I. Potential II. Classification III. Clinical research IV. Patient demand V. Regulatory and legal framework - USA - Europe VI. Professional societies https://www.aretezoe.com/stem-cells

1. A S P E C I AL C AS E O F T H E R AP Y & R E S E AR C H
STEM CELL THERAPIES

2. CONTENT
• I. POTENTIAL
• II. CLASSIFICATION
• III. CLINICAL RESEARCH
• IV. PATIENT DEMAND
• V. REGULATORY AND LEGAL FRAMEWORK
• USA
• Europe
• VI. PROFESSIONAL SOCIETIES

3. I. STEM CELLS POTENTIAL
BASIC RESEARCH – DRUG TESTING - THERAPIES

4. • Basic research
• Cell division and differentiation
• Genetic and molecular controls
• Testing new drugs
• Safety testing on pluripotent lines
• Cancer cell used for efficacy
testing of new treatments
• Cell-based therapies
• Renewable source of
replacement cells and tissues
Stem cells offer tremendous
promise for advancing
health and medicine: They
hold the potential to
replace damaged cells and
organs or else by supporting
the body’s intrinsic repair
mechanisms. One day they
may be used to treat such
debilitating conditions as
Parkinson’s disease,
diabetes, and spinal cord
injury
POTENTIAL

5. ©2008 Terese Winslow

6. Source: NIH
• Proliferate extensively and generate sufficient quantities of
cells for making tissue.
• Differentiate into the desired cell type(s).
• Survive in the recipient after transplant.
• Integrate into the surrounding tissue after transplant.
• Function appropriately for the duration of the recipient's life.
• Avoid harming the recipient in any way.
• Avoid immune rejection.
Stem cells must be manipulated so that they possess the necessary
characteristics for successful differentiation, transplantation, and engraftment.

7. II. CLASSIFICATION
DIFFERENTIATION POTENTIAL & ORIGIN

8. • TOTIPOTENT
• Embryonic, first 4 days
• Most versatile, can form the
whole body
• PLURIPOTENT
• Embryonic, after 4 days
• Inner layer (excl. placenta)
• MULTIPOTENT
• Less plastic
• More differentiated
• ADULT (multipotent)
• Undifferentiated cell present
in differentiated tissue
STEM cells are classified by
their origin and ability to
differentiate in specialized
tissues and organs.
Embryonic stem cells can
form wide range of cells.
Adult stem cells are
multipotent stem cells
present in differentiated
tissue that can specialize
in any cell within the tissue
in which it originated.
CLASSIFICATION

9. Morula
Blastocyst
Inner Cell Mass (ESCs)
Epiblasts (ESCs)
ENDODERM MESODERM ECTODERM
TotipotentPluripotentMultipotentUnipotent
EMBRYONICADULT
Tissue-Specific Stem Cells (TSSCs)

10. ENDODERM MESODERM ECTODERM
MultipotentUnipotent
ENDODERM
LUNG PANCREAS LIVER GIT UGT
Pulmonary
Epithelial SCs
Pancreatic
SCs
β - cells
α - cells
γ - cells
Hepatic
Oval Cells
Hepatocytes
Gastro-
Intestinal
Tract SCs
Uro-
Genital
Tract SCs

11. ENDODERM
MultipotentUnipotent
ENDODERM
KIDNEY BONE & BONE MARROW
BLOOD
VESSELS
HEART
Kidney Hematopoietic
SCs
Leukocytes
Erythrocytes
Thrombocytes
Mesenchymal
Stromal SCs
Osteoblasts
Chondrocytes
Adipocytes
Myoblasts
Endothelial
SCs
Cardiac
SCs
ECTODERMMESODERMMESODERM

12. Bonfield, TL: Adult Mesenchymal Stem Cells: An Innovative Therapeutic for Lung Diseases (Discovery Medicine, 2010)

13. ENDODERM
MultipotentUnipotent
ENDODERM
NERVOUS SYSTEM SKIN
Ocular SCs Neural SCs
Neurons
Astrocytes
Oligodendrocytes
Skin SCs
ECTODERMMESODERM ECTODERM
EYE

14. EMBRYONIC STEM CELLS
M O U S E E M B R Y O N I C S T E M C E L L S F O R M I N G S T E M C E L L C O L O N I E S
O N A F I B R O B L A S T F E E D E R L A Y E R ( P E R K I N E L M E R ) .

15. ADULT STEM CELLS
A D U L T S T E M C E L L S C A N B E E X T R A C T E D F R O M M A N Y A R E A S O F T H E
B O D Y , I N C L U D I N G T H E B O N E M A R R O W , F A T , A N D P E R I P H E R A L B L O O D .

