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Integrative Celerity Research

Roadmap and Critical Path for

Japanese Clinical Research and Development Strategies

Hiroo Imura, M.D.

Principal Fellow (Chairman), Japan Science and Technology Agency

Center for Research and Development Strategies

Professor Emeritus, Kyoto University

Chairman, Foundation for Biomedical Research and Innovation

PROBLEMS IN

TRANSLATIONAL RESEARCH �TR�

Basic

Life Science

Clinical

Research

Clinical

Practice

Industries

IP Publications

Translation

WHAT IS INTEGRATIVE

CELERITY RESEARCH �ICR� ?

• Based on Basic Research and Data of Clinical

Epidemiology

• Looking Ahead Towards the Goal of

Clinical Practice or Industries

• Integrating Each Steps of Clinical Research

• Establishing Tools for Rapid Evaluation of

Efficacy or Safety �Toxicity�

• Evaluating Cost-Effectiveness of Products

CLINICAL RESEARCH :

FROM TR TO ICR

INTEGRATIVE CELERITY

RESEARCH �ICR�

Basic Research

Clinical Epidemiology

Pre-clinical Research

Clinical Research

Clinical Research

Approval

Industries

Clinical Practice

Clinical ResearchForesight

Phase1

Phase2,3

Phase 4

Bedside to Bench

RESEARCH TOOL KITS OF EACH

STEP OF CLINICAL RESEARCH

Pre-clinical Research

Clinical Research

Clinical Research

Industries

Clinical Practice

Approval

Micro-dosing

Humanized Mouse

PG and ADME

Genome

Proteome

SNPs

Imaging

New Biomarker

Regulatory Science

Medical Economics

Foresight

Phase1

Phase2,3

Phase 4

Clinical Research

REGENERATIVE MEDICINE

• In Vivo Expansion of Somatic Stem Cells

– Drug Therapy

– Gene Therapy

• Transplantation of Autologous Somatic Stem

Cells

– Procedure �Instruments, Media, Chemicals�

– Scaffold

• Allogenic Somatic Stem Cells of Differentiated

Cells

• Embryogenic Stem Cells

PLATFORMS OF

CLINICAL RESEARCH

• Medical Education

• Co-Medical Workforces

– Biostatistician, Data Manager

– Nurse for Clinical Research, CRC

• Clinical Research Unit in Hospitals and

Clinical Research Coordinating Centers

• Budgets for Clinical Research Initiated by

Clinical Investigators

• International Collaboration Networks

CLINICAL TRIALS AND

INTERNATIONAL HARMONIZATION

Drugs

Clinical Trials Harmonization

ICH

Exploratory IND

Microdosing

Global Trial

Difference in PK/PD

Dose-response

Cell Therapy

Regenerative Therapy

Medical Devices

NoneFew

GHTF / ISOGlobal Trial

Registry Study

�Post -Marketing Study�

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Scope of Talk

– Overview of FDA, and CBER’s Office of

Cellular, Tissue and Gene Therapy (OCTGT)

– General FDA authorities and review paradigm

– Approach to Regulation of Tissue

Engineering/Regenerative Medicine Products

Regenerative Medicine

and Tissue Engineering:

An FDA Perspective

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FDA &CBER Centennials

Office of Commissioner

Andrew von Eschenbach, M.D., Acting Commissioner

Food and Drug Administration

Center for Biologics Evaluation and Research

Center for Devices and Radiological Health

Center for Drug Evaluation and Research

Center for Veterinary Medicine

Center for Food Science and Nutrition

National Center for Toxicological Research

Center Director

Jesse Goodman, M.D., M.P.H.

Center for Biologics Evaluation and

Research

Office of Cellular, Tissue, and Gene Therapies

Office of Blood Research and Review

Office of Vaccine Research and Review

Office of Biostatistics and Epidemiology

CBER Regulated Products

Blood DerivativesBlood Derivatives

Devices

Whole BloodWhole Blood

TissuesTissues

XenotransplantationXenotransplantation

Somatic Cell Somatic Cell

TherapiesTherapies

VaccinesVaccines

Blood

Components

GeneGene

TherapiesTherapies

Tissue Engineering/ Tissue Engineering/

RegenerativeRegenerative

MedicineMedicine

Celia M. Witten, Ph.D., M.D. Office Director

Stephanie Simek, Ph.D., Deputy Director

Richard McFarland, Ph.D., M.D., Associate Director for Policy

Suzanne Epstein, Ph.D., Associate Director for Research

Deborah Lavoie, J.D., Chief Regulatory Management Staff

Division of Cellular and Gene Therapies

Raj Puri, M.D., Ph.D. Director

Kimberly Benton, Ph.D., Acting Deputy Director

Division of Human Tissue Products

Ruth Solomon, M.D., Director

Division of Clinical Evaluation and Pharmacology/Toxicology

Ashok Batra, M.D., Director

CBER

Office of Cellular, Tissue and Gene

Therapies

Legislative History

• 1902 Biologics Control Act

• 1906 Food and Drug Act

• 1938 Food Drug, and Cosmetics Act

• 1962 Kefauver-Harris Amendments to

FD&C Act

• 1976 Device Amendments to FD&C Act

• 1992 PDUFA I

• 1997 FDAMA I

Basis for FDA Actions

• Statutes

– a.k.a, Acts or Public Laws (FD&C Act, PHS Act,

etc.).

– Passed by Congress and signed by the President

• Regulations

– Implementation of the Statutes

– Rulemaking Process

• Agency Drafts Regulations

• Public Comment

• Approved by the Executive

– Has force of law

Basis for FDA Actions

• Guidance

– Agency’s current interpretation of Statues

or Regulations

– Good Guidance Practice (includes public

comment)

– Non-binding advice

Forces Shaping Biological Products

in the 21st

Century

• New Discovery Biomedical Research and

Technology

• Demand for New Biological Products and

Faster Access

• Safety and Ethical Issues

• Changing Health Care Environment

• Global Market: International Harmonization

and Competition; Consolidation/Mergers

• Information Management

• Counter-Terrorism

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How does Research Directly

Inform Policy of Product

Evaluation?

FDA Critical Path Initiative

• In these days of increasingly complex medical

products and biotechnologies, the FDA needs to be

proactive, explicit and transparent to support new

safe and effective products moving efficiently through

the Critical Path of product evaluation…the path that

biological products take on the way from initial

discovery to patient use

• In many cases, a regulatory historical path does not

exist—Critical Path serves as an explicit science

base to inform novel regulatory policy

• www.fda.gov/oc/initiatives/criticalpath.htm

Who Does Research at CBER?

• Research-Regulators: Regulatory scientists

who:

– Review complex biological products and

– Address major regulatory hurdles through

intramural and collaborative laboratory,

epidemiological, clinical trial design, and

statistical research.

FDA Review is

Product-based

• Parallels prudent product development

• Dependent on characteristics of specific

product

• Preclinical studies designed to support

use of specific products

• Clinical trial design supported by

manufacturing, preclinical data

• Framed by regulations

Regulation of Clinical Trials

• IND Regulations

– Drug

– Biologic

– Combination

• IDE Regulations

– Device

– Combination

IND and IDE Comparison

• IND and IDE regulations contain differing

specific requirements and language that

reflect both scientific differences between

product areas and history of the rules

BUT

• IND and IDE regulations are both focused

on prudent development with the goal of

assuring safe, effective products


• Cellular Products, Devices, Combination

Products (cells combined with scaffold)

• Regulated under IND/ BLA Regulations or

IDE/PMA Regulations

• Specifics of which regulations will vary based on

the science inherent in the product

• Combination products

– Primary mode of action- RFD process (Office of

Combination Products)

– Previous intercenter agreements and precedents

Cell-Scaffold Scientific Issues

• What questions need to be asked by

testing of final products or their

components?

• At what stage of product assembly is the

most accurate information obtained?

• What testing methods are currently

available and what methods need to be

developed or standardized?

CBER/CDRH Tissue Engineering

Cross-Center Teams

• Facilitate intercenter co-operation and solutions of TE

issues

– Provide a core resource of TE review expertise to

CBER, CDRH, OCP

– Participate in development of regulatory policy and

pathways

– Facilitate FDA participation in Standards

Organizations

– Provide a strong, consistent FDA voice in outreach

activities with academia, industry, other governmental

programs

– Provide an educational resource for reviewers within

CBER and CDRH

CBER/CDRH Tissue Engineering

Cross-Center Teams-Composition

• CBER

– Office of Cellular, Tissue and Gene Therapies

– Office of Compliance and Biologics Quality

• CDRH

– Office of Device Evaluation

– Office of Science and Engineering Laboratories

– Office of Compliance

Regulatory Issues

for Clinical Studies

• Does the submission contain “sufficient information to

assess risks to the subjects in the proposed trial?”

