1. FDA Update on Cord Blood
Regulation: New Guidance
Ellen F. Lazarus, M.D., FCAP
Director, Division of Human Tissues
Office of Cellular, Tissue, and Gene Therapy
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2. How does FDA regulate cord blood for
autologous use and use in first or
second-degree relatives?
Regulated solely under Section 361 of the Public Health
Service Act, from which the HCT/P regulations derive
(21 CFR 1271 Subparts A-F), unless more than
minimally manipulated; for non-homologous use; or
combined with another article with some exceptions
such as preserving and sterilizing agents (§1271.10)
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Establishment registration and listing rule
Donor eligibility and CGTP rules
Reporting and labeling requirements
Inspection, import, and enforcement provisions
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3. How does FDA regulate cord blood
from unrelated donors?
• Regulated as HCT/P under 21 CFR Part 1271 Subparts
A-D (Registration, DE, and CGTP rules)
• Also regulated as a drug under the FD&C Act and as a
biological product under Section 351 of the PHS Act, and
therefore additional regulations apply
–
–
–
–
Labeling and advertising (21 CFR Part 201 and 202)
CGMPs (Part 211)
IND regulations (Part 312)
Licensing and general biological products standards (Parts 600,
601, 610)
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4. Phase-in period for IND and BLA
requirements
Until very recently (last week), FDA has
delayed implementation of Investigational
New Drug and Biologics License
Application requirements for minimally
manipulated unrelated allogeneic
hematopoietic stem/progenitor cell
products (HPC)
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5. Cord Blood Guidance - History
• 1997 - FDA initiates HCT/P regulations
• 1998 - FR notice: Request for Proposed Standards –
Minimally manipulated unrelated allogeneic cord blood
and PBSCs intended for hematopoietic reconstitution
– Requested that interested public submit data and
recommendations for
• Establishment controls
• CMC - processing and product standards
– Stated that if adequate information is submitted to show
safety and efficacy, FDA intends to issue guidance containing
controls and standards (pathway to licensure)
– Announced intention to phase-in implementation of IND and
BLA requirements
– Most of the docket information pertained to cord blood
• 2003 – Convened Advisory Committee (BRMAC) on
C
cord blood scientific issues
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6. Draft Guidance – Provided
recommendations for streamlined
pathway to cord blood licensure
• 2007 – CBER published draft
• Applies to minimally manipulated allogeneic unrelated
HPC-C intended for hematopoietic reconstitution in
patients with hematological malignancies
• Manufacturer can rely on data in docket – does not
have to submit clinical data if follow recommendations
in guidance
• License would apply to current and previously
manufactured HPC-C, where comparability and
conformance with CGMPs are demonstrated
• Applicant can use an alternative approach if it
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satisfies the applicable regulatory requirements
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7. Comments to the Docket
• Comment period Jan - April 2007
• 23 comments submitted
• Received comments on scope/clinical
indications; access to cord blood already
banked in public inventories; and
international exchange of cord blood
• Other major comments addressed specific
CMC and regulatory issues
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8. Public Discussion of Draft Guidance
FDA Advisory Committee
Cell, Tissue, and Gene Therapy AC meeting on March
30, 2007 convened to discuss draft guidance
– FDA provided overview of the guidance
– Dr. Rubinstein (NYBC) presented current and historical data on
cord blood manufacturing, utilization, and clinical outcomes
– Open Public Hearing – comments from representatives of
industry
– Committee members addressed FDA questions
• Discussed access to cord blood units already in inventories
• Recommended additional clinical indications – other malignancies
and nonmalignant conditions normally considered for BMT
• Expressed concern about feasibility of licensure of HPC-C at all nonUS banks that list their products in international registries
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9. Cord Blood Guidance – Hot Off
the Press
• Final Guidance for Industry: Minimally Manipulated, Unrelated
Allogeneic Placental/Umbilical Cord Blood Intended for
Hematopoietic Reconstitution for Specified Indications (HPC-C
Licensure Guidance) - 10/20/09
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplian
• Draft Guidance for Industry and FDA Staff: IND Applications for
Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical
Cord Blood Intended for Hematopoietic Reconstitution for
Specified Indications (Draft HPC-C IND Guidance) – 10/20/09
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplian
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10. Phase-in period for IND and BLA
requirements, and comment period
• With publication of these HPC-C guidance documents,
FDA is also announcing that the phase-in
implementation period for IND and BLA requirements for
these products will end in 2 years after date of
publication (October 20, 2011)
• Sponsors are encouraged to send in IND and BLA
applications as soon as possible to allow sufficient time
for review, comment, and resubmission as needed to
complete all actions by the end of this 2 yr period
• Submit your comments on the draft IND guidance within
90 days of publication, to ensure that we can consider
your comments before beginning work on the final C B
version
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11. What is the purpose of the HPC-C Licensure
Guidance, and why is there companion Draft
HPC-C IND Guidance?
