GFP cell

Academicaccomplishment

Number of publication andpresentation in national
workshopPresentation: Study for the pre-validation of
20 alternative developmental neurotoxicity test
using Sox1-GFP mouse stem cell

Academicaccomplishment

Number of publication andpresentation in national
workshop2020 KSVS Autumn Workshop – best
workshop poster-Establishment of a21
developmental neurotoxicant screening using
Sox1-GFP mouse embryonic stem cells

social evaluation

Education and promotion
material about the study
outcome2021 KALAS Winter Symposium best poster
award-Establishment of a developmental
neurotoxicant screening using 46C cells

social evaluation

Education and promotion
material about the study
outcome

Preparation of the draft DNT test method using
23
Sox1-GFP stem cells

Establishment ofscientific basis forregulation

Number of TG
development

14

22

144

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Major accomplishment
11. Publication: Combined Exposure to Diazinon and Nicotine Exerts a Synergistic Adverse Effect In
Vitro and Disrupts Brain Development and Behaviors In Vivo

145

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

12. Publication: Establishment of a developmental neurotoxicity test by Sox1-GFP mouse embryonicstem cells146

Ⅳ. Latest studies on NAMs and their regulatory acceptance

13. Publication: Pre-validation of an alternative test method for prediction of developmental
neurotoxicity

147

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes4

Study on evaluation of drug interaction using big data and machine learning

Supervising
Division

Pharmacological Research Division of NIFDS

Type

Entrusted project

Title

Study on evaluation of drug interaction using big data and machine learning(19182MFDS407)□ Background for the study●

Drug interaction can be the cause of negative clinical outcome including increasein occurrence of adverse effects or reduction in drug efficacy.
- It was reported that, of all combination of drugs on the market, about 10% of druginteraction has yet been identified.

●

When approving new drugs, MFDS requires to label as much drug interaction informationas possible by performing as many drug interaction clinical trials as possible.
- Clinical trials demand a lot of time and cost, and a system that is able to predict
drug interaction results using algorithm is needed.

□ Study in brief●

Development of algorithm for prediction of drug interaction using information on drugs
and authorization- Prediction of interaction between drugs, food ingredients and drug metabolizing
enzyme (CYP450, etc.)- Prediction of Korean-specific drug interaction and adverse effects based on gene
information of Koreans●

Establishment of a platform for prediction of drug interaction based on machine learning- Prediction model for predicting effects of drug interaction on absorption, distribution,
metabolism and excretion- Prediction model for predicting drug-induced toxicity and adverse effects caused bydrug interaction- Prediction model for predicting CYP 450 reactions at a molecular level and drug
metabolism derived from genetic differences between Koreans and Westerners

148

Ⅳ. Latest studies on NAMs and their regulatory acceptance●Establishment of big data-based platform for evaluation of drug interaction- Establishment of DM model for prediction of interaction between drugs and foods- Suggestion of combination and alternative drugs that would reduce adverse drug
reactions- Establishment of prediction model for drug metabolism and active metabolic
pathways at a network level based on Korean-specific genetic information- Evaluation of the platform using CDW dig data of medical records of hospitals□ Overview of the study outcome●

Establishment of prediction model of interaction between drugs and between foodingredients- DDIP – NNP (Drug to drug interaction prediction neural network platform) system
has been established.
* Target: regulatory body, pharmaceutical companies developing drugs, clinical experts (e.g.
physicians and pharmacists), etc.
* Where to use

 To predict interaction of new drugs being developed
 To identify and (or) predict interaction between drugs taken by patients in clinicalpractice To predict interaction of drugs that have been developed, but rarely have known
interaction due to lack of clinical evidence

149MFDS NAMs Report: Regulatory Acceptance and Research Outcomes- Prediction of appropriate pharmaceutical and adequate dose volume in Korean basedon drug interaction- Suggestion of combination and alternative drugs that reduce drug adverse effects<Screenshot of suggested drug pairs when drug to drug interaction is searched>- Establishment of prediction model for predicting drug metabolism and active
metabolic pathways at a network level based on Korean-specific genetic information- Evaluation of platform using CDW big data of medical records of hospitals<Providing information on proteins involving in interaction >150

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Excellence and advantage●

Development of a system for prediction of drug interaction based on accumulated
medical big data
- Development of machine learning algorithm can be used as an independent
technology specialized in pharmaceutical sector, and can also be utilized in otherdrug related projects.
* A new technology to generate valuable data by integrating and editing information related todrug interaction has been obtained.