– Are source materials, manufacturing process, and final product

sufficiently characterized to provide adequate assurance of

safety?

– Were adequate preclinical studies performed?

– Were data submitted in sufficient detail to conduct an

independent review?

– Does the design of the clinical trial contain adequate safeguards

for subject safety?

– Is the design of the clinical trial adequate to achieve stated aim?

• If sufficient data are present, are the risks to human

subjects unreasonable?


• Guidances for Cellular, Gene Therapies, and

Devices

• Leveraging existing guidances to support

specific areas of tissue engineered medical

products

– CMC guidances for cellular products

– General (CT and GT) preclinical guidances

– Guidances for devices may be applicable to scaffolds

– Many clinical guidances cross-cut product areas

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FDA Information/Outreach

• Product specific confidential enquires during

pre-IND, IND process

• FDA talks at scientific meetings

• Guidance documents

– (http://www.fda.gov/cber/guidelines.htm)

– (http://www.fda.gov/cdrh/guidance.html)

• Advisory Committee Discussions

– (http://www.fda.gov/cber/advisory/ctgt/ctgtmain.htm)

• Workshops

Advisory Committee Meetings

• Hematopoietic stem cells for hematopoietic

reconstitution (February 2003)

• Allogeneic islet cell therapy for diabetes

(October 2003)

• Somatic cell therapies for cardiac disease

(March 2004)

• Somatic cell therapies for joint surfaces (March

2005)

• Potency measures for cell, tissue and gene

therapies (February 2006)

Contact Information

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Proposal for Translational Research

Foundation of Biomedical Research and Innovation (FBRI)

Cell Processing Center

Shin Kawamata

JST-CRDS Regenerative Medicine Strategy Work Shop @ Kyoto Univ. Shiran Hall

061101

Do we need Regenerative Medicine/Cell Therapy ?

patients

Companies

Medical

Institutions ResearchersAdministrative

agencies

Yes, some disorders cannot be cured by conventional therapies

…BMT for leukemic patients… islet cell transplantation for IDDM..

Healing of some disorders can be promoted by cell therapies

….osteoblasts, chondrocytes + scaffold implantation….

isolation and processing of the cells prior to transplantation to

the patients require a designated tissue culture facilities, known as CPC

before the patients enjoy the benefit, the quality and safety of the cell

products shall be certified by the regulations and laws concerned.

To meet this requirement, we need GMP based CPC.

And we need one successful example in TR, but how can we operate CPC ?

Translational Research (Start & Goal)

Basic science

Preclinical

study

the Pharmaceutical Affairs Law

the Health Insurance Law

the Medical Service Law

the Health Insurance Law

Development

of new

medical

technology

Sales of

• Bio-products

• Medical Devices

• Drugs

Merge to

Insurance system

company

academia

StartGoal

Translational Research (frame work in theory��)

Basic science

Non-clinical

study

Clinical study

(Investigator)

Clinical trial

�sponsor ��Preclinical

study

Entry as the

evaluation therapy

Clinical Trial

�sponsor ��/��

filing

the Pharmaceutical Affair Law

the Medical Service Law (doctor)

Development

of new

medical

technology

applicationfiling

Approval for

Bio-products

Devices

Drugs

Merge to

Insurance system Hurdles at the entry of

the evaluation therapy

Several hurdles for

business profit

company

academia

Seeds

Non-clinical

study

Clinical study

�Investigator ��/��

Clinical trial

�sponsor ��/��/��

Clinical study

(Investigator)

preclinical

study

filing

Pharmaceutical Affair Law

Medical Service Law (doctor)

Development

of new

medical

technology

applicationfiling

filing

filing

Approval for

products

Merge to

Insurance system

Clinical trial

�sponsor ��

Clinical Trial

�Investigator ��/��

Translational Research (Approach to goal)

Entry as the

evaluation therapy

filing

filing

Key word:

Clinical Trials

support company

medical institution

support academia

GMP grade CPC

Core facilities for clinical trials/studies in Kobe

Foundation of Biomedical Research and Innovation (FBRI)

IBRI TRI

Medical Device

Developing Center

��

New Kobe General

Hospital (year 2010)

Riken CDB

Port liner

Station

Riken

Molecular Imaging Center

HIDEC

Rental CPC for clinical trials/studies in FBRI

Bio-Products

GMP grade CPC

Protocol prep. ethics committee/IRB

60 Test Beds

+ 640 beds hospital

(year 2010)

Legend:

Class 100

Class 10,000

Class 100,000

Class 100,000 equiv.

Regular air conditioning

Operation

Room2

Operation

Room�

Tissue

culture

room

Proposals for the “realization “of a translational research

1. Selection of TR projects (criterion for selection):

Only the projects aiming for clinical trials or entry to “the evaluation therapy” shall be adopted.

2. Designation of joint use core medical centers :

a) dealing inter-institutional projects.

b) TR traning center.

c) establish “Standards and SOP

3. Secure TR specialists or coordinators:

TR key persons at core facilities with the knowledge of:

medical science, protocol design, related laws and regulations, and ability of coordination

with patient leagues if any, doctors, authorities concern, manufacturers and funding agencies..

Proposals for the “realization “of a translational research

4. New Budget for TR:

a) sponsor the projects for the investigator’s (doctor’s) clinical study or trials for bio-products.

b) recruit TR personnel at the core facilities.

c) projects to solve the present hurdles in TR

such as development of next generation CPC, establishment of SOP, documentations..

5. Initiative role of administrative offices:

A working group from inter-sectional administrative agencies, industries, medical institutions,

researcher, patients’ leagues should be formed to issue a guide line for TR.

Question and Answer

Q1: What is a desirable TR project ?

Q2: What is the requirement to be a regional TR medical center?

Q3: What type of standard or guide line is required for CPC operation?

A1: A clinical trial or clinical study aiming for clinical trials or the evaluation therapy as a part

of clinical trials. Clinical study without goal or disagreeable with a current scientific finding

shall be re-validated at hearing committee of the institution.

A2: A joint use medical center with test beds able to handle clinical trials of regional institutions.

The clinical studies in an advanced stage or aiming at clinical trials shall be transferred to

and conducted at the center.

A3: Operational grade of CPC may differ depending on the goals of the institutions. CPC carrying

out clinical studies under the medical service laws do not require GMP operation. While

CPC in clinical trials should operate in GMP grade in accordance with the pharmaceutical laws.

Two types of CPC might be utilized depending on the stage of TR.

GMP grade operation of CPC is indispensable for clinical trials, but needs huge maintenance

cost. A rental type GMP grade CPC at core facilities could be a solution.

We need a successful example in regenerative medicine utilizing rental GMP grade CPC.

��

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Trends in Therapeutic Angiogenesis

Gene/Cell Therapy

Need Multiple Technologies

Isolation of cells�

selection�proliferation

Regulation of gene

expression

Production

of vector

vector

Therapeutic

genes

Genetic

regulation

Optimizing Genetic Therapy Puzzles

qGenetic therapy is a puzzle centering on

the genes.

qOne therapeutic concept and one specific

gene give rise to many different puzzles.

1

#

B

2

X

B

Puzzle 1 Puzzle 2

1

4

23

5 67

Vectors Genes

A

F

DE

C

G H

+ *x

#

>

Why is TR difficult in Regenerative Medicine?Why is TR difficult in Regenerative Medicine?

1. Regenerative Medicine is different than traditional

pharmaceuticals

- different skill set

- expanded skill set.

2. The assets of Big Pharma are primarily applicable to later stage

development.

3. Biotech skills are primarily applicable to earlier stage development.

However, only few Biotech are working in this field in Japan.

4. Thus, combining Big Pharma and Biotech skills does not create the

critical mass required for optimal therapy development in Japan.

- requirement to network and partner

- role of supplier and ‘experts’ will be necessary and critical.

Role of Bioventures

• Innovation from Academia should be translated

into Big Pharma through Bioventures.

