Cord blood banking in the UKdata.parliament.uk/DepositedPapers/Files/DEP2009... · The UK national cord blood bank purchased 10 imported samples in 2007, at a cost of £170,000 or

September 2008

Cord blood banking in the UK

An international comparison of policy and practice

www.technopolis-group.com

Ingeborg Meijer

Madeleine Knight

Pauline Mattson

Bastian Mostert

Paul Simmonds

Wieneke Vullings

Cord blood banking in the UK i

Table of contents 1. Introduction 1

1.1 Background 1 1.2 Study objectives 1 1.3 Scope of the assignment 1 1.4 Main report and Annex 2

2. Executive Summary 3

2.1 Recommendations 5 3. Stem cells from cord blood 7

3.1 Stem cells and umbilical cord blood 7 3.2 Allogeneic and autologous transplantation 7

4. Cord blood collection, banking and use in the UK 9

4.1 Policy 9 4.2 Collection 10 4.3 Storage/banking 15 4.4 Use 20 4.5 Cost 25 4.6 Summary of UK review 26

5. International comparison of UK policy and practice 28

5.1 Benchmarking UK with selected comparator countries 28 5.2 Benchmark data from international organisations 35

6. Conclusions & recommendations 37

6.1 Conclusions in the context of the UK & benchmark data 37 6.2 Issues discussed at the workshop 39 6.3 Recommendations 40

Appendix A Cord blood review workshop

Cord blood banking in the UK ii

Table of figures Figure 1 Stakeholders in cord blood collection 10 Figure 2 Collection of cord blood in the UK 15 Figure 3 Banking of cord blood 19 Figure 4 Organisation of use 22 Figure 5 Evolution in the geography of sourcing of cord blood units, national and international (%) 22 Figure 6 Use of cord blood units 23 Figure 7 Cost of cord blood collection and banking 25 Figure 8 Cord blood banks in comparator countries 29 Figure 9 Blood sample units stored in the different countries 31 Figure 10 Cord blood use of all HPC transplants 32 Figure 11 Costs of collection and storage 33 Figure 12 Spanish Cost Model example 33 Figure 13 Private cord blood banks in comparator countries 34 Figure 14 Summary in numbers 35 Figure 15 Relation between units provided and exported to units present 36

Cord blood banking in the UK 1

Cord blood banking in the UK: an international comparison of policy and practice

1. Introduction

1.1 Background

The UK is recognised as a world leader in the field of embryonic stem cell research. Government policy supports and encourages research using stem cells derived from all types of tissue, of embryonic, foetal or adult origin. In 2005, the UK Stem Cell Initiative (UKSCI) was asked to develop a comprehensive strategy to underpin the next decade of stem cell research in the UK.

The UKSCI report made 11 recommendations, which were all accepted by Government. The final UKSCI report stated that “the development of placental or umbilical cord stem cell banking services and therapies could be a potential area of interest”, which the report could not examine in sufficient detail.

1.2 Study objectives

As part of the continuing implementation and assessment of the UKSCI strategy for stem cell research, the Department of Health requested an investigation of policies and practices for placental and umbilical cord stem cell banking services, both in the UK and comparator countries.

The purpose of the review was to examine the effectiveness of the UK policy and practice on the collection, storage and use of umbilical cord blood (UCB). The analysis of the UK position was then used to benchmark six comparator countries, which included: Canada, China, France, Japan, Spain and the United States.

1.3 Scope of the assignment

In order to obtain an overview of the arrangements for UCB collection, storage and use in the UK, desk research and (telephone) interviews were conducted. This provided a starting point for (i) developing a model framework for benchmarking policies and practices in selected comparator countries, and (ii) cataloguing the outputs and achievements of the comparator countries in comparison with the UK situation.

In line with the framework, case studies were performed to benchmark the countries with UK policies and practices. For each country, the case study provided an overview of the policies, practices and costs related to the collection, storage and use of umbilical cord blood in the respective countries. The international reviews focused on initiatives that are federal, public, private or a combination, and highlighted options and choices that have the potential to affect the effectiveness of cord blood banking. The research for each country was not limited to initiatives that were part of globally active (accrediting) organisations, but also included a comprehensive overview of the main initiatives mapped in a pragmatic way. However, the search for data relating to China and Japan was limited due to language barriers. Nonetheless, a sub-set of foreign data was arrived at, which we considered to be suitable to review the UK situation in light of international good practice, in order to provide lessons and insight for the Department of Health.

The benchmark data and the UK review analysis were presented in a stakeholder workshop that was held in London, on 28 May 2008, chaired by Ruth Warwick (Consultant Specialist for the NHS Blood and Transplant [NHSBT]). Representatives of all relevant stakeholder organisations were invited. The workshop included short expert introductions on collection, storage, use and research as well as extensive discussions with participants. Participants pointed at several issues at stake, which are


summarised in the notes on the workshop and are included in the main report where appropriate.

Several sub questions are addressed in the following sections, including:

• The role of NHS Trust’s, and the interaction between collectors and bankers

• The number of cord blood samples needed in the UK to cover demand

• The future use for autologous stem cell transplantation

• The role of public and private banking, both in the UK and internationally

1.4 Main report and Annex

The main report includes analysis of the implications of cord blood collection and storage, banking and use in the UK and comparison this situation with policies and practices in six selected comparator countries, with the report organised as follows:

• Section 3 presents a very brief introduction to the issues surrounding stem cells from cord blood

• Section 4 presents an overview of the UK situation

• Section 5 presents an analysis of the international comparison, discussing the UK situation in light of the position in the selected benchmark countries and where possible in the context of more global data from international organisations such as World Marrow Donor Association (WMDA) and NETCORD

• Section 6 presents our conclusions and recommendations

• In addition, the study has benefited from the organisation of a deliberative workshop in May 2008 involving representatives of the relevant stakeholders (the agenda, presentations, notes and list of delegates are appended)

The separate annex report contains the individual country benchmark reports, including a selection of data from international organisations. The notes on the workshop are also presented in the annex report.


2. Executive Summary

Umbilical cord blood banking has attracted growing worldwide interest in recent years, driven by an expansion in the therapeutic use of adult stem cells, the gathering promise of research extending application to a broader spectrum of health issues and the aspiration of many to pursue medical science in an area without the apparent moral hazard of work on embryonic stem cells.

A number of UK stakeholder groups are pressing the government to adopt a more active policy with respect to cord blood, reflecting international trends in cord blood collection and use.

The UK government has no specific, published policy regarding cord blood collection. In practice, policy makers, hospitals and healthcare professionals work within the context of the EU guidelines and the published advice of relevant professional bodies. The Royal College of Obstetricians and Gynaecologists’ position paper on umbilical cord blood banking (2006) is used widely as a key text and source of advice.

In July 2008, new rules came into force requiring the collection of cord blood to take place under licence from the Human Tissue Authority, which means cord blood can be collected only by people with specialist training and on premises that meet essential standards. This is the first time that collection of cord blood at birth has been regulated in the UK, and is intended to ensure the safety of mother and child while also seeking to make sure that samples collected are of a high quality.

It is against this backdrop that the UK government commissioned this international comparative analysis, to provide intelligence as to current policies, practices and trends as an input to its deliberations around the need to increase umbilical cord blood collection and use, and its potential practicable options.

This report presents a comparison of the UK situation with the policy and practice in six selected countries: Canada, China, France, Japan, Spain and the USA.

The annual number of cord blood samples used for transplantation proved difficult to establish due to different reporting methodologies, however we estimate usage falls in the range 50 (Canada) to 500 (Japan) transplants each year, with around 100 in the UK. In proportionate terms, this amounts to some 15-18% of all HPC transplants. Interviews suggest the number of cord blood transplants is increasing quite rapidly.