• The HPC-C Licensure Guidance provides
recommendations to manufacturers applying for
licensure of minimally manipulated, unrelated allogeneic
placental/umbilical cord blood, for specified indications
• Comments received on the December 2006 draft
guidance were considered; this HPC-C Licensure
Guidance finalizes the draft guidance
• Some comments expressed the importance of access to
and availability of HPC-C products that do not meet
standards for licensure and therefore cannot be licensed;
agency recognizes importance of these products and
published draft guidance addressing IND submissions
for them
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12. HPC-C Licensure Guidance
contents
•
•
•
•
•
•
•
Background/Scope
Applicable regulatory requirements
License application procedure
CMC section
Establishment description section
Guidance on applicable regulations
Postmarketing activities
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13. What information is contained in
the HPC-C Licensure Guidance?
• Scope of the Guidance (products covered),
historical background, and how to use the
Guidance when you apply for a BLA
• Applicable regulatory requirements – explains
which regulations apply to HPC-Cs for unrelated
allogeneic use
• License application procedure – Form FDA
356h, information to include, and actions that
FDA will take
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14. What HPC products does the HPC-C
Licensure Guidance cover?
• Placental/umbilical cord blood products that are:
– Minimally manipulated
– Intended for hematopoietic reconstitution in patients with any of
the following diseases:
• Hematological malignancies
• Certain lysosomal storage and peroxisomal enzyme deficiency
disorders
– Hurler Syndrome (MPS I)
– Krabbe Disease (Globoid Leukodystrophy)
– X-linked Adrenoleukodystrophy
• Primary immunodeficiency diseases
• Bone marrow failure
• Beta thalassemia; and
– Intended to be used in recipients unrelated to the donor
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15. What about HPC-C for family-related use?
We encourage manufacturers of cord blood
products for autologous use or use in first- or
second-degree relatives to follow the
recommendations concerning manufacture and
how to comply with the regulatory requirements
in the HPC-C Licensure Guidance, even though
their products may not require premarket review
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16. Information in the HPC-C Licensure
Guidance – CMC
• Contains a Table summarizing characteristics of
the cord blood used to obtain the clinical data
submitted to the docket to demonstrate safety,
purity, and potency of HPC-C; applicant
expected to obtain similar results if citing docket
• Describes manufacturing information that should
be submitted, including SOPs, validation data
(including data on HPC-Cs in inventory to
demonstrate comparability), control of aseptic
manipulations, and processing and test methods
validation data
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17. HPC-C already in inventories
• License would apply to HPC-C previously manufactured
using the same procedures where documentation is
provided:
– Demonstrating their comparability, and that they were
manufactured in accordance with CGMP and other applicable
regulatory requirements
• License would apply to HPC-C in inventory that were
previously manufactured using different procedures,
provided that:
– Manufacturer submits a separate validation summary, and
– Includes data demonstrating comparability of previously
manufactured HPC-C to the currently manufactured HPC-C, and
providing evidence that methods, facilities, and controls used for
manufacture conformed to CGMP and other applicable
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regulatory requirements
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18. Information in the HPC-C Licensure
Guidance: Establishment Description
• Provides guidance on the content and
format of information to be submitted in
this section of the BLA
• Floor diagram, personnel and product
flow, HVAC, facility controls, computer
systems
• Contamination/cross-contamination issues
including equipment cleaning and
validation; containment features
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19. Information in the HPC-C Licensure
Guidance – cont.