Basic Research

�Innovation�TR (early & late) toward

to industrialization

Preclinical

Clinical trial

IND/NDA/Production

/Marketing

Acadeia BiobentureBiobenture Big Pharma

�Funding

�Bioventures

�Human Resource

��are necessary

Basic R TR from Basic to

Industrialization

Market

Easy

Difficult

Death

Valley

Death Valley in Regerative Medicine

Obstructers Toward to Industrialization in RM

Efficacy

Preclinical

GLP

TR (early & late)

Clinical trial

GCP

Safety

Toxicity (acute & chronic�

GLP

Pharmacokinetics�animal &

human�

GLP�GCP

PL

Stability

CMC

Stability

GMP�SOP

Production

GMP�SOP

Storage

GMP�SOP

Clinical Pharmacology in Gene/Cell Therapy

Monitoring

Gene/Cells (Blood, Urine, Tissues�

Produced Protein (Blood � Tissues�

Effects (e.g. angiogenesis)

Clinical Efficacy

QC&QA

Production of Gene/Vector/Cells

Validation

How Should we do ?

1) Set up Road Map of Regenerative Medicine!

Goal of Industrialization

(Market or Common Therapy)

2) Divide Individual Role between Academia & Ventures

Academia: Basic Research (efficacy, molecular biology, molecular imaging)

Education (TR, Ethics, Regulatory Science, GLP, GCP, GMP),

Clinical Trial (TR early)

Industry: Clinical Trial (TR late & sponsored)

CMC, Production

3) More Tight Relationship between Academia & Industry

Funding, Large Corroboration, Resolve COI

Look UK!

1) Cambridge is largest Biocluster in EU

2) Pipelines from Cambridge ventures

(>200) over all of German ventures

3) UK resolved the problems between

Academia & Industry early 1990.

4) Model is more closed us than USA

(less investment money, more

academia activity …)

UCL & Imperial College have the complex that contains

Academia & Industry in one building related to stem cell

research.

Translational ResearchTranslational Research

in Osaka Universityin Osaka University

--Medical center for translational research in Osaka University HoMedical center for translational research in Osaka University Hospitalspital--

Osaka University

Cardiovascular Surgery

Yoshiki Sawa

Importance of Translational ResearchImportance of Translational Research

Translational research

Death Valley

Discovery of

new seeds

Advanced clinical

application in the

Hospital

IRB

Contribution

from

company

Relationship

among the

other countries

Clinical trial

As a bridge against

Death Valley

High levels of

experimental

study

MCTR

��

Osaka University Hospital

In 2002, MCTR was established in Osaka

University Hospital as a translational research

center for the future medical technology.

�Translational Research

Regenerative Medicine, Cell therapy, Robotics Surgery, Surgical

Assistance system, Surgery Training System, New Diagnostic Imaging

�CPC Operation

�Future Medical Technology

Development of novel medical technology

Introduction of IT to Surgical Suite

�Physician-oriented Clinical Trial

�Education / Human Resource Development

�Patent Counseling, Intellectual Property Strategy

MCTR’s activity

Benefit

Risk

Evidence of Objective Science

Experimental Clinical trialExperimental Clinical trial

11 Projects of Translational Research11 Projects of Translational Research

in Osaka Universityin Osaka University

�� Regeneration therapy in the BoneRegeneration therapy in the Bone

�� Protection for ischemic Optic nerveProtection for ischemic Optic nerve

�� Regeneration in the HeartRegeneration in the Heart

�� Regeneration in the CorneaRegeneration in the Cornea

�� Magnetically treatment for HeadacheMagnetically treatment for Headache

�� Immunological treatment for Colon cancerImmunological treatment for Colon cancer

�� Regeneration therapy in the CartilageRegeneration therapy in the Cartilage

�� Myocardial Regeneration using Myoblast sheetsMyocardial Regeneration using Myoblast sheets

�� Regeneration for Spinal cord injury Regeneration for Spinal cord injury

10. Immunological treatment for Esophageal cancer10. Immunological treatment for Esophageal cancer

1111��Allograft transplantation of islet cell for DMAllograft transplantation of islet cell for DM

Space in MCTR is 1600m2

��

Medical Center for Translational ResearchMedical Center for Translational Research

in Osaka University Hospitalin Osaka University Hospital

Office

Zone

Preclinical Research Zone Collaboration

Zone

Therapy

Zone

Transplantation

Ward

Skywalk

PartneringPartnering -- Promotion of collaborationPromotion of collaboration

AcademicAcademic--industrial allianceindustrial alliance

seeds from basic research � clinical application and industrialization

Collaboration research 12 companies

Association for future medicine exchange

Alliance, matching and information exchange for industrialization

55 companies

MedicalMedical--engineering allianceengineering alliance

nano-biotechnology,

robotics surgery,

surgical guidance system,

surgical training system

International academic exchangeInternational academic exchange

McGowan Institute for Regenerative Medicine, Pittsburgh, PA. U.S.A.

Hannover Clinical Trial Center, Hannover, Germany

Cambridge University, UK

Yonsei University, Korea

Industrializatio

n

Specialists for Translational Research

Innovation

Translatio

nal

Research

Review for Clinical protocol�FDA�

Medical statistics

Medical technology for TR

TR coordinator (TRC)

Strategy for intellectual property

Matching for technology (connoisseur �

Regulation for GLP,GMP and GCP

Bottom –up System

Fast First Success

Translational ResearchTranslational Research

GMP

Phase III

Phase I

Phase II

Pre-clinical

study

Mega Study

Phase I/II

Clinical

trial

GCPGLP

Planet OsakaPlanet Osaka

�Practical system for Clinical study

�International Harmonization

�Phase I (micro dose), I/II promotion

Academia

Doctor

Industry

Company

Role of Translational Research Role of Translational Research

--Planet OsakaPlanet Osaka--

Training for genetic

and cell biology

Cooperative study in Bio-

Industry Fields

Experts for TR

Other Institute in the worldOther Institute in the world

Cell processing Gene transfer

technology

Development of Tissue

engineering

Robotically simulation

Analysis of Data base

Guideline and Regulatory rule

Training for

Biomaterial and

Nanotechnology

Reviewer for Clinical protocol�FDA�

Medical Statistician

Expert and approved physician for TR

TR coordinator (TRC)

Strategic Expert for intellectual property

Matching coordinator for technology

(connoisseur �

Inspector for GLP,GMP and GCP

Educational system for TR expertsEducational system for TR experts

Students both in Medical

and Engineering

Basic Research

Simulation

��

��

��

��

��

��

��

��

Gene and cell therapy

Translational

Research

Robotically supported therapy

Clinical trial

From bench to bedside

Feedback from clinical data

Medical school

Phamaceutical

Dental

Lifescience

Engineering

Experimental Laboratory for preclinical study under Experimental Laboratory for preclinical study under

GLP regulationGLP regulation --From bench to bedsideFrom bench to bedside--

Pre-Clinical study using large animal

Problems for TR in the Academic instituteProblems for TR in the Academic institute

� Specialists, Experts, Staff members

� Experimental laboratory systems under GLP regulation

� Clinical support facilities under GMP regulation

� Clinical protocol under GCP regulation

� Financial supports for clinical trial

� Cooperation between University and Industry

� Ethical level of IRB in each institute

� Practical Guidelines of Government Regulation

� Treatment fee supported by Private Insurance

� Insurance system for compensation

� Strategy for Intellectual property

Stem Cell Research and

Regenerative Medicine in Japan

Stem Cell Research and

Regenerative Medicine in Japan

Hiro Nakauchi, M.D., Ph.D.

Laboratory of Stem Cell Therapy

Institute of Medical Science University of Tokyo

Hiro Nakauchi, M.D., Ph.D.

Laboratory of Stem Cell Therapy

Institute of Medical Science University of Tokyo

��

Japan is one of 35 countries that allow derivation of ES cells

from surplus IVF embryos.

Japan is one of 35 countries that allow derivation of ES cells

from surplus IVF embryos.

Use of human ES cells for research: Yes

Establishment of human ES cells: Yes

Use of human ES cells for therapy: (Yes)*

Establishment of ntES cells: (Yes)

Use of cloned embryo for research: (Yes)

Use of materials from aborted fetus (No)

Reproductive cloning: Illegal

Use of human ES cells for research: Yes

Establishment of human ES cells: Yes

Use of human ES cells for therapy: (Yes)*

Establishment of ntES cells: (Yes)

Use of cloned embryo for research: (Yes)

Use of materials from aborted fetus (No)

Reproductive cloning: Illegal

* Guideline is not yet formulated.* Guideline is not yet formulated.

So far, only 3 hES cell lines established, 35 projects approved since 2001.

(Yes) means officially Yes, but practically No.

So far, only 3 hES cell lines established, 35 projects approved since 2001.

(Yes) means officially Yes, but practically No.

News

Nature 438, 263 (17 November 2005) |

Japan's embryo experts beg for faster ethical reviews

David Cyranoski, Tokyo

Researchers accuse review boards of holding them back.

