Clin Eval 41（4）2014

Translation

Nonclinical data required for clinicalapplication of induced pluripotent
stem cells (iPSCs)-based products─ Critique of Japanese Notifications comparedwith the policies of FDA and EMA ─ ＊Yasuko Kimura 1）
Chieko Kurihara 2）

Hideo Nishimura 1）
Masanori Fukushima 1）

1）Translational Research Informatics Center, Foundation for Biomedical Research and Innovation
2）Molecular Imaging Center, National Institute of Radiological Sciences

Abstract
Clinical development of regenerative medicine using somatic stem cells is making steady progress
toward practical application all over the world. Needless to say, clinical trials of cellular-based products are
regarded as being in the experimental stage in the world and mostly have been conducted under the
Pharmaceutical Affairs Law (PAL). Therefore, their efficacy and safety are rigorously evaluated byregulatory authorities based on quality-assured preclinical and clinical data, aiming at the goal of marketing
authorization.
Currently in Japan, several investigator-initiated regenerative medicine clinical trials under the PAL
have steadily achieved planned progress. On the other hand, “ clinical research of iPSCs (induced
pluripotent stem cells)” outside the control of PAL has been rapidly accelerated toward clinical application.
Considering this situation, we reviewed Japanese regulations related to preclinical assessment ofcellular-based products, comparing with the regulatory policies of the U.S. Food and Drug Administration(FDA) and European Medicines Agency (EMA). We found that Japanese regulations of regenerative
medicine using cellular-based products mainly focus on quality control and manufacturing of cell
preparations, while both the FDA and EMA intensively discuss about preclinical studies of cell preparations
and risk factor examination, apart from the issue of manufacturing.
We conclude that in Japan all the clinical trials of cellular-based products should be conducted under
the control of PAL and that regulatory science concerning preclinical and clinical assessment of suchproducts should be discussed in greater depth based on the examination of FDA/EMA policies.
Key words
regulatory science, induced pluripotent stem cells (iPSCs), cellular-based products, risk based approach,research ethics
Rinsho Hyoka（Clinical Evaluation）2014；41：907−21.

＊ This article is English translation of original Japanese version, published in
395-406．
− 907 −()．2013；41（2）：

臨 床 評 価 41 巻 4 号

2014

future innovative technologies are also expected to

1．Introduction

be subjected to clinical trials as they are developed 1）.

Development of regenerative medicine using

On the other hand, against the background of asomatic stem cells is making steady progress toward

strong desire for the practical use of regenerative

practical application all over the world. As of

medicine using induced pluripotent stem cells

September 2013, 358 stem cell clinical trials have

(iPSCs), aggressive movements pushing “Clinicalbeen registered with ClinicalTrials.gov. In accor-

studies” exempt from the PAL and aimed at clini-dance with the accumulation of clinical trial data,

cal application have become prominent in Japan

our knowledge of human stem cell physiology andwith the enthusiastic support of the media. However,pathology has deepened dramatically. It goes with-there are some unresolved safety issues without saying that in order to use stem cellular-based

iPSCs, including the possibility of

products in medical practice, the efficacy and safety

genicity and the expression of a totally unexpectedshould be assessed and confirmed by strict non-phenotype by undifferentiated cells. Therefore,clinical experimentation and clinical trials undermany researchers both inside and outside Japan are

the Pharmaceutical Affairs Law (PAL), and theexpressing concern over the situation in which the

products should be strictly reviewed and approved

research institute and government in Japan jointly

by the regulatory authorities. As is well known,

continue to push for clinical application without

legitimate clinical trials for regenerative medicine

sufficient assessment and verification of preclini-

under the PAL are now proceeding smoothly incal studies by the regulatory authorities.
Coincidently,

Japanese academia. With the support of thetumori-published a review

Coordination, Support and Training Program foron the tumorigenicity of iPSCs in the August issue

Translational Research and the Network Program(Vol. 19) 2）in 2013. The authors cited a large num-for Accelerating Translational Research by theber of papers, reviewed the risk of tumorigenicity

Ministry of Education, Culture, Sports, Sciencein human pluripotent stem cell (PSC) therapy, andand Technology, four somatic stem cell clinical tri-

discussed how the research should be. In that arti-

als are going on under the PAL (Table 1), andcle, the authors referred to human embryonic stem

Table 1

Regenerative medicine clinical trials using somatic stem cells in Japanese academia
As of August 2013

Product

Classification

Clinical trial

Target disease

StatusAutologous bone marrow stem cells
1．
(CD34+)

Pharmaceuticals

Investigatorsponsored

Severe leg ischemia

PI/IIcompleted

2．Autologous articular cartilage cells

Medical devices

Investigatorsponsored

Knee cartilage

Underway

3．Autologous myoblast sheet

Medical devices

Company

Severe heart failure(adult)Underway

Bone marrow derived autologous
4．
cultured stem cells (MSC)

Pharmaceuticals

Investigatorsponsored

Cerebral infarction

Underway− 908 −

Clin Eval 41（4）2014

cells (ES) clinical trials by Geron and Advancedin November 2012, the Center for Biologics

Cell Technology and the iPSCs clinical trial in

Evaluation and Research (CBER)/OCTGT at FDA

preparation by the RIKEN Center for Developmental

proposed the “FDA Draft Guidance”, which deals

Biology, and described the following conclusion:

with the range of materials and preclinical infor-“Our duty as PSC biologists and clinicians should

mation that serve as the basis for conducting clini-be to thoroughly understand these cells of our own

cal trials aimed at application for approval of cell

creation before we move PSC-based therapies toand gene therapies (Table 2). This draft guidance

the patient bedside.”clarified what the FDA expects from the applicant

In this article, we will discuss the data required
before clinical application of iPSCs can be carried

upon Investigational New Drug Application (IND)
and Biologic License Application 3）.

