New York Blood Center Position on the
National Cord Blood Stem Cell Bank Network
The Institute of Medicine study was requested because of the apparently irreconcilable
controversy between the vision of the initiators of the legislation and the objections of the
National Marrow Donor Program (NMDP) over the operation and structure of the National Cord
Blood Bank Network.
A. The Controversy.
The legislation calls for an independent Network of high quality Cord Blood Banks with its
own Board of Directors. The NMDP proposes, instead, that the Network Banks should operate
under NMDP. NMDP asserts it is ready now to take on this responsibility because of its broad
array of resources and its experience in facilitating donation by volunteer donors (it is the
world’s largest bone marrow donor Registry, partially funded by federal resources). NMDP
proclaims it has developed the necessary mechanisms to govern the Network (choose Banks,
serve as conduit for funding from HRSA, organize Banks through a standing Cord Blood
Subcommittee, evaluate Bank performance, provide information technology support for Banks,
perform searches for matching cord blood units through a “one-stop shopping” resource, help
educate donors and patients, provide patient advocacy services, conduct recipient follow up and
promote and fund research). The NMDP argues that an independent Cord Blood Bank Network
would need to duplicate everything it has created, which it considers a wasteful and unnecessary
effort.
The issues at stake are essential, not just trivial differences between alternative approaches.
We show below that the Cord Blood Bank Network must operate as an independent entity and,
further, that the Banks must control the search mechanism, whether performed by the Network
itself or out-sourced to another organization under contract. Analysis indicates that
independence is critical to the success of the Network and of cord blood banking in general and,
consequently, is vital for the patients who need this resource, because of the absolute
requirement for Bank responsibility and accountability, effective inventory management,
collegial competition, full transparency and the expectation of eventual financial self-sufficiency.
These issues are explored more fully below, followed by specific recommendations to the IOM
panel.
B. Critical Requirements for the National Cord Blood Bank Network.
1. Cord Blood Bank Responsibility and Accountability.
The Cord Blood Bank has the technical, regulatory and legal responsibility for a stem
cell product used in clinical transplantation and will be held accountable for it. It is
expected that a participating Cord Blood Bank will be a recognized, experienced, high quality
entity operating within a reputable sponsoring institution. A Bank must accomplish a variety of
tasks, including collection of cord blood units, assessment of donor eligibility, testing,
processing, freezing, storage, unit selection, distribution and shipping, as well as tracking
transplant outcomes as quality control in a comprehensive cGMP-GTP quality management
1
environment. A Bank must have a well-functioning data and inventory management system.
Banks must be accredited by an appropriate, independent agency and ultimately licensed by the
U.S. Food and Drug Administration. Banks may contract with a separate entity for one or more
specific tasks such as infectious disease testing, blood grouping or HLA typing. Ultimately,
however, the Bank bears all responsibility for making a clinically appropriate hematopoietic
stem cell product that meets all clinical and regulatory requirements. The Bank’s responsibility
cannot be diluted by or assigned to a third party. Thus, the proposed legislation designates the
Network Board of Directors as responsible only for monitoring Bank compliance with
accreditation and regulatory requirements, not for meeting them.
2. Cord Blood Bank Accountability to the Federal Government through HRSA.
Each participating Cord Blood Bank will be accountable for meeting its obligations as
a recipient of federal funds. The legislation expects that Banks participating in the Network
will be geographically dispersed and will obtain high quality cord blood units from an ethnically
diverse donor population so that all ethnic groups in the U.S. population may be served
effectively. Each Bank, however, will be individually accountable to the government for
meeting numerical and all other obligations it has agreed to undertake. The legislation assigns
the Network Board of Directors responsibility for reporting to HRSA on Bank performance.
3. The Mechanisms to Search for, Reserve and Distribute Matching Cord Blood Units
Need to be Optimized to Fit Bank Requirements for Inventory Management.
Cord Blood Banks must manage their own inventories of available cord blood units.
Cord blood units are currently distributed through multiple mechanisms, including marrow donor
registries, NetCord, Bone Marrow Donors Worldwide (BMDW) and even intramurally for Banks
that operate in institutions also having Transplant Centers. Multiple distribution options foster
potential unit reservation conflicts. That cord blood grafts do not have to be perfect HLA
matches improves patients’ chances to find suitable cord blood units, but also makes it much
more likely that one unit will match multiple patients and increases the likelihood of
encountering reservation conflicts. Acceptability of mismatched transplants provides patients
with another advantage that depends on access to the most current inventory. Unlike the case
with bone marrow, a Center need not commit to a specific unit until the actual time of shipment.