News

Nature 438, 263 (17 November 2005) |

Japan's embryo experts beg for faster ethical reviews

David Cyranoski, Tokyo

Researchers accuse review boards of holding them back.

Japan is a world leader in embryonic stem-cell research involving mice and monkeys

(> 30 % of the publication by Japanese researchers) , but work involving human cell

lines is another matter (only 3 out of 259 papers on human ES cells). That is because

review committees regularly take far longer to approve such projects than other

countries do, researchers charge (average over 12.5months).

Japan is a world leader in embryonic stem-cell research involving mice and monkeys

(> 30 % of the publication by Japanese researchers) , but work involving human cell

lines is another matter (only 3 out of 259 papers on human ES cells). That is because

review committees regularly take far longer to approve such projects than other

countries do, researchers charge (average over 12.5months).

In other countries, where there is usually only one level of approval, say it generally

takes a fraction of the time — two to three months in Singapore, South Korea,

Australia and Britain. In the United States, despite its reputation for restrictive policy,

approval to work with permitted stem-cell lines can take as little as a few weeks.

In other countries, where there is usually only one level of approval, say it generally

takes a fraction of the time — two to three months in Singapore, South Korea,

Australia and Britain. In the United States, despite its reputation for restrictive policy,

approval to work with permitted stem-cell lines can take as little as a few weeks.

��

��

Proposal of derivation or usage of human ES cells must be approved by the

institutional review board and also by the Government

Same reviewing process is required for the derivation of hES cell lines

and the use of established hES cell lines (now usually it takes> 10 months).

Proposal of derivation or usage of human ES cells must be approved by the


Same reviewing process is required for the derivation of hES cell lines

and the use of established hES cell lines (now usually it takes> 10 months).

Derivation and Research Usage of Human ES Cell Lines

Sept. 2001

Derivation and Research Usage of Human ES Cell LinesDerivation and Research Usage of Human ES Cell Lines

Sept. 2001Sept. 2001

Guide lines for clinical protocols using adult stem cells

(excluding the usage of human ES and fetal cells)

Sept. 2006

Guide lines for clinical protocols using adult stem cellsGuide lines for clinical protocols using adult stem cells

(excluding the usage of human ES and fetal cells)(excluding the usage of human ES and fetal cells)

Sept. 2006Sept. 2006

Clinical research using adult stem cells must also be approved by the


Clinical research using adult stem cells must also be approved by the


The Ministry of Education, Culture, Sports, Science

and Technology

Leading Project on the realization of regenerative medicine

U.S.$ 200 million (total) over 10 years (human ES cell studies excluded)

Special Priority Area Grant

U.S.$ 12 million (total) over 5 years on stem cell research in general

The Ministry of Economy, Trade and Industry

U.S.$11 million (total) over 5 years on human ES cells studies.

The Ministry of Education, Culture, Sports, Science

and Technology

Leading Project on the realization of regenerative medicine

U.S.$ 200 million (total) over 10 years (human ES cell studies excluded)

Special Priority Area Grant

U.S.$ 12 million (total) over 5 years on stem cell research in general

The Ministry of Economy, Trade and Industry

U.S.$11 million (total) over 5 years on human ES cells studies.

New Jersey is going to fund >$380 million.

California is going to fund $2950 million over 10 years.

EU is going to fund $74000 million over 7 years.

Nationally supported Stem Cell Institutes in Australia, Singapore etc.

New Jersey is going to fund >$380 million.

California is going to fund $2950 million over 10 years.

EU is going to fund $74000 million over 7 years.

Nationally supported Stem Cell Institutes in Australia, Singapore etc.

��

Relatively stringent/conservative ethical view in general.

Due to different religious/cultural background?

Less trust/expectation on the development of life science

Technological science is preferred?

Less respect for scientists and medical doctors?

Government-centered policy and regulations

Bureaucratic system does not want to take any risks.

Relatively stringent/conservative ethical view in general.

Due to different religious/cultural background?

Less trust/expectation on the development of life science

Technological science is preferred?

Less respect for scientists and medical doctors?

Government-centered policy and regulations

Bureaucratic system does not want to take any risks.

��

Japan is greatly behind other countries in human ES cell research

and in a system to translate it into clinical medicine.

Japan is greatly behind other countries in human ES cell research

and in a system to translate it into clinical medicine.

��

We should facilitate stem cell research, in particular, of human ES cells.

Establishment of efficient TR system is also necessary.

We should facilitate stem cell research, in particular, of human ES cells.

Establishment of efficient TR system is also necessary.

Simple and faster review process for the use of hES cells and

for clinical protocols using stem cells.

Permission should be obtained within 2-3 months.

Need to establish more clinical-grade hES cell lines

ES cell lines vary in their characteristics.

Need to get more political support

Positive leadership / grants to support stem cell research

Need more Stem Cell Research Institutes/Centers

Simple and faster review process for the use of hES cells and

for clinical protocols using stem cells.

Permission should be obtained within 2-3 months.

Need to establish more clinical-grade hES cell lines

ES cell lines vary in their characteristics.

Need to get more political support

Positive leadership / grants to support stem cell research

Need more Stem Cell Research Institutes/Centers

We need a strategic plan to support stem cell research.We need a strategic plan to support stem cell research.

��

Even in immunology, the most advanced scientific field

over the decades, its contribution to clinical medicine

is still limited. Antibody medicine is one such example,

but this provides symptomatic treatment but not a cure.

Immunology still can not provide cure for allergies,

autoimmune diseases, rejection and so on.

Even in immunology, the most advanced scientific field Even in immunology, the most advanced scientific field

ooverver the decades, its contribution to clinical medicine the decades, its contribution to clinical medicine

is still limited. Antibody medicine is one such example, is still limited. Antibody medicine is one such example,

but this provides symptomatic treatment but not a cure.but this provides symptomatic treatment but not a cure.

Immunology still can not provide cure for allergies, Immunology still can not provide cure for allergies,

autoimmune diseases, rejection and so on.autoimmune diseases, rejection and so on.

TR is not easy!

A big gap between basic medical science and understanding

of the disease process still exists.

TR is not easy!TR is not easy!

A big gap between basic medical science and understanding A big gap between basic medical science and understanding

of the disease process still exists.of the disease process still exists.

Translational Research from basic research should

be considered from mid- to long-term viewpoint.

Translational ResearchTranslational Research from basic research should from basic research should

be considered from be considered from midmid-- to longto long--term viewpointterm viewpoint..

Translational Research is a clinical research to

develop better diagnostic means, effective

therapies, or ways to prevent disease initiated

and conducted by clinicians.

Translational ResearchTranslational Research isis a clinical research to a clinical research to

develop better diagnostic means, effective develop better diagnostic means, effective

therapies, or ways to prevent disease therapies, or ways to prevent disease initiatedinitiated

and conducted by clinicians.and conducted by clinicians.

Hematopoietic stem cell (HSC) are the best studied stem cells.

Still not much is known about how HSCs self-renew or how

they differentiate. No way to manipulate HSCs, yet.

However, bone marrow transplantation has been made

possible by the clinicians who understood the concept of stem

cell and translate it to clinical medicine.

Hematopoietic stem cell (HSC) are the best studied stem cells. Hematopoietic stem cell (HSC) are the best studied stem cells.

Still not much is known about how HSCs selfStill not much is known about how HSCs self--renew or how renew or how

they differentiate. No way to manipulate HSCs, yet.they differentiate. No way to manipulate HSCs, yet.

However, bone marrow transplantation has been made However, bone marrow transplantation has been made

possible by the clinicians who understood the concept of stem possible by the clinicians who understood the concept of stem

cell and translate it to clinical medicine.cell and translate it to clinical medicine.