Within the seven countries, national cord blood bank capacities vary widely, ranging from a low of around 2,000 samples for Canada to a high of over 200,000 samples for China. The UK national cord blood bank holds around 11,000 samples at present. The variability is in large part a reflection of population size, however there is a perception that the national capacities of Canada, France and the UK are sub-critical at present.

Collection rates across the seven countries fall into two clusters, with Canada, Spain and the UK collecting proportionately fewer samples, at around 0.1% of births annually, while China, France, Japan and the USA are collecting proportionately more samples, at around 0.3% of births annually. The UK national blood bank collected more than 2,400 samples in 2007, a collection rate of around 0.13% of total births in the year.

There is a high attrition rate of samples between collection and banking in all countries. International figures suggest that typically 30-40% of collections result in a viable sample suitable for banking, where the UK achieves a much higher utilisation rate, of around 75%.


Conventional wisdom suggests that 20,000 samples is the threshold for a medically and economically viable national cord blood bank. Canada, France and the UK each has rather fewer samples than this.

The UK national blood bank has made a public commitment to expand its repository over the next several years, building towards 20,000 samples.

The figure of 20,000 samples is a rule of thumb, rather than a definitive reference. Clearly, local populations and economic conditions differ from one country or region to the next, and in some cases are likely to have a significant bearing on the required size of national banks. Other parameters loom large too, from the quality of samples and storage to the range of uses to which the samples are put. Moreover, national banks can deliver the necessary medical service through means other than a singular bank, so for example international alliances or more commercial collaborations wherein samples are purchased at full economic cost on an ad hoc basis.

The UK national cord blood bank purchased 10 imported samples in 2007, at a cost of £170,000 or £17,000 for each sample.

International collaboration is an important feature of umbilical cord blood banking, due to the inherited nature of tissue type, and the need for vast numbers of stored samples in order to have adequate representation of ethnic minority groups.

The cost of (unrelated) cord blood collection and storage is not inconsiderable, with estimates of full economic costs ranging from £200 (China) to around £1,400 (UK). Annual unit storage costs range from around £35 (China) to £75 (UK, USA).

Oral presentation of the results of very recent research carried out for the Anthony Nolan Trust suggests that, with the application of more formal models and empirical data, the medical threshold is much higher than the 20,000 figure in widespread use, and possibly double that sample size. The research is to be published in due course, and the results, and the calculations, will be of great interest to policy makers and executives responsible for developing national blood banks.

International trends demonstrate an increase in the use of cord blood. In terms of haematopoietic stem cell (HPC) transplantation, there is an increase in both the absolute number of cord blood samples used for transplant, and the proportion of transplants using cord blood, in comparison with other sources of HPCs from bone marrow donations or peripheral blood stem cell donations.

A combination of factors is at work. Cord blood transplants demonstrate equivalent patient outcomes to bone marrow transplants, even when there is a lower degree of tissue type match, between the donor and patient. The advancement of new procedures utilising 2 or 3 cord blood samples for a single transplant has made cord blood transplant a credible treatment for adults as well as children, which has increased the size of the basic treatment population. Cord blood also provides an alternative source of HPCs for transplantation for patients of ethnic minority origin, who are underrepresented on bone marrow registries in the UK.

There is an increase in the use of cord blood for treatments other than HPC transplantation, particularly in the USA. Evidence shows successful use of cord blood in treating Type I Diabetes Mellitus, Hurler’s syndrome as well as for tissue repair. Clinical results suggest a much broader potential for the medical use of naïve immune cells and mesenchymal stem cells in cord blood. Future application might be wider still. Recent published research has claimed that a total of 85 conditions are treatable or supportable with cord blood. However, many of these potential uses of cord blood rely on the future development of mesenchymal stem cell expansion techniques.

Collection is increasing around the world, blood banks are being launched and getting bigger, therapeutic use is expanding and extending and medical science holds out the promise that many more conditions might be treated or supported with cord-blood based therapies within 5-10 years, with equivalent or improved patient outcomes.


The UK faces a number of challenges in considering the expansion of cord blood collection. These include the capacity of the system, the workload of professionals attending births and concerns over legal liability and early clamping of the umbilical cord, which is currently routine practice regardless of cord blood collection.

Currently, very few hospitals in the UK are committed to collecting cord blood at an institutional level, either for public or private cord blood banks. The private banks, for the most part, gain access to collection through private hospitals.

According to current rates of collection, banking and use in the UK, it will take another 6 years for the national cord blood bank to reach the target of 20,000 stored units. Due to attrition rates from collection to storage, the desired uplift of 9,000 units means that around 12,000 units would need to be collected across the period.

Assuming the UK cost base remains unchanged, where any scale economies are expected to be offset by inflation, the estimated cumulative additional costs of reaching 20,000 samples amount to around £17 million, or around £3 million a year, while annual storage costs might increase from around £0.9 million presently to £1.7 million by the end of the 6-year period. The annual additional costs of creating and maintaining a bank of 20,000 samples might be offset to some extent by a reduction in the number of imported units, which ranged from £0.1 million to £0.4 million a year.

The option of using a public-private partnership might be considered as a practicable means by which to increase the rate of collection for the public bank, potentially permitting the UK to create a national bank of 20,000 samples within two to three years, as the private sector has substantially greater collection capacity than the public system. However, the UK has little experience of this model, and arriving at a workable solution would take time to devise, pilot and implement.

Further detailed analysis is required to assess the above issues including methods of collection, future need and health economics, in order to form relevant policies regarding cord blood collection.

2.1 Recommendations

Based on the results from the international review, and having heard the discussions on the several issues at stake at the workshop in London, we recommended the UK government consider:

• Developing an explicit national policy on cord blood, which amongst other things aims at increasing future rates of collection of cord blood for public banks

• Creating a high-level advisory committee to provide the minister and policy teams with advice on the detail of such a policy. The high-level group should consist of representatives of all parties in the chain of cord blood collection (inclusive of private parties), storage and use, to continue discussion on issues presented in this report and as a follow up to the workshop. A multi-stakeholder committee will ensure the advice is practicable, and should facilitate implementation and generally improve communication between all stakeholders in the community

• Requesting the advisory committee to address each of the questions that were raised at the end of the workshop

• Commissioning further research to obtain detailed information on public-private banking models, from a variety of perspectives and with fully worked through cost models, with examples sourced from various international practices

• Developing marketing guidelines for private cord blood companies, in order to prevent misleading information to the public

• Developing further insight into the place of cord blood stem cell research in relation to other stem cell research (cf. UKSCI’s recommendation)


• Investigating the perceptions of British citizens on the issue of altruistic donation as opposed to private donation of cord blood, possibly making use of the public dialogue expertise and funds available to all government departments through the Sciencewise resource centre


3. Stem cells from cord blood

3.1 Stem cells and umbilical cord blood

Pluripotent stem cells are primitive stem cells capable of differentiation into multiple tissue types and cell lineages. This ability offers great potential for regenerative medicine. A specific type of stem cell found in humans, the haematopoietic progenitor cell (HPC) is a multipotent stem cell with the capacity to differentiate into the three classes of blood cells (erythroid, myeloid and lymphoid). Multipotent stem cells are committed stem cells with a restricted differentiation capacity.

Umbilical cord blood is rich in haematopoietic stem cells (HPCs), which are biologically similar to their adult counterparts. However umbilical cord blood appears to have advantages over HPCs obtained from bone marrow or peripheral blood, making it especially suited for haematopoietic stem cell transplantation. Umbilical cord blood is a richer source of both stem cells and early immune system cells that are immunologically more naive and have a greater potential to proliferate. In addition, umbilical cord blood carries a low potential for infectious disease transmission, and cord blood derived stem cells are biologically younger and have been subject to less genotoxic damage and epigenetic modification than their adult counterparts.