16. III. CLINICAL RESEARCH
I N D I A , C H I N A , M E X I C O , U S A , E U
S U B S T A N T I A T E D C L A I M S O F T E N A B S E N T
R I S K : B E N E F I T U N C L E A R
Stem cell treatments offered around the world:
• Allogeneic (from other humans), xenogeneic (animals and plants)
• Autologous stem cells: extracted from an individual, manipulated, and
reinfused or re-implanted back into the same person
• The use of tissue-specific stem cells
• Procedures offered by clinics vs. online (skincare)
The FDA “is concerned that the hope that patients have for cures not yet available may leave them vulnerable
to unscrupulous providers of stem cell treatments that are illegal and potentially harmful [and that] FDA will
pursue perpetrators who expose the American public to the dangers of unapproved stem cells” (FDA, 2012).

17. CLINICALTRIALS.GOV
ALL STEM CELL TRIALS
Total: 5,101 studies
Europe: 1,157 studies
Poland: 328
Germany: 287
Italy: 239
UK: 203
Spain: 198

18. CLINICALTRIALS.GOV
ALL STEM CELL TRIALS
Approved for marketing: 1
Available: 12
Recruiting: 1,702
Enrolling by invitation: 77
Completed: 1,769
Active, not recruiting: 782
Not yet recruiting: 234
No longer available: 7
Temporarily not available: 2
Suspended: 40
Terminated: 352
Withdrawn: 123
Interventional: 4,514
Observational: 565
Expanded access: 22
RESULTS:
Available: 366
None posted: 4,735
44
835 799
1418
113
401
125
1000
0
200
400
600
800
1000
1200
1400
1600
0 I I - II II II - III III IV not
stated
STEM CELL TRIALS BY RESEARCH PHASESTOTAL: 5,101 STUDIES

19. CLINICALTRIALS.GOV
ALL STEM CELL TRIALS
2627
750
494
456
320 88
Other
Other + NIH
Industry
Other + Industry
NIH
Combinations
TRIALS BY SOURCE OF FUNDING
Sponsor Trials
Fred Hutchinson Cancer Research Center 192
National Cancer Institute (NCI) 177
M.D. Anderson Cancer Center 148
Memorial Sloan Kettering Cancer Center 100
National Heart, Lung, and Blood Institute (NHLBI) 91
Masonic Cancer Center, University of Minnesota 80
City of Hope Medical Center 72
Children's Oncology Group|National Cancer Institute
(NCI) 59
St. Jude Children's Research Hospital 57
Baylor College of Medicine 53
Mayo Clinic 51
National Institute of Allergy and Infectious Diseases (NIAID) 44
Dana-Farber Cancer Institute 42
Northwestern University 42
Stanford University 40
Royan Institute 39
Washington University School of Medicine 39
Assistance Publique - HĂ´pitaux de Paris 38
Emory University 38
Sidney Kimmel Comprehensive Cancer Center 38
Hadassah Medical Organization 33
Case Comprehensive Cancer Center 31
Seoul National University Hospital 30
University of Michigan 29
University of California, San Francisco 28
Duke University 27
National Institutes of Health Clinical Center (CC) 27
Genzyme, a Sanofi Company|Sanofi 25
Massachusetts General Hospital 23
Medical College of Wisconsin 22
Asan Medical Center 21
Barbara Ann Karmanos Cancer Institute 21

20. CLINICALTRIALS.GOV
ALL STEM CELL TRIALS
Bacterial and Fungal Diseases
Behaviors and Mental Disorders
Blood and Lymph Conditions
Cancers and Other Neoplasms
Digestive System Diseases
Diseases and Abnormalities at or Before Birth
Ear, Nose, and Throat Diseases
Eye Diseases
Gland and Hormone Related Diseases
Heart and Blood Diseases
Immune System Diseases
Mouth and Tooth Diseases
Muscle, Bone, and Cartilage Diseases
Nervous System Diseases
Nutritional and Metabolic Diseases
Occupational Diseases
Parasitic Diseases
Respiratory Tract (Lung and Bronchial) Diseases
Skin and Connective Tissue Diseases
Substance Related Disorders
Symptoms and General Pathology
Urinary Tract, Sexual Organs, and Pregnancy
Conditions
Viral Diseases
Wounds and Injuries
0
500
1000
1500
2000
2500
NeoplasmsbyHistologicType
ImmuneSystemDiseases
LymphoproliferativeDisorders
HematologicDiseases
ImmunoproliferativeDisorders
Leukemia
Lymphoma
Lymphosarcoma
VascularDiseases
LymphaticDiseases
Leukemia,Myeloid
Neoplasms,PlasmaCell
BoneMarrowDiseases
MultipleMyeloma
Leukemia,Myeloid,Acute
BloodCoagulationDisorders
HemostaticDisorders
HemorrhagicDisorders
AcuteMyelocyticLeukemia
Conditions tested

21. CLINICALTRIALS.GOV
37 EMBRYONIC STEM CELL TRIALS

22. CLINICALTRIALS.GOV
285 UMBILICAL STEM CELL TRIALS

23. CLINICALTRIALS.GOV
529 MESENCHYMAL STEM CELL TRIALS
Middle East: 47
Iran (30)
Europe: 123
Spain (49)

24. CLINICALTRIALS.GOV
4,968 ADULT STEM CELL TRIALS
Poland: 322
France: 276
Italy: 235
Spain: 195
UK: 190
Israel: 110
Iran: 51
Turkey: 28

