Massach
usetts
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Institute of Technolo
Technology
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Harvarrd Me
Medical
dical School
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Brig
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Brigha
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Boston Heal
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2.782J/
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82J/3.961J
.961J//BEH.451
BEH.451J/HST524
HST524J
FEDERAL REGULATORY ISSUES:
RECOMMENDED BIOCOMPATIILITY TESTING
AND REGULTION OF TISSUE ENGINEERED
PRODUCTS
M. Spect
Spector, Ph.D.
Required Biocompatibility Training and
Toxicology Profiles for Evaluation of Medical
Devices
•
•
•
http://www.fda.gov/cdrh/g951.html
FDAFDA-modified matrix that designates the type of testing
needed for various medical devices.
It also includ
includes a flow chart entitled "Biocompatibility
Flow Chart for the Sele
ction
n of Toxicity Te
Selectio
Tests for
510(k)s.“
510(k)s.“
The guidance wi
will be effec
effecttive
ive for
for al
all submission
submissions that will
will
be received on or after July 1, 1995. The former guidance,
#G87#G87- 1 entitled "Tripa
"Tripartite Bi
Biocompatibility Guidance,"
Guidance,
may continue to be applied until a final decision is reached
on each submission received
received prior to July 1, 1995.
Page 1
Required Biocompatibility Training and
Toxicology Profiles for Evaluation of Medical
Devices
• Biological evaluation of medical
medical devices is performed to
determ
determine the potential
potential toxicity resulting from contact of
the component mater
materials of the devi
device with the body.
• The device material
materials sh
should not, either directly or through
the release of their materia
materiall constituents:
– (i) produce adverse loca
locall or
or systemic
emic effe
effects;
cts;
– (ii)
(ii) be carcino
rcinogenic;
genic; or
– (iii)
opmen
(iii) produce adverse
adverse repro
reproductiv
ductive and devel
develo
pmental effects.
• Therefore, evaluation of any
any new device intended for
human use requires data from systematic testing to ensure
that the benefits provided by the final product w
wiill exceed
excee
any potential risks produced by device
device materials.
Required Biocompatibility Training and
Toxicology Profiles for Evaluation of Medical
Devices
• When sele
priate test
uation of a medical
selecting the appro
approp
tests for biolog
ologiical eval
evalu
medical
device,
teristtics
device, one mu
must consid
nsider the chem
chemical charac
aracteris
ics of device
device materials
terials and
the nature, degree,
y and
on of its ex
degree, frequenc
frequency
and durati
duratio
exposu
posure to the
the body.
body.
• In genera
general, the
the tests
tests in
include:
clude:
– acute, subnic and
sub- chro
chron
and chron
chroniic toxici
toxicity;
– irritati
al su
irritation to sk
skin, ey
eyes and
and mucos
mucosa
surfaces;
rfaces;
– sensitiz
sensitization;
– hemocompatibility
hemocompatibility;
– genotoxicity
genotoxicity;
– carcinogen
carcinogeniicity
city; and
and
– effects on repro
duction inclu
ding developm
reprod
includ
velopment
ental effects
effects..
• Additi
onal
al test
Addition
tests for specific
specific targe
targett organ
organ toxicity,
toxicity, such as neurotoxic
neurotoxiciity and
an
immunotoxicity
s.
immunotoxicity may be nece
necessary
ssary for some device
devices.
– For example, a neurological device with direct
rect cont
contact with brain
ain pare
parenchyma and
cerebros
pinal
cerebrosp
inal flu
fluid (CSF
(CSF) may requ
require an ani
animal impl
implant
ant te
test to eval
evaluate its effects
effect
on the brain parenchyma
bility
y to seizure,
parenchyma,, suscepti
susceptibilit
seizure, and effects on the functional
mechanism of choroid plex
plexus and arachnoid villi to secrete and
and absorb (CSF).
• The specific
specific clinical
clinical application
pplication and the materials used in
in the manufac
manufactture of
the new devic
nes which tests
device determi
determines
tests are
are appropriate
appropriate..
