Stem Cell Therapeutic & Research Act and a Critical Appraisal of Cord Blood Quality

Opinion Article: This is an article written by Ivan N. Rich of HemoGenix, Inc., Colorado Springs, CO, USA. It is an opinion piece that reflects views and positions of the author. It does not reflect the views of BioInformant Worldwide, LLC.

As a stem cell and cord blood industry blog, it is our role to spread discussion and allow a voice to varying opinions, perspectives, and areas of scientific expertise. If you have a reaction to this article, ask yourself, why am I reacting? How do I perceive current techniques for cord blood testing and assessment? If you have thoughts, they are encouraged in the comments section below.

November 24, 2015; HemoGenix, Inc. – The passage by voice vote of H.R. 2820, otherwise known as The Stem Cell Therapeutic and Research Reauthorization Act of 2015 through the U.S. House of Representatives [1] has been lauded by many in the cord blood community, including the Cord Blood Association (CBA) that promoted the bill. There is a good chance the Bill will become law, because health issues usually have bipartisan support. Although patients requiring a cord blood stem cell transplant have been helped by previous Bills, they have nevertheless not benefited from the principle purpose of this Bill, namely to provide high-quality cord blood stem cells for transplantation.

Those that have the most to gain from passage of this law are the public cord blood banks in the U.S. and the National Marrow Donor Program (NMDP). Together, they would reap most of the $23 million/year over the next 5 years [1]. These funds would be for collecting and storing cord blood units and uploading the information to the National Cord Blood Inventory (NCBI). The latter was developed by the NMDP under a sub-contract from the Health Resources and Services Administration (HRSA). For every unit collected for which the data are stored in the NCBI database, a cord blood bank receives about $1,100 to offset the cost of about $1,850/unit [2,3]. Cord blood banks in the U.S. only store about 10-25% of all units collected for the NCBI and of that, only about 1-2% of the inventory is actually sold for transplantation purposes [4,5].

It now costs a patient and/or their healthcare provider upwards of $50,000 for a single unit of cord blood (which is reduced to 15-25mL of frozen cells in a bag after processing) without any treatment whatsoever [2]. This does not include the cost of the search for a compatible unit charged by the NMDP. If the cord blood community could guarantee that every unit used for patient transplantation was of “high-quality”, as required by the Stem Cell Therapeutic and Research Act, the high cost of a few milliliters of precious cells might be defended.  However, this is far from the case; indeed, it has never been the case since the Law was first enacted in 2005. In fact, not a single cord blood unit that has been collected, stored and paid for by the government has been tested to ensure “high-quality” and as such, the cord blood banks have been, and will continue to be, in non-compliance with the Law.

The long title of the original Stem Cell Therapeutic and Research Act [6] is “To provide for the collection and maintenance of human cord blood stem cells for the treatment of patients and research, and to amend the Public Health Service Act to authorize the C. W. Bill Young Cell Transplantation Program”. Note that the term “stem cells” is used in both the long and short title. This is not a coincidence. The authors of the original Bill wanted to emphasize that without the stem cells, there would be no transplantation and no Law. The term “high-quality umbilical cord blood unit” that appears throughout the original and reauthorized statutes refers to the cord blood stem cells being of “high-quality”. No other cell types are mentioned, because the authors realized the importance of the stem cells. Not so the Food and Drug Administration (FDA) [7], and the standards organizations, AABB [8], NetCord-FACT [9] and NMDP [10], all of which either do not use the term “stem cells” or falsely define stem cells by lumping them with progenitor cells (cells derived from stem cells, but do not exhibit the properties of stem cells).

This misrepresents the purpose of this potentially life-saving procedure and misleads people into thinking that stem cells are actually being measured using the testing parameters recommended or specified by these organizations. In fact, nothing could be further from the truth. (The “stem cell” CD34 marker only detects a small proportion of mature stem cells, but mostly progenitor cells). These same erroneous guidelines and standards have now been adopted by regulatory agencies around the world without a thought as to whether they are scientifically sound and reliable or would benefit the patient. According to the NMDP website, more than 622,000 cord blood units can be accessed and 209,000 units are on “Be The Match” registry (NCBI) [11]. More than 6,000 allogeneic cord blood transplants have been performed in the United States [12]. Yet not a single cord blood unit so far collected and stored by public cord blood banks and used for transplant has ever been tested to ensure that the stem cells are of “high-quality”, let alone high potency.