��

��

Improvement in medical education:

More emphasis on experimental medicine

Flexibility in curriculum to have opportunities to

spend time in the laboratory (e.g., MD, PhD

course in the US)

Lectures by the experts in clinical research

Improvement in medical education:

More emphasis on experimental medicine

Flexibility in curriculum to have opportunities to

spend time in the laboratory (e.g., MD, PhD

course in the US)

Lectures by the experts in clinical research

Qualified clinicians who can lead the research project

An expert clinician in the field

Can follow the progress of basic medical science

Can initiate and coordinate a team to conduct clinical

research

Trusted by patients and medical staffs

Qualified clinicians who can lead the research projectQualified clinicians who can lead the research project

An expert clinician in the fieldAn expert clinician in the field

Can follow the progress of basic medical scienceCan follow the progress of basic medical science

Can initiate and coordinate a team to conduct clinical Can initiate and coordinate a team to conduct clinical

researchresearch

Trusted by patients and medical staffsTrusted by patients and medical staffs

Absolute lack in human resources:

Requires establishment of core institutions that

focuses on implementation of clinical research

and staff training

Absolute lack in human resources:

Requires establishment of core institutions that

focuses on implementation of clinical research

and staff training

System to support and facilitate clinical research

Research hospital with:

Sufficient number of clinicians,

Basic researchers,

Clinical statisticians,

Nurses and other clinical staffs

Experienced IRB

Coordinator who can design a clinical protocol

System to support and facilitate clinical research

Research hospital with:

Sufficient number of clinicians,

Basic researchers,

Clinical statisticians,

Nurses and other clinical staffs

Experienced IRB

Coordinator who can design a clinical protocol

��

Governing legal authority should be positive and prompt in

Formulation of guideline

Processing of review on clinical protocols

Handling in ethical issues

Appointment and training of specialist personnel

More PhDs and MDs in the agency

Governing legal authority should be positive and prompt in

Formulation of guideline

Processing of review on clinical protocols

Handling in ethical issues

Appointment and training of specialist personnel

More PhDs and MDs in the agency

��

We need a strategic plan here, tooWe need a strategic plan here, too

061101@Kyoto

Regenerative Medicinein

Tokyo Women’s Med. Univ.and

Comments on Guidelines

Masayuki YamatoTokyo Women’s Medical University

We have experienced“cell sheet”-based

regenerative medicine.

skin (2000)cornea (2002)esophagus (coming soon?)

VitreousLensCornea

Retina

Eye

Conjunctiva

alkali injury Stevens-Johnsonsyndrome

unilateral bilateral

Endoscopic transplantation of“Cell Sheets” after endoscopic

submucosal dissection

Olympus

control

Transplanted

LESSCONSTRICTION

September 11 or September 1 ?

“Guideline for Clinical Research Using Human Stem Cells”

by Japanese FDA

went into EFFECT on September 1, this year.

Concerns about

The Guideline and Central IRB

Overquality, Too awkward?

Is only one guideline sufficient?

or

Target-dependent is better?

body surface

skin, cornea, oral cavity, esophagus...

internal organ

heart, liver, islet...

in blood

hematology, blood vessel...

Surgeon or physician?

different philosophy, different discipline

Needs for evidence-based guideline

negligible residual conc. of FBS, antibiotics,

cytokines...

Who has the responsibility for the cost?

private company, tax, donation, patient,

or doctor?

We need

Guidelines for Preclinical Animal Study.

Final goal

First, clinical research

Finally,

a) commercial productEpicel , Carticel , Apligraf ...

b) limited

organ transplantation,

bone marrow transplantation

However,

we have very few seeds.

Basic research is more needed

to achieve

Translational Research.

11

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� � � �Yuji Tokumasu

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1

Product Development Challenges In


Jeff Teumer, PhD

Director of Research, US

Intercytex

2

Overview

1. The Business Opportunity

2. The Regulatory Environment

3. Cell Therapies

4. ICX-TRC: A Cell Therapy for Hair Restoration

3

The Business Opportunity

4

DiseaseDisease

AgingAging

TraumaTrauma

The Need

5


Cells Matrix Factors

Cell Therapy Tissue Engineering

Family of strategies

Products

6

Receptive Financial Markets

Source: Yahoo Finance; Company Websites; SEC

7 Public Companies7 Public Companies

Average: $124M each

• Aastrom

• Cell Genesys

• Cell Therapeutics

• Geron

• Lifecell

• Stem Cell Innovation

• Stem Cells Inc.

Average: $124M each

• Aastrom

• Cell Genesys

• Cell Therapeutics

• Geron

• Lifecell

• Stem Cell Innovation

• Stem Cells Inc.

Plus 2Plus 2

Average: $111M each

• Curis

• Isolagen

Average: $111M each

• Curis

• Isolagen

Plus 6Plus 6

Average: $234M each

• ACT

• Intercytex

• Stem Cell Sciences

• Stem Cell Therapy International

• Viacell

• Osiris

Average: $234M each

• ACT

• Intercytex

• Stem Cell Sciences

• Stem Cell Therapy International

• Viacell

• Osiris

$870M

$1.0B

$3.5B

0

500

1000

1500

2000

2500

3000

3500

4000

2000 2003 2006

$ M

illio

ns

7

Over 60 Regenerative Medicine Programs in the US

UCSF

UC, Berkeley

Stanford

UCLA

USC

UC, Irvine

Salk Institute

UC, San Diego

Burnham Inst.

La Jolla Inst.

Mol. Med.

U. Washington

Oregon Health Sciences

UtahColorado

Arizona

UT Dallas

Baylor

Rice

UT Galveston

UT Southwestern

Minnesota

UW, MadisonMichigan

Wash U

UABGA Tech

GA Med College

Emory

Clemson

Wake

Duke

USF

U Florida

U Miami

Purdue

Case Western

UVA

Harvard

MIT

Tufts

UMass

Brown

UConn

Yale

Columbia

Mt. Sinai

Sloan Kett.

Rockefeller

UMDNJ

Princeton

Th Jefferson

Penn

Pitt

Carnegie

Hopkins

Cornell

Rochester

Northwestern

U Illinois

Source: TFG Analysis

Potential New Technology

8

Over 90 Programs In Development; 30 Are In Clinical Trials

Over 25 Products Launched

Products in Development By StageProducts in Development By Stage Products in Devel. by Therapeutic AreaProducts in Devel. by Therapeutic Area

Source: ADIS R&D Insight

61

19

11

3

0

10

20

30

40

50

60

70

Preclin Phase I Phase II Phase III

n = 94

2

2

2

2

2

3

4

6

# Products

Other

TiGenix

StemCells

Sangamo

Saneron

ReNeuron

Osiris

Company

Gamida

Freserius

CellMed

Cellerant

Bioheart

Isolagen

Living Cell

Geron

Company

47

2

2

2

2

2

2

# Products

• Skin disorder cell therapy

• Chondrocytes

• ICX PRO (varicose ulcer)

Orthopedic

5%

Derm

7%

Rheum

7%

Endo

15%

SOT

1%Neph

1% Infectious

1%

Ophth

3%

Onc

7%

Hem

10%

Neuro

14%

Other

4%

CV

20%

Hep

4%

GI

1%

New Products under Development

9

Product Sales Revenues Are Increasing

Source: PJB Publications 2003; Equity Research; Company websites; SEC; N/A=Information not publicly available or product not on market; *=Estimated

~$900M~$130MTotal

40.0*10.0VariousVariousOthers

8.80.0SkinAutologous FibroblastsIsolagen

1.2*0.6*CartilageAutologous Chondrocyte ImplantationGenzyme

0.60.5Cartilage (US Trials)Collagen Meniscus ImplantReGen

2.0*1.1*Bone (US)HealosOrquest (DePuy)

23.0*0.5*BMP (US)OP-1Stryker

0.4*1.6CartilageChondrotransplantCo.don

2.0*1.3Skin, Cartilage, BoneBioSeed-S, BioSeed-C, BioSeed Oral BoneBioTissue

20.86.7Skin (US)TransCyte & DermagraftSmith & Nephew

86.08.7Skin, Orthopedics (US)Cell Therapy Product LineIntegra

21.0*20.1OrthobiologicsAGF, Pro Osteon, Bone PlastInterpore

40.0*20.0*Skin (US)ApligrafOrganogenesis

30.0*12.8BoneTutoplastTutogen

52.0*

80.0*

500.0*

2005 ($US,M)

18.4

26.6

0.0

2001 ($US,

M)

Skin, Urology (US)AlloDerm, Cymetra, RepliformLifeCell

Cartilage (US)CarticelGenzyme

BMP (US)INFUSEMedtronic

MarketProductCompany

10

The Regulatory Environment

11

Detlef Niese

Novartis

Nov 2005

Major Business Decisions are Profoundly

Influenced by Regulations

12

Decision to Discontinue Dermagraft

• “Dermagraft is working as a product very well; it’s the

regulatory and reimbursement climate for this particular

dermal fibroblast technology where we have decided that

we had to exit….on a global basis the regulatory framework

for tissue engineering products are not sufficiently well

defined, and we have not been able to get approval for

Dermagraft or Transcyte in either Europe or Japan.”

