Briefing Document
Cellular, Tissue and Gene Therapies Advisory
Committee
Meeting #43
Draft Guidance for Industry for minimally
manipulated, unrelated allogeneic cord blood, and the regulatory approach to
minimally manipulated unrelated allogeneic peripheral blood stem/progenitor
cells
INTRODUCTION
FDA has regulatory authority over two types
of hematopoietic stem/progenitor cells (HPC) that are used for replenishing the
bone marrow (i.e., hematopoietic reconstitution) in patients exposed to
myeloablative chemotherapy or total body irradiation for treatment of a variety
of diseases—those sourced from placental/umbilical cord blood (HPC-C) and those
obtained by apheresis (HPC-A). When the
HPC are minimally manipulated, and collected from unrelated allogeneic donors,
these cells are regulated as human cells, tissue, and cellular and tissue-based
products (HCT/P) subject to licensure. Other
unrelated allogeneic HPC, such as those that are more than minimally
manipulated, and certain autologous and related allogeneic HPC, such as those
that are more than minimally manipulated, are also regulated as HCT/P subject
to licensure; however, these products are not under consideration for this
meeting.
Transplant
physicians, laboratory scientists, and medical technologists have amassed
extensive clinical and non-clinical laboratory experience with HPC-C since the
first reported transplant in a child with Fanconi anemia in 1988. By 1993, large public repositories of HPC-C
were established, in
Prior to the advent
of large scale banking of HPC-C in public inventories, HLA-matched bone marrow
and peripheral blood stem/progenitor cells obtained by apheresis of healthy
mobilized donors (HPC-A) were the major sources of HPC for transplantation.
Each source has relative limitations and advantages. For example, HPC-A consist of large numbers of
mononuclear cells and therefore are associated with rapid neutrophil and
platelet engraftment. Rapid access to a
large inventory of immediately available, HLA-matched unrelated allogeneic HPC
is one of the most significant advantages of banked cord blood.
The regulatory
approach to both HPC-A and HPC-C has been proposed in several workshops and FDA
publications (described below). Although
HPC-A have been used for transplantation for a longer period of time and in
greater numbers than HPC-C, the availability of extensive HPC-C manufacturing
and clinical outcome data in a public repository allowed for development of
recently published draft guidance for industry describing an approach to
licensure for these products.
BACKGROUND
In 1997, we proposed a new regulatory
framework for human cellular and tissue-based products, including hematopoietic
stem/progenitor cells. The proposed
framework provided a tiered approach to the regulation of human cellular and
tissue-based products, now referred to as human cells, tissues, and cellular
and tissue-based products (HCT/Ps). We
implemented this approach by promulgating three final rules, which comprise 21
CFR Part 1271.
On
On
On
On
o
are
more than minimally manipulated (processing alters the biological
characteristics of the cells);
o
are for
a use other than homologous use as reflected by the labeling, advertising, or
other indications of the manufacturer’s objective intent;
o
the
manufacture involves the combination of the cell or tissues with another
article, to include water, crystalloids, or a sterilizing, preserving, or
storage agent provided the addition of water, crystalloids, or the sterilizing,
preserving, or storage agent raises new clinical safety concerns with respect
to the HCT/P; or
o
has a
systemic effect or is dependent upon the metabolic activity of living cells for
its primary function, and is not for:
§
autologous
use;
§
allogeneic
use in a first- or second- degree blood relative; or
§
reproductive
use.
We consider unrelated allogeneic
hematopoietic stem/progenitor cells to have a systemic effect and are therefore
regulating them as biological products and drugs under the Public Health
Service (PHS) Act and the Federal Food, Drug, and Cosmetic Act (FDCA).
On
To provide a scientific basis for the
proposed standards, we requested the submission of comments proposing
establishment controls, process controls, and product standards designed to
ensure the safety and effectiveness of minimally manipulated unrelated
allogeneic hematopoietic stem/progenitor cell products derived from peripheral
and cord blood for hematopoietic reconstitution. Submitted comments were to include supporting
clinical and nonclinical laboratory data and other relevant information. To
allow sufficient time for the development of data and standards for these
products, the notice also announced our intention to phase in implementation of
an
The Biological Response Modifiers Advisory
Committee (BRMAC) met on
The committee’s deliberations focused on:
·
factors
the agency should consider in determining the safety and effectiveness of
placental/umbilical cord blood transplantation for hematopoietic
reconstitution;
·
the
role of CD34+ cell count in selection of cord blood units for transplantation;
and
·
other
measures of quality that should be considered.