Page 2
International Organization for Standards, ISO
http
alogueList
ueListPag
Pagee.Catalog
ueList?IICS1=11&ICS2=
100
http://www.iso
//www.iso..ch/iso/
ch/iso/en/Cat
en/Catalog
atalogueList?
11&ICS2=100
&ICS3=
ISO 10993ologi
ogiccal evaluat
10993-1:1997Bi
1:1997Biol
valuatiion of medical devi
devices -Part 1: Evaluation and testing
ISO 10993ologi
ogiccal evaluat
10993-2:1992Bi
2:1992Biol
valuatiion of medical devi
devices -Part 2: Animal we
welfare requirement
requirementss
ISO 10993ologi
ogiccal evaluat
10993-3:1992Bi
3:1992Biol
valuatiion of medical devi
devices -Part 3: Tests for genotoxicity,
genotoxicity, carcinogenicity and
reproductive
reproductive toxi
toxicity
ISO 10993ologi
ogiccal evaluat
10993-4:2002Bi
4:2002Biol
valuatiion of medical devi
devices -Part 4: Selection of tests for interactions
interactions wi
with blood
ISO 10993ologi
ogiccal evaluat
10993-5:1999Bi
5:1999Biol
valuatiion of medical devi
devices -Part 5: Tests for in vitro cytotoxi
cytotoxicity
ISO 10993ologi
ogiccal evaluat
10993-6:1994Bi
6:1994Biol
valuatiion of medical devi
devices -Part 6: Test
Tests for loca
locall effects after implantation
implantation
International Organization for Standards, ISO
http
alogueList
ueListPag
Pagee.Catalog
ueList?IICS1=11&ICS2=
100
http://www.iso
//www.iso..ch/iso/
ch/iso/en/Cat
en/Catalog
atalogueList?
11&ICS2=100
&ICS3=
ISO 10993ologi
ogiccal evaluat
10993-7:1995Bi
7:1995Biol
valuatiion of medical devi
devices -Part 7: Ethy
Ethylene oxide
oxide steriliza
sterilization residuals
residuals
ologi
ogiccal evaluat
ISO 10993valuatiion of medical devi
devices -10993-8:2000Bi
8:2000Biol
Part 8: Selection and qualification
qualification of reference material
materials for
biological tests
ISO 10993ologi
ogiccal evaluat
10993-9:1999Bi
9:1999Biol
valuatiion of medical devi
devices -Part 9: Fr
Framework
amework for identification
identification and quantification
quantification of
potential degradation products
ISO 1099310993-10:2002Biological
10:2002Biological evalua
evaluation of medical devices -Part 10: Tests for irritation and delayeddelayed-type hypersensitivi
hypersensitivity
ISO 10993evaluation of medical devices -10993-11:1993Biological
11:1993Biological evalua
Part 11: Tests for systemic toxi
toxicity
ISO 1099310993-12:2002Biological
12:2002Biological evalua
evaluation of medical devices -Part 12: Sample preparation and reference materia
materialls
Page 3
International Organization for Standards, ISO
http
alogueList
ueListPag
Pagee.Catalog
ueList?IICS1=11&ICS2=
100
http://www.iso
//www.iso..ch/iso/
ch/iso/en/Cat
en/Catalog
atalogueList?
11&ICS2=100
&ICS3=
ISO 1099310993-13:1998Biological
13:1998Biological evalua
evaluation of medical devices -Part 13: Identification and quantification
quantification of de
degradation
products from polymeric medical devices
ISO 1099310993-14:2001Biological
14:2001Biological evalua
evaluation of medical devices -Part 14: Identification and quantification
quantification of de
degradation
products from ceramics
ISO 1099310993-15:2000Biological
15:2000Biological evalua
evaluation of medical devices -Part 15: Identification and quantification
quantification of de
degradation
products from metals and alloys
ISO 1099310993-16:1997Biological
16:1997Biological evalua
evaluation of medical devices -Part 16: Toxicokinetic study design for degradation products
and leachables
ISO 1099310993-17:2002Biological
17:2002Biological evalua
evaluation of medical devices -Part 17: Establishment of allowa
allowable
ble limits for leachable
substances
American Societ
y for
Society
for Testing and Materials
http://www.astm.org
Search “Biocompatibility”
Page 4
FDA
TISSUE ENGINEERING PRODUCTS
FDA's Tissue Reference Group Workshop
August 29, 2001 - Slide Presentation
Human Cells, Tissues, and Cellular and TissueBased Products (HCT/Ps) Regulated as Devices
Mark N. Melkerson
CDRH / FDA
Tissue Reference Group (TRG)
(TRG
“FDA’s TRG Process”
http://www.fda.gov/cber/summaries/melkersontrg.htm
http://www.fda.gov/cber/summaries/melkersontrg.htm
Premarket Review of Biological Products &
Medical Devices
•
•
•
Biological Products
Medical Devices
Combination Products
Page 5
Definition of a Medical Device
• “...apparatus,…, implant, in vitro reagent,
including any component…or accessory...