- The drug interaction prediction system has higher accuracy and predictivity as itis built based on medical-related big data accumulated for the past.
* In particular, it can be used as a major part of the AI drug administration proposal system
in conjunction with other algorithms that help precise customization of drug administration whenbuilding prediction and evaluation models that reflect characteristics of Koreans.

□ Utilization of the outcome and its impact●

Providing personalized medication that minimizes adverse effects- The quality of medical services and for the general public has enhanced. This
contributes to improving public health and quality of life, and thereby satisfactionof the people.

●

Medical professionals are able to provide medication-related services more accurately.
- Medical professionals would be constantly exposed to expert knowledge by using
the platform and this can hel reduce the time and cost required for repeatededucation and training.

●

Prioritization of drug interaction information considering the clinical situation can
reduce unnecessary notification.
- The platform can become more trustworthy by the medical professionals. Also, it
can reduce unnecessary fear of adverse effects among the public and correct theunderstanding of drugs in the long term.

151

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes□ Performance of the study
Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

Patent: 10-2022-0119792
1 Pharmacokinetic change prediction device andmethodIntellectual property

Number of patentapplications

Publication: An annotated corpus from
2 biomedical articles to construct a drug-foodinteraction database

Building on Expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

Publication: Machine learning-based
quantitative prediction of drug exposure in
drug-drug interactions using drug label
information

Building on Expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

3152

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Major accomplishment
2. Publication: An annotated corpus from biomedical articles to construct a drug-food interaction database

153

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes

2. Publication: An annotated corpus from biomedical articles to construct a drug-food interaction
database154

Ⅳ. Latest studies on NAMs and their regulatory acceptance5

Study on establishment of big data-based model for prediction of drug
cardiovascular safety

Supervising
Division

Pharmacological Research Division of NIFDS

Type

Entrusted project

Title

Study on establishment of big data-based model for prediction of drug cardiovascularsafety (19182MFDS406)□ Background for the study●

Drug adverse reactions in cardiovascular system are integral part in hazard evaluation,and many drugs have been withdrawn from the market due to their potential to cause
deep vein thrombosis* New drugs applied for approval are evaluated using safety pharmacology test methods●

New drugs have been commercialized after non-clinical and clinical studies in accordancewith international guidelines, but issues related to false negatives or false positives
are persisting.
- Cardiotoxicity evaluation using animal models have limitations including variability
caused by experimental environment and interspecies differences.

□ Study in brief●

Selection of arrhythmia drugs based on big data and development of prediction algorithm- Establishment of clinical big data for prediction of drug safety in cardiovascular system- Development of clinical big data-based algorithm for prediction of cardiovascular safety●

Preparation of non-clinical test method for verification of cardiovascular safety
prediction platform- Establishment and validation of in vitro cardiovascular hazard evaluation model: Multi
electrode array using hiPS-CMs- Validation of in vivo cardiovascular hazard evaluation model: Telemetry using beagle dogs●

Validation of big data-based model for prediction of cardiovascular safety- Validation of prediction rate using non-clincal model for evaluation of cardiovascularhazard155

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes●

Establishment of a single ion channel measuring assay for major channels related to
cardiac action potential●

Obtention of data on evaluation of single channel effect induced by drugs●

Obtention of non-clinical data-based prediction model for deciding QT extension inclinical situation□ Overview of the study outcome●

Establishment of a platform for prediction of effects on clinical ECG using in vitro
single ion channel assay●

Establishment of clinical biological signal big data for prediction of cardiovascular safety- Clinical electrocardiogram data and electronic medical records have been collected
to create database.
* As for standard 12-lead ECG, 1,040,752 ECG data from 447,632 people have been collected.