Umbilical cord blood also contains non-haematopoietic stem cells, most notably mesenchymal stem cells. Mesenchymal stem cells are another class of multipotent stem cell that is capable of differentiating into multiple lineages of structural and supporting tissues such as muscle, bone, and other soft tissue. Unlike bone marrow, mesenchymal stem cells are only present in low numbers in cord blood. They are also present in the Wharton’s Jelly, a thick layer surrounding the blood vessels in the umbilical cord.

3.2 Allogeneic and autologous transplantation

The potential of HPCs to reconstitute bone marrow and peripheral blood has been used for the treatment of patients with bone marrow damage from either chemotherapy or underlying haematological failure. Transplanting HPCs is effective for the treatment of for example leukaemia, selected genetic metabolic disorders and immunodeficiency’s and sickle cell anaemia. HPCs can be obtained from several sources including bone marrow, mobilised peripheral blood and umbilical cord blood collected from the placentas of recently delivered infants.

Transplantation is either allogeneic or autologous:

• Allogeneic stem cell transplantation is performed with stem cells that are collected from a related or unrelated donor, and transplanted into the patient to reconstitute bone marrow

• Autologous stem cell transplantation is performed with stem cells that are collected from the patient before treatment and are re-infused to reconstitute the bone marrow

An appropriate Human Leukocyte Antigen (HLA) match is important for all types of HPC transplantation regardless of the graft source. Individuals have three pairs of HLA-A, -B and DR antigens and a full tissue match is termed a 6/6 match. Matching is important: non-matching grafts are rejected by the immune system of the recipient. The inheritance pattern of the highly polymorphic HLA types means that the chance of finding a related fully matched donor is only 30%. For the remaining 70% of patients, an unrelated donor stem cell source must be found.

In an attempt to make HPCs more widely available to the large number of patients who do not have an HLA-identical sibling, large international volunteer adult (bone


marrow and peripheral blood) donor registries were created in the 1980s. Today, more than 12 million registered, and tissue typed, adult donors are listed in more than 40 registries worldwide. In the UK, the British Bone Marrow Registry (BBMR) is taking care of the enrolment, testing/typing and registry of bone marrow donors1 (see Box 1). Still, registries and transplant physicians face several challenges, such as:

• Finding a full match for patients in many ethnic groups, especially those of mixed race, remains a challenge. For many ethnic groups no more than 20-30% of patients can be matched, whereas a match can be found for up to 75% of patients of Western European origin

• Unavailability of some potential donors, even if an individual was identified in a registry on the basis of HLA match. Also, prolonged intervals between the time of a search request and the time of HPC acquisition (median time is greater than 4 months)

• Risks associated with bone marrow and peripheral blood donation. For bone marrow to be collected, the donor needs a full anaesthesia, which carries risks to the donor. Peripheral blood as a source of HPC depends on aphaeresis, which can take several hours and requires the prior stimulation by G-CSF (Granulocyte Colony-Stimulating Factor) of the donor. The risk-benefit profile of G-CSF stimulation is currently not entirely positive for donors

Large and accessible cord blood collections could resolve several of these issues. Given there are 130 million babies born each year worldwide, umbilical cord blood represents the largest potential source of stem cells for transplantation and regenerative medicine. Regenerative medicine is still in its infancy, however many expert scientists and doctors believe that its potential could bring many benefits with new treatments for certain illnesses and conditions.

Box 1 The British Bone Marrow Registry (BBMR) The British Bone Marrow Registry (BBMR) is a voluntary bone marrow donor registry, which is run by the National Blood Service (NBS) on behalf of the other UK blood transfusion services. The BBMR works in conjunction with other blood transfusion services in the UK. Bone marrow donors are recruited from the blood donor population. In order to register, individuals must be between the ages of 18 and 49, provided no medical reasons, specified in detailed criteria, prevent them from donating. Where a bone marrow donor is required in the UK, searches will include the Anthony Nolan Trust register and the Welsh Bone Marrow Donor Registry. For patients under the age of 16 the search will also include the UK cord blood banks. The BBMR is part of the Bone Marrow Donors Worldwide (BMDW) register, an international internet-based organisation with more than 6 million registered donors. This way, where a donor is not found within the UK, the international registers can be searched for potential donors registered abroad. Facilities wishing to use the BBMR must be accredited with an appropriate body such as the Foundation for the Accreditation of Haematopoietic Cell Therapy (FAHCT) or the Joint Accreditation Committee-ISCT & EBMT (JACIE) and an appropriate national or international transplant outcome organisation such as the National Marrow Donor program (NMDP) or the European Group for Blood and Marrow Transplantation (EBMT).

1 Also the Welsh Bone Marrow registry and the Anthony Nolan Trust keep registries.


4. Cord blood collection, banking and use in the UK

4.1 Policy

Not many policies exist in relation to cord blood collection, except for regulations on the collection and storage process.

4.1.1 The Human Tissue Authority

The Human Tissue Authority (HTA) regulates umbilical cord blood collection in the UK. The HTA was set up under the Human Tissue Act 2004 (see Box 2) and is one of the UK’s competent authorities under the European Union Tissues and Cells Directive (EUTCD 2004/23/EC) (see Box 3).

Box 2 The Human Tissue Act The Human Tissue Act (2004) set out a new legal framework for the storage and use of human tissue from the living and removal, storage and use of tissue and organs from the deceased. The HTA applies to England, Wales and Northern Ireland where it came into place on 1 September 2006. Similar regulations are in place in Scotland under the Human Tissue (Scotland) Act 2006. The HT Act replaces several previous acts, which covered these individual regions. The aim of the HT Act is to create a framework for donation that is clear and that patients, families and professionals can have confidence in. The Human Tissue Authority (HTA) is responsible for giving advice on the HT Act and for ensuring that establishments performing these activities are regulated. In order to provide this support, the HTA issue guidance, codes of practice and licensing guidance for the professional sectors they regulate as well as carrying out inspections to ensure licence conditions are being met. The HTA issued two directives summarising the requirements of the Parent Directive and the First and Second Technical Directives of the EUTCD for establishments storing human tissues and cells for human application. The HTA regulates the removal, storage, use and disposal of human bodies, organs and tissue from the living and deceased. The donor selection and evaluation, procurement, processing, testing and storage and distribution of umbilical cord blood are activities, which come under the Human Application sector of the HTA remit.

Box 3 The European Union Tissues and Cells Directive (EUTCD) The EUTCD creates a common framework to ensure high standards in the procurement, testing, processing, storage, distribution and import or export of human tissues and cells across the European Union. The European Parliament Directive adopted the EUTCDs in 2004 and they came fully into force in the UK in April 2007. The Directive aims to ensure the safety and quality of tissues and cells used for human application. Approximately a third of the European member states have fully incorporated the EUTCD. The UK has been in the vanguard of member states that have put into operational effect the requirements of the EUTCD. The UK partially implemented the EUTCD via the Human Tissue Act 2004. Establishments intending to store human tissue or cells for human application should have been licensed for this activity from 7 April 2006 – including the storage of cord blood. The EUTCD Parent Directive, published in March 2004, sets out the framework of the directive. There are two further detailed technical Directives that accompany the Parent Directive, which stipulate the standards for carrying out the activities of procurement, testing, processing, storage, distribution and import or export of tissues and cells across the European Union.


The EUTCD came into force on 7 April 2006 throughout the European Union. The Directive was fully transposed into UK law via the Human Tissue (Quality and Safety for Human Application) Regulations on 5 July 2007.