A transcript and summary minutes of the
meeting can be obtained from the CBER Advisory Committee Meeting Transcripts
web page
(www.fda.gov/ohrms/dockets/ac/cber03.html#BiologicalResponseModifiers).
A task group composed of CBER scientists,
medical officers, and regulatory staff reviewed and assessed the submitted
information, data presented at the BRMAC and other public meetings, and the
large body of published literature on this subject. The task group prepared and published a draft
Guidance for Industry entitled “Minimally Manipulated, Unrelated, Allogeneic
Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution in
Patients with Hematological Malignancies” (1/17/07), recommending ways for
manufacturers to apply for licensure of these products, a copy of which has
been provided to Advisory Committee Members.
The draft guidance is divided into sections,
some of which contain the applicable regulatory requirements and others which
describe the license application procedure.
The draft guidance provides detailed information that should be included
in the chemistry, manufacturing and controls (CMC) section and the
establishment description (ED) section of their biologic license applications. The CMC section provides guidance on HPC-C
description and characterization, methods of manufacturing, container closure
system, methods validation/verification procedures, and labeling. The ED section provides guidance on facility
layout, utility systems (water, heating/ventilation/air conditioning), facility
controls, computer systems, and prevention of cross-contamination.
The information that follows provides an
overview of the specific issues in the Draft Guidance to be addressed in the
questions for the Committee.
Chemistry,
Manufacturing and Controls Recommendations in the Draft Guidance
The Product
standards proposed in Table A are based on product data submitted to the docket,
review of the scientific literature, and recommendations received from the
Biological Response Modifiers Advisory Committee at the 2003 meeting. We have proposed the use of CD34+cell dose and
the total nucleated cell (TNC) content to demonstrate purity and potency of the
HPC-C products. Applicants for a BLA for
HPC-C would be expected to achieve similar product characteristics using the
recommended or other appropriate tests in order to rely on the clinical data
from the docket instead of submitting their own clinical data.
Table A. Required and recommended Tests and Test Results 1
Product Characteristics 2 |
Testing |
Sample (Type and Testing) |
Results of Product Testing |
Safety |
Infectious diseases- Testing Required (21 CFR1271.45 through 1271.90)
|
Maternal peripheral blood collected within 7 days of cord blood collection-Type and Timing Required (21 CFR 1271.80(a) and (b))
|
All tests negative except non-treponemal test for syphilis when confirmatory test is negative. (Cytomegalovirus (CMV) results are recorded).
|
| CMV - Report | |||
| Sterility - Bacterial & fungal cultures –Testing Required (21 CFR 211.165(b) and 21 CFR 610.12) | Cord blood* and HPC-C (pre-cryopreservation) ** | Negative | |
| Hemoglobin | Cord blood* | No homozygous hemoglobinopathy | |
| Purity and Potency | Total nucleated cells (TNC) | HPC-C (pre-cryopreservation) | = 5.0 x 10 8 TNC *** / unit HPC-C |
| Viable nucleated cells | HPC-C (pre-cryopreservation) | =85% viable nucleated cells | |
| Viable CD34+ cells (flow cytometry) | HPC-C (pre-cryopreservation) | = 1.25 x 10 6 viable CD34+ cells**** / unit HPC-C | |
| Identity | Human leukocyte antigen (HLA) Typing | Cord blood | Report |
| Confirmatory HLA typing | Attached segment of HPC-C | Confirms initial typing | |
| Blood Group and Rh Type | Cord blood | Report |
Table A. Required and
recommended Tests and Test Results1
1 Testing, Sample (Type and Timing) and Results are
recommended unless specifically noted as required Collected cord blood = cord
blood product before undergoing volume reduction
2 The PHS Act requires a demonstration that the
product is safe, pure, and potent
* Cord blood= cord blood
before undergoing volume reduction
** Sample may be obtained
before or after addition of the cryoprotectant
***Based on 20 kg
recipient @ ≥2.5 x 107 NC/kg & ≥70% post-thaw
recovery = 1.7 x 107 nucleated cells/kg
****Based
on CD34+ cells ≥0.25% of TNC prior to freezing
Cord blood
processing is currently performed using volume reduction methods. The most commonly cited volume reduction
method was developed by Rubinstein et al (PNAS 1995). This processing involves the addition of a
plasma volume expanding medium, hydroxyethylstarch (Hespan or Pentastarch) to
the cord blood and centrifuging to cause the red cells to rouleaux and
sediment; this facilitates the separation of red blood cells from the white
cells containing the progenitor cells. The
leukocyte-rich supernatant is separated into a plasma transfer bag that is
further centrifuged. Surplus supernatant plasma is then expressed into a second
plasma bag and the sedimented leukocyte fraction is resuspended in supernatant
plasma to a volume of 20 ml. The
leukocyte-enriched HPC-C is then mixed with DMSO (in dextran); DMSO protects
the cells from damage as a result of the freezing process. The HPC-C cell suspension is cryopreserved
and then stored in liquid nitrogen, until ready to use for transplantation. The final volume of the each cryopreserved HPC-C
product after volume reduction is between 25-40 ml. The purpose of volume reduction is to allow
for the storage of a large number of HPC-C in a finite amount of space,
ultimately resulting in an increased number of available HPC-C. Some establishments use slight modifications of
this volume reduction procedure, however, they essentially achieve the same
goal.