• intended for the diagnosis, mitigation, treatment,
or prevention of disease...
• or intended to affect the structure or function of
the body...
• and does not achieve its primary intended
purposes through chemical action within or on
the body…and which is not dependent upon
being metabolized…”
Examples of Medical Devices &
Combination Products
• Medical Devices - collagen, hyaluronic acid
and synthetic implants
– FocalSeal-L - aqueous PEG solutions modified
to photo-polymerize in situ
– Emdogain - porcine enamel matrix proteins
• Combination Products – Apligraf - cells on bovine collagen
Page 6
Marketing Applications
• Premarket Notification (Class II Devices)
Section 510(k) of the FD&C Act (21 CFR 807)
• Premarket Approval Application (Class III
Devices)
Section 515 of the FD&C Act (21 CFR 814)
• Humanitarian Device Exemption (requires HUD
Designation)
Section 520(m) of the FD&C Act (21 CFR
814.100)
Premarket Notification Review
• Case-by-case approach, except if can
demonstrate “equivalent” to predicate device
• Basic elements:
– Same Intended Use(s)
Use(s)
– Preclinical
Preclinical equivalence of Product Manufacture, In
vitro and/or in vi
vivo testing
– May need to demonstrate equivalence of Clinical
Perfor
Performance, if seeking specific indication(s
indication(s)) for
for use
under general intended use(s)
es in
use(s) or differenc
differences
technologi
technological charac
characteristics
Page 7
Food and Drug Administration
Modernization Act of 1997
• Gave CDRH authority to recognize
national and international standards in
product reviews
– Allows for “Declaration of Conformity”
– Somewhat mirrors device marketing
authorities used in Europe
CDRH Standards Program
www.fda.gov/cdrh/stdsprog.html
• Standards Participation
– ASTM F04
• Division IV - Tissue Engineered Medical
Medical Pr
Products
(TEMPS)
– ISO TC 150
• Working Group 11 - Tissue Engineered Implan
Implants
(Reviewi
(Reviewing Other Standards Development
Activi
Activities)
Page 8
Premarket Approval Review
• Case-by-case approach
• Both safety and effectiveness evaluations
• Basic elements:
– Product Manufacture
– In vitro and in vi
vivo testing
– Clinical Performance
– Product Labeling
• Product Manufacture
– Cell, tissue & biomater
iall sourci
biomateria
sourcing
– Product Processing
– InIn-process and final product tests
– Adventitious
Adventitious agents & coco-purifying impurities
– Lot - to - lot consistency
– Quality control
control procedures
Premarket Approval Review
• In vitro and in vivo testing
– Toxicity / Genotoxicity
– Biomaterials biocompatibility
– Immunogenici
Immunogenicity /inflammatory
/inflammatory responses
responses
– Models of pr
product effectiveness
effectiveness
– Product resorption/decomposition
• Investigating product safety and clinical
benefit:
– Patient population
– Investigatio
nal and control
ments
Investigational
control treat
treatm
– Study endpoints
– Study conduct
– Data analysis
– Labeling claims
Page 9
Investigational Human Studies
• An exemption from marketing approval is
required when unapproved products are
studied in humans.