The UK is at the forefront of complying with EU regulation. On 30 April 2008, the Human Tissue Authority announced new rules for the procurement of umbilical cord blood, which will be regulated for the first time in the UK in order to ensure the quality, safety and traceability of umbilical cord blood. The new rules stipulate that umbilical cord blood can only be procured by trained staff and only on premises that meet essential standards. The new rules came into place on 5 July 2008 and means that all premises that wish to carry out cord blood collection must apply for a licence to do so by that date – or, alternatively ensure that the procurement is taking place on behalf of a licensed establishment under a suitable third party agreement.

The licence, issued by the HTA, will ensure:

• “Staff have training in collecting cord blood, raising standards and making sure best possible quality of sample is taken

• Procedures which will help prevent any medical attention being drawn away from mother or child during collection

• A system is in place to make sure that the cord blood cells are traceable from collection to their use in treatments”

The HTA has developed a one-year interim licence fee for those organisations collecting cord blood, pending a broader licence fee review across all sectors. This fee is £2,900 and will be chargeable in the 2008/09 financial year.

4.2 Collection

Several stakeholders are involved in the collection of cord blood. These are depicted in Figure 1. The formal role and position of these stakeholders is shown in glossaries; the facts and figures concerning each of the stakeholders relevant for the review are presented here.

Figure 1 Stakeholders in cord blood collection

Source: Technopolis Group analysis


4.2.1 Ethical considerations and clients perspective

Parents might wish to collect the cord blood of the baby they are expecting. Directed donation of cord blood is recommended for siblings born into a family where there is a known genetic disease amenable to HPC transplantation. If the cells are HLA-compatible, they may be used for the affected child. If the newborn child itself develops the disease, its own cord blood may potentially be used in the future. Directed cord blood collections would normally be initiated by the clinician caring for the potential recipient.

Directed donation in families at low risk of genetic disease is not encouraged. The likelihood that a child will ever need its own stem cells for treatment in their early years is very small – estimates range from 1 in 5,000 to 1 in 20,000. Children with an illness such as leukaemia are more likely to need healthy, donated cells and not their own.

In 2004, the European Group on Ethics in Science and New Technologies (EGE) issued an Opinion to the European Commission on the ethical aspects of umbilical cord banking, Opinion number 19 (see Box 4). At the time issued, most European countries did not have specific legislation on cord blood banking and practices varied in many cases.

Box 4 Opinion number 19 of the European Group on Ethics in Science and New Technologies (EGE), 16 March 2004

Several ethical principles are considered relevant to the issue of cord blood banking:

The principle of respect for human dignity and integrity, which asserts the principle of non-commercialisation of the human body The principle of autonomy or the right to self-determination on the basis of full and correct information The principles of justice and solidarity, as regards to fair access to healthcare services The principle of beneficence, or the obligation to do good, especially in the area of health care The principle of non-maleficence, or the obligation not to cause harm, including the obligation to protect vulnerable groups and individuals, to respect privacy and confidentiality The principle of proportionality, which implies a balance between means and objectives.2

The key ethical issues that apply to cord blood banking are those that apply to any tissue bank: body integrity, respect of privacy and confidentiality of data, promotion of solidarity, fairness of access to healthcare and information and consent of the donors. In respect to umbilical cord banking EGE Opinion 11 states that “the information provided to the woman or to the couple must clearly explain these prospective new treatments, but stress that they are still very much at the experimental stage” and goes on to say that “in principle, tissue bank activities should be reserved to public health institutions or non-profit making organisations” but “tissue banks set up by industry should be subject to the same licensing and monitoring requirements as non-commercial operators”.3


The EGE expressed some specific concerns about cord blood banking for potential future autologous use, which include:

• Altruistic donations versus for-profit collection reflecting the paradigm shift from a form of social cohesion and solidarity to services that are paid for by parents, may call into question issues of trust

• Accuracy of information to potential customers

• The risk of bankruptcy for long-term storage facilities offered by banks

• Competition between private banks and public banks for potential donations, and the potential effect on attaining the greatest possible diversity of cord blood units

• Fairness of access to healthcare if the potential use of autologous stem cells is realised; in that case patients who lack stored cord blood would be at a disadvantage

On the other hand, it is argued that the child (and by extension his/her parents) owns his/her umbilical cord blood, and that all pregnant women should be made aware of the option of cord blood collection/banking, according to the Human Rights Law. In the USA, the American Medical Association is positive about doctors encouraging women willing to donate the cord blood of their babies to public cord blood banks. Following this line of reasoning, hospital trusts are said to put themselves at legal liability if refusing to help with cord blood collection.

4.2.2 The professionals and hospitals

Cord blood collection needs to take place just after delivery of an infant, in or close to the delivery unit in a maternity ward of a public (NHS Trust) or private hospital. Collection of cord blood requires the cooperation of obstetricians and midwifes, and there should be no conflict of interest between the care of the mother and baby and cord blood collection. Ideally, after clamping the umbilical cord, cord blood is collected aseptically by trained staff. Antenatal written informed consent is given by the mother, either to store and use the cord blood for any patient in a public cord blood bank, or to store it in a private (family) bank for the exclusive use of the family.

A considerable logistical burden is imposed on the obstetrician, the midwife and the hospital involved in a request for (personal) umbilical cord blood collection and storage. The consent procedure and associated paperwork put an additional workload on midwifery staff, which is usually not paid for.

As a response to requests from patients and professionals, a Scientific Committee to the Royal College of Obstetricians prepared and published a policy paper on the collection of cord blood. The Royal College of Midwives responded with a position paper (see Boxes 5 and 6). Essentially, both organisations acknowledge the need for public and altruistic cord blood collection albeit under stringent conditions. Both organisations however reject the medical need for autologous, cord blood collection, as they currently see no evidence in research supporting any added value to be gained from commercial banking. Most professionals refer to these position papers when asked about cord blood collection.

2 The European Group on Ethics in Science and New Technologies (EGE) is an independent group of 15 experts appointed by the European Commission, which considers the ethical dimensions of science and technology associated with Commission legislation and policies on an ad hoc basis. It issued a full Opinion on the ethical aspects of umbilical cord blood banking, Opinion 19, 16 March 2004.

3 EGE Opinion 11, on the Ethical Aspects of Human Tissue Banking (21 July 1998).


Box 5 The Royal College of Obstetricians and Gynaecologists (RCOG) Use of HPC obtained from umbilical cord blood has become an established alternative to bone marrow transplantation, especially in haematological, immunological and metabolic storage disorders in children and young adults. Storage of cord blood for therapeutic purposes will require a licence from the HTA under terms of the Human Tissue Act (2008): • Collection of non-directed donations and directed donations for at-risk families are

acceptable procedures through established public sector cord blood banks. There is still insufficient evidence to recommend directed commercial cord blood collection and stem-cell storage in low-risk families.

• Future non-haematopoietic stem cell use is still speculative, but it is understandable that some patients who can afford to do so may wish to avail themselves of commercial services offered. However if this is done, it needs to be undertaken safely and will be dependent on the resources of the hospital in which the birth takes place.

• Each NHS trust or hospital providing intra-partum care needs to develop its own policy on how to respond to prenatal requests for cord blood storage through commercial providers, including full economic cost recovery. Because some patients may incur financial obligations by registering with commercial providers before telling their doctors, we advise that this policy should be made available to prospective patients at an early stage. Written advice setting out the hospital’s policy should be made available to all patients when they book for maternity services.

• The RCOG offers the following specific recommendations to NHS trusts who do decide to support cord blood collection:

− There should be no alteration in ‘usual management’ of the third stage.

− To maximise safety for the mother and infant, collection should be made from the ex utero separated placenta.

− Collection should be by a trained third party (that is, not by the attending obstetrician or midwife) using methods and facilities appropriate to meet the European Tissues and Cells Directive.