25. WHO REGISTRY ICTRP
5,401 RECORDS FOR 4,804 TRIALS

26. STEM CELLS IN PUBMED
233,458 RESULTS, OF WHICH 4,412 ARE CLINICAL TRIALS

27. IV. PATIENT DEMAND
COMMUNICATION OF BENEFITS AND RISKS

28. CHALLENGES
IN RESEARCH AND THERAPY INVOLVING STEM CELLS
The best ways to regulate stem cell therapies remain unclear. Stem cells have characteristics that
distinguish them from drugs, biologics, or medical devices. Considerable body of science has not
yet been accumulated to develop and deliver safe and effective treatments.
Regulatory uncertainty:
Countries have taken different approaches to
the regulation of stem cell research and
therapies, and enforcement of existing
regulations also differs. As a result, patients
who are willing and able to travel from one
country to another can access treatments
that are not available in their home countries.
Advertising strategies:
In an effort to attract patients, clinics offering
stem cell therapies have engaged in
advertising on the Internet and elsewhere
which is often misleading. This advertising can
lead patients to spend large amounts of
money on treatments that may not be
effective and may even be harmful.
Generating needed information:
Governments, professional associations,
patient groups, and other organizations all
can help generate the information needed to
develop effective regulations and allow
patients to make informed choices. Self-
regulation by the providers also could help
protect patients and the legitimacy of stem
cell research and therapies.
Needs and autonomy of patients:
Patients are frustrated at not being able to
access potentially effective stem cell
treatments, some of which are being studied in
clinical trials, some not. Governments have an
obligation to protect patients from ineffective
therapies and fraudulent advertising; public
policies could also reflect the needs of patients
autonomy in making medical decisions.
NAP: Stem cell therapies (Nov 2014)

29. KNOWNS AND UNKNOWNS
NAP: Stem cell therapies (Nov 2014)
• •Objective outcome measures would be useful for assessing the
effectiveness of stem cell therapies
• Marketing claims by clinics offering stem cell therapies are not
necessarily supported by clinical evidence in the scientific literature
• Unproven stem cell treatments can harm patients by leading to
complications such as tumors, meningitis, or even death
• Patients who have no other treatment options may be willing to take
these risks if there is a slight chance of success. •
Improved communication of clear information about treatment benefits and risks as
well as about the value of safety regulations would be useful for patients.

31. • Patients
• Difficult to estimate true numbers of
patients seeking stem cell
treatments in the U.S. and overseas
• Main destinations
• China, Mexico, Germany, the
Dominican Republic, India, Russia
• Conditions treated
• Blindness, paralysis, multiple
sclerosis, cerebral palsy, brain
injuries and brain damage
• Within or outside a clinical trial
• Complications
• Tumor growth, meningitis, death
• Effectiveness highly uncertain
• Financial: $20,000 to 50,000
When patients are
desperate, they may
turn to experimental or
unproven treatments:
“I may die anyway, but
at least I died fighting.
This is an experiment.
What did I have to
lose?”
PATIENT
PERSPECTIVE

32. I N N O V A T I V E S U R G E R Y I S G O V E R N E D B Y T H E C O M M O N R U L E W H I C H
I M P O S E S R E S T R I C T I O N S S I M I L A R T O T H A T O F C L I N I C A L T R I A L S .
PATIENT EXPERIENCES

33. IV. STEM CELLS AS REGUATED
THERAPEUTICS

34. APPROVED STEM CELL TREATMENTS
ARE FEW AND FAR BETWEEN

35. APPROVED STEM CELL TREATMENTS
ARE FEW AND FAR BETWEEN

36. REGULATORY AND LEGAL FRAMEWORKS
Stem cell therapies are regulated as biologics and are subject to premarket approval
under the risk-based approach to approving cellular and tissue-based products.
Treatments that are “minimally manipulated” are exceptions to this regulation.
European Union law states that cells or tissues that are “substantially manipulated”
are subject to regulation; however, an exemption is given to member states in the
non-routine case of custom-made treatments for individual patients.
Innovation, including innovation in stem cell research, was made a national priority,
and new laws regarding regenerative medicine products are expected to provide a
more efficient path to the translation of these therapies to the clinic.
Mexico has benefited economically from offering stem cell therapies that are not
available in other countries. Regulations for cells and tissues treatments based on
evidence would address challenges relating to therapy, safety, and efficacy.
While stem cell therapies offered in China must be registered, there are not yet
approved quality control guidelines available.