out in accordance with the scientistʼs conscience,

On the other hand, the notifications on cellular-

responsibility, and honor, with reference to thebased products in Japan began with “Quality anddraft guidance proposed by the Food and Drugsafety assurance of pharmaceuticals manufactured

Administration (FDA), the United States Depart-using human or animal-derived components as raw

ment of Health and Human Services in November

materials” (Notification of Pharmaceutical and2012 (Draft Guidance for Industry: Preclinical

Medical Safety Bureau (PMSB), the Ministry ofAssessment of Investigational Cellular and Gene

Health and Welfare (MHLW); No.1314) 5） on

Therapy Products) (hereafter referred to as “FDA

December 26, 2000, followed by: the notification

Draft Guidance”) 3） and the draft guideline pro-

“Guideline for quality and safety assurance ofposed by the European Medicines Agency (EMA)

pharmaceuticals and medical devices based on

on January 19, 2012 (Draft guideline on the risk-

human autologous/allogeneic cells or tissue” (here-

based approach according to Annex I, part IV ofafter referred to as “Human (autologous) cells” 6）

Directive 2001/83/EC applied to Advanced Ther-and “Human (allogeneic) cells”) 7） in 2008; “How to

apy Medicinal Products) (hereafter referred to ascomplete the application form for ensuring the4）quality and safety of pharmaceuticals and medical“EMA Draft Guideline”) .

devices based on processed cells or tissue” 8） in

2．History of notifications issued
in Japan and FDA guidance2010 (the system of application for verification ofpharmaceuticals from processed cells or tissues
and pharmaceuticals for gene therapy has been

The FDA notifications on cellular-based prod-

abolished in association with the transfer to theucts began with the “Application of current statu-

Pharmaceutical Affairs Consultation on R&D

tory authorities to human somatic cell therapy

Strategies); the notifications on “Guideline on

products and gene therapy products” on Octoberensuring the quality and safety of human autolo-

14, 1993, and the FDA has continually revised andgous/allogeneic somatic stem cells-derived medical

appended the recommendations “to reflect our cur-devices or pharmaceuticals” (hereafter referred torent knowledge gained through advancements in theas “Human (autologous) somatic stem cells” 9） andfield and through experience gained through“Human (allogeneic) somatic stem cells” 10） (revised

OCTGTʼs (Office of Cellular, Tissue, and Gene

from notifications of “Human (autologous) cells” 6）

Therapies) review of CGT (cell and gene therapy)

and “Human (allogeneic) cells” 7）, respectively),

products” (FDA Draft Guidance, Chapter I). Then,“Guideline on ensuring the quality and safety of− 909 −

臨 床 評 価 41 巻 4 号

2014

Table 2

Guidance and notifications concerning cell preparationsin the United States related to this paper

October 1993

Application of current statutory authorities to human somatic cell therapy products andgene therapy products

May 1996

Guidance on applications for products comprised of living autologous cells manipulated exvivo and intended for structural repair or reconstruction

January 1997

Guidance for the submission of chemistry, manufacturing, and controls information andestablishment description for autologous somatic cell therapy products

March 1998

Guidance for Industry: Guidance for human somatic cell therapy and gene therapy

August 2007

Guidance for Industry: Eligibility determination for donors of human cells, tissues, andcellular and tissue-based products

February 2008

Draft Guidance for Industry: Validation of growth-based rapid microbiological methods forsterility testing of cellular and gene therapy products

April 2008

Guidance for FDA Reviewers and Sponsors: Content and review of Chemistry,
Manufacturing, and Control (CMC) information for human somatic cells therapy
Investigational New Drug Applications (INDs)

January 2011

Guidance for Industry: Potency tests for cellular and gene therapy products

November 2012

Draft Guidance for Industry: Preclinical assessment of investigational cellular and genetherapy products

July 2013

Draft Guidance for Industry: Considerations for the design of early-phase clinical trials ofcellular and gene therapy products

human autologous/allogeneic induced pluripotent

medical devices or pharmaceuticals (hereafter

stem (-like) cells-derived medical devices or phar-referred to as “Human ES cells” 13） on September

maceuticals (hereafter referred to as “Human

7, 2012 (Table 3). Although these notifications do(autologous) iPSCs”

11）

and “Human (allogeneic)

contain chapters describing nonclinical safety tests,, and “Guideline on ensuring the quality

most of the chapters are on the manufacture andand safety of human embryonic stem cells-derived

quality control of cellular-based products. As noti-

iPSCs”)

12）

Table 3

Laws and notifications concerning regenerative medicine in Japan related to this paper

December 26, 2000

Quality and safety assurance of pharmaceuticals manufactured using human or animalderived components as raw materials (1314 notification)

February 8 and
September 12, 2008

Guidelines for quality and safety assurance of pharmaceuticals and medical devices
based on human autologous/allogeneic cells or tissues

April 20, 2010

How to complete the application form for ensuring the quality and safety of pharmaceuticals and medical devices based on cells or tissue (abolished on July 1, 2011 because ofshift to the Pharmaceutical Affairs Consultation on R&D Strategies)

September 7, 2012

Guidelines on ensuring the quality and safety of human autologous/allogeneic somatic
stem cells-derived medical devices or pharmaceuticals
Also guidelines on human autologous/allogeneic iPS (-like) cells, and human ES cells

May 10, 2013

Act on the general promotion of measures to enable people to receive regenerative
medicine rapidly and safely

May 24, 2013

Bill on safety assurance of regenerative medicine (under Diet deliberation)− 910 −