Sir Christopher O’Donnell: CEO – Smith and Nephew

27th October 2005

13

Cellular wound care products

Regulations to cover how we obtain the tissue, culture the

cells, make the product and test it. (US/UK)

Drug

Regs

(US/UK)

ICX-PRO

(UK)

Device

Regs

(US/UK)

Apligraf

Dermagraft

Biologics

Regs

(U.S. Only)

ICX-PRO

(US)

ATMP

Regs

(Europe Only)

ICX-PRO

(EU)

Unregulated

(UK, and

other

EU states )

MySkin

Cellspray

14

New EU Regulations for Cell Therapies

Richard Woodfield

9th

Nov 2005

15

Discovery

and Preclinical

Phase I

(10 volunteers)

Phase II

(90 patients)

Phase III

(200 patients)

Regulatory review

Development Process

16

Cell Therapies

17

Tissues &Tissues &

organsorgans

Undifferentiated Undifferentiated

cellscells

Differentiated Differentiated

cellscells

MesenchymalMesenchymal

condensatescondensates

OrganOrgan

rudimentsrudiments

Tissues &Tissues &

organsorgans


cellscells


cellscells



OrganOrgan

rudimentsrudiments

TransplantTransplantTransplantTransplant TransplantTransplantTransplantTransplant TransplantTransplant

Cell Therapies

2000-2005

MANUFACTURE OUTSIDE THE PATIENTMANUFACTURE OUTSIDE THE PATIENT

Increasing CostIncreasing Cost

‘‘MANUFACTUREMANUFACTURE’’ INSIDE THE PATIENT: REGENERATION INSIDE THE PATIENT: REGENERATION in situin situ

Increasing FunctionalityIncreasing Functionality

18

Manufacturing a Cell Therapy Product

Procurement Isolation Expansion Formulation Implantation

19

ICX-TRC:

A Cell Therapy for Hair Restoration

20

Structure of a Hair Follicle

Hair Biology

21

Hair Formation in the Embryo

22

The Adult Hair Cycle

Hair Biology

23

Hair Inductive Power of the Dermal Papilla:

Transplanted DP Induces Follicle Regeneration

Truncated

FollicleRegenerated

Follicle

��

Cohen, 1964; Oliver, 1967

24

1964- Cohen shows hair induction from transplanted dermal papilla (DP).

1967- Oliver demonstrates whisker induction using dermal papilla.

1984- Dermal Papilla cells first cultured (human and rat) but without

significant expansion before loss of hair induction.

1984- Jahoda et al show induction of hair growth by cultured dermal

papilla cells.

1992- Jahoda and Reynolds demonstrate cultured dermal papilla cell

induction of hair in non- hairy skin (rat foot pad). (shows

interfollicular epidermis can form hair)

1992- Horne and Jahoda show dermal sheath induction of hair growth

(shows functional equivalence of DP and dermal sheath cells).

1996- Yoshizato et al. culture method to expand DP cells and maintain

hair inductive activity.

40 Years of Supporting Research

��

25

� ��

� ��

��

26

ICX-TRC: A Cell Therapy for Hair Restoration

Autologous cells from a small number of follicles are expanded in

culture and then implanted to induce the growth of many new follicles.


27

ICX-TRC: Practical Challenges

• Manufacture under cGMP

– Cell expansion

• Maintain functionality

– Formulation

• Optimize for hair induction

• Product stability

• Implantation

28

Hair Induction of Human DP Cells in a Mouse Model

Hair Inductive Potency of Cultured Cells

29

Cultured DPC Form DP Structures in Nascent Follicles

Bright Field Hoechst DiI

Hair Inductive Potency of Culture Cells

30

ICX-TRC


31

1. Placement of cells: close

proximity of DP cells with

keratinocytes/epidermis

2. Cell dose: achieve critical

mass and proper hair

thickness.

3. Repetition: many 100’s to

1000’s of doses.

Practical Challenges: Implantations

32

Tissues &Tissues &

organsorgans


cellscells


cellscells



OrganOrgan

rudimentsrudiments

Tissues &Tissues &

organsorgans


cellscells


cellscells



OrganOrgan

rudimentsrudiments

TransplantTransplantTransplantTransplant TransplantTransplant

MANUFACTURE OUTSIDE THE PATIENTMANUFACTURE OUTSIDE THE PATIENT

ICX-TRC Implant Options

Increasing CostIncreasing Cost

33

ICX-TRC: Development

• Iterative Development

• Gradual Emergence of Efficacy

34

35

Conclusions

• Regenerative Medicine as an industry is growing and is

starting to live up to its hype.

• Thoughtful regulation can provide a climate that will

ensure product safety while helping to usher innovative

products to market.

• Regulatory consistency across international borders will

continue to be a challenge.

36

Summary

• In order to reach its potential, regenerative medicine

must be shown to be commercially successful.

• ICX-TRC has the potential to be a huge commercial

success as a permanent solution to hair loss in people

suffering from pattern baldness.

• Its success will encourage further growth in the industry

by demonstrating the principal of regeneration in situ and

through the demonstration that a cell therapy can be a

blockbuster commercial success.

Autologous Skeletal Myoblast Transplantation

For

Cardiac Repair

JST-CRDS workshop

November 1, 2006

TERUMO Corporation

Inductive strategy:

Cell therapy for Angiogenesis

Restorative strategy�Cell therapy for Cardiomyoplasity

Ischemic Myocardium

Regenerative medicine for Ischemic Heart Disease

Blocked

Coronary

Artery

Injured Tissue

Myobalst Transplantation for IHD

Diacrin Inc. (Mytogen Inc. at present, Boston, USA)

Phase 1 Clinical Trial had started in 2000

In 2002 Terumo alliance with Diacrin

Technology transfer for

• Establishment Cell processing with GMP

• Pre Clinical Test

• Design of clinical study in Japan

Myoblast processing with GMP

Quality Control

Skeletal Muscle

Biopsy

Cell

Transplantation

Cell Separation

Cell Culture

Package

Present situation of Terumo

1st

step

Review by MHLW for application for verification of

drugs and medical devices using cells and tissues

Notification No.906, 1314 of the Evaluation and Licensing Division

(��906� �� !)

(��1314� "#$%��&'��(��)*+,-)

2nd

step

Clinical trial consultation by the PMDA

Review of Clinical Study Protocols as a drug or a device

TERUMO

Submitted table of contents

• Origin or background of

discovery, conditions of use in

foreign countries

• Manufacturing

• Quality Control and Quality

Assurance

• Stability

• Pre Clinical Study

• Discussion of risk and benefit

based on quality, safety,

stability and efficacy.

• Facility and Equipment

• Clinical protocol and informed

consent

Problem examples on QA/QC

Purity

There are non-Myoblast cells in the muscle.

What is an acceptable purity?

Function

Myoblast is a progenitor cell of muscle fiber.

How to evaluate the potency?

Tumorigenicity

How to contradict tumorigenic ability?

Problems in Terumo’s case example

Opinion from Terumo’s experience

• There are two notifications (No. 906, 1314 ) concerning with

Human cells and tissues products in Japan.

• These notifications were based on some working studies

with MHLW grant system 7-9 years ago. There were a few

cellular products at that time.

• Update and New Guideline is required.

Alternative researches and test procedures are developing in this field.

A step-wise approach to regulation requirements is acceptable or not?

Advisory Committee and continual on-time meeting

for Cellular/Tissue products are necessary

�� Towards Industrialization Promotion of the Towards Industrialization Promotion of the

Regenerative MedicineRegenerative Medicine

�� Demand for Regulation and GuidelineDemand for Regulation and Guideline

JST-CRDS Regenerative Medicine Strategy Workshop

November 1, 2006

BCS, Inc.

Masaharu Inami

JST-CRDS Regenerative Medicine Strategy Workshop

November 1, 2006

BCS, Inc.

Masaharu Inami

The Current SituationsThe Current SituationsThe Current Situations

� There is no industrialized regenerative medicine material

(or cell tissue medical devices) based on the

manufacturing approval

��

� The number of the applicant is changing within one digit

range and there is no more company follows after 2004

!"#$%&'()*+,--./0123456�7�

� There is no industrialized regenerative medicine material

(or cell tissue medical devices) based on the

manufacturing approval

��

� The number of the applicant is changing within one digit

range and there is no more company follows after 2004

!"#$%&'()*+,--./0123456�7�

Why are the Applicant is Little?Why are the Applicant is Little?

