˘ˇˆ˙˝˛˚ - jstintegrative celerity research icr basic research clinical epidemiology...
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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�
7
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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
Regenerative Medicine
• 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?
Regenerative Medicine
• 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
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).
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
institutional review board and also by the Government
Clinical research using adult stem cells must also be approved by the
institutional review board and also by the Government
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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cellculture
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Inhibition of the self-sustaining innovation
in the regenerative medical field
����� ������
� � � �Yuji Tokumasu
Director of Biochemical Industry Division,
Ministry of Economy, Trade and Industry
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As scientific technology is rapidly evolving, can physicians themselves
understand and use leading-edge technologies in all fields of medicine?
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The abstruse discussion of “whether cells are medical devices or
drugs” is meaningless. We should consider not how to apply new
technologies and products to the existing systems/regulations, but how
to use them safely in medical practice.
���������For whom is regenerative medicine needed?
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The balance between risks and benefits that responds to the rapid
progress of scientific technology and changes in the social situation.
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of new technologies and products.
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Consideration for the business status and the social (national) meanings
of venture companies and new technologies without markets.
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in the medical field.
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We should consider a new institutional framework to address
new technologies,
decide what direction we should take as a nation (or for the
people), and take concrete measures for it.
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1
Product Development Challenges In
Regenerative Medicine
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
Regenerative Medicine
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
Undifferentiated Undifferentiated
cellscells
Differentiated Differentiated
cellscells
MesenchymalMesenchymal
condensatescondensates
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
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� ��� ��������������������
��������������� ��������
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.
Procurement Isolation Expansion Formulation Implantation
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
Procurement Isolation Expansion Formulation Implantation
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
Undifferentiated Undifferentiated
cellscells
Differentiated Differentiated
cellscells
MesenchymalMesenchymal
condensatescondensates
OrganOrgan
rudimentsrudiments
Tissues &Tissues &
organsorgans
Undifferentiated Undifferentiated
cellscells
Differentiated Differentiated
cellscells
MesenchymalMesenchymal
condensatescondensates
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
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Demand for Regulation and Guideline Demand for Regulation and Guideline --33
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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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ES cell
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��
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��
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stem cell
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Mesenchymal
stem cell
�
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Fetal
stem cell
Q6; What do you think
about regenerative
medicine with ES cells,
mesenchymal stem
cells, somatic stem
cells, fetal stem cells ?
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.
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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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Proposal (macroscopic & microscopic)
Superstar for Regenerative Medicine
Judges?
Field Players?
Rule book?
Sciences
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Impossible to get cell source with definite quality
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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