37. 1995 2000 2005 2010 2015
U.S. POLICY
REGARDING STEM CELL RESEARCH
1996 The Dickey-
Wicker Amendment
2000 NIH guidelines for
research using human
pluripotent stem cells
go into effect
2001 President Bush
prohibits federal
funding of most
human embryonic
stem cell research
2005 Congress passes the Stem
Cell Research Enhancement Act
(H.R. 810), vetoed by Pres. Bush
2007 Congress passes the
Stem Cell Research
Enhancement Act (S. 5),
vetoed by President Bush
2011 U.S. District Court rules
in favor of hESC research in
Sherley v. Sebelius
2009 Sherley v.
Sebelius filed
2009 President
Obama reverses
2001 executive order
2013 SCOTUS
declines to hear
Sherley v. Sebelius
Source: Research America

38. U.S. POLICY
REGARDING STEM CELL RESEARCH
Executive Order 13505
Removing Barriers to Responsible
Scientific Research Involving Human
Stem Cells
The March 9, 2009 EO changes the way
NIH can support and conduct human
stem cell research.
NIH Guidelines on Human Stem Cell
Research (July 2009)
The guidelines pertain primarily to the
donation of embryos for the derivation
of hESCs, human induced pluripotent
stem cells, and research involving
human adult stem cells.
Presidential
statement
Aug 2001
EO 13435
June 2007
EO 13505
March 2009
NIH Guideline
July 2009
The EO revokes:
• the Presidential Statement of Aug 2001
(federal funding for research on hESCs)
• Executive Order 13435 of June 2007

39. UNITED STATES
REGULATORY AND LEGAL FRAMEWORKS
1995 2000 2005 2010 2015
1997
Proposed
Approach to
Regulation of
Cellular and
Tissue-Based
Products
2001
Human Cells,
Tissues, and
Cellular and
Tissue-Based
Products:
Establishment
Registration
and Listing
2004
Current Good
Tissue Practice for
Human Cell, Tissue,
and Cellular and
Tissue-Based
Product
Establishments,
Inspection and
Enforcement
21 CFR 1271 (Title 21 of the Code of
Federal Regulations, Part 1271
Current Good Tissue Practices (CGTPs)
21 CFR (FDA)
2009
EO 13505
Removing
Barriers to
Responsible
Scientific
Research
Involving
Human Stem
Cells
2007
EO 13435
Expanding
Approved
Stem Cell Lines
in Ethically
Responsible
Ways
1995
NIH Human
Embryonic
Research Panel
requested
embryos left over
from IVFs for
research

40. 21 CFR 1271: CGTP
GENERAL PROVISIONS
PURPOSE and SCOPE:
• Unified registration and listing system
• Manufacturing establishments, domestic or foreign must register with the FDA
• Donor-eligibility
• Current good tissue practice (CGTP)
• Procedures to prevent communicable diseases
• HCT/P’s must be registered regardless their distribution in interstate commerce.
A
MINIMAL MANIPULATION MEANS:
(1) For structural tissue, processing that does not alter the original relevant
characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or
replacement
(2) For cells or nonstructural tissues, processing that does not alter the relevant
biological characteristics of cells or tissues.

41. 21 CFR 1271: CGTP
GENERAL PROVISIONS
HCT/P’s
Articles containing or consisting of
human cells or tissues that are
intended for implantation,
transplantation, infusion, or transfer
into a human recipient:
• Bone, ligament, skin, dura mater,
heart valve, cornea
• Hematopoietic stem/progenitor
cells derived from peripheral and
cord blood
• Manipulated autologous
chondrocytes
• Epithelial cells on a synthetic matrix
• Semen or other reproductive tissue.
NOT HCT/P’s
• Vascularized human organs for
transplantation
• Whole blood or blood
components or blood derivative
• Human secrets and extracts: milk,
collagen, and cell factors
• Minimally manipulated bone
marrow for homologous use
• Ancillary products used in the
manufacture of HCT/P
• Animal cells, tissues, and organs
• In vitro diagnostic products
A

42. HCT/P is regulated solely under the Section 361 of the PHS Act if:
(1) The HCT/P is minimally manipulated;
(2) The HCT/P is intended for homologous use
(3) The manufacture of the HCT/P does not involve the combination with another
article, except for crystalloids, preservative or a sterilizing / storage agent
(4) And either:
(i) The HCT/P does not have a systemic effect and is not dependent upon the
metabolic activity of living cells for its primary function;
(ii) The HCT/P has a systemic effect and:
(a ) Is for autologous use;
(b ) Is for allogeneic use for a relative
(c ) Is for reproductive use.
A
21 CFR 1271: CGTP
GENERAL PROVISIONS
HCT/P that does not meet this criteria and does not qualify for exceptions will be
regulated as a drug, device, and/or biological product under section 351 of the
PHSA, and applicable regulations in title 21, chapter I.

43. A
21 CFR 1271: CGTP
GENERAL PROVISIONS
EXCEPTIONS for REGISTRATION:
HCT/P’s solely
for nonclinical
scientific or
educational
purposes.
Individual under contract
with a registered
establishment
Same individual and
surgical procedure
A carrier who accepts, receives,
carries, or delivers HCT/P's
Only receives
or stores
HCT/P's
solely for
implantation,
transplantatio
n, infusion, or
transfer within
a facility.
Recovers reproductive cells or
tissue and transfers them into a
sexually intimate partner of the
donor.