� No clear inspection guideline there to be shown

��

� The load of the document preparation is large

��

� No way to conjecture the endpoint (time required for the inspection)

�� !"#$)�%&'��

� Due to the frustration to draw up an accurate budget, the explanation to VC

is difficult then results in financial difficulties

(��)*�+,��'VC-.�/��012�345��67�80

� There is no guarantee that medical insurance will cover some patient’s

payment

9:;<��"9=��

� Whether the corresponding value will be obtained equivalent to the amount

of the investment is not guaranteed

>�?�@ABCD�EF�"G�9=��

� No clear inspection guideline there to be shown

��

� The load of the document preparation is large

��

� No way to conjecture the endpoint (time required for the inspection)

�� !"#$)�%&'��

� Due to the frustration to draw up an accurate budget, the explanation to VC

is difficult then results in financial difficulties

(��)*�+,��'VC-.�/��012�345��67�80

� There is no guarantee that medical insurance will cover some patient’s

payment

9:;<��"9=��

� Whether the corresponding value will be obtained equivalent to the amount

of the investment is not guaranteed

>�?�@ABCD�EF�"G�9=��

In the cell tissue medical devices, the hurdle of

the manufacturing approval is high

(especially, for confirmation application)

��

Which is ahead, the chicken or the egg?Which is ahead, the chicken or the egg?Which is ahead, the chicken or the egg?

What the inspection side says

��

� The applicant (Venture Business) does not well understand

the regulation law and the government system

��VB� !"�#$%&'()*+�,�

� The document writing is childish in the description and

format

-./0�12345�678"�9:etc.�

� Because the concrete guideline is not ready yet, the

adequate instruction is difficult to show

;<=,>?�@?A�BC�DE+�5FG�=�,HI�J*�KLM

45

What the inspection side says

��

� The applicant (Venture Business) does not well understand

the regulation law and the government system

��VB� !"�#$%&'()*+�,�

� The document writing is childish in the description and

format

-./0�12345�678"�9:etc.�

� Because the concrete guideline is not ready yet, the

adequate instruction is difficult to show

;<=,>?�@?A�BC�DE+�5FG�=�,HI�J*�KLM

45

Which is ahead, the chicken or the egg?Which is ahead, the chicken or the egg?Which is ahead, the chicken or the egg?

What the applicant side says

��

� Not yet a clear inspection criterion for references

��

� Not yet a document format guidance for references

��

� Neither enough instruction nor advice is available

��

What the applicant side says

��

� Not yet a clear inspection criterion for references

��

� Not yet a document format guidance for references

��

� Neither enough instruction nor advice is available

��

Since there is neither a clear inspection criterion nor a guideline available, the

applicant can not prepare an expected document

�� !�"

The venture business is a supporter for the challenging product development

over the world

#$%& '()*�+,-.�/�0123456�7"89�:;"�

It is necessary to assume the similar situations, and to change the mind of the

inspection officers

<&'=>9?@A��%B ��CDE�FG�H�

Demand for Regulation and GuidelineDemand for Regulation and Guideline

The guideline of each human tissue should be clear one

by one. It should be necessary to show earlier the

inspection criterion and guideline, as the common

contents in the human tissue inspection

�� !��

��"#$%��&'()*�+,-.�

The guideline of The guideline of eacheach humanhuman tissue should be clear tissue should be clear oneone

by oneby one.. ItIt should beshould be necessary tonecessary to show earlier the show earlier the

inspectioninspection criterion and guideline, as the criterion and guideline, as the commoncommon

contentscontents inin the human the human tissue inspectiontissue inspection

�� !�� !��

��"#$%��&'()*�+,-.��"#$%��&'()*�+,-.�

• Expected consideration

��IJKL

• Set up a new category in which cell tissue medical device is included

MNOPQRSTCUVW�XYZ[2%\]

• Distinguish the autograft and allograft

^_9=`%ab

• Evaluate the safety and risk for the material and manufacturing

c��+de�fW�ghij[6klme

• Evaluate the safety and risk for the ectopic graft as well as other products

• (autograft cultured skin and cultured cartilage, etc.)

nopq9r%s+,t^_uvwx�uvyz{|%ghij[6klme

• Risk & benefit

}[6k~/5��

Demand for Regulation and Guideline Demand for Regulation and Guideline --11

� Set up a new category in which cell tissue medical device

is included

��

� Due to its different nature, function, features from the usual

medicine and medical equipment, a new category is necessary

�� !� "�#$%&'(�)*��+(��,-./01�

� It can be considered that inspection criterion will become clear if

there is new category

��, �2�345�6789:;<3��=>?�

� Distinguish the autograft and allograft

@A�BC�DE

� Autograft and allograft are obviously different in applying purpose,

manufacturing, and handling, so it is necessary to distinguish

between them

@A�BC��FGHI�JKL�M5N(3O(';PQ3��:�015�DR �./-1�

� Set up a new category in which cell tissue medical device

is included

��

� Due to its different nature, function, features from the usual

medicine and medical equipment, a new category is necessary

�� !� "�#$%&'(�)*��+(��,-./01�

� It can be considered that inspection criterion will become clear if

there is new category

��, �2�345�6789:;<3��=>?�

� Distinguish the autograft and allograft

@A�BC�DE

� Autograft and allograft are obviously different in applying purpose,

manufacturing, and handling, so it is necessary to distinguish

between them

@A�BC��FGHI�JKL�M5N(3O(';PQ3��:�015�DR �./-1�

� To evaluate the safety and risk for material and manufacturing

ST�JKL3U �VW X�YZ[\

� The analysis method, Quality Control Standard Code, the stability evaluation

method, and the safety evaluation method, etc. are established for medicine,

while not yet for cell tissue medical equipment

��E]8L��!^_`a�Vb [\L�VW [\Lc-b*P?'(�-��

��3O('�deb

� Evaluate the safety and risk for the ectopic graf as well as other

products (autologous cultured skin and cultured cartilage, etc.)

�fgh�i�jJ�k@Almno�lmpqcr��YZ[\

� It is considered that a basic risk difference between the ectopic graft and the

materials only returning to the human body by simply culturing, though the

ectopic graft is considered as an autograft materials expected to be the

transformation

@A��(s��fghkt!uvwx �STcr��X��yzlm+{|3} ~��ST

��`�I��YZ�-�� sP?�

� To evaluate the safety and risk for material and manufacturing

ST�JKL3U �VW X�YZ[\

� The analysis method, Quality Control Standard Code, the stability evaluation

method, and the safety evaluation method, etc. are established for medicine,

while not yet for cell tissue medical equipment

��E]8L��!^_`a�Vb [\L�VW [\Lc-b*P?'(�-��

��3O('�deb

� Evaluate the safety and risk for the ectopic graf as well as other

products (autologous cultured skin and cultured cartilage, etc.)

�fgh�i�jJ�k@Almno�lmpqcr��YZ[\

� It is considered that a basic risk difference between the ectopic graft and the

materials only returning to the human body by simply culturing, though the

ectopic graft is considered as an autograft materials expected to be the

transformation

@A��(s��fghkt!uvwx �STcr��X��yzlm+{|3} ~��ST

��`�I��YZ�-�� sP?�

Demand for Regulation and Guideline Demand for Regulation and Guideline --

� "Risk & benefit”

��

� "Risk & benefit" should be only based on to patient's standpoint

��

� It should be a common theme between the manufacturer and the

inspection officer the to quickly provide the cell tissue medical

equipment which safety and quality are guaranteed, and efficacy

can be expected

!"#$%&'()�#*��+,-./�0123456789&:;<=>?1@�ABCD

EFG�HIJK�L1

� "Risk & benefit”

��

� "Risk & benefit" should be only based on to patient's standpoint

��

� It should be a common theme between the manufacturer and the

inspection officer the to quickly provide the cell tissue medical

equipment which safety and quality are guaranteed, and efficacy

can be expected

!"#$%&'()�#*��+,-./�0123456789&:;<=>?1@�ABCD

EFG�HIJK�L1

Demand for Regulation and Guideline Demand for Regulation and Guideline --33

For an efficient regulation and guideline operationFor an efficient regulation and guideline operation

NIID

University &

research institutes

Company

Doctors

Patients

Researches on analysis, Quality

Control, stability, and safety

evaluation applied in inspection

Inspection and approval

Application

for approval

Product

supply

Create an environment in which research to reach a rational judgment reflecting

academic level at that time and the research results can be industrialized

�� !"#$!

NIHS

Research, Data Control,

Data Evaluation & Report

PMDA MHLW

Report

13

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Nov. 1, 2006 Mitsuaki Yamamoto, M.D., Ph.D.

The Promotion Strategy for Life Sciences based

on the 3rd

Science & Technology Basic Plan

� Preferentially allocate resources on selected subjects.