− The service should not be made available in cases where the attending clinician believes it to be contraindicated: this will be likely to include all premature births and cases where there appear to the attendants to be specific contraindications, such as nuchal cord or maternal haemorrhage.

Box 6 The Royal College of Midwives (RCM) The RCM supports the collection of umbilical cord blood if it is medically indicated and for research purposes only. The RCM does not support the commercial collection of umbilical cord blood for stem cell harvesting. The RCM believes that the current research evidence has not demonstrated that there is any value to be gained from the routine harvesting and storage of stem cells on demand, and that further research is needed in this area. The RCM welcomes new technologies that enhance the quality of maternity care and provide clear benefits for the great majority of women and their babies. Further, the introduction of new practices should not impact adversely on the quality of midwifery care or the immediate care of the mother and newborn. Whilst the RCM supports women’s informed choices and decisions, it believes that, there is a need for a wider debate in the NHS on the ethical, legal and safety implications of introducing commercial initiatives into practice where there is insufficient evidence to support its benefits. RCM Recommendations state amongst others that: • All midwives should acquaint themselves with the evidence and issues around stem cell

harvesting so that they can discuss with women as appropriate.

• The routine collection of umbilical cord blood on demand is likely to have adverse impact on midwives’ ability to provide high quality care for the mother and infant in the third


stage. Trusts should therefore consider whether they have the necessary resources to provide support for cord blood collection on demand.

• Directors of Midwifery service should discuss the legal and practice implications of both assisting and refusing to assist with cord blood collection on demand with Trust management and lawyers.

Maternity services should develop guidelines/policies, which explicitly state that:

• Midwives are not obliged to collect commercial umbilical cord blood samples.

• Midwives will not be held responsible for the quality or quantity of the sample collected or for delays in transportation or storage if they chose to assist the mother. Such information should be made available to all women and the companies involved.

• Supervisors of midwives should be involved in all discussions and the development of local guidelines.

Maternity services should develop an information leaflet (in consultation with geneticists, neonatologists and obstetricians) to offer unbiased, evidence-based information on the indications for collecting cord blood.

NHS trusts vary in terms of cord blood collection. Five hospitals collect specifically for the public banks; four for the NHS cord blood bank and one for the Anthony Nolan Trust cord blood bank (Kings Hospital, London). These NHS hospitals were chosen to increase the numbers of non-Caucasoid ethnic cord bloods, as they serve multi-ethnic areas of the country. The NHS cord blood bank and the Anthony Nolan Trust provide trained staff to recruit donors, obtain consent and collect the donations so that the care of mother and baby is not compromised.

All hospital trusts vary in their policies, or appear to lack recognised policies regarding cord blood collection for private banks. However, it seems that the decision to collect remains that of the midwife and staff attending the birth. Organisations that collect cord blood for storage include the public sector, private organisations, and charity. Whenever an organisation is not allowed to collect the cord blood directly, as is the case for private cord blood banks, and where obstetric or midwifery staff are not able to cooperate on collection, the services of a so-called ‘third-party’ may be used. Private hospital trusts are more open to private cord blood collection, and are also more accessible for third parties. New HTA regulation requires anyone who collects cord blood to be trained to do so.

4.2.3 Figures on collection

The UK figures on collection are shown in Figure 2. This data was kindly provided by the organisations listed in the left column. Collection is subdivided in three different steps:

• Admitted to procedure: From 5,800 annual Expressions of Interest at the NHS cord blood bank, 4,359 were admitted to the procedure of cord blood collection

• Collected and processed refers to the actual numbers of cord blood collected before processing. The 2,426 collected samples are 55% of the numbers admitted, indicating that almost half are lost before collection due to external complications in connection with the pregnancy or delivery, or as a result of no suitable collector being present at the birth. Thus, based on 2,826 (including Virgin) public collections a year and the annual UK birth rate, cord blood is collected for 0.13% of all births

• Retained for storage each year. From the collected samples 75% are retained for storage. On the public side Virgin also collects about 400 samples of which around 320 are suitable for storage. Future Health yearly adds 7,500 private samples to its bank, of which 10-25% are from the UK


Figure 2 Collection of cord blood in the UK

Collection (unrelated)

Admitted to procedure

Collected and processed

Retained for storage and

banking/year

NHS-CBB (NHSBT) 4,359 (o7/08) 5,800 EoI

2,426 (07/08) 1,792 (07/08) 1,239 (06/07)

Anthony Nolan Trust 20

Virgin Health bank 400/y (07) ~ 320 (07)

Future Health Technologies

7,000 – 8,000 (04)$


EoI = Expression of Interest; $ = not only in UK

4.2.4 Issues regarding collection

• Cord blood collection requires early clamping of the cord, which has been a routine procedure for many years. However, some research suggests that the outcome of umbilical cord clamping at birth is not well understood and may not be beneficial for the baby

• There are only a few NHS hospitals available for altruistic cord blood donation, which limits the opportunity for voluntary donation

• NHS Trusts generally do not have policies on cord blood collection and defer to professionals

• Typically, 40% of admissions for birth in a collecting centre result in a unit suitable for banking. The majority of attempts are lost between the stages of admission and attempted collection. Of the 40% of admissions that result in collection, 75% are successfully retained for banking, suggesting that handling of samples is fairly efficient

• Private companies and third parties have limited access to NHS trusts. It should be noted that obstetricians might have double assignments as consultants, and act according to public or private practice

4.3 Storage/banking

Initially, cord blood was stored using the same processes for storing peripheral blood, however cord blood is fundamentally different from peripheral blood and should be processed and cryo-preserved appropriately. There are a number of steps for processing cord blood, which include; testing the blood, tissue tying (MHC-HLA) and cell counting, and processing by red cell depletion (which leaves the Mono Nucleated Cells (MNO)) or plasma depletion (to reduce the volume).

Cord blood banking requires substantial initial investment to organise processing and cryo-preservation. Despite this, western governments agree that it is important to organise a public cord blood service and to add data to a worldwide registry, as patients often require donors from abroad. In the UK, the NHS Cord Blood Bank is public but covers only a fraction of the necessary tissue types of the UK. The Anthony Nolan Trust has recently started a cord blood bank, which also provides publicly available units.

4.3.1 NHS-CBB (NHSBT)

At NHS-CBB (see Box 7) cord blood is collected, stored and issued for three different purposes:


• In Oxford, cord blood is collected for research and units are issued for this purpose within England. In 2007 and 2008, 479 frozen units were made available, however most researchers prefer fresh samples. From 2004-2008 there were 1,468 fresh units collected and issued

• Directed cord blood donations are collected for at risk families who are UK citizens in Oxford, Bristol, Birmingham, Leeds and Sheffield. These samples are designated to treat siblings with an inherited anaemia, metabolic disorder, immunodeficiency, or malignancy. Since 1995, a total of 412 collections have taken place (till May 2008), and two-thirds of which were intended for inherited non-malignant diseases

• After 10 years of directed collections 24 samples have been issued, and the majority (> 80%) have been issued for the treatment of an inherited disease. Related cord blood collection has been extremely efficient; 97% of samples were successfully collected and 88% of the samples met the usual criteria for cell count and volume. However it is policy in the case of directed donation, not to reject units based on these criteria. It is recommended that fully matched designated related units are used for transplantation

• Unrelated Cord Blood Bank Altruistic Collections are collected at Watford, Barnet, Luton & Dunstable and Northwick Park. The samples are stored at Edgware and are available for issue both nationally and internationally. Unrelated altruistic collection commenced in 1996, with the aim to bank 20,000 unrelated donations by 2013. Today (April 2008), 11,270 units are banked, and the number of units is increasing at rates that are somewhat higher than in the early days. The NHSBT public cord blood bank has the second highest percentage of rare tissue types, with 41% of units derived from ethnic minority donors