<Dashboard of Ajou University Hospital in October 2020 showing statistics of patient biological signal collection>●

Establishment of an active cardiovascular risk monitoring system and dashboard basedon clinical big data
- A total opf six tabs* are configured to display overall data collection and provide
guidance and contextual monitoring systems* Dashboard, Tutorial, Standard 12-lead ECG, ICU continuous ECG, Patient specific, andpre-clinical risk evaluation156

Ⅳ. Latest studies on NAMs and their regulatory acceptance<Dashboard>□ Excellence and advantage●

Establishment of clinical biological signal big data for prediction of cardiovascularsafety- By utilizing the data of single cardiac ion channel experiment in non-clinical stage,risk of extending QT interval in clinical stage can be predicted during new drug
development.
* This is expected to reduce cost and complexity of clinical trials by helping set the direction
and scale of the trials●

An active cardiovascular risk monitoring system and dashboard based on clinical big
data- Safe medical environment would be created thanks to early detection of drugs withdeep vein thrombosis risk and timely countermeasures.
* Through commercialization, it can be utilized as a decision support system when physiciansprescribe drugs with cardiac toxicity risks□ Utilization of the outcome and its impact●

Improvement of national health care by enabling monitoring and early screening ofpotential cardiovascular threats caused by drugs prescribed frequently as well as analysisof the causes●

Utilization of a big data-based cardiovascular safety prediction platform during new
drug development that requires a lot of cost157

MFDS NAMs Report: Regulatory Acceptance and Research Outcomes<Example of the use of a clinical data-driven cardiovascular safety prediction model >- Minimizing trial errors caused by interspecies differences, reducing cost for new drug
development and improving the competitiveness of national pharmaceutical industry.

□ Performance of the study
Title

MFDS Performance Evaluation Standards
Type

Performance Indicators

1

Publication: Data-driven drug-induced QT
prolongation surveillance using adverse
reaction signals derived from 12-lead andcontinuous electrocardiogram data

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals

2

Publication: Risk of QT prolongation throughdrug interactions between hydroxychloroquineand concomitant drugs prescribed in real worldpractice

Building on expertisethrough academic
accomplishment

Number of papers
published in SCI-grade
journals3

Publication: Development of a Risk Score for
QT Prolongation in the Intensive Care Unit
Using Time-Series Electrocardiogram Dataand Electronic Medical Records

Building on expertisethrough academic
accomplishment

Number of papers
published in
non-SCI-grade journals

158

Ⅳ. Latest studies on NAMs and their regulatory acceptance□ Major accomplishment
1. Publication: Data-driven drug-induced QT prolongation surveillance using adverse reaction signals
derived from 12-lead and continuous electrocardiogram data

159

MFDS NAMs Report: Regulatory Acceptanceand Research OutcomesIssuedinDecember 2023

Issued by

Director of National Institute of Food and Drug Safety Evaluation(NIFDS), Ministry of Food and Drug Safety (MFDS)

Chief Editor

Jae-Ho Oh, Director of Toxicological Evaluation and Research
Department

E d i t o r s

Yoonsook Lee, Nam-hee Kang, Joo Hwan Kim, Gaae Gil(Toxicological Testing and Screening Division)
Il-Woong Oh, Jin-Hee Less, Tae-Sung Kim (Toxicological Research
Division)
Ki-Kyung Jung, Sung-Hye Park (Parmacological Research Division)
Mi-Ryung Ahn, Kye-Lim Less (Clinical Research Division)
Young-Min Shin, Hye-Jin Cho (Food Safety Risk Assessment
Division)Translator

Minhee Cha (Toxicological Testing and Screening Division)

Cantact us

Toxicological Testing and Screening Division of NIFDS Tel:
043-719-5155 Fax: 043-719-5150

A d d r e s s

National Insititute of Food and Drug Safety at Ministry of Food andDrug Safety
187, Osongsaengmyeong 2-ro, Osong-eup, Heungdeik-gu,
Cheongju-si, Cheungcheongbuk-do, Republic of Korea