44. REGISTRATION:
• Register establishment
• Submit a list of every HCT/P that the
establishment manufactures
• Submit any changes
• Registration does not mean the facility is
compliant
• Form FDA 3356 (pdf)

45. B
PUBLIC RECORDS
Filled 3356 Forms will be available
for public inspection
• A list of all HCT/P's
• A list of all HCT/P's manufactured by
each establishment
• A list of all HCT/P's discontinued
• All data or information that has
already become a matter of public
record.
• Office of Communication, Training,
and Manufacturers Assistance,
CBER, FDA
• Find a tissue establishment (query)
• Also available for inspection at FDA
district offices
21 CFR 1271: CGTP
REGISTRATION & LISTING

46. C
Donor-eligibility determination required:
• Manufacturer must screen and test donors for eligibility
• Concern: relevant communicable disease agents and diseases
• Embryos: eligibility determination required for both oocyte and semen donor.
Prohibition on use: HCT/P from ineligible donors, exceptions apply
21 CFR 1271: CGTP
DONOR ELIGIBILITY
ELIGIBILITY OF DONORS
• Determination based on Screening and Testing
• A responsible person must determine and document of donor’s eligibility
• A donor is eligible if:
• Is free from risk factors and evidence of communicable disease
• Is free from risks associated with xenotransplantation
• The results of donor testing are negative or nonreactive Guideline

47. DONOR SCREENING
All donors
• Risk factors and clinical evidence of
HIV, hepatitis B and C, CJD, syphilis
• Xenotransplantation risks
• Donors of viable leukocyte-rich cells or
tissue: Human T-lymphotropic virus
• Reproductive HCT/P’s: medical
records, Chlamydia trachomatis,
Neisseria gonorrhea.
Ineligible donors.
• A risk factor for or clinical evidence of
any of the relevant communicable
diseases including social behavior
• Xenotransplantation risks
• Abbreviated procedure for repeat
donors
DONOR TESTING
C
Testing for relevant communicable
diseases is required.
• Infants: test mothers
• Collection up to 7 days before or after
specimen recovery, exceptions apply.
• FDA-licensed/approved tests
Ineligible donors.
• Tested reactive on a screening test
• Plasma dilution that affects results
• 12 years or younger after transfusion
21 CFR 1271: CGTP
DONOR ELIGIBILITY

48. C
21 CFR 1271: CGTP
DONOR ELIGIBILITY
INELIGIBLE DONORS’ HCT/PS CAN BE USED:
• For a close blood relative
• Reproductive cells for a sexual partner
• Documented urgent medical need
• Limited use clear from labelling
• Nonclinical use (labelled as such)
EXCEPTIONS
Donor-eligibility determination not
required:
• HCT/P’s for autologous use
• Reproductive cells or tissue donated by
a sexually intimate partner
• Cryopreserved cells or tissue for
reproductive use, other than embryos,
• If additional donations are unavailable
• Appropriate measures are taken to
screen and test the donor(s)
• A cryopreserved embryo intended for
directed or anonymous donation
• Appropriate measures are taken to
screen and test the donor(s)
REQUIRED LABELING:
"FOR AUTOLOGOUS USE ONLY,
"NOT EVALUATED FOR INFECTIOUS SUBSTANCES"
"WARNING: Advise recipient of communicable
disease risks"
Biohazard legend if the results of any screening
or testing were positive.
QUARANTINE & STORAGE
Eligible and ineligible must be separate

49. C
ESTABLISH AND MAINTAIN PROCEDURES
Design, Define, Document, Implement,
Follow, Review and Revise
• All steps in testing, screening,
determining donor eligibility
• Review and approval by Responsible
Person before implementation
• Readily available to personnel
• Record and justify any departure
from procedures
21 CFR 1271: CGTP
DONOR ELIGIBILITY
RECORDS
• Accompanying records with identification and results
• Determination of eligibility without PHI of the donor, who made the assessment
• Tests performed, certification of the laboratory, retention requirements
• Records must be retained at least 10 years after the expiration date.

50. Regulations more specifically applicable will supersede the more general.
21 CFR 1271: CGTP
CURRENT GOOD TISSUE PRACTICE
Section 505
of the FD&C Act
DRUGS
Section 351 of the
PHS Act
BIOLOGICS
Device provisions
of the FD&C Act
DEVICE
Section 361 of the
PHS Act only
Minimally
manipulated
Sec. 505 New drugs
Section 351 of the Public Health Service (PHS) Act defines a biological product as a
“virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or analogous product, … applicable to the prevention,
treatment, or cure of a disease or condition of human beings.” Biological products
subject to the PHS Act also meet the definition of drugs under the FD&C Act.