– Investigational Device Exemption (IDE) 21
CFR 812
• For significant risk medical devices:
– FDA approval of IDE
– IRB approval
Humanitarian Device Exemption
• Requires HUD (maximum of 4000 cases/per
year) and requires no alternatives be
marketed
• Case-by-case approach
• Both safety and probable benefit
evaluations
– Product Manufacture
– In vitro and in vivo testing
– Clinical Perfor
– Product Labeling
Page 10
Internet Access to FDA Documents
• Proposed Approach to Regulation
Regulation of Cellular and
TissueTissue-Based Products - 2/28/97 http://www.
fda.gov/cber/gdllns/CELLTISSUE.txt
http://www.fda.gov/cber/gd
ns/CELLTISSUE.txt
• Tissue Action Plan http://www.fda.gov/cber/tissue/tissue.htm
• Intercenter Agreement Between
Between The Center for
for Biol
Biologics
ogics
Evaluation and Research and The Center for Devices
and Radiological Health http://www.f
http://www.fda.gov/oc/ombudsman/bio
da.gov/oc/ombudsman/bio--dev.htm
dev.htm
• Guidance on Applications for Products Comp
Comprised of
Living Autologous Cells Manipulated Ex Vivo and
Intended for Structural Repair or Reconstruction (5/96)
- http://www.fda.gov/cber/gd
lns/GDEXV.TXT
http://www.fda.gov/cber/gdlns/GDEXV.TXT
Internet Access to FDA Documents
• Guidance Fo
For the Submission
Submission of Chemistry,
Manufacturing and Controls
Controls Information and
Establishment Description for Autologous Somatic Cell
Therapy Products - 1/10/97 http://www.fda.gov/cber/gd
http://www.fda.gov/cber/gdllns/xvcmc.txt
• Required Biocompatibility
Biocompatibility Training
Training and Toxicology
Profiles for Evaluation of Medical
Medical Devices 5/1/95 (G95(G95-1)
- http://www.fda.gov/cdrh/g951.html
• Public Health Service Guidel
Guideline on
on Infectious Disease
Issues in Xenotransplantation
http://www.fda.gov/cber/gdl
http://www.fda.gov/cber/gdlns/xenophs0101.htm
ns/xenophs0101.htm
• FDA PMA
PMA Database Se
Search Engine
http://www.accessdata.fda.gov/scri
pts/cdrh/cfdocs/cfPM
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfP
A/pma.cfm
Page 11
Tissue Related Documents
http://www.fda.gov/cber/tissue/docs.htm
• Guidance for Industry: Availability of Licensed Donor
Donor
Screening
Screening Tests Labeled for Use wi
with Cadave
Cadaveric Blood
Specimens - 6/23/2000
• Suitability Determination for Donors of Human Cellular
and TissueTissue-Based Products; Proposed Rule; reopening of
comment period - 4/18/2000
• Establishment Registration and Listing for
Manufacturers of
of Human
Human Cellular and TissueTissue-Based
Products - 5/14/98
• Guidance for Industry - Screening and Testing of Donors
of Human Tissue Intended for Transplantation - 7/29/97
• Guidance for the Preparation of a Premar
Premarket Notification
Notificatio
Applicat
Application for Process
Processeed Human Dura Mater http://www.fda.gov/cdrh/ode/054.html
http://www.fda.gov/cdrh/ode/054.html
Specific Product Information
• FocalSeal-L Sealant- Focal - SSE
– http://www.fda.gov/cdrh/pdf/p990028b.pdf
• Apligraf - Organogenesis - SSE
– http://www.fda.gov/cdrh/pdf/p950032.pdf
• CCS - Ortec, Inc. - SSPB (H990013)
– http://www.fda.gov/cdrh/pdf/h990013b.pdf
Page 12
Multi-Agency Tissue Engineering Science
(MATES) Working Group
The Multi-Agency Tissue Engineering Science
(MATES) Working Group is proposed as a
means for the various federal agencies
involved in Tissue Engineering to stay
informed of each other’s activities and better
coordinate their efforts.
http
://www.
www.ttissueengi
http://
ssueengineering.