Box 7 National Health Service Blood and Transplant (NHSBT) Tissue Services The NHS cord blood bank (NHS-CBB) was set up in 1996 to collect, process, store and supply cord blood. The NHS-CBB is public, it is part of the NHSBT and it is free to donate cord blood. By donating cord blood after the birth of a baby, parents are making a voluntary donation that could help any patient who is in need of an unrelated cord blood transplant, in the UK or elsewhere in the world. As NHSBT also provide 2.5 million blood and tissue components each year, the organisation is in a unique position to provide the infrastructure for the NHS-CBB to collect, test, store and issue cord blood in order to provide the opportunity of stem cell transplantation for patients for whom no compatible stem cell donors are available via the registries. The NHS-CBB provides diagnostic laboratory activities, as well as quality management systems and expertise to ensure good management and practice. Furthermore, NHS-CCB provides medical and scientific expertise, IT systems, the ability to search and provide expert advice on the most suitable HLA match for patients and peer reviewed transplant outcome follow-up data from patients transplanted with NHS-CBB units. The NHS cord blood bank process and test the donations and enter them on international registries, as well as performing final checks and testing prior to issue. The bank is accredited by the European organisation FACT/NETCORD, the Human Tissue Authority and the Medicines and Healthcare Products Regulatory Agency (MHRA) for these activities.

At NHS-CBB 70-80% of collected units are suitable for banking and the average volume is around 70-80 ml (range: 30-300ml). Samples may not be suitable for banking due to (in decreasing order); low volume, low nucleated cell count, refusals, medical exclusions, language exclusions, and processing errors. The average volume and average number of total nucleated cells is slightly higher in people of Caucasoid origin than in Asian or black people.

Cord blood stem cell transplantations serve the treatment of different diseases, and for each type of transplantation a minimum total nuclear cell count is recommended; for malignant disorders 3 x 107 cells/kg are needed, for non-malignant disorders 5 x 107


cells/kg, and for double transplants 1.5 x 107 cells/kg. The distribution of cell count reveals that about 50% of all stored samples contain between 50 and 100 x 107 cells (indicating that a child of no more than 17 kg can be treated with such a unit), around 30% between 100 and 160 x 107 cells, and less than 20% more than 160 x 107 cells. Hence, about 7,800 samples comply with the TNC recommendations and are suitable for all kinds of treatment. From the issuing overview, it is clear that higher cell count units are more suitable for the matched patients, than the lower count units.

4.3.2 Anthony Nolan trust

The Anthony Nolan Trust (ANT) (see Box 8) is a charity organisation involved in recruiting bone marrow donors and keeping a registry. As the number of people coming forward to donate for the bone marrow registry is declining, this has been a key push factor for the ANT to set up a cord blood bank to accompany their bone marrow registry in December 2007 under a research protocol. They have collected 20 units and are in the process of validating their collecting and processing procedures. The ANT has tissue typing and virology facilities in place for bone marrow donation. A new storage facility in Nottingham will keep the UCB units. Donating to the ANT bank will be free of charge and funded through the ANT. Collection takes place at King’s College Hospital where the ANT pays for an extra midwife who supervises and trains the other midwives. The ANT is hoping to collect 1,500 units a year, approximately a third of the ~5,600 births at King’s College Hospital each year. It is expected that 40% of donations will be fit for transplant and will therefore be included on the register. The remaining units, which are unsuitable for transplants will be donated to research. Future expansion to ten further hospitals is also in the process of negotiation with an aim to increase these figures tenfold. Hospitals are selected for the greatest diversity of ethnicities within the patient population with the aim of gaining a diverse range of units for transplant.

Box 8 The Anthony Nolan Trust (ANT) The Anthony Nolan Trust (ANT) provides lifesaving donors for patients in need of a bone marrow transplant. A critical factor in the success of a transplant is the accuracy of the match between the patient’s and donor’s cell tissue. Timing is also critical: once a patient has chosen to proceed with a transplant, the donor’s tissue must be available as soon as the conditioning treatment has finished. The Anthony Nolan Trust connects one person, whose immune system needs a boost – with another person, who is prepared to share a little of theirs. The donor recruitment and management teams organise recruitment clinics, they keep in touch with donors in case they are found to be a match for a patient, they keep records of their tissue-type and they search those records to look for matches. Since 1974, the Anthony Nolan Trust has helped to give over 5,800 children and adults a new chance of life.

4.3.3 (Public-)private cord blood banks

Private cord blood banks store cord blood samples for autologous use. These samples are usually not tissue typed, and are not part of a registry. The samples stored are also intended for family use, which is not autologous but may be a partial match. Private banks produce forceful advertising, describing the storage of “your own lifesaving” stem cells, and present private collection as a life insurance for a number of serious conditions. They focus more on present use than on future use, which can be misleading, suggesting to the potential client that allogeneic uses of cord blood apply to autologous use. There is currently no standard for marketing messages and the EU regulations do not dictate what can or cannot be said for marketing purposes. Not all private banks are accredited by the Human Tissue Authority and some do not adhere to the regulations (e.g. do not follow appropriate consent procedures and do not


perform the required blood tests). The lack of standards for cord blood banking in the UK is an issue, which needs to be addressed. The (public-)private organisations described below are fully accredited and would welcome more open deliberations with all stakeholders involved, especially in connection with collection.

4.3.3.1 Virgin Health Bank

The Virgin Health Bank (VHB) (see Box 9) receives applications from approximately 400 individuals per year who plan to collect their cord blood, which is ten times less than anticipated when Virgin Health Bank was initiated. From the number of attempts approximately 20% fail each year due to low volume or complications at birth or the midwife refusing to collect the cord blood. They currently store approximately 400 units, 10% of which are for directed donation for families, who due to medical reasons, do not meet the acceptance criteria of the public bank. Around 300-400 units are added to the bank each year, which is expected to increase. No units have been issued for transplant or research. The public-private character of the bank is executed by splitting the samples; 80% of each sample is available for public use, whereas 20% is kept for private use only. Virgin relies on the prospect of advances in research allowing expansion of cells in cord blood, which would be necessary for the cells to be used autologously in due time.

Units collected by the Virgin Health Bank are stored at BioVault in Plymouth. Donations are not treated or enriched before freezing and are stored for 20 years. The average cell dose per sample is TNC 9.28 x 108 cells/ml. The quality storage procedure follows a standardised method based on the Rubinstein method and all processes have been fully validated. Before freezing samples are tested for: HLA type; infectious disease including HIV and Hepatitis B/C; rhesus factor and blood group factor; rare inherited diseases including Haemophilia, sickle cell anaemia; and all mandatory blood tests.

Box 9 Virgin Health Bank Virgin offers parents-to-be the opportunity of storing their baby's umbilical cord blood stem cells in a dual private and public stem cell storage bank. As parents’ priority is the health of the family, Virgin acknowledges that it is important to let people know that, in a child's early years; their own stem cells are unlikely to help if they fall ill – they'd need healthy, donated cells – which is why they designed the dual private and public stem cells storage bank in 2006. The chance of a child needing his or her own cord blood for any childhood condition (known as autologous transplantation) is extremely small. In practice, cell expansion technology is likely to be required to provide a usable number of cells for regenerative medicine regardless of how many are in the original unit collected. The promise of regenerative medicine is not here today, but many expert scientists and doctors believe in its potential. The Virgin Health Bank was the first private cord blood bank to be accredited by the MHRA in 2004. In 2006 Virgin Health Bank set up the first dual public-private cord blood bank. The dual bank consists of a public bank, which customers donate to, but a part of the sample is stored privately for regenerative medicine purposes. The Virgin Health Bank works on the premise that the greatest benefit can be derived from access to both allogeneic cord blood from a public pool and access to autologous stem cells for regenerative medicine. The idea is to give parents the “best of both worlds” in the form of access to their child’s privately stored portion and access to a greater public pool. They believe that the uptake for these services will increase in the future.