Clin Eval 41（4）2014

fications leading to the conduct of regulatory sci-

3．Summary of “FDA Draft
Guidance” on the potential riskof stem cellular-based products

ence, however, in Japan the description of the
preclinical studies that should be conducted before
clinical trials and the application for marketing
approval is poor in terms of the type of risk factors
listed and the details explained, and the notifica-“FDA Draft Guidance” states that “Stem cell-tions are nowhere near the content of “FDA Draft

derived products are characterized by a variable

Guidance”.

capacity for self-renewing replication throughThe regulatory authorities should ask for a strict

cycles of cell division and the capacity for differ-evaluation based on the highest level of science

entiation into a variety of cell types with special-available at that time. This is the reason why theized properties/functions. Such differentiation and

FDA has prepared “FDA Draft Guidance” and is

replication are primarily controlled by the physio-

asking for public comments. It is the national policy

logic milieu of the host in which the cells resideof Japan to be a science and technology-oriented

followingnation and medical innovations are the basis on

ination of a differentiated CT (cell therapy) prod-which to enhance this national strength. It is theuct with undifferentiated stem cells or incompletely

breadth and depth of basic science that drives thedifferentiated progenitor/precursor cells posescreation of innovations. Innovation cannot be pro-potential safety concerns,” (FDA Draft Guidance,

moted by relaxing regulations. Rather, regulations

Chapter IV.A.1) and points out that “Conditions

have been tightened in the U.S./E.U. because theyfound within the local microenvironment into which

are aiming for the highest level of science. In con-the cells are placed are likely to have an impact on

trast, against the background of the recent rise in

the safety and/or bioactivity of the CT product.

expectations for regenerative medicine using

Given the biological attributes of some CT prod-

iPSCs, clinical application is being promoted with-ucts, the potential for ectopic expression in target

out sufficient risk assessment in Japan. This isand non-target tissues also exists. Depending on

clearly inconsistent with worldwide trends in state-

their differentiation status and the extent of manip-of-the-art science.

ulation the cells undergo prior toadministration. Similarly, contam-

adminis-In this article, we will compare, and discuss thetration, parameters such as cell morphology,

details of the regulations on cellular-based prod-

phenotype, and level of differentiation following

ucts by FDA, EMA, and Japan based on the FDA

administration should be assessed in the animal

Draft Guidance and the EMA Draft Guideline. We

studies” (FDA Draft Guidance, Chapter IV.E.3). In

demand the abolition of the five notifications

addition, “FDA Draft Guidance” states that func-

including “Human (autologous) iPSCs” and thetionally differentiated tissue-derived CT products

release of notifications on the preclinical evalua-“may retain some cellular characteristics of theirtion of cellular-based products in reference totissue of origin. Additionally, their characteristics“FDA Draft Guidance.”

may change afteradministration, based on

numerous specific extracellular cues.” (FDA Draft
Guidance, Chapter IV.A.2) Based on these perspectives, “FDA Draft Guidance” refers to the risk
factors of cellular-based products: 1. Administration− 911 −

臨 床 評 価 41 巻 4 号

2014site reactions, 2. Potential inflammatory response(EMA Draft Guideline, Section4.3).

in target and/or non-target tissues, 3. Host immune

1st step: To identify risks associated with the

response to the cells, 4. Migration from the site ofclinical use of the Advanced Therapy
Medicinal Product (ATMP)

administration, 5. Potential to differentiate into annd

2 step: To identify product specific risk factors

unintended/inappropriate cell type (ectopic tissue

contributing to each identified risk

formation), 6. Unregulated/dysregulated proliferardtion of the cells within the host, and 7. Potential

3 step: To map the relevant data for each iden-

tumorigenicity. Furthermore, in the case of using

tified risk factors against each of theidentified risks

transduced cells or vectors, as it should bethaddressed before beginning clinical trial , aberrant

4 step: To conclude on the risk factor ‒ risk

localization to non-target cells/tissues, inappropri-

relationships (EMA Draft Guideline,
Chapter 4.3)

ate immune activation or suppression, Phenotype/activation state of target cell(s), and potential for

The guideline addresses risk-based approaches

germline transmission (FDA Draft Guidance,

to ATMPs from a broad perspective and meticu-

Chapter IV.D, V.D.1).

lously illustrating by examples for matrices associ-In conclusion, “FDA Draft Guidance” states “theated between risk factors and risks of ATMPs such

adequacy of any specific preclinical study or pro-as tumor formation, unwanted immunogenicity,

gram will depend on the specific study design, sub-treatment failure, disease transmission, unwanted

sequent implementation, and on the resulting data.

tissue formation, unintended alteration of thera-

Accordingly, it is important to submit a compre-

peutic gene expression, unintended alteration ofhensive preclinical assessment in the IND.” (FDA

cell homeostasis, unwanted targeting of cells/

Draft Guidance, Chapter VII)

organs, and toxicity (EMA Draft Guideline, Chapter
4.2, Annex 1-3).