Thus, a last minute repeat of the search may identify a superior unit. Centers often tentatively
reserve several units for one patient, while confirmatory typing and other pre-release testing is
being completed. Thus, cord blood inventories change dynamically reflecting unit reservations
by multiple “clients” as well as changes in unit status (out and back into the list of available
units), unit shipments and daily acquisition of new units. An active Cord Blood Bank, therefore,
must have its own effective, computer-based system to manage its own inventory at the local
level.
Patients optimize their chances of finding the best unit for them if the unit search
mechanism is based on the Banks’ most up-to-date, current inventories. A centralized database,
such as proposed by NMDP, unnecessarily duplicates local Bank databases. In order to be
current, however, such duplication must be complete (reflecting what is actually available in the
Bank) and instantaneous. Some months ago, for example, staff at the Cardinal Glennon Cord
2
Blood Bank explained that they had several hundred units available that had not been entered
into the NMDP database. Other Banks considering accepting NMDP funds for collecting units
are anxious about adopting NMDP programs because they may not allow inclusion of data in a
local database. A more modern, economical and labor-saving system, instead, would distribute
the search requests to each Bank, thereby automatically accessing the Bank’s current inventory
and avoiding the unnecessary, cumbersome and technologically antiquated duplication in a
centralized database. So-called “one-stop shopping” can be accomplished for the benefit of
Transplant Centers and their patients by either mechanism, but the duplicative centralized
database clearly limits the system’s possibilities if units listed centrally, in fact, do not include all
units that are actually available.
4. Competition and Transparency.
Cord Blood Banks, whose financial stability depends on “sales”, inevitably compete with
each other for distribution of units. Banks must be assured that their units have a fair opportunity
to be selected. Each Bank must know that its units are listed appropriately in any combined
Match Report sent to Transplant Centers. Thus, each Bank must approve any algorithm that
consolidates individual Bank Reports and must receive copies of all Match Reports. Further, the
Bank must know whether unit selection was appropriate. Banks should bear some responsibility
for, and participate in unit selection when there is any contention. Thus, each Bank must receive
a report on units that are selected for transplant. Finally, where there is any ambiguity, the
Transplant Center should explain its choice. Such transparency and accountability also will
ensure that patients truly get the most appropriate cord blood unit available.
Cord blood is no longer just an option for patients who have no other choice. As
experience has increased (now approaching 6,000 transplants worldwide), cord blood is
becoming competitive with bone marrow as a source of hematopoietic stem cells for one and the
same patient. Patients and their physicians now have two options to choose from, not just a first
choice and a last resort. Several Transplant Center physicians now preferentially choose cord
blood grafts over bone marrow or peripheral blood, even for adults. As a consequence, Cord
Blood Banks and Marrow Donor Registries understandably and unavoidably have become
competing organizations. It is even plausible that cord blood could eventually replace bone
marrow as the hematopoietic stem cell source of choice in unrelated transplants. If unrelated
marrow donors are no longer needed or justifiable, the rationale for and ethics of recruiting
donors and harvesting marrow or peripheral blood stem cells will become difficult if not
untenable. Moreover, the primary source of Registry funds (reimbursement fees of diverse
kinds) will progressively decline. Thus, the Marrow Donor Registry concept may be threatened
by the success of cord blood banking and vice versa. On the other hand, competition might
actually work to improve the performance of both organizations, to the benefit of all patients.
Each organization, therefore, must control its own operations. Neither should be allowed to
control the other. Their futures should be determined, instead, by independent scientific and
clinical evaluation of their reciprocal contributions and advantages.
NMDP, nevertheless, is a marrow donor organization that recently also undertook to
distribute cord blood units for existing Cord Blood Banks, sponsoring affiliated Banks under an
“umbrella” FDA IND. Its cord blood unit distributions thus far, however, have been meager.
3
The table below summarizes, for comparison, data from NMDP, NYBC and the Japanese
National Cord Blood Program (through June 30th 2004).
Program
NMDP*
NYBC**
Japan***
Current
Inventory
35,707
22,420
19,294
2004 Search
Requests
~3,000
819
~3,000
Total
#
340
1,734
1,769
CB Units Distributed
.
2004 to June 30, 2004
.