4.3.3.2 Future Health Technologies

Future Health Technologies (see Box 10) has 33 staff to carry out marketing, procurement, processing and storage for cord blood collection and has applied for a HTA license for these activities. Future Health Technologies has purpose built


laboratories and storage facilities in Nottingham. Cord blood units are held under conditions in line with the HTA license and according to the EU directives for storage of human tissue. Cord blood units are treated with DMSO before freezing and are stored for up to 20 years. Units are tested for; HLA compatibility; infectious diseases including HIV and Hepatitis B/C; inherited diseases including haemophilia and sickle cell anaemia; Rhesus factor and blood group factor; maternal blood is tested for all mandatory infections. Patient data stored includes; date of birth; nationality; ethnic background; medical and family history, etcetera in line with HTA requirements. Written informed consent is acquired from parents prior to collection. Quality procedures in place consist of following HTA directives.

Over 16,000 samples are currently in storage, sourced from all over Europe, especially Spain, Italy and Greece, as well as the Middle East. No samples have been used for treatment to date. However, four samples are currently in the process of release.

Box 10 Future Health Technologies Future Health Technologies offer non-invasive cord blood collection and processing, and was the first HTA licensed and MHRA accredited private cord blood stem cell bank in the UK. Future Health processes stem cells according to the strictest UK guidelines and has successfully stored thousands of samples since 2003. The company are anticipating an increase in their activities in the future due to parent demand. Future Health performs blood counts on all cord blood samples on arrival. The standards set for a useful cord blood sample stipulate that a sample should, as a minimum, have a 250 million total nucleated cell count. If a sample contains less than this, the parents are automatically informed and it is then their decision as to whether they wish the discard of the sample or continue with full storage and pay the associated fee. The widely varying levels of stem cells likely to be present in collected samples is a key reason why they store 100 per cent of each successful sample to maximise the cells available for future use. Future Health has created two different payment plan options. The plans include the stem cell collection kit, cord blood processing and storage. A client can choose to pay for service yearly or choose a 20-year block to begin.

4.3.4 Figures on banking

The UK figures on storage as described above are depicted in Figure 3. These data were kindly provided by the organisations listed in the left column. 0.019% of the total population have their cord blood stored in a public cord blood bank.

Figure 3 Banking of cord blood

Storage Total number of samples stored

NHS-CBB (NHSBT) 11,270 Altruistic donations since 1996 412 Related donations since 1995 (high risk families) 479 Research (frozen), 07/08

ANT 20

Virgin Health Bank 400 (not for research), 10% related donation

Future Health Technologies > 16,000



4.3.5 Issues on banking

• NHS-CBB has 11,270 samples in storage of which approximately 7,800 have a total nucleated cell count (TNC) suitable for all types of transplantation

• The total number of directed cord blood samples in public storage is small in comparison with both unrelated public banking and autologous private banking

• The size of private cord blood banks exceeds the size of public banks

• The aim of the NHS-CBB is to accumulate a sufficient number of units such that all combinations of HLA type are represented. The figure NHS-CBB aim for in order to achieve this is 20,000 units. At the current rate of collection this is expected to take another five or six years

• The figure of 20,000 to achieve a fully representative bank is not used by all public banks. The ANT presented alternative calculations at the Department of Health workshop on cord blood collection, 28th May 2008, as follows. In the UK, 30% of patients requiring a haematological transplant do not find a donor from the UK or international registries for a 5/6 HLA match. To provide 80% of patients with a 5/6 match it would imply for the UK that 44,472 samples were to be stored, which in turn would require 111,180 collections (given the attrition rate of 60%). With the current yearly rate of accumulation of samples into public storage, it will take another 18 years to reach 44,472 (15 years if Virgin increases the annual number stored from 1,800 to 2,200)

• The above figures show that there would still be a requirement international collaboration of registries to maximise the potential of finding a match for the remaining 20% of patients

4.4 Use

This sub-section discusses the clinical use of cord blood stem cells for haematological disorders, as well as for other clinical use and research into future uses of cord blood.

4.4.1 Clinical haematological use

The initial use of umbilical cord blood stem cells in transplantation was as a replacement for stem cells from bone marrow donation. To date the major clinical indication of cord blood has been for haematological malignancy in children. It is estimated that unrelated cord blood transplants worldwide now account for over 20% of all stem cell transplants. The main limitation to the use of cord blood transplants has been that the yield of cells in a single cord blood is generally too small to use for adult bone marrow transplant, since for a bone marrow replacement a large cell dose is required. However, it is getting increasingly common to use a double or even triple cord transplant for adult bone marrow transplantation. Cord blood units from more than one donor are used, in order to increase the number of cells transplanted, however only the cells from one of the donations will be engrafted. This form of transplantation allows, to some extent, HLA-mismatches with no adverse reactions. Since 2005, more cord blood transplants have been done in adults than in children.

Data from Eurocord (see Box 11) and a meta-analysis study show that the long-term survival rate after cord blood transplantation in both children and adults is now comparable to bone marrow transplantation from other graft sources. Moreover, patients transplanted with one- and two-allele mismatched cord blood samples demonstrate transplant-related mortality (TRM) and leukaemia free outcomes that are comparable to fully matched unrelated bone marrow donors. This is an important result that can make stem cell transplantation available to those groups currently underrepresented by the large bone marrow donor registries. Successful cord blood transplantation depends on the quality of the collected cord blood. Volume and cell count are important parameters but also the freezing and storage procedures affect the quality, which is why NETCORD (see Box 12) have developed joint standards for cord blood banking, including standard operating procedures and quality control


guidelines. Although this has not been verified, there are some concerns that the quality of samples stored before 2006 cannot be guaranteed.

Box 11 Eurocord The European Group for Blood and Marrow Transplantation (EBMT), an international scientific organisation on haematopoietic stem cell transplants operates a cord blood registry, Eurocord. Eurocord was set up by Professor Eliane Gluckman and is financed by the European Union. Eurocord works in collaboration with NETCORD cord blood banks and EBMT centres. It collects and validates clinical data of patients transplanted with NETCORD cord blood units or patients receiving cord blood units in EBMT centres. During the period from 1988 to 2000, 4,343 cord blood transplants, in adults and children, have been reported to the Eurocord registry from 43 European and non-European countries. The Eurocord database increases each year with approximately 100 cases reported.

Box 12 NETCORD/FACT The NETCORD Foundation was established in 1988 with the aim of promoting the use of umbilical cord blood for allogeneic stem cell transplantation. It is a non-profit organisation to promote high quality banks and has issued statues and guidelines to promote further research on the collection, processing and preservation of cord blood. NETCORD has established quality standards, in collaboration with the Foundation for the Accreditation of Cellular Therapy (FACT). There are 16 banks registered with NETCORD from 12 countries, this includes the UK NHS cord blood bank. In order to facilitate searches by transplant centres for cord blood units NETCORD has established an on-line search programme, the Virtual Office.

Allogeneic and autologous stem cell transplants are distinctly different procedures, with different clinical indications and different outcomes. Autologous stem cell transplants are used in cases where the underlying disease process does not involve the patient’s bone marrow, in particular as consolidation treatment for some childhood (neuroblastoma) and adult solid tumours (Wilms’s tumour), for salvage treatment of relapsed lymphomas, and for treatment of progressive multiple myeloma. Autologous transplants have a limited role in the treatment of diseases involving the bone marrow itself, which is illustrated by the fact that of the 3,372 umbilical cord transplants that have been performed worldwide in 43 countries (source Eurocord), 2,965 were for unrelated donor transplants, 359 for related and only three were autologous. In 15 years one autologous cord blood transplantation for acute lymphocytic leukaemia has been carried out. Currently, only for acquired aplastic anaemia, has autologous cord blood treatment an unequivocal benefit. Thus, autologous banking of cord blood as biological insurance for haematological disorders is not clinically justified today.