It is impossible to believe that cord blood banks and transplantation centers are naive to the fact that if they are providing a stem cell product for stem cell transplantation and being subsidized or funded under the Stem Cell Therapeutic and Research Act, examination of the stem cells, upon which the whole process is dependent, must be performed. Since most cord blood banks, regardless of whether they are public or private, publicize the usefulness and importance of saving the umbilical cord blood for an eventual hematopoietic (blood) stem cell transplant, failing to actually measure the stem cells is misleading and false advertising to the public and patients. It is obvious that determining cord blood stem cell quality and potency is not a priority for the banks and transplantation centers. It therefore follows that providing a quality product to a patient is also not a priority. If the opposite were true, cord blood banks and stem cell transplantation centers would compare and optimize processes and procedures to allow standardization and measurement assurance of the products across the industry. This, in turn, would dramatically improve quality and clinical outcome and reduce cost. Unfortunately, no two cord blood banks perform the same procedure in the same manner. Given this mindset, why and how does the newly established Cord Blood Association think it can implement new standards as one of its priorities? [13]

Another priority of the CBA is to rapidly adopt “novel technologies” [13]. However, according to the CBA, any new technology must first be compared to present testing methods [14]. The process of comparing a new assay to an older, established assay is called assay verification and is a relatively simple process. Assay validation, on the other hand, is more complicated and more important, because several parameters have to be documented that provide the measurement assurance required to trust the results [15].  Advanced technology that could be used to improve quality and potency has not only been verified against current tests multiple times, but also validated, with results published in peer-reviewed journals [16,17,18,19]. Regulatory agencies require validated assays. Cord blood community standards stipulate validated assays [8,9], but with the exception of one test (CD34 measurement) all currently used assays have been “grandfathered” in without any proper validation, and no new validated technology has ever been adopted by the cord blood community since the first cord blood transplant in 1988 [20]. Instead, there is a reliance on scientifically flawed, inaccurate and unreliable tests (see below) that do not measure stem cell quality and potency, waste time and taxpayer’s money and result in patient fatalities due to graft failure that might have been prevented if “best practices” had been implemented. This flawed strategy is why, at the September 2014 meeting of the Advisory Council on Blood Stem Cell Transplantation (ACBSCT), which receives funding under the Stem Cell Therapeutic and Research Act, members could not define the meaning of a “high-quality” cord blood unit [21]. It is also one of the reasons why, at the September 2015 meeting of the ACBSCT, the primary focus was not on defining cord blood quality, but on collecting cord blood units with higher cell counts [22]. This was also the focus of testimony to introduce the Stem Cell Therapeutic and Research Reauthorization Act of 2015 to the House of Representatives on June 25, 2015 [23].

To understand why the CBA and NMDP have called for cord blood banks to collect “bigger” cord blood units described in the Summary Notes of the ACBSCT meeting from September, 2015 [22], the question raised by House Representative Murphy at the meeting of the Energy and Commerce Subcommittee on Health when the Stem Cell Therapeutic and Research Reauthorization Act of 2015 was introduced to the House, is worth considering [23]. The answer to the question, “what is your definition of a high-quality cord blood unit?” provides insight that epitomizes the simplistic and misleading approach to this question by the CBA. “A high-quality cord blood unit needs to be sterile. It needs to be checked incapable of transmitting genetic or infectious diseases, and most importantly, it needs to be potent, and potency can be measured by the number of cells that are in the unit, and we now know that we need a certain dose of cells to transplant individual patients and that many of the units are too small and don’t contain that number of cells”. In addition, “HRSA needs to help the (cord blood) banks to be incentivized to collect bigger units with more cells, and right now their policy does not do that”. It is obvious that a certain number of cells needs to be transplanted into a patient. What is not obvious is that these cells must be stem cells. Currently, patients receive a “soup” of cells which mask the stem cells that represent only a minute proportion of the total cells present [19]. As such, members of Congress have been misguided into thinking that only total cell number is the important parameter and that everything will be better with “bigger” cord blood units.

In this testimony quality and potency are considered equivalent parameters [23]. Scientifically, they are two different quantitative measurements of stem cell proliferation [18,19]. Neither quality nor potency has anything to do with the size of the unit being collected. The argument proposed by the CBA and NMDP for “bigger” cord blood units appears to be a smokescreen to deflect the focus away from major problems that have plagued the cord blood field for years. They include the increasing cost of a cord blood unit and the lower number of transplants performed [12], high graft failure rates of about 1 in 5 attributed primarily to lack or low potency of the cord blood units [24], long engraftment times (between 21 and 25 days), and long immune recovery periods [23,24]. It is worth noting that the last three problems were discussed during the first meetings of the ACBSCT in 2008 [25]. Seven years later and the problems still exist with no resolution in sight.