4．“EMA Draft Guideline”
advancing “Risk-based approach”

5．Avoidance of responsibility inthe iPSCs notifications in Japan

In the “EMA Draft Guideline” 4）, “Risk-based
approach” is defined as a strategy aiming to deter-

The chapter entitled “Nonclinical safety tests” inmine the extent of quality, nonclinical and clinicalboth of the “Human (autologous) iPSCs” anddata to be included in the Marketing Authorisation“Human (allogeneic) iPSCs” notifications in Japan

Application, in accordance with the scientificstates that “Regarding the safety-related matters

guidelines relating to the quality, safety and effi-

whose evaluation is considered necessary because

cacy of medicinal products and to justify any devia-of the product characteristics and application method,tion from the technical requirements as defined in

tests should be conducted within scientific ratio-

Annex I, part IV of Directive 2001/83/EC

14）

. In

nality if technically possible” and encourages the

addition, “EMA draft guideline” said that “It isassessment of the potential risk of iPSCs-based

important to appreciate that the risk-based approachproducts. It also states that “If there is a possibil-

profiles each risk inherent to the product and not

ity of tumorigenesis and carcinogenesis, the valid-

the risk of a product as whole.”

ity and rationality of the use should be explained

The methodology of risk profiling is follows

taking the relevance to the expected efficacy into

− 912 −

Clin Eval 41（4）2014

consideration” (Chapter 4-6) and “Regarding thephysical and mental status of patients caused bypatientsʼ risk due to the tumorigenicity of the end

medical intervention. Obtaining informed consent

product, evaluation should be conducted in a rea-cannot be exempted of this responsibility. It is thesonable manner taking into consideration the bal-consensus of medical jurisprudence that informed

ance with the benefits for the patient of treatingconsent of the patient should not be regarded as thethe target diseases” (Chapter 4-6). In addition, it iswaiver of liability from the possibly-illegal experi-

described in “Introduction 2” that “It is important

mental intervention of which efficacy and safety

to evaluate the product taking into consideration

have not been established. These notifications are,the degree of risks of the ʻunknown risksʼ that still

so to speak, a shift of responsibility from regula-remain after the productʼs anticipated risks havetory authorities to physician-patient relationship.

been excluded using all current scientific and tech-On the other hand, the FDA plays a social respon-

nological means and the scientific validity has been

sibility by practicing faithfully conducts of regula-made clear, and the ʻRisks that may be posed bytory science.

losing the chance of a new treatmentʼ in a patient

6．Logical and ethical problems in
the notifications of Japan

who has a serious and life-threatening disease, adisease that significantly impairs bodily function,
or a disease that significantly impairs QOL bycompromising bodily function and morphology to a

iPSCs are typically derived by reprogramming

certain degree, but who cannot overcome the dis-of somatic cells and are these new type of stemease because of the limitations of existing thera-cells are different from natural stem cells. Extreme

pies, and having the perspective of leaving thecare including an assessment of safety is required

decision to the patientʼs right of self-determination

for their clinical application. We regard it criti-

after all this information has been disclosed; i.e. itcally dangerous that Japanese researchers areis important to evaluate the product after disclo-going to initiate clinical research without prepar-

sure of the information on the risks and expected

ing sufficient nonclinical data for risk assessment

benefits and from the perspective that patientsto justify their administration of iPSCs-based

should decide whether or not to participate in a

products to human. The researchers seem to watch

clinical trial.”

the balance between the risks of these products

Notifications of “Human (autologous) iPSCs” andwhich “possibly causes tumorigenesis and carcino-“Human (allogeneic) iPSCs” in 2012 state that thegenesis to the patients” and the “risks of patientsrisks of using cell products could be relativized to

who may lose the chance of access to a new treat-

the benefits and, after this has been explained, thement” and seem to leave the decision to the patientʼs

decision is left to the patientʼs right of self-deter-

right of self-determination after explanation of themination. That is to say that the strict scientificrisk of the products. This kind of thought contra-

assessment required for the minimization of risks

venes the spirit of the Declaration of Helsinki,

was abandoned and the responsibility of risk assess-which requires the “special protection of vulnera-

ment seems to be shifted to physicians andble groups” in the 2013 revision draft 15）. Such apatients.

thought also contradicts the Medical Care Law

It is obvious that physicians have responsibilities

requesting delivery of “qualified and appropriate”

to assess and predict the adverse events affecting

medicine. The researchers say about the chance of− 913 −

臨 床 評 価 41 巻 4 号

2014

patients to access a “new” treatment, however, theincluded as a usage if it can be reasonably explained“new” treatment itself may pose an unexpected riskthat systemic administration is beneficial to treatedto the patients. It could not be achieved until evalu-

patients in terms of efficacy. For example, taking

ation by clinical trials has been completed that themeasures to minimization of the distribution tochance of “new” treatment becomes the chance of

places other than the organ to which engraftment is“useful” treatment: the chance of a “new” treatment

expected is assumed to be a reasonable method.

cannot be replaced with the chance of a “useful”

Furthermore, even if ectopic engraftment occurs,

treatment. If a patient does not receive a “newthe usage may be acceptable provided that no dis-treatment” with an unknown risk, the patient will

advantage (adverse effect on vital functions) tojust follow the natural course. We must say that ittreated patients emerges. Bone formation of thegoes against logic to balance the natural course

relevant cells after ectopic engraftment in theagainst risks such as “possible tumorigenesis andheart and initiation of arrhythmia are assumed tocarcinogenesis.”be examples of the disadvantages of ectopic dif-

“Therapeutic misconception” (physiciansʼ mis-

ferentiation” (Chapter 6-2).

conception that treatment will always be adequate)

This chapter indicates that a usage in which

is a well-known concept in bioethical discussion

ectopic engraftment occurs by systemic administra-but, in Japan, it is the regulatory authorities thattion may be acceptable if disadvantages such as

are promoting this misconception. The 2013 draft

arrhythmia to treated patients do not emerge.

revision of the Declaration of Helsinki 15） included

However, this is an issue that cannot be discussed

a new provision stating that risk minimization andwithout presentation of the evidence supporting themonitoring are the ethical duty of medical research-

usage even though systemic administration clearly

ers. Moreover, the previous declaration had

results in ectopic engraftment at unexpected site.