Prior to the
development of the volume reduction methods, cord blood was processed by
alternate procedures. Any change in
methodology has the potential to affect the quality and stability of
HPC-C. For HPC-C processed or
manufactured using different procedures than those currently recommended in the
draft guidance document, establishments would need to provide separate
validation summaries and demonstrate comparability of the previously
manufactured products to the currently manufactured products, in order for
these HPC-C to be included under the license. We propose the use of product characteristics
such as TNC count, viable CD34+ cells content and colony forming units (CFU),
for the comparability data to support licensure of these previously
manufactured HPC-C in storage.
Establishments may opt to use alternate product attributes from
stability or other studies to demonstrate comparability. Clinical outcome data on these HPC-C or
information from the medical literature may also be cited to support product
comparability.
Our recommendation
to use TNC count, viable CD34+ cells content and colony forming units (CFU) in
comparability studies is supported by the scientific and medical
literature. The nucleated cell dose
(Gluckman et al, 1997; Rubinstein et al., 1998) and CD34+ cell dose (Wagner et
al., 2002) have been shown to correlate to consistent engraftment. Increases in
the nucleated cell dose are shown to be associated with a shortened time to
engraftment, whereas the CD34+ cell dose has been associated with predicting
the speed of recovery. Hence these two attributes have been used as indices for
faster engraftment and disease-free survival in cord blood cell
transplantation.
Most establishments
generally enumerate the viable CD34+ cells in the product as a surrogate for
committed and uncommitted progenitor cells in the context of validating the
collection and processing methods. Assessment of colony forming units (CFU)
have also been used as a measure of in-vitro function of the progenitor cells,
however, this assay has problems with reproducibility. Because of this problem some establishments
discard HPC-C which do not grow colonies.
The assessment of CFU, although not a good quantitative measure, is an
in-vitro function assay that may be useful for validating the processing,
storage and shipping procedures, and in comparability studies. As depicted in Figure 1, a correlation
between the numbers of viable CD34+ cells and CFU in HPC-C has been reported
(Cairo et al 2005).
Figure 1 Correlation of CFU and CD34+ cells in
HPC-C. From; “Cord Blood Log CD34+ and
CD34+ Subsets (CD38-, CD61+, CD90+) are Significantly Correlated to Log Total CFU, CFU-GEMM, CFU-GM and BFU-E: A Report
From The COBLT/NHLBI Program”. Mitchell
S. Cairo, Elizabeth Wagner, Geoff Cohen, John Fraser, LeeAnn Jensen, Shelly
Carter, Carmella van de Ven, Nancy Kernan, Joanne Kurtzberg. Blood, Volume 104, issue 11,
Comparability
studies will likely include assays performed on cryopreserved samples from
previously manufactured and stored HPC-C. For HPC-C stored in plastic containers,
samples may be obtained from an integral segment of contiguous tubing that is
heat-sealed, cryopreserved, and stored under the same conditions as the HPC-C
unit. HPC-C samples may also be stored
in separate aliquots, such as in a small volume vial, in separate freezers.
These separate aliquots may not have been exposed to the same freezing and
storage conditions as the HPC-C unit and thus may not be representative of the
unit. Procedures and conditions for
freezing and storage may have an effect on the quality of the HPC-C Some reports have shown a correlation of test
results (such as TNC count, viable CD34+ cells content, CFU) between samples
from the segment and those taken directly from the HPC-C container (Rodriguez et
al. 2004; Goodwin et al. 2003 ). Other
studies have evaluated cryovial samples and determined that it is
representative of the hematopoietic content of the HPC-C unit (Solves et. al.