The idea that larger units are needed to solve these problems is based on the assumption that if a larger number of cells is transplanted into a patient, there is a higher probability that more stem cells will also be transplanted, without spending the the time and money to actually measure them and ensure that the quality and potency are above specified acceptable levels that would predict engraftment [19,26]. The call for larger cord blood units became apparent at the 2014 Cord Blood Symposium in San Francisco. It just so happened that the establishment of the Cord Blood Association was also voted into existence by many of the attending delegates, including this author. The resulting mission and the priorities of the CBA were not new; in fact they should have been addressed years ago when the Stem Cell Therapeutic and Research Act first became law. The call for larger cord blood units, the establishment of the CBA and lobbying Congress together with the NMDP, to pass the Stem Cell Therapeutic and Research Reauthorization Act of 2015, is no coincidence. Over the years the leaders of the cord blood community have dug themselves into a hole from which they cannot emerge and expect Congress and the taxpayer to help bail them out for their own failures to the tune of $23M/year [1]. Unfortunately, nothing can be expected to change. Reauthorization of the law without amendments to improve safety for the patient essentially legitimizes all past and future aspects of cord blood collection, testing, storage and use and therefore allows the CBA and NMDP to continue on the same path for another five years.

The priority of the CBA to “rapidly adopt novel technologies” [13], or any of the other four priorities for that matter, will not occur unless the CBA can also take credit for the change. The consequences of this overarching and dictatorial approach affects everyone in the field, but particularly the patients and their families. If a test produces inaccurate and unreliable results it should be discarded for something better. If an already validated and trusted “novel technology” is incorrectly performed, as was the case for a cord blood study for HRSA in 2008, and on that basis, purposely prevented from being used, [27], then the only conclusion is that other agendas and possibly conflicts of interest are at play. The recommendations by the NMDP Cord Blood Advisory Group for new potency assays published in 2011 [28] have never led to the adoption of any validated potency assay. The inclusion of text fields into the EmTrax database of the NCBI by the NMDP that would provide results from validated “novel technologies” to stem cell transplantation centers, required the action of HRSA to achieve this; the NMDP was not going to do this voluntarily. These and probably many other examples, illustrate the inexplicable unwillingness to change course and use “novel technologies” that might benefit the patient. Nevertheless, the situation was recently reversed when “novel technology” was used to demonstrate the inadequacy and unreliability of current tests and procedures, and why the assumptions presently used by the cord blood community worldwide were incorrect [19]. The results published in a “highly accessed” peer-reviewed article [19] call into serious question the very fabric upon which cord blood banking and transplantation are based, as well as the underlying motivation of the CBA and NMDP.

There is no doubt that better clinical practice has benefited the transplant patient. The cord blood community continues to try and improve its outward appearance and financial income by finding new applications (“novel therapies”, such as cerebral palsy) for cord blood without the concomitant investment and improvement of its practices. In 2015, new perspectives to improve the quality and potency of cord blood units based on “novel technology” were published [26]. These new perspectives would help cord blood banks to become compliant with the Stem Cell Therapeutic and Research Act and drastically improve practices and measurement assurance so that results could be trusted by the banks themselves, transplantation centers and patients [26]. Although the article has been accessed more than 2,000 times, there has not been any open discussion and no attempt has been made to improve the situation.  This state of inertia and lack of motivation to even try and elevate and improve safety for the patient is unconscionable.

The blame lies squarely with those responsible for propagating false and misleading information and impeding any advancement in the field. When medical and/or laboratory directors of cord blood banks believe that quality and potency can be obtained simply by performing a cell count, there is something fundamentally wrong with the system. And since the Cord Blood Association is part of the same system, the situation cannot be expected to get any better. The government, Congress and the public should not be led up the garden path with half-backed, meritless schemes, such as collecting large cord blood units, in an attempt to steer away from basic problems that have not and cannot be solved with current methods [26]. They should not be rewarded with taxpayer’s money for doing so. It is now up to those responsible to stop talking about what they are going to do and why they should be trusted and actually prove what they preach. A good starting point would be to rewrite and implement standards that require best practices and measurement assurance and not “minimal guidelines” [9] in the manufacture and production of cord blood stem cell products. Perhaps the procedure would then be worth its name, cord blood stem cell transplantation.

Literature Cited

1. The Stem Cell Therapeutic and Research Reauthorization Act of 2015. https://www.govtrack.us/congress/bills/114/hr2820.
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11. Be The Match Registry. https://bethematch.org/Transplant-Basics/Cord-blood-and-transplants/.
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23. Transcript of the House of Representatives Energy and Commerce, June 25, 2015 on the Stem Cell Therapeutic and Research Reauthorization Act of 2015. http://docs.house.gov/meetings/IF/IF14/20150625/103685/HHRG-114-IF14-Transcript-20150625.pdf.
24. Page KM et al. Total colony-forming units are a strong, independent predictor of neutrophil and platelet engraftment after unrelated umbilical cord blood transplantation: a single center analysis of 435 cord blood transplants. Biol Blood Marrow Transplant 2011, 17:1362-1374. doi: 10.1016/j.bbmt.2011.01.011.
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