approved the use of unproven therapy for rescuing

Even though it is not easy to determine whether orsevere patients provided that a research plan was

not an ectopic engraftment is disadvantageous tosubsequently prepared, but in the present draft

treated patients, their benefit/risk balance isrevision the request to prepare a research plan fol-determined by physicians, who perform the medical

lowing use in one patient is stressed. Although theprocedures, leading to the possibility that they will

declaration is the ethical norm for individual physi-

make self-righteous decisions. How in the world

cians, approval by the government of the repeatedcan physicians and patients determine the unknown

conduct of an unapproved method would clearlyrisks? At present, there is no official guideline forcontradict international ethical standards.

the evaluation of tumorigenesis related to CT
products and their derived cells. Under these cir-

7．The physical risks of systemic
administration

cumstances, the first priority should be the patientʼssafety and ectopic engraftment should not be permitted. This is the duty of those who take medical

The chapter entitled “kinetics” in thepractices.

“Human (autologous) iPSCs” and “Human (allogeneic) iPSCs” notifications states that “local administration is preferred to systemic administration”(Chapter 6-2) and “systemic administration can be− 914 −

Clin Eval 41（4）2014(autologous) iPSCs” notification.

8．Defects of approach in the
notification about the iPSCs
in JapanIn these five notifications, it is described in thesame content in common to chapters of “Nonclinicalsafety tests” and “kinetics”. The first place,is not to be described in the same content, the notiThe FDA Draft Guidance and EMA Draft

fications of “Human (autologous) cells” and “Human

Guideline starts with the characteristics of cellu-(autologous) iPSCs”, but should be discussed inlar-based products and shows the points of atten-

difference position.

tion for the evaluation of pre-clinical studies taking

It is evident that these notifications are not writ-into account the risks inherent in such products. In

ten from the perspective of a risk-based approachcontrast, the “Human (autologous) iPSCs” andthat asks for strict evaluation of each cellular-“Human (allogeneic) iPSCs” notifications in Japan

based product.

focus exclusively on efficacy regarding the evalua-

Cellular-based products are totally novel andtion of the data of nonclinical studies and toxicity

much about them is still unknown, but the current

is evaluated only from the viewpoint of efficacy.

science is immature. Therefore, in terms of meth-

On the other hand, the FDA Draft Guidance andodology, a risk-based approach should be adopted,

EMA Draft Guideline have detected and identified

making full use of all current scientific knowledge,as many risk factors as possible and have had thor-

and the guidelines/notifications for cellular-basedoughevaluation.

products should recommend/make obligatory care-

Application of novel or unknown treatments in

ful evaluation based on the risks inherent in using

humans requires careful investigation using a risk-

cells.

discussion

based

on

strictbased approach. Data required for the marketing

9．The future of regulatory
science in Japan

approval should not be thoughtlessly collected, butnecessary data concerning the inherent risks ofeach cellular-based product should be collected.
This is a thoroughly risk-based approach, which isConsidering that cell phenotype can change justessentially different from the method of benefit/

as a result of passage culture whether temporarilyrisk assessment. One needs to be cautious whenor persistently a gene is transfected to the cell, theusing the latter method because one may lose theguidelines for iPSCs in Japan clearly lack the mul-essence of the issue.

tifaceted approach of practical risk evaluation likeBy the way, the approach to thinking about toxic-that in the FDA Draft Guidance and EMA Draft

ity relative to efficacy in the “nonclinical safety

Guideline because of an overexpectation of thetest” (Chapter 4-6) and the approach to ectopic

efficacy of iPSCs. We cannot help having legiti-

engraftment in “

kinetics” (Chapter 6-2) inmate questions and profound concerns on this issue.

the “Human (autologous) iPSCs” and “Human (allo-

With respect to the methodology for the regulatory

geneic) iPSCs” notifications were absent in thescience of cellular-based products, the only alter-“1314 notification” in 2000, “Human (autologous)

native should be detecting/identifying risk factors

cells” and “Human (allogeneic) cells” notifications

inherent in the relevant cellular-based products

in 2008. Those were described for the first time inand solving the issues one by one from the stand-the five notifications in 2012, such as the “Humanpoint of a risk-based approach as performed by− 915 −

臨 床 評 価 41 巻 4 号

2014

occur, the validity and rationality of the use should

FDA Draft Guidance and EMA Draft Guideline.
Regarding the issue of tumorigenicity, because

be explained taking the relevance to the expected“There is currently no scientific consensus regard-

efficacy into consideration” (Chapter 4-6). Hereing the selection of the most relevant animal models

also, the discussion on toxicity is replaced withto evaluate tumorigenic potential or the ability ofthat on efficacy, and the faithful pursuit of regula-current animal models to predict clinical outcome”

tory science is abandoned. If tumorigenesis or car-

(FDA Draft Guidance, Chapter IV.E.4), the evalu-

cinogenesis is a possibility, clinical trials using

ation should be conducted even more carefully.

such products should be abandoned and it is“FDA Draft Guidance” points out that, especially

improper to discuss a benefit/risk relationshipwhen associated with gene transfer, “Prolonged

with reference to efficacy. If a possibility of tum-expression of transgenes such as growth factors,

origenesis or carcinogenesis arises in a nonclinicalgrowth factor receptors, or immunomodulatory

study, the regulatory authorities should at least

agents, may be associated with long-term risks due

ask for submission of data that can disprove car-to unregulated cell growth, malignant transforma-

cinogenesis, with a valid test system and a highlytion, autoimmune reactions to self-antigens, alteredreliable method such as GLP (Good Laboratory

expression of the hostʼs genes, or other unantici-

Practice), and evaluate the data; we believe thatpated adverse effects. The conduct of long-term

this is proper conduct of regulatory science and thepreclinical studies should be considered to evaluate

duty of regulatory authorities.

these concerns” (FDA Draft Guidance, Chapter
V.D.3).