• Guidance on applicable regulations –
Establishment registration and listing; CGMP;
and CGTP, and recommendations for complying
with those regulations
• Postmarketing activities
– Recommendation for clinical outcome data received
from transplant centers - analyze to determine
whether adverse outcomes may be due to problems
with product manufacture
– Explanation of the BLA reporting requirements:
changes to the approved BLA, adverse experiences,
and biologic product deviations
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20. What are the major changes from
the draft guidance?
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21. Title
The title has changed, to reflect the difference in
the scope of the HPC-C Licensure
guidance:
• Draft Guidance for Industry: Minimally
Manipulated, Unrelated Allogeneic
Placental/Umbilical Cord Blood Intended for
Hematopoietic Reconstitution in Patients with
Hematologic Malignancies
• Guidance for Industry: Minimally Manipulated,
Unrelated Allogeneic Placental/Umbilical Cord
Blood Intended for Hematopoietic Reconstitution
for Specified Indications
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22. Scope
• The scope of the guidance was changed
to expand the list of intended clinical uses
for the HPC-C covered by the Guidance;
based on public comment, AC
recommendations, and additional data
submitted to the docket
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23. What HPC products does the HPC-C
Licensure Guidance cover?
Placental/umbilical cord blood products that are
– Minimally manipulated
– Intended for hematopoietic reconstitution in patients with any of
the following diseases:
• Hematological malignancies
• Certain lysosomal storage and peroxisomal enzyme deficiency
disorders
– Hurler Syndrome (MPS I)
– Krabbe Disease (Globoid Leukodystrophy)
– X-linked Adrenoleukodystrophy
• Primary immunodeficiency diseases
• Bone marrow failure
• Beta thalassemia; and
– Intended to be used in recipients unrelated to the donor
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24. CMC section changes
HPC-C Description and Characterization section
revised to address comments to the docket on
types of samples and frequency of testing for
some of the recommended and required safety
tests listed in the Table
– Now only recommends a single HPC-C sample for
sterility testing, rather than both a cord blood
(unprocessed) sample and a HPC-C precryopreservation sample; sample for sterility testing
may be obtained before or after addition of
cryoprotectant
– Includes option to perform Hb testing using an
appropriate donor sample; red cell sample obtained
after processing may be used with appropriately
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validated reagents or test systems
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25. Product
Characteristics
Testing
Infectious diseases –
Testing required
(21 CFR 1271.45 through
1271.90)
Sample
(Type and Timing)
Maternal peripheral blood
obtained within 7 d of
cord blood collection –
Type and timing required
(21 CFR 1271.80(a), (b))
Results of Product Testing
All tests neg except nontreponemal test for syphilis
when confirmatory test is neg
(CMV results are recorded)
CMV - Report
No growth
Cord blood or donor
sample obtained at time
of cord blood recovery
No homozygous
hemoglobinopathy
HPC-C (pre-cryopres)
≥ 5.0 x 108 TNC/unit HPC-C
Viable nucleated cells
HPC-C (pre-cryopres)
≥ 85% viable nucleated cells
Viable CD34+ cells (flow)
HPC-C (pre-cryopres)
≥ 1.25 x 106 viable CD34+
cells/unit HPC-C
HLA Typing
Identity
HPC-C (precryopreservation)
Total nucleated cells (TNC)
Purity and
Potency
Sterility: Bacterial and
fungal -Testing required
(21 CFR 211.165(b), and 21
CFR 610.12)
Hemoglobin
Safety
Cord blood
Report
Confirmatory HLA typing
Attached segment
Confirms initial
ABO and Rh Type
Cord blood
Report
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26. CMC section changes – cont.