51. CGTP governs the methods used in, and the
facilities and controls used for, the
manufacture of HCT/Ps including all steps in
recovery, donor screening, donor testing,
processing, storage, labeling, packaging,
and distribution.
ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
CURRENT
GOOD
TISSUE
PRACTICE
21 CFR 1271: CGTP

52. 21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
PERSONNEL:
Manufacturer must have sufficient, competent
and appropriately trained personnel to ensure
compliance.
PROCEDURES:
Procedures appropriate to meet core CGTP
requirements for all manufacturing steps and
design these procedures to prevent
circumstances that increase the risk of the
introduction, transmission, or spread of
communicable diseases
ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION

53. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
QUALITY PROGRAMS
• Manufacturer must establish and maintain
a quality program
• Procedures must be reviewed, approved
and revised as appropriate.
• Procedures for receiving, investigating,
evaluating, and documenting core CGTP
requirements, including complains and
possible contaminations
• Provisions on risk assessment and
appropriate follow-up (recall, FDA
reporting)
• CAPA, audits, re-audits, deviations from
procedure, monitoring systems
• Training and education
• Validated performance of computer
software

54. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
FACILITIES:
• Suitable size, construction, and location
• Clean, sanitary, and orderly
• Operations: control systems to prevent
improper labeling, mix-ups,
contamination, cross-contamination, and
accidental exposure to communicable
disease agents.
ENVIRONMENTAL CONTROL:
• Temperature and humidity controlled via
ventilation and air filtration
• Cleaning and disinfecting of rooms and
equipment to ensure aseptic operations
• Maintenance of equipment used to control
aseptic conditions

55. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
EQUIPMENT
• Appropriate design, suitable location and
installation
• Must produce valid results.
• Must be properly maintained, sanitized,
calibrated and routinely inspected
RECOVERY
Establishment that recover HCT/Ps, must do so
in a way that does not cause contamination
or cross-contamination during recovery.
SUPPLIES AND REAGENTS
• Verified supplies and reagents that meet
specifications
• Production of in-house reagents must be
validated
• Records and receipts of al operations,
equipment, supplies and reagents

56. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
PROCESSING AND PROCESS CONTROLS
• Prevent contamination or cross-contamination
Do not pool cells or tissue from different donors
• Representative in-process control and testing
Dura mater: validated process to prevent CJD
• Any change to a process must be verified or
validated and approved before
implementation by a responsible person.
• Changes have to be communicated to staff.
PROCESS VALIDATION
• Validation activities and results must be
documented and signed off
• Any written representation must be based on
a fully verified or validated process.
• Changes in process must be validated, and
process revalidated.

57. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
LABELLING
• Establish and maintain procedures
• Ensure identification, prevent mix-ups
• Verify accuracy, legibility and integrity
• Donor eligibility
• Type of HCT/P
• Expiration date, storage temperature
• Warnings if applicable
• Instructions for use
• Name and address of the establishment
STORAGE
• Control storage areas and stock rooms
to prevent mix-ups, contamination, and
unapproved release
• Appropriate temperature
• Expiration dates
• Any corrective actions documented

58. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
RECEIPT, DISTRIBUTION
• Evaluate each incoming HCT/P
• Pre-established criteria  Determine:
• Accept
• Reject
• Quarantine
• Pre-distribution: HCT/P not available for
distribution must be shipped in quarantine.
• Availability for distribution: release criteria
have been met, shipment signed off
• Packaging and shipping: establish
appropriate shipping conditions
• Procedures: release criteria, identification,
audit trail for all activities, quantity of
HCT/P subject, disposition of the HCT/P,
and return to inventory.
• Traceability: HCT/P must be traceable.

59. ENVIRONMENTFACILITIES
EQUIPMENT
SUPPLIES
REAGENTS
PROCESSRECOVERY
LABELLING STORAGE
DONORSDISTRIBUTION
21 CFR 1271: CGTP
CURRENT GOOD
TISSUE PRACTICE
RECORDS
• Maintain records of each step as required
• Accurate, indelible, and legible, identifiable
and retrievable
• Identify Responsible Person
• Records management system
• Records must be retained for 10 years
• Contracts and agreements must be kept.
COMPLAINT FILE
Maintain, record, and review complaints
EXEMPTIONS AND ALTERNATIVES
• Exemptions may be requested
• Provide justification and alternative
Operation under exemption or alternative
can only begin once granted.

60. ADVERSE REACTIONS
• Non-reproductive only
• Manufacturers must investigate and
follow-up any adverse reaction involving a
communicable disease related to an
HCT/P that it made available for
distribution.
• Adverse reactions are reportable to FDA if:
• fatal;
• life-threatening;
• result in permanent impairment or
permanent damage
• necessitate medical or surgical
intervention, including hospitalization.
Form FDA-3500A within 15 calendar days
(Guidance for industry)
21 CFR 1271: CGTP
REPORTING, IMPORT, INSPECTIONS