With respect to this concern, the February 28,
2013 issue (Vol. 494) of

16）

cited a commentby the chief scientific officer at Advanced Cell

10．Tumorigenicity and long-term
toxicity tests

Technology, “I cannot imagine any regulatory
agency permitting such a trial without years ofextensive pre-clinical testing,” regarding the start

The “FDA Draft Guidance” states that there isof a clinical trial on Takahashiʼs iPS.

currently no scientific consensus regarding the

11．Serious problems of the Billon safety assurance ofregenerative medicine in Japan

most relevant animal models to evaluate the tumorigenic potential of CT products (FDA Draft
Guidance, Chapter IV.E.4). However, it also statesthat prolonged expression of transgenes may be
associated with long-term risks, and thus the con-

As is evident from the difference in the regula-duct of long-term preclinical studies should be con-tions for cellular-based products in the U.S./E.U.

sidered to evaluate these concerns (FDA Draft

and Japan, we are bound to say that the safety-

Guidance, Chapter V.D.3).

related items in the notifications on the develop-

On the other hand, the “Human (autologous)

ment of cellular-based products in Japan are

iPSCs” and “Human (allogeneic) iPSCs” notifica-

extremely sloppy compared with those in the U.S./

tions state that the possibility of tumorigenesis andE.U.. Furthermore, the “Act on the general promo-

carcinogenesis should be assessed and discussed

tion of measures to enable people to receive

using appropriate animal models and that “If it isregenerative medicine rapidly and safely” was pro-possible for tumorigenesis and carcinogenesis tomulgated on May 10, 2013 in Japan and the “Bill on− 916 −

Clin Eval 41（4）2014

ensuring the safety of regenerative medicine” wasU.S., leading to the proposal of consumer rights

submitted to the Diet on May 24, aiming to ease(the right to safety, the right to be informed, theregulations in order to create innovations in theright to be heard, and the right to choose) by

field of regenerative medicine. We have addressed

President John F. Kennedy. Human society started

many serious concerns about these subjects

17）

down the path toward patient-based medicine by.

We must venture to question the abnormality inadopting these rights for patients who receive med-

Japan that the first-in-human study is approved toical treatment. A year later, the GMP regulation,

be conducted as a “clinical study” exempts from the

IND regulation, and regulations on monitoring

PAL. “In Focus” in the February 28, 2013 issue

pharmaceuticals came into effect, and this can be(Vol. 494) ofalso mentioned that the clinicalinterpreted as the completion of the organization of

trial of Takahashiʼs iPSCs is a clinical trial that,the implementation system for regulatory sciencein “Japanʼs somewhat confusing system,” cannot bethat we now use in the modern world. In Japan, theused for the application for approval 16）. If atten-

Ministry of Health & Welfare enforced the former

tion be paid to human ethics, the results of non-

GCP in 1990, and the new GCP ordinance based onclinical safety tests should be finalized based on a

the ICH-GCP, the global standard, was enforced

risk-based approach under the PAL and a clinicalcompletely eight years later in 1998, 36 years

trial based on GCP (Good Clinical Practice) should

behind the U.S. Finally, medical administration

be conducted. The problem lies with the fact that abased on scientific evidence had gone into action.

“clinical trial” exempt from the PAL is possible.

Moreover, in response to the Creutzfeldt-Jakob
disease and HIV- contaminated blood scandals in

12．Origin and development ofregulatory sciencethe 1990ʼs, the laws and regulations on the engraftment and formulation of human-derived cells andtissues were enacted rapidly in the U.S./E.U. andWhen human beings utilize science as technology,

so on in the early 21st century. In Japan, the “1314

it often happens that a technological defect brings

notification,” 5）in which consent requirements wereabout an adverse effect. To minimize this risk, theincluded with a focus on manufacturing control

advantages and disadvantages of the relevant tech-

exclusively for cases with the purpose of applica-

nology need to be fully evaluated in advance.

tion for marketing approval, was released and theRegulatory science has the duty to control by laws

subsequent regulations were introduced based on

and regulations the use and spread of such technol-

this notification. The direction on human tissues

ogy.

and cells in the E.U. 18） and the regulations on the

The origin of regulatory science goes back to thehuman cellular and tissue-based products in the

Kefauver-Harris Drug Amendments in the U.S. in

U.S. 19, 20）have comprehensively organized a system

1962. These amendments stated explicitly the legal

for registration and inspection of the bank andframework of modern regulatory science, such as

manufacturing sites of human tissues and cells,

safety assurance/premarket proof of efficacy ofwhether or not they are intended for application

pharmaceuticals, report of GMP (Good Manufac-

for approval, from the perspective firstly of theturing Practice) and adverse reactions, andresponse to the ethical issues of using the human

informed consent. At that time, the movement tobody commercially as a resource and secondly ofprotect consumer rights had become strong in thesafety assurance in clinical application. By these− 917 −

臨 床 評 価 41 巻 4 号

2014

regulations, the system for securing traceability

conscience and humanity possible at any given time

was established while ensuring protection forand the strictness must be controlled and assured

donors of human materials. The guidance for cellu-

by laws. Despite this, the leading of regulations inlar-based products by the FDA and EMA, which

the easy direction, with the aim of promoting inno-

was organized under the comprehensive regulatory

vations in health and safety in peopleʼs lives andsystem that segments and integrates issues specificthe environment may lead to a collapse of science.