neering.gov
Multi-Agency Tissue Engineering Science
(MATES) Working Group
Five Year Plan; Subcommittee
Subcommittee on Biotechnology
The term “Tissue Engineering”
Engineering” was coined at an NSFNSF-sponsored
meeting in 1987(1). At a subsequent
subsequent NSF sp
sponsored wo
workshop,
Tissue Engineering wa
was defined as “the application of principles
and methods of engineering and life
life sciences towa
toward fundamental
understanding of structurestructure-function relationships in normal and
pathological function”
ary technology
function” (2). This multidisciplin
multidisciplinary
involves the development of biological
biological substitutes for the re
repair
pair or
o
regeneration of tissue or organ function and has led to a br
broad
range of products.
1. Heineken FG and Skalak
Skalak R. Tissue Engineering: A Brief
Overview,
Overview, Journal of Biomechanical Engineering 113,
113, 111 (1991).
2. Skalak R and Fox CF, eds. Tissue Engineering, Proc
Proceedings for a
Workshop held at Gran
Granlibakken,
libakken, Lake Tahoe, California,
California,
February 2626-29, 1988, Alan Liss,
Liss, New
New York.
York.
http
://www.
www.ttissueengi
http://
ssueengineering.
neering.gov
Page 13
Multi-Agency Tissue Engineering Science
(MATES) Working Group
To date, some of these products have been approved by the U.S.
Food and Drug Administration while many are under either
preclinical
preclinical investigation
investigation or regulatory evaluation (3, 4). Since
1990, the Tissue Engineering industry
industry has grown to become more
than a $3.5 billion wo
worldwide
rldwide R&D
R&D effort by over seventy
biotechnology startstart-ups and business units (5, 6). Less than ten
percent of this effort is funded by th
the U.S. government, bu
but this
this
contribution is rapidly increasing.
3. Hellman
Hellman KB, Knigh
Knightt E, and Durf
Durfor CN. Tissue
Tissue Engineering: Product
Product
Applications
atory
6, Fron
tierrs in Tissue
Applications and Regul
Regula
tory Issues
Issues,, pp
pp. 341-36
341-366,
Frontie
Tissu
Engineering
o G. Miko
Engineering,, Cha
Charrles W. Patrick, Antoni
Antonio
Mikoss, and Larry
Larry V.
V. McIntir
McIntiree
(eds.),
m, Elsevi
ds.), Am
Amsterda
sterdam,
Elsevier Science (1998).
(1998).
4. Hellman
Hellman KB., So
Solomon RR
RR, Gaffey
Gaffey C, Durfor
Durfor C and Bish
Bishop JG, III
III.
Tissue Engineering: Regula
Regulatory
tory Consider
Considerations, Principles
Principles of Tiss
Tissue
Engineering,
n, Ro
Engineering, 2nd Editio
ition
Robert
bert Lanza,
Lanza, Robert Langer, and Joseph P.
Vaca
Vacanti (eds.),
ds.), Ac
Academic
ademic Press, San Diego, Cali
California
fornia (in pres
press).
5. Lysag
ht MJ,
Lysagh
MJ, Nguy
Nguy AS, and Sullivan
Sullivan K. An Economic Survey
Survey of the Emergin
Emerging
Tissue Engineering Industr
y, Tissue Engineering:
231 (1998)
(1998)..
Industry
Engineering: 4, 23
6. Lysag
ht MJ, and Reyes
Lysagh
Reyes J. The Growth of Tissue
Tissue Engineering,
Engineering, Tiss
Tissue Engr
Engr.
FDA APPROVAL PROCESS
Classification of Product as I, II, or III
TE products
I. General
Controls
II. Special
Controls
No approval of Equival
ent to Market
ed
Equivalent
Marketed
FDA prior to
Device?;
Device?;
selling the
Premar
Premarket Notification
product.
510 (k)
Good Manuf.
nuf.
Practice
GMP
GMP
Analysis of composition
and properties, and in vitro
and in vivo studies
Page 14
III. Premarket
Approval (PMA)
Human Trial
Investigational
Device
Exemption IDE
PMA
Good Lab Pract.
Pract.
GLP