#
Rate/1000 Searches
~80
100
371
.
<30
122
124
* from D. Confer, IOM meeting 8/18/04. 1999 through June 30, 2004.
** NYBC data, February 1, 1993 through June 30, 2004.
*** from Tsuneo Takahashi, January 1, 1998 through June 30, 2004.
Thus, while NMDP has distributed some units from its affiliated Banks, its track record cannot
be seen as reassuring regarding its effectiveness, despite having access to most U.S. patients who
seek a transplant. In the absence of evidence to the contrary, the data could suggest that the
involvement of NMDP and its mechanisms may even have been detrimental to the Banks and,
quite possibly, to the many patients who did not get a graft and who might have been helped.
The corollary is unavoidable. Cord Blood Banks must participate in the establishment of
criteria and control the mechanism for cord blood unit selection and distribution. The
mechanism must be fully acceptable not only to the Banks, but also to the other interested parties
including Transplant Center physicians and patients. The legislation assigns the independent
Network Board of Directors (which includes Bank, Transplant Center and patient representation)
the responsibility for establishing the specifics of the search mechanism. An outside agency
might compete for and be selected to perform searches for the Network. Any organization that
performs searches for Network Banks, however, must answer to the Banks. If the organization
does not perform effectively, the Banks must have the authority to replace the organization. To
assure accountability, Banks should pay, under contract, any outside agency selected to perform
the search mechanism and the Banks must own the search programs the organization develops in
order to guarantee transferability. The cost for establishing and operating the search mechanism,
thus, should be part of each Bank’s budget.
5. Financial Self-Sufficiency.
Cord Blood Banks differ from other organizations involved in tissue or organ donation
because they produce a tangible asset that, when sold, allows for cost recovery, and makes selfsufficiency possible. Legislators that sponsored the FY 2004 appropriation and pending
legislation expect Cord Blood Banks to become self-sufficient after the five years of federal
funding. Self-sufficiency is only feasible, however, if the Banks own the cord blood units they
collect and are allowed to charge for those they distribute for transplantation. Ownership of the
units must also take into account the fact that existing Cord Blood Banks already have made
considerable upfront and continuing investment in establishing operations and building inventory
(so far, more than $50 million in our case). Moreover, Banks that succeed in becoming part of
4
the Network will likely continue to invest some of their own resources since federal funding
probably will not cover all costs. At the first IOM panel meeting, we provided several scenarios
regarding Banks’ self-sufficiency based on their ability to charge for units distributed, demand
for cord blood units and the transplant community’s level of trust in the reliability of cord blood,
including the level of safety and effectiveness.
C. What the Legislation Does Not Do.
1. Fund Research.
The legislation will provide that a portion of the cord blood units collected be made
available for research. Funding for research is already the responsibility of other agencies such
as the NIH, CDC, NSF, etc. This legislation does not create another funding agency.
2. Create an Infrastructure that Duplicates NMDP.
The legislation is intended to fund the rapid building of a high quality cord blood unit
inventory on a national scale; the critical resource that patients need. Much of the infrastructure
that is essential for a bone marrow registry is irrelevant to cord blood banking and
transplantation. The logistics required to coordinate donation, harvest and transplantation of
bone marrow are not needed in cord blood. Cord blood is not faced with same issues of
protecting donor confidentiality and privacy. Thus, the Transplant Center can go to the Bank
directly with no need for a protective intermediary. Many of the patient advocacy issues that
plague unrelated marrow donor registries do not apply to cord blood. Most importantly, there
need be no upfront charges to patients. NYBC, for example, does not charge for the search,
confirmatory HLA typing of the unit or patient, nor for other pre-release testing; samples are
provided free to the Transplant Center as are shipping and post-transplant HLA typing, all
elements that we consider integral to the transplant. We recently began to charge Centers for
class I HLA typing by DNA sequencing, however, since we currently consider such testing not
necessary for unit selection.
D. Recommendations.
1. Cord Blood Bank Selection.
Cord Blood Banks should be selected to participate in the Network along the following
principles:
(1) Selection should be by open, fair competition with defined selection criteria
published in advance of the actual competition.
(2) Selection should be based on applications to HRSA from individual Banks that
demonstrate the Bank’s experience, quality of performance, capability to contribute to the
Network goals for the national inventory and costs.
5
(3) Quality of candidate Bank performance should be evaluated based on pre-defined
criteria, including validation of procedures and transplant outcome (engraftment and
survival), appropriate accreditation and FDA licensure.