to each cellular and tissue-based product and highly

Regulatory science can be properly implemented

processed product, is a result of in-depth assess-

only by means of laws and regulations. This isments of not only manufacturing control but also

because current science is intrinsically immature,

preclinical safety tests specific to cellular-based

and thus the highest level of quality demanded by

3, 21）

ismodern society needs to be pursued thoroughly andbased on the concept of collecting additive preclin-

continuously for technical development. Delivering

ical data while monitoring clinical reactions andpatients a product for which the quality control andsearching thoroughly for information both on safety

the reliability of the efficacy and safety data can-and the characteristics of products, and shapes the

not be assured can by no means be regarded as

basis of the life cycle management after marketing

medicine. Such behavior is inhuman and non-scien-

approval. In Japan, corporate toxicologists havetific. Patients of course do not want to be provided

products. In particular, the FDA guidance

22）

and

with “medicine” that does not assure efficacy andS6 23）purely from the viewpoint of what safety data

safety, and we strongly make an accusation thatare required in each step toward the marketing

medical ethics is totally ignored in such “medi-

approval of chemically-synthesized products, butcine.”

trained themselves to comply with ICH-M3

the clinical trials on human stem cells and gene

13．Conclusion

therapy have been placed outside the regulation ofpharmaceutical affairs and have been regulated byadministrative guidelines. Accordingly, we have

To be a science and technology-oriented nation is

failed to create an environment in which knowledge

the national policy of Japan and medical innova-of the biochemistry, pharmacology, toxicology,

tions are the basis for enhancing this national

pharmacokinetics, pharmaceutics, and analyticalstrength. As a measure to create innovations in thescience of human cellular-based products is accu-

regenerative medicine field, a bill on safety assur-

mulated and integrated at regulatory agencies andance of regenerative medicine was submitted to theacademia. The bill on safety assurance of regenera-

Diet in May 2013. We can appreciate the points

tive medicine and iPSCs notifications make very

that all regenerative medicines including medical

apparent the situation in Japan whereby research-treatment at oneʼs own expense must be notified

ers have been getting ahead of themselves by going

and that the violation of regulations and directions

with the clinical application of iPSCs without fill-is subject to penalties such as imprisonment anding in these gaps between itself and the U.S./E.U.

punishment depending on the details. However, theRegulatory science has the characteristic of hav-fact is that the bill not only permits the conduct ofing a direct stake in business activity. Therefore,

regenerative medicine exempt from the PAL but

regulatory science is a type of science that calls

also enables marketing of unapproved regenerative

for the highest level of strictness guided by oneʼs

products after neatly shifting the responsibility to− 918 −

Clin Eval 41（4）2014

physicians by legally defining the delivery of regen19）

using human stem cells in Japan, which gave the. Itgreen light for iPSCs clinical trials, bears grave

is naive to think that innovations will be promoted

responsibility. To begin with, considering that suchby easing regulations. The basis of the creation of

a “clinical trial” is exempt from the PAL and isinnovation is the power of science, and the U.S./

based on the “Guidelines for clinical researches

E.U. has recently strengthened the regulations forusing human stem cells,” 24） which has little legal

regenerative medicine just because they are seek-basis, the problem lies in the fact that the review

ing for stronger and more precise science.

committee is referred to as a regulatory author-

erative medicine as a part of medical practice

The principle of science in the modern world isity.

to “conduct science by statute and revise statute by

Now that we should be aware that we alreadythe progress of science.” It is stated in the preface

have been severely criticized from internationalof the PAL that “the aim is to improve health andcommunity of science, we are obligated to accept

hygiene by implementing necessary regulations to

the fact that as a matter-of-course we should

assure the quality, efficacy and safety of pharma-develop not only iPSCs but also all stem cellular-

ceuticals, quasi-drugs products, cosmetics, andbased products, under the framework of PAL, withmedical devices and by taking measures for the

rigorous quality assurance and strict assessment ofregulation of designated drugs as well as by taking

safety and efficacy.

necessary measures to promote the research andReferencesdevelopment of pharmaceuticals and medical devices
that are in particular clinical need. In disregard ofthis law, the efficacy and safety of pharmaceuticals
and medical devices cannot be evaluated, and muchless can reliability of them be assured. Developmentof pharmaceuticals exempt from the PAL, which is
harmonized internationally, can hardly be accepted1）Fukushima M．
［Present status & scope of innovationin the academic sector ─ Where are we now and whereshould we go? ─］．

．

2013；41（1）：151-66．Japanese．
2）Lee AS，Tang C，Rao MS，Weissman IL，Wu JC．
Tumorigenicity as a clinical hurdle for pluripotent

by the world. Therefore, the “Human (autologous)stem cell therapies．

iPSCs” and “Human (allogeneic) iPSCs” notifica-

998-1004．

．2013 Aug；19（8）：tions and the bill on regenerative medicine under3）U.S. Department of Health and Human Services, Food

Diet deliberation only inhibit the creation of inno-

and Drug Administration (FDA)，Center for Biolog-

vation, in contrast to the initial purpose.

ics Evaluation and Research (CBER)．Guidance forWith reference to the start of a clinical trial
using Takahashiʼs iPS, the February 28, 2013
issue (Vol. 494) of

16）

cited a comment on the

Industry: Preclinical assessment of investigational
cellular and gene therapy products［draft guidance］．
November 2012．
4）European Medicines Agency (EMA)，Committee forinsufficient regulations in Japan by the chief scien-

