Dr. Joanne Kurtzberg's Vision for Harmonization of Standards at USA Cord Blood Banks

Background

When it comes to advancing the frontiers of diseases treated with cord blood stem cells, Dr. Joanne Kurtzberg of Duke University Medical Center is the world's leading innovator. Dr. Kurtzberg, who leads the Robertson Clinical and Translational Cell Therapy Program at Duke University, pioneered the use of allogeneic cord blood transplants for metabolic disorders such as Krabbe, Hurler, and others.  Dr. Kurtzberg subsequently pioneered the use of autologous cord blood stem cells for neurological conditions such as cerebral palsy, autism, etc. Currently, Dr. Kurtzberg and her team are continuing to pursue autologous trials as well as examining the safety and efficacy of allogeneic cord blood stem cells for neurologic disorders.

In 1998, Dr. Kurtzberg established the Carolinas Cord Blood Bank, a public bank that participates in the national Be The Match® network. In addition, Dr. Kurtzberg has more experience than any other licensed US physician at treating children with autologous cord blood units from family banks around the world.

In the United States, the Food and Drug Administration (FDA) regulates both public and private/family cord blood banks. All public and private cord blood banks are required to register with this federal agency. The FDA conducts sporadic mandatory facility inspections for all registered cord blood banks to confirm that proper practices are being upheld and to ensure compliance with federal regulatory requirements.

However, the FDA imposes an additional regulatory requirement on public cord blood banks that is not required of private cord blood banks:  Since 2009, public cord blood banks are required to submit a Biologics License Application (BLA) to the FDA; the BLA is equivalent to the licensing of pharmaceutical companies that manufacture drugs. To date, only 6 public cord blood banks have received FDA licensure, including the Carolinas Cord Blood Bank which Dr. Kurtzberg directs at Duke.

Question 1

Dr. Kurtzberg, you have been a vocal opponent of BLA licensing for public cord blood banks, arguing that the BLA imposes huge initial and ongoing costs on public banks while doing nothing to improve the safety or quality of cord blood transplants.  Do you believe there is an opportunity for dialogue with the FDA regarding the existing stringent quality standards for publicly banked units, or is the BLA here to stay?

The BLA regulations were developed for drugs, not cells or biologics.  This creates several problems where the regulations do not make sense for cells.  One example of this would be the requirement to place an expiration date on the cord blood unit.  As the expiration date is not known and as it is known that cord blood units, properly stored, for over 2 decades have resulted in successful engraftment, the requirement to set an expiration date is problematic.  This has been ‘solved’ by requiring banks to perform annual stability testing which is labor intensive, expensive and relies on the use of banked cord blood units that could otherwise potentially be used by patients.

On an encouraging note, one year ago, the directors of the 5 public banks who had been granted a BLA and representatives from the NMDP met with members of the the Center for Biologics (CBER) from the FDA to discuss some of the challenges associated with the BLA process for public cord blood banks.  A meaningful and productive exchange of information and ideas occurred.  There was a follow-on telephone call a few weeks ago with the now 6 licensed banks during which the FDA provided additional information and follow-up of questions that were raised in the in-person meeting one year ago.  The FDA provided meaningful and useful advise during this telecon.

To directly address your question, the current regulations for BLA for publically dosed cord blood units, focuses on aspects of manufacturing that do not directly impact the quality of the cord blood unit.  Thus, more focused cell-specific regulations would be better.

Question 2

Dr. Kurtzberg, you have also expressed concern that many of the cord blood units stored in family banks may not meet the stringent quality standards required to participate in clinical trials.  Would you please elaborate on those comments, and clarify whether you are referring to autologous or allogeneic use of units stored in family banks? In the future, what requirements will cord blood units from family banks need to meet in order to participate in  clinical trials at Duke?

Yes, it is true that the quality of cord blood units stored in family banks varies tremendously from bank to bank.  In our experience using units from family banks in our clinical trials, we found that some banks did not sufficiently test the unit, or stored very small units without enough cells for the types of treatments currently used in the clinic, or failed to store test samples that we needed to confirm the identity and potency of the cord blood unit.    

Ideally a cord blood bank needs to have the following information on a cord blood unit:

1. A total cell count
2. The chemicals, drugs, solutions used in processing the cord blood.
3. The final volume and type of container used to store the cord blood unit after freezing.
4. Sterility testing showing that the unit is sterile.
   1. If sterility cultures are positive, the isolate must be subcultured and antibiotic sensitivities tested.
5. Extra small samples for HLA, potency, and future testing.
6. Donor screening testing on the mother of the baby within 30 days of the delivery.
7. A medical history on the mother and the baby’s extended family.
8. While not absolutely required, it is also best if the cord blood bank tests the cord blood unit for viable CD34 cells.
9. Today, banks should store cord blood units in cryopreservation bags (freezing bags) with attached segments for identity, potency, and other future testing (see #3).
10. Cord blood units should be stored under liquid nitrogen or in the vapor phase of liquid nitrogen at equivalent temperatures.
11. Frozen cord blood units must be shipped in special containers that can maintain ultra-cold temperatures.  Data loggers should be used to monitor the temperature of the unit during shipment to ensure that the unit did not warm and refreeze during shipping.

Question 3

Recently, you have been advocating for "harmonization" of public and private cord blood bank standards. Beginning with the US, what exactly is your vision for this consistent set of standards? Would it entail simultaneously lowering public bank standards and raising family bank standards, or only raising family bank standards?

I believe that a cord blood unit should be processed, tested and stored using identical methods, chemicals, solutions and procedures whether it is stored in a private or a public bank.  Having said this, there are difference specifications that may apply to private versus public banks.  For example, a private bank may store smaller collections than a public bank.  Also, a private bank may defer HLA typing until the unit is selected for use by the family.  With these types of small differences in what are called specifications, the other aspects of banking should be the same.

Question 4

To be really specific about the steps needed to achieve harmonization of standards, can you provide a list of minimum procedures and tests which you believe family banks should be required to perform as a prerequisite to being licensed to operate? For instance, what are your thoughts on implementing a mandatory accreditation requirement (AABB and/or FACT) for all family cord blood banks currently operating in the United States?

I believe that all Family banks should be accredited by FACT or AABB.  In addition, the banks should have whatever accreditation or certification that is required by local authorities. They should also particpate in proficiency programs when available. 

Prior to implementing operations (e.g. handling family products and charging for services), banks should:

1. Develop specifications for:
   1. Temperature of product
   2. Temperature for storage of reagents/supplies
   3. Acceptance criteria for cord blood units
   4. Acceptance criteria for maternal blood tubes
   5. Acceptance criteria for donor screening test results and questionnaire results
   6. Recovery specifications post processing
   7. Addition of DMSO or other cryoprotectant
   8. Freezing curves
   9. Monitoring of freezers
   10. Test results
2. Validate
   1. Shipping boxes (kit boxes) to show they maintain temperature within range
   2. Processing methods
   3. Testing methods
      1. TNCC
      2. Viable CD34
      3. CFU (if performed)
      4. Sterility cultures
   4. Freezing methods
   5. Long term storage
   6. Release to a treatment center
   7. Shipping in dry shipper to treatment center

Question 5

Finally, what do you believe is the pathway to shape this harmonization in the United States? Should it come through proposed modifications to existing FDA regulations or via the legislative process?

I sincerely hope that there will be opportunities to meet and collaborate with the FDA to jointly develop and optimize regulations for banking of cord blood and cord tissues.  However, if FDA is not able to participate in these types of discussions, then legislative pressures may need to be applied