• The Manufacturer section addresses
appropriate precautions to prevent crosscontamination when the same area or
equipment is used to process more than one
HPC-C at a time; previously this section only
recommended avoiding the simultaneous
manipulation of more than one HPC-C in a
single area
• A section providing a more detailed
description of container closure systems and
related requirements and recommendations
is added
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27. Computer Systems
• The Establishment Description section on
Computer Systems includes more
information about resources for
information on software regulation and
validation
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28. Reserve Samples
• According to 21 CFR 211.170(a), an
appropriately identified reserve sample that is
representative of each product shall be
retained for 1 year after the expiration date of
the product
• The Reserve Samples section (VII.B.14.f.)
contains a clarification that the expiration date
of the thawed HPC-C may be used to
determine the length of time that the HPC-C
reserve samples must be retained
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29. References and footnotes have
been updated
• Guidance for Industry on container closure
systems for packaging human drugs and
biologics; and
• Draft Guidance for Industry on labeling for
human prescription drug and biological products
– implementing the new content and format
requirements
• Draft Guidance for Industry on validation of rapid
microbiological methods for sterility testing of
cellular and gene therapy products
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30. Draft Guidance for Industry and
FDA Staff: Investigational New
Drug Applications for Minimally
Manipulated, Unrelated Allogeneic
Placental/Umbilical Cord Blood
Intended for Hematopoietic
Reconstitution for Specified
Indications
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31. Draft HPC-C IND guidance
• Published for comment
• Describes FDA’s current thinking and should be
viewed as a recommendation except where
specific regulatory requirements are cited
• Submit comments within 90 days of publication
of the draft guidance to ensure that we consider
your comment before we begin work on the final
version
– Electronic comments to http://www.regulations.gov
– Written comments to: Division of Dockets
Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061,
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Rockville, MD 20852
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32. Purpose of the Draft HPC-C IND
Guidance
•
•
•
Situations when there will not be a suitable licensed cord blood
product for a patient in need and an unlicensed product may be
the best match
If unlicensed HPC-C are made available for clinical use, an IND is
required
Advice for potential sponsors for submission of an IND for HPC-C
for specified indications, when the HPC-Cs are not licensed and
are needed for treatment of a patient with a serious/lifethreatening disease and there is no satisfactory alternative
treatment
– Sponsor may be cord bank, registry, or physician (sponsorinvestigator)
– Outlines the minimum information to be included in an IND
– Sponsors may submit one IND to cover the use of multiple HPC-C, or
submit a separate IND for each single-patient use
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33. To which unlicensed HPC-C does
the Draft HPC-C IND Guidance
apply?
• Made available for transplantation in
cases when no satisfactory alternative
treatments are available
• Intended for hematopoietic reconstitution
in patients with the clinical indications
listed in the HPC-C licensure guidance
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34. Products the Draft HPC-C IND
guidance covers
• Placental/umbilical cord blood products that are:
– Minimally manipulated
– Intended for hematopoietic reconstitution in patients with any of
the following diseases:
• Hematological malignancies
• Certain lysosomal storage and peroxisomal enzyme deficiency
disorders
– Hurler Syndrome (MPS I)
– Krabbe Disease (Globoid Leukodystrophy)
– X-linked Adrenoleukodystrophy
• Primary immunodeficiency diseases
• Bone marrow failure
• Beta thalassemia; and
– Intended to be used in recipients unrelated to the donor C B
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35. Draft HPC-C IND Guidance
addresses access issues
• Manufactured in non-US cord blood
establishments, listed in international registries,
and selected for treatment of a patient in the US
• Manufactured in US cord blood establishments
before BLA approved and not shown to meet
licensing criteria (e.g., not shown to be
comparable to other licensed HPC-C in
inventory – see slide #15)
• Prospectively manufactured in the US and do
not meet licensing criteria but for which there is
no satisfactory alternative (e.g., for purpose of
assuring diversity of HLA phenotypes)
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36. Category A
• Non-US HPC-C establishment - existing and future
inventory
• May choose not to apply for licensure
• Products may not meet criteria for licensure
• Examples
– DE determination performed in accordance with standards of