� Comprehensively promote clinical research including regenerative

medicine with a Strategic Prioritized S&T, Clinical Research and

Translational Research.

Main points:

1) Develop and strengthen the infrastructure to support the researches.

2) Develop and secure human resources for the researches.

3) Improve infrastructure for promoting the researches and for the

examination of applications for approval, especially by improving

the infrastructure of Pharmaceuticals and Medical Devices Agency.

4) Promote people engagement in and commitment on the researches.

Nov. 1, 2006 Mitsuaki Yamamoto, M.D., Ph.D.

CSTP Activities for Promoting Clinical

Research and Translational Research

� Coordinate related projects/programs for clinical research/ translational

research in ministries and promote them as a harmonized one.

Main projects/programs are:

� Coordination, Support and Training Program for Translational

Research (MEXT)

� Project for Developing Clinical Study Infrastructure (MHLW)

� Development of Technology for Promotion of Translational

Research (METI)

� Presented the importance of the regenerative medicine in a recent

Council’s Meeting hosted by the Prime Minister (Oct. 27) .

11

Industrialization of Cellular TherapyIndustrialization of Cellular Therapy

Hiromichi KimuraHiromichi Kimura

The University of TokyoThe University of Tokyo

November 1, 2006November 1, 2006

22

Patients and Public: suspiciousPatients and Public: suspicious

�� Risk averse in accepting new technologyRisk averse in accepting new technology

�� Huge perceptual gap between Huge perceptual gap between ““safetysafety”” andand ““comfortcomfort””

Industry: major players do not participateIndustry: major players do not participate

�� Pharma companies: different business model Pharma companies: different business model

�� BioBio--ventures: low credibilityventures: low credibility

Government: do not have enough incentive to promoteGovernment: do not have enough incentive to promote

�� Insufficient capability, experience, budget and networkInsufficient capability, experience, budget and network

�� Healthcare expense control is of their top priorityHealthcare expense control is of their top priority

Medical Communities: cannot take initiativeMedical Communities: cannot take initiative

�� Unmet medical needs, e.g. corneaUnmet medical needs, e.g. cornea--autograftautograft

�� Not enough incentive to participate in clinical trialsNot enough incentive to participate in clinical trials

Academia: not interested in businessAcademia: not interested in business

�� Reasonable quality of cell biologists, butReasonable quality of cell biologists, but……..

�� Starving for research fundStarving for research fund

Different agenda: Are they in the same boat?Different agenda: Are they in the same boat?

Stakeholders in Japan Market Stakeholders in Japan Market

33

Return on Investment is UnpredictableReturn on Investment is Unpredictable

�� ReturnReturn

�� Pricing is out of control: Outcome research is not applied.Pricing is out of control: Outcome research is not applied.

�� Limited market size: highLimited market size: high--end niche marketend niche market

�� Competitive original technology? To cover global market?Competitive original technology? To cover global market?

�� Will payment be fully insured?Will payment be fully insured?

�� InvestmentInvestment

�� Expensive R&D for challenge of science and technologyExpensive R&D for challenge of science and technology

�� Timing to launch is uncertain due to moving regulationsTiming to launch is uncertain due to moving regulations

�� Personalized market with high COGS, cost of MSG Personalized market with high COGS, cost of MSG

Can it really make money?Can it really make money?

Do you really invest ?Do you really invest ?

44

Human Resource Development for Human Resource Development for

MManagement Leaders anagement Leaders

How to How to ““make it happenmake it happen”” under difficult business environment?under difficult business environment?

------ Right person should be on the driverRight person should be on the driver’’s seat.s seat.------

��Mind set: Challenge for Innovation, entrepreneurshipMind set: Challenge for Innovation, entrepreneurship

��Skill set : Science and technology, business, medical ethicsSkill set : Science and technology, business, medical ethics

Job Rotation and Cross Internship among Job Rotation and Cross Internship among

FDA/EMEA/PMDA/Medical Center/Industry/Academia FDA/EMEA/PMDA/Medical Center/Industry/Academia

could be of help.could be of help.

1

OUTLINE OF SURVEY

1.CONCEPT; To know the public thoughts about regenerative medicine

2.AIM; In the process of development of new medical technology, the stage of

experimental challenge involved with patients is unavoidable. To prevent

troubles derived from misconception, mutual understanding between patients

and doctors is necessary. To establish good and meaningful communication,

we have to know the thoughts, impression, and the level of medical and ethical

base of the public.

3.DATE PERFORMED; Jan, 2006 (FYR; Korean ES cell scandal disclosed on Oct,

‘05)

4.STUDY POPULATION; Public member of (NPO) HAB Research Institute. Most

people are interested in progress in medical research.

5.PERCENT OF RESPONDERS; 49.8% (217 out of 450)

6.CONTENTS; 10 questions (choice and comments) about regenerative medicine

classified by types of stem cells, I.e., ES cells, mesenchymal stem cells, adult

somatic stem cells, fetal stem cells. Answer anonymous

7.Sponsored by Japan Science and Technology Agency (JST)

SURVEY OF PUBLIC OPINIONAIRE ABOUT

REGENERATIVE MEDICINE

Shin Enosawa, National Research Institute for Child health and Development, Tokyo, Japan

2

Although the assent to use of ES cells and fetal stem cells was low, there is a large

expectation toward regenerative medicine.

On the other hand, individual thoughts were diverse. Doctors should know and be

tolerant of different views.

ex. I will accept any fate and will not try advanced medical care (male, 50’s). I can

not imagine who donates fertilized eggs (female, 40’s, under fertility treatment). To

keep Japanese scientific technology at the world top level, we should promote the

research of regenerative medicine (male, 60’s)

PROPOSAL

1. To promote sound development of regenerative medicine, persons who support

mutual understandings between patients and doctors is necessary.

2. Based on general framework of protecting human subjects including the system

suggested above, clinical research is performed under clinical doctor’s professional

discretion and responsibility (the development of living-related liver transplantation in

Japan may be relevant).

BRIEF SUMMARY OF THE SURVEY

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Hope active research careful advance reluctant to push do notadvance no way of telling no answer

15

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Clinical Studies in Particular Medical Institutions (approx. 20 cases)

Safety confirmation of this medical procedure

Establishment of Infallible Medical Treatment Procedures

From investigation to practice

Therapy by medical treatment at patient’s expense

Product Approval as Drugs or Medical Devices

Adoption of New Regenerative Medicine SystemAdoption of New Regenerative Medicine System

Prompt adoption of system that certifies the advanced medical treatments using the

new operative procedures and the unapproved regenerative medicine materials

Clinical Studies in Some Medical Institutions

(ex. 3 institutions, 5 – 10 cases)

Establishment of operative procedure

Operation fees and Material fees (based on manufacturing cost)

Health Insurance Treatment

Akira Kitagawa,Ph.D. ArBlast Co.,Ltd.

PALPAL

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November 1, 200November 1, 20066

Japan Tissue Engineering Co., LJapan Tissue Engineering Co., Ltdtd��

Senior Managing Director Toshihiro Osuka

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Superstar for Regenerative Medicine

Judges?

Field Players?

Rule book?

Sciences

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Impossible to manufacture by definite process

Impossible to get definite products

New guideline should be established for contract manufacturing

Faster delivery of more efficient and more safety cell/tissue-

based product for patient’s benefit

Business model for autografts is contract manufacturing

under medical prescription

Existing Guidelines are not applicable to Autografts

Approval for contract manufacturing by private sector in place of

manufacturing of cell/tissue-based products in medical

institutions/hospital for clinical research and advanced medical therapy

To establish guidelines on standardization of cell/tissue source,

manufacturing process and products and guidelines on safety test and

efficacy test, private sector should be involved in clinical research and

advanced medical therapy and should provide GMP/GCP support.

Background:

Not correspond to traditional category( traditional guideline for drug and

medical device is not adjusted to cell/ tissue products)

Biological safety test for drug is not applicable to cell/tissue-based products

Animal model is not always available for efficacy test and is not easy

to evaluate because of immunological response

Contamination of immunogenic materials derived from animals is unavoidable

Biological safety tests for tumorigenecity and immunogenicity

for cell/tissue-based products.

Basic methods for efficacy test and evaluation

Risk evaluation criteria for usage and residual quantity

Establishment of new category for cell/tissue-based products

Guideline for auto, allo and xeno graft (Primary: autograft)

Requirements for safety verification and requirements for manufacturing

approval for production is not clear and it is impossible to estimate when

screening process will finish and what stage we are in the screening process

Requirements for screening and time clock

Design for Guideline toward cell/tissue-based products

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