(4) Banks should be selected by an independent panel of experts with no real or
apparent conflict of interest. Individuals employed by any organization which benefits
financially from collection or distribution of cord blood units must be disqualified
automatically from serving on the selection committee. Thus, employees of a candidate
Cord Blood Bank or of marrow donor registries that distribute cord blood units (such as
NMDP) should be disqualified.
2. Selection of an Organization to Perform Searches of Matching Cord Blood Units.
If outsourced to a separate organization, selection of the organization to perform the
searches must follow the same principles outlined above for selection of Cord Blood Banks. The
legislation assigns the Network BOD the responsibility of defining the specifics of the search
mechanism that applicants must meet.
3. HRSA Should Distribute Federal Funds Directly to the Banks as Grants.
Funding Banks should be through grants rather than the contract mechanism to assure there
will be no ambiguity about who owns the cord blood units, an essential condition for selfsufficiency. Our own experience and that of COBLT illustrate the desirability for this approach.
The legislation mandates, however, that the Banks’ sponsoring institutions must guarantee
continued access to Network Bank cord blood units. Thus, the sponsoring institution must agree
to maintain the units if collections cease or the Bank closes for any reason or, alternatively, agree
to transfer the units to another sponsor, with appropriate financial protections.
4. FDA has the Responsibility to Define the Standard for Cord Blood Units.
FDA has the legally mandated responsibility to the public to assure the safety and utility of
clinical products. The FDA, therefore, licenses products and the facilities that make them, based
either on published guidelines and/or on Biological License Applications (BLA). FDA licensure
of cord blood has been under consideration for several years, was recommended by an FDA
subcommittee two years ago and, in all probability, is inevitable. The IOM panel could help in
this regard by insisting that Banks be FDA licensed in order to be part of the Network and
receive federal funding. We also hope to accelerate licensure through the BLA route. This week
we submitted our SOPs to the FDA as the first step in a BLA application and our pre-BLA
meeting is already scheduled.
Accrediting agencies such as AABB and FACT have contributed by setting minimum
standards and helping Banks improve their operations. They have published criteria (AABB and
NetCord/FACT Standards, respectively) and procedures in place to assess Cord Blood Bank
operations on a voluntary basis from a peer review perspective. Banks pay for the accreditation
process. NMDP also evaluates Banks, but the assessment determines whether a Cord Blood
6
Bank becomes NMDP affiliated and, therefore, whether NMDP will facilitate distribution of its
cord blood units. NMDP may not charge the Bank directly, but does levy charges to Transplant
Centers for units it distributes. Thus, NMDP evaluation of Banks incurs an inherent conflict of
interest. While accrediting agencies have helped enormously in raising cord blood banking
standards, they do not serve the same function as the FDA which is under none of the collegial or
conflict of interest pressures that are inherent to these organizations.
The legislation assigns the Network BOD responsibility for policies related to
characteristics of cord blood units that will become part of the National Network inventory such
as minimum cell number and donor ethnic distribution, neither duplicating nor conflicting with
the responsibilities of FDA or accrediting agencies.
5. One-Stop Shopping for Cord Blood and Bone Marrow.
Transplant physicians desire single point access to both available cord blood units and
potential bone marrow donors. This can be accomplished if the Cord Blood Bank Network and
marrow donor registries collaborate in creating a common web site for submission of search
requests, distributed to each organization and with each organization performing their own
searches for a suitable match and reporting back to the Transplant Center. The IOM panel
should recommend this approach.
E. Summary and Conclusions.
Cord Blood Banks must not be forced to abdicate their operational, regulatory, legal and
financial responsibilities to a third party. Inevitably, Banks become operationally crippled if
they depend on a third party for critical management services. NMDP, for example, provides an
array of “services” for affiliated Banks, from data management, performing searches and
invoicing Transplant Centers, to follow up of transplant outcome. Relying on these services
erodes the Bank’s ability to live up to some of its responsibilities, yet NMDP does not and
cannot assume the Bank’s regulatory, legal and financial responsibilities. Under the NMDP
model, Banks would inevitably become dependent on NMDP for unit distribution, yet NMDP
would not be accountable to the Banks. In effect, NMDP would have all of the control but none
of the responsibilities. The Banks’ independence, responsibility and authority are essential and
must not be subsumed under or relinquished to any other party.
7