another country, but do not meet all of the requirements in the
DE rule (21 CFR 1271 subpart C)
– Release criteria different from those recommended in the HPC-C
licensure guidance
• Minimal information to be included in the IND is
summarized in Table A, Column A
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37. Category B
• Pre-licensure inventory of unlicensed
HPC-C that cannot be shown to be
comparable to a US establishment’s
licensed HPC-C, and needed for
treatment of patients with specified
serious/life-threatening conditions
• Minimal information to be included in the
IND is summarized in Table A, Column B
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38. Category C
• Prospective manufacture of unlicensed HPC-C
in a US HPC-C establishment
• HPC-Cs not licensable due to failure to meet
donor eligibility or other manufacturing criteria
• Expected to be uncommon situation
• Example
– Donors from under-represented populations who may
have ID testing results indicating likely recovery from
HBV infection, and collection from such donors may
be necessary to assure sufficient HLA diversity
• Minimum information to be included in the IND is
summarized in Table A, Column C
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39. Information to include in the IND
• Minimum information summarized in
Table A
• Items listed are examples of the type of
information to be included in the IND
application; regulations in 21 CFR 312
not listed also apply, except where
indicated
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40. Labeling element examples
• Non-US HPC-C
– Supplemental labeling must be in English and
include limited summary of manufacturing
information and donor eligibility summary of
records (for products manufactured after
5/05), among other information
• US HPC-C
– Supplemental labeling must also include all
labeling content described in HPC-C licensure
guidance (Section VII.B.12)
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41. IND content and format
• Cover sheet (Form FDA 1571) required for
all categories
• Investigator’s brochure describes
– Product and its formulation (cell content and
additives)
– Description of possible risks
– Recommended instructions for thaw and
administration
– Note: IB not required for sponsor-investigators
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42. IND content and format – cont.
• Protocol section for all categories provides
– Brief summary of the study including dosing,
recipient safety monitoring and reporting
during infusion and post-transplant
– Plan for review of clinical outcome data, to
determine whether any adverse experiences
or other serious or unexpected outcomes may
be due to problems with product manufacture
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43. IND content and format – cont.
• CMC section in IND applications for all categories
describes procedures for DE determination for HPC-C
manufactured on or after 5/05
– Manufacturers (including non-US) must follow DE rule (21 CFR
1271 Subpart D); if not all requirements for donor screening and
testing were met, specified warning statements must appear on
label
– Category C HPC-C from ineligible donors need appropriate
labeling and other manufacturing controls
• CMC section in IND applications for category A and B
HPC-C manufactured before 5/05 describes donor
screening and testing performed to prevent spread of
communicable disease
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44. IND content and format – cont.
• CMC release specifications for non-US HPC-C
(category A) include
– No evidence of contamination; describe sterility
testing performed and provide results
– TNC count - define minimum and report
– Cell viability – define minimum and report; alternative
specifications for cell viability to those recommended
in the HPC-C licensure guidance may be submitted in
the IND for consideration
– HLA, ABO/Rh, and hemoglobin testing results
• CMC release specifications for US HPC-C
(categories B and C) same as described in
licensure guidance, or provide alternative C
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45. Sponsor and investigator responsibilities
21 CFR 312 Subpart D
• Applicable to INDs described in the draft
guidance
• Draft guidance summarizes
responsibilities of sponsors and
investigators, and explains who is
considered a sponsor or sponsorinvestigator
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46. Where to seek advice
• Pre-IND and pre-BLA meetings are encouraged
• Contact OCTGT Regulatory Project
Management Branch to schedule:
301-827-5102 Riggins.Patrick@fda.hhs.gov
Contact Office of Communication, Outreach and
Development (OCOD) with questions about the
guidance documents and related issues:
1-800-835-4709 or 301-827-1800
MATT@cber.fda.gov
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47. Thanks to AABB, FACT/NETCORD, NMDP,
CIBMTR, HRSA, NIH NHLBI, Cord Banks that
submitted information to the docket, AC
members, and all of you who provided
invaluable input and data all along the way! We
look forward to hearing from you and reviewing
your applications.
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