Advanced Therapies (CAT)．Draft guideline on thetific officer of Advanced Cell Technology, “I can-risk-based approach according to Annex Ⅰ , part Ⅳ of

not imagine any regulatory agency permitting such

Directive 2001/83/EC applied to Advanced Therapy

a trial without years of extensive pre-clinical test-

Medicinal Products［draft］．19 January 2012．EMA/

ing”. To be singled out like this by

is nothing

but a disgrace for the commonwealth of science inJapan. The review committee for clinical researcher− 919 −

CAT/CPWP/686637/2011．
5）Pharmaceutical and Medical Safety Bureau, Ministryof Health and Welfare．Quality and safety assur-

臨 床 評 価 41 巻 4 号

2014
cal devices or pharmaceuticals．September 7, 2012

ance of pharmaceuticals manufactured using humanYakushoku-hatsu No. 0907-5．

or animal-derived components as raw materials．
December 26, 2000

13）Pharmaceutical and Food Safety Bureau, Ministry

Iyaku-hatsu No. 1314．

6）Pharmaceutical and Food Safety Bureau, Ministryof Health, Labour and Welfare．Guideline on ensur-of Health, Labour and Welfare．Guideline for qual-ing the quality and safety of human Embryonic Stem

ity and safety assurance of pharmaceuticals andcells-derived medical devices or pharmaceuticals．
September 7, 2012

medical devices based on human autologous cells or
tissue．February 8, 2008

Yakushoku-hatsu No.

Yakushoku-hatsu No. 0907-6．

14）Commission Directive 2003/63/EC of 25 June 2003;
amending Directive 2001/83/EC of the European

0208003．
7）Pharmaceutical and Food Safety Bureau, Ministry

Parliament and of the Council on the Communityof Health, Labour and Welfare．Guideline for qual-

code relating to medicinal products for human use．

ity and safety assurance of pharmaceuticals and．2006 Jun 27；
L159：46-94．

medical devices based on human allogeneic cells or
tissues．September 12, 2008

Yakushoku-hatsu No.

15）World Medical Association Declaration of Helsinki
─ Ethical Principles for Medical Research Involving

0912006．
8）Pharmaceutical and Food Safety Bureau / Evalua-

Human Subjects．WMA Declaration of Helsinkition and Licensing Division, Ministry of Health,Working Group，Draft revised text for public consultation；15 April - 15 June 2013．

Labour and Welfare．How to complete the application form for ensuring the quality and safety of16）Cyranoski D．Stem cells cruise to clinic．
2013 Feb 28；494（7438）：413．

pharmaceuticals and medical devices based on cells
or tissue．Spring 20, 2010

Yakushokushinsa-hatsu．

17）Kimura Y，Nishimura H，Kikuchi K，Fukushima M．
［Concerns about Bill on Safety Assurance of Regen-No. 0420-1．

erative Medicine］．

9）Pharmaceutical and Food Safety Bureau, Ministryof Health, Labour and Welfare．Guideline on ensur-．2013；44（8）：594-601．Japanese．

ing the quality and safety of human autologous18）Directive 2004/23/EC of the European Parliament

somatic stem cells-derived medical devices or phar-and of the Council of 31 March 2004 on setting stan-maceuticals．September 7, 2012

dards of quality and safety for the donation, pro-

Yakushoku-hatsu

curement, testing, processing, preservation, storage

No. 0907-2．

and distribution of human tissues and cells．

10）Pharmaceutical and Food Safety Bureau, Ministry．2004 Apr 7；L 102：of Health, Labour and Welfare．Guideline on ensur48-58．

ing the quality and safety of human allogeneic
somatic stem cells-derived medical devices or pharmaceuticals．September 7, 201219）U.S. Department of Health and Human Services, Foodand Drug Administration (FDA)．21 CFR Parts

Yakushoku-hatsu

207, 807, and 1271．Human cells, tissues, and cellu-

No. 0907-3．

lar and tissue-based products; Establishment regis-11）Pharmaceutical and Food Safety Bureau, Ministryof Health, Labour and Welfare．Guideline on ensur-

tration and listing．

ing the quality and safety of human autologous

66（13）：5447-69．

．2001 Jan 19；

induced Pluripotent Stem (-like) cells-derived medi-20）U.S. Code of Federal Regulations, Title 21 Foodcal devices or pharmaceuticals．September 7, 2012and Drugs, Part 1271 Human cells, tissues, and cel-

Yakushoku-hatsu No. 0907-4．

lular and tissue-based products．Revised as of April
1, 2013．

12）Pharmaceutical and Food Safety Bureau, Ministryof Health, Labour and Welfare．Guideline on ensur-21）U.S. Department of Health and Human Services, Fooding the quality and safety of human allogeneic

and Drug Administration (FDA)，Center for Biolog-

induced Pluripotent Stem (-like) cells-derived medi-

ics Evaluation and Research (CBER)．Guidance for− 920 −

Clin Eval 41（4）2014
Industry: Potency tests for cellular and gene therapy

Labour and Welfare．Preclinical safety evaluation

products．January 2011．

of biotechnology-derived pharmaceuticals．March
23, 2012

22）Pharmaceutical and Food Safety Bureau / Evalua-Yakushokushinsa-hatsu No. 0323-1．

tion and Licensing Division, Ministry of Health,24）Ministry of Health, Labour and Welfare．Guideline

Labour and Welfare．Guidance on nonclinical safety

for human stem cell therapy clinical research．July 3,

studies for the conduct of human clinical trials and2006, Revised as of November 1, 2010．（After themarketing authorization for pharmaceuticals．Febru-

publication of the original Japanese version of thisary 19, 2010

article, this guideline was revised as of October 1,

Yakushokushinsa-hatsu No. 0219-4．

2013．）

23）Pharmaceutical and Food Safety Bureau / Evaluation and Licensing Division, Ministry of Health,＊＊− 921 −＊