2004). Limited information is currently
available in the literature on the utility of segments and cryovial samples to
assess the quality of the HPC-C unit and to determine whether a correlation
exists between tests of small product aliquots stored separately from the
HPC-C, and samples obtained directly from the HPC-C.
We request that the
Committee discuss the scientific aspects of demonstrating comparability between
previously manufactured HPC-C and HPC-C manufactured currently. (See question 1)
Clinical Indication
The Draft Guidance
describes a path to licensure for HPC-C intended for hematopoietic
reconstitution in patients with hematological malignancies. Regulatory
requirements for licensure of biological products include demonstration of
potency. Potency has long been
interpreted to include efficacy; in other words, the “specific ability or
capacity of the product to effect a given result” (21 CFR 600.3(s)). Therefore
the draft guidance is limited to this indication based on data submitted to the
public docket, which supports safety and efficacy of HPC-C for hematopoietic
reconstitution in patients with hematologic malignancies.
HPC-C transplant
outcome data reported to the docket by HPC-C establishments summarized the
primary outcomes of engraftment and survival in recipients with a multitude of
different underlying life-threatening diseases. For example, a large proportion of the
clinical data were provided by a single center that categorized the disease conditions
into 3 basic categories: hematological malignancies, genetic diseases, and
acquired marrow failure syndromes, with reported outcomes including rate and speed
of engraftment, graft versus host disease, and transplantation-related events.
Table 2:
Diseases treated by Cord Blood Transplantation
Rubinstein
et al., 1998
From the table it is apparent
that about 2/3 of HPC-C were used to treat hematological malignancies, a
quarter were used to treat genetic diseases and 8-10% were used to treat
acquired marrow failure syndromes such as aplastic anemia and MDS. Overall, about 15% of all the cord blood
transplants in this series were performed for congenital and acquired marrow
failure syndromes.
The number of specific genetic
and marrow failure diseases treated by cord blood transplantation is large;
however, information regarding safety and efficacy of cord blood
transplantation is available for relatively few specific diseases. In contrast, there is considerable clinical
data supporting the use of cord blood for hematopoietic reconstitution in
patients with hematological malignancies. We request that the Committee discuss whether
there are data available to support additional indications. This will be
discussed in question 2 (below).
Questions:
1. Please discuss the types of data that
could be submitted to demonstrate comparability between the previously
manufactured HPC-C and HPC-C manufactured currently. The Draft Guidance states these data could
include TNC count, viable CD34+ cell content, and colony forming unit content,
other product attributes obtained from stability or other studies, data cited
from the medical literature, and clinical outcome data. In the discussion please address the
following:
·
relationship
of data obtained from viable CD34+ cell content and colony forming unit content
·
alternate
test methods
·
the
types of samples that are available from the previously manufactured HPC-C and
HPC-C manufactured currently, and how they might impact comparability studies
2. Please comment
on the clinical indication described in the Draft Guidance; i.e., hematopoietic
reconstitution in patients with hematological malignances, and describe any
additional data of which you are aware that could potentially support
additional indications.
3. Please discuss any additional comments
you have about the recommendations provided in the Draft Guidance to assist
cord blood manufacturers in preparing information to be submitted in the
Biologics License Application (BLA) for their HPC-C.
4. Please discuss
what data would be adequate to demonstrate safety and efficacy of HPC-A, and to
consider an approach to licensure of HPC-A similar to the one proposed for cord
blood.
References
1. Rubinstein P, et al. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci U S A 1995;92:10119-22
2. Gluckman E, et al. Outcomes of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med, 1997 Aug;337(6):373-81
3. Wagner JE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002 Sep;100(5):1611-18
4. Rodriguez R, et al. Predictive utility of the attached segment in the quality control of a cord blood graft. Biol Blood Marrow Transplant. 2005 Apri;11(4):247-51
5. Goodwin HS, et al. Long term cryostorage of UC blood units: ability of the integral segment to confirm both identity and hematopoietic potential. Cytotherapy. 2003;5(1):80-6
6. Solves P, et al. Utility of the segment and cryovial samples for quality control and confirmatory HLA typing in umbilical cord blood banking. Clin Lab Haematol. 2004 Dec;26(6):413-8
7.
8. Rubinstein
P et al., Outcomes among 562 recipients of placental blood transplants from
unrelated donors. N Engl J Med. 1998 November;339(22):1565-1577