61. BIOLOGICAL PRODUCT DEVIATION REPORT
Manufacturers must report HCT/P deviations relating to the core CGTP
requirements within 45 days of discovery
21 CFR 1271: CGTP
REPORTING, IMPORT, INSPECTIONS
INSPECTIONS
Establishment that manufactures HCT/Ps must permit the FDA to inspect
its facilities, equipment, finished and unfinished materials, containers,
processes, HCT/Ps, procedures, labeling, records, files, and papers.
IMPORT
The importer must notify the FDA which the HCT/P is offering for import
Exceptions include reproductive HCT/Ps of the PHSA and to peripheral blood
stem/progenitor cells regulated solely under section 361.
RETENTION, RECALL, DESTRUCTION, CESSATION OF MANUFACTURING
• written order that the HCT/P be recalled and/or destroyed
• take possession of and/or destroy the violative HCT/P
Form
FDA-3486
Guidance
for industry

62. INTERNATIONAL LAW
“Practices which are contrary to human dignity, such as reproductive cloning of
human beings, shall not be permitted. States and competent international
organizations are invited to co-operate in identifying such practices and in taking, at
national or international level, the measures necessary to ensure that the principles
set out in this Declaration are respected."
Universal Declaration on the human genome and human rights, UNESCO, Article 11, 1997
UNESCO
Source: Drze
Report of the International Bioethics Committee (IBC), UNESCO
"The Use of Embryonic Stem Cells in Therapeutic Research" (2001)
“Research involving human embryonic stem cells is an ethical question and it is not
only the right but also the obligation of each individual society to discuss this question
in its own right.”
• Promote free and informed public debates in all countries
• Suggests state regulation
• The use of "surplus" embryos should be tied to donors’ informed consent
• Research projects should be reviewed by Ethics Committees
• Careful assessment of advantages and risks of alternative of stem cell derivation.

63. EUROPE
RESEARCH ON EMBRYOS
2000 2005 2010 2015
2000: Opinion on
the Ethical Aspects
of Human Stem Cell
Research and Use
2002: Decision of the
European Parliament
and of the Council
Council Decision
September 2002
2003: European
Commission proposal
2006: Federal Patent
Court in Germany
2002: Sixth Framework Programme of
the EC for Research, Technological
Development and Demonstration
Activities, Contributing to the
Creation of the European Research
Area and to Innovation (2002 to 2006)
2011: European stem cell
patent has been answered
with the judgment of the
Court of Justice of the EU
2013: European Citizens'
Initiative (ECI) “One of Us”:
the landmark decision of
ECJ suggests that funding
of the embryo-consuming
research at European level
should be terminated.
2014 EC response
to One of Us

64. EUROPE
RESEARCH ON EMBRYOS
The Biopatent
Directive (98/44/EC)
Human Tissues and Cells
Directive (2004/23/EC)
2013 The European
Patent Convention
2011: The Brüstle
case (ECJ)
2012 Resolution on voluntary and
unpaid donation of tissues and cells
Heterogeneous implementation of this legislation across the EU, with
stances ranging from very permissive to very restrictive

65. EUROPE
RESEARCH ON EMBRYOS
• 63% fall into the first two categories
• Legal sources of human embryonic stem cells (hESCs) vary
across Europe
• Some authorize the creation of embryos exclusively for research
• Most only allow for the derivation of hESCs from surplus (IVF)
embryos.
• Few countries ban the derivation of these cells altogether,
• Some permit cell line imports under strict conditions.
• At the national level, positions vary widely from one country to
another.
THE ESF AND THE EUROPEAN MEDICAL RESEARCH COUNCILS (EMRC)
• Support human stem cell research and regenerative medicine
• Science Policy Briefings 20013, 20023 and 20104
THE EUROPEAN SCIENCE FOUNDATION (ESF) REPORT VERY
PERMISSIVE
PERMISSIVE WITH
RESTRICTIONS
RESTRICTIVE BY
DEFAULT
VERY
RESTRICTIVE
UNLEGISLATED

66. EUROPE
RESEARCH ON EMBRYOS
• Human embryos excluded from patentability for industrial or
commercial purposes
• “Embryo” not defined, many interpretations across Europe
• Patentability of pre-existing cell lines remains
• EPO only affects signatories of the European Patent
Convention2.
• Consumables, procedures, protocols, devices patentable
• Research on adult stem cells, mesenchymal stem cells (MSCs)
or induced pluripotent stem cells (iPSCs) is less restricted
BIOPATENT DIRECTIVE (EPO)
Support of research and innovation in regenerative medicine
VERY
PERMISSIVE
PERMISSIVE WITH
RESTRICTIONS
RESTRICTIVE BY
DEFAULT
VERY
RESTRICTIVE
UNLEGISLATED

67. EUROPE
RESEARCH ON EMBRYOS
VERY
PERMISSIVE
PERMISSIVE WITH
RESTRICTIONS
RESTRICTIVE BY
DEFAULT
VERY
RESTRICTIVE
UNLEGISLATED
Very permissive: hESC often can
derive from different sources,
including surplus IVF embryos and
embryos created for research
Permissive with restrictions: hESC
only on surplus IVF embryos
Restrictive by default: Legislation
explicitly prohibits hESC research
Very restrictive: Legislation clearly
prohibits hESC research
Unlegislated: There is no specific
legislation concerning hESC
research

68. EUROPE
RESEARCH ON EMBRYOS
UK
Sweden
Belgium
Romania
Turkey
Lithuania
Germany
Italy
Slovakia
Croatia
Austria
Ireland
Poland
Luxemburg
Cyprus
Czech Republic
Denmark
Estonia
Finland
France
Greece
Hungary
Iceland
The Netherlands
Norway
Portugal
Slovenia
Spain
Switzerland
(Bulgaria)
VERY
PERMISSIVE
PERMISSIVE WITH
RESTRICTIONS
RESTRICTIVE BY
DEFAULT
VERY
RESTRICTIVE
UNLEGISLATED

69. STEM CELL RESEARCH IN EUROPE
ADVANCED-THERAPY MEDICINAL PRODUCTS
Advanced-therapy medicinal products (ATMPs) are medicines for human use that
are based on gene therapy, somatic-cell therapy or tissue engineering.
Gene-therapy medicines
Somatic-cell therapy medicines
Tissue-engineered medicines
Combined advanced-therapy medicines
The Agency's Committee for Advanced Therapies (CAT) plays a central role
in the scientific assessment of advanced-therapy medicines. It provides the
expertise that is needed to evaluate advanced-therapy medicines.

70. HOLOCLAR
APPROVED AS ATMP IN EUROPE
FIRST STEM-CELL THERAPY RECOMMENDED FOR
APPROVAL IN EU
The applicant is Chiesi Farmaceutici S.p.A.
The active substance is ex-vivo expanded autologous
human corneal epithelial cells containing stem cells.
Holoclar was designated as an orphan medicine and an
advanced therapy medicinal product (ATMP) and EMA
provided protocol assistance to the applicant during the
development of the medicine on multiple occasions.
ATMPs are innovative medicines that are intended for gene
therapy, cell therapy or tissue engineering. The CHMP
recommendation follows the draft opinion of the Committee
for Advanced Therapies (CAT), the Agency’s expert
committee for ATMPs.
Conditional approval allows the marketing authorization of
medicines that target areas of unmet medical need before
comprehensive data sets are available, to speed up patient
access to much needed new medicines.
• EPAR Summary for the public (pdf)
• Summary of Risk Management Plan (pdf)
• EMA Approval (pdf)

71. STEM CELL RESEARCH IN EUROPE
ADVANCED-THERAPY MEDICINAL PRODUCTS

72. REGULATORY AND LEGAL
FRAMEWORKS IN CHINA
NEW REGULATIONS:
• Ethical guidelines and regulations for human embryonic stem cell research
• Guidelines on quality control and preclinical research on SC preparations
Isolation, purification, culture, amplification, modification, differentiation, cryopreservation
and resuscitation, and in vivo implantation of stem cells, including hESCs, iPSCs,
mesenchymal stem cells, hematopoietic stem cells, and other progenitor cells.
OVERSIGHT OF STEM CELL TREATMENTS
• Since June 2012, all organizations conducting SC therapy have to register
• Security evaluations include the detection microbes
• The Chinese government has been halting illegal stem cell therapies
The Ministry of
Science and
Technology
Chinese
Academy of
Sciences (CAS)
National Science
Foundation of
China
National Stem Cell
Research Supervision and
Coordination Committee
• Funding of SC research in China totaled almost $500 million over 5 years
• About 200 hospitals and many institutions are working on stem cell research
• China now publishes the second largest number of stem cell publications

73. IV. PROFESSIONAL SOCIETIES
THE INTERNATIONAL SOCIETY FOR STEM CELL RESEARCH (ISSCR)
• the largest professional organization of stem cell scientists, encourages responsible
clinical translation through the education of scientists and medical practitioners on
professional standards
GUIDANCE FOR STEM CELL RESEARCHERS
• In 2007, ISSCR impaneled a broad international taskforce with 30 members from 14
countries to develop a set of professional guidelines for responsible translational
stem cell research.
• Bedrock principles were conceived, including high standards of pre-clinical
evidence, peer review, scrupulous review of clinical protocol by IRBs, rigorous
informed consent, and publication of results whether positive or negative.
• The panel also developed principles for preserving medical innovation.

74. IV. PROFESSIONAL SOCIETIES
THE INTERNATIONAL SOCIETY FOR CELLULAR THERAPY (ISCT)
• The general scientific consensus is that most stem cell therapies are not ready for
marketing or commercialization.
• Industries that are providing these treatments are increasingly sophisticated and
organized and are challenging established regulatory frameworks.
• ISCT has an interest in the promotion of stem cell research and development,
immune cell interventions, reproductive medicine, and gene therapy.
• 2013: Presidential taskforce on the use of unproven cellular therapies
• Working groups on definitions, scientific evidence and biological rationale,
laboratory cell processing, clinical practice, regulation, commercial implications,
communications, and policy.
• The taskforce will be looking at the ethics of unregulated direct-to-consumer
marketing of therapies as well as the implications for industry.

75. THANK YOU