4.4.2 Organisation of use

The organisation of use is depicted in Figure 4.

A Transplant Centre or Consultant Haematologist will always instigate the search for a donor. The service is for patients who require a stem cell transplant and do not have an HLA compatible family member. In the UK, a number of umbilical cord blood transplantations (UCBT) have been performed for paediatric patients in centres with several years of experience. UCBT for adults has been performed in the UK at King’s College Hospital as well as in Nottingham, although this is not yet routine.

Efforts to find a donor for a patient will include searches of both UK national registries and registries abroad. The NHS-CBB both imports and exports samples. The ANT also imports cord blood samples. Exhibit 4 shows the global nature of cord blood transplantation according to the WMDA in general 40% of the stem cells samples are provided internationally.


Figure 4 Organisation of use


Figure 5 Evolution in the geography of sourcing of cord blood units, national and international (%)

Source: World Marrow Donor Association (WMDA), 2006 annual report on cord blood registries

4.4.3 Figures on use

Between 1996 and May 2008, NHS-CBB issued 210 units. Around 50% of all samples were issued to patients under 20 years of age. Once the NHS-CBB exceeded 8,000 units there was a significant increase in units issued. The first 100 issues took 7.5 years, whereas the second 100 issues were made in the subsequent 2.5 years. Based on current numbers, it is predicted that next year 72 samples will be issued. In terms of ethnic background, 34% of the units issued were from donors from ethnic minorities and 30% of the units were issued to ethnic minorities. It is also important to note that about 30% of the issued samples were used for double cord transplants, indicating that adult transplantation with cord blood is increasing. Furthermore, Future Health Technologies is in the process of releasing 4 samples.

About a quarter of units issued by UK banks were used in the UK and the remainder were issued to 22 other countries (27% to North America and 36% within Europe).

Both the NHSBT and the Anthony Nolan Trust have imported cord blood samples from abroad for use in the UK. NHSBT have imported 26 units from non-UK registries, 24 of which were issued for UK transplants. In addition, The Anthony Nolan Trust has imported 112 cord blood units since September 2005. The total units

(Public-) Private Bank

NHSBT

ANT

abroad UK transplantation Centre

Transplantation abroad


imported constitute 72% of the transplants performed in the UK. In total, 155 units have been sent abroad, and 191 units have been issued from UK banks for use in the UK. The figures used for transplantations in the UK come from Eurocord and they state that 123 cord blood transplantations were carried out up to February 2007 in the UK since 1996. More international data are presented in section 5.2.

Figure 6 Use of cord blood units

Use Issued samples Imported into UK

NHSBT 210 unrelated: 55 for UK (26%) 155 abroad 130 for research (07/08) 24 for related (95/08)

26 (24 issued)

ANT 112 since 2005: 74 (07) 52/11D (06/07) 38/6D (05/06)

Total publicly issued and imported for unrelated transplantation

210 138

Future Health Technologies 4


D = used for double cord transplants

4.4.4 Current use beyond haematological disorders

Cord blood stem cells may be supportive or part of a therapy for non-haematological disorders. Although further evidence is required, preliminary results suggest that cord blood contains unique immune cells, which may provide many therapeutic uses. The list of diseases that are potentially treatable with cord blood-derived cells is growing rapidly, and is reported to encompass some 80-85 diseases.

Cord blood has been used for the treatment of metabolic disorders affecting the brain. Most notably this is the case for Hurlers disease, a serious genetic metabolic disease (Mucopolysaccharidosis) affecting young babies from the age of 6 months. Cord blood contains cells that appear to have similar traits to Natural Killer (NK) cells, which have a strong local repair function. This has been used to treat infants with cerebral palsy caused by oxygen starvation at birth. There are also some developments in the treatment of autoimmune diseases like Multiple Sclerosis.

Another development comes from a FDA approved clinical trial in Florida using autologous umbilical cord cells to treat 23 newly diagnosed type-1 diabetes patients. Results showed the autologous cord blood cells provided protection of the pancreas, in comparison with normal disease progression. In Paris, umbilical cord blood has been used to support severe trauma, such as burns. Other pioneer programmes are starting to use stem cells for cardiac surgery (in Berlin). Previously bone marrow had been used in this way to extend life expectancy. Preclinical studies are also taking place in New Jersey and Korea for the use of cord blood to treat spinal cord damage. Again, cord blood is a potential source of ameliorating rather than curing such damage. In general, more research is needed to fully understand the immunological and repair-like functions of cord blood.

4.4.5 Research

Research has shown that up to 20 different tissues can be derived from cord blood. The pluripotent potential is due to the immature nature of cord blood cells in


comparison with bone marrow stem cells. The greater number of “early” cells in cord blood express the entire array of embryonic cell markers, implying opportunity for diverse differentiation. In particular, liver and nervous tissues have been produced by research groups, both would have great potential for treating disorders. In terms of clinical research, studies using mesenchymal stem cells from cord blood indicate possible use to develop bone, cartilage and fat cell precursors. Indeed, mesenchymal stem cells are currently being used in regenerative, orthopaedic medicine. The multipotent adult progenitor cells (MAPCs) in cord blood have proven to be able to differentiate into neural, muscle and, most notably, liver cells. It is questionable whether cord blood is the ideal source of mesenchymal stem cells, due to low numbers present in cord blood. Furthermore, although autologously derived cells will be the cell source for gene therapy of cancer and genetic disorders, autologous cord blood stem cells appear to have no special advantage over similar stem cells of adult origin. This might be the case in light of rapid advanced in stem cell technology, such as the development of induced pluripotent stem cells.

Not all cord blood tissues are suitable for transplantation. However some cord blood products may be suitable for other uses, for example pharmacological testing of novel compounds in vitro. The British Toxicology Society has now endorsed the possibility of cord blood stem cell use for pharmacological testing. Donations, which are not of the required volume or cell count for transplant, may therefore be put to use and provide a potential source of funds to support cord blood banks.

One of the key advances required for future uses of cord blood is a reliable technique for cell expansion. This would mean that much smaller samples could be stored for future use. It has been demonstrated that 200 divisions of cord blood cells can be obtained without karyotypic change (alteration of the cell’s DNA). Some experts question the likelihood of successful cord blood cell expansion without introducing differential growth of all cells within the sample from 20-40 cell cycles, which could potentially call into question the splitting of samples. It will be difficult to validate standardisation of expansion for clinical use.

The stem cell research centre at Newcastle University focuses primarily on cord blood stem cell research, with the aim of developing new therapies for immune diseases. Some developments have reached the stage of pre-clinical trials, but none have yet reached the clinical stage. The charity, Novus Sanguis has recently been created to support further research work by a number of research groups across Europe to feed in to clinical trials.

4.4.6 Issues on use

• There has been a steep increase in the number of cord blood samples issued and imported in the last 2.5 years

• The number of double cord blood transplants, i.e. in adults, is increasing

• Stem cell transplantation for groups currently underrepresented by the large registries may benefit from the fact that the outcome of 4/6 and 5/6 matched cord blood transplantation is comparable to fully matched bone marrow, providing a strong argument to increase the number of publicly available cord blood samples

• Given the global nature of issuing cord blood samples, and the fact that 70% of UK samples are imported, it should be discussed whether a national view is too narrow and what role there might be for global bodies

• Autologous transplants have a limited role in the treatment of diseases involving bone marrow, which in turn suggests that autologous banking of cord blood as a biological insurance is not clinically justified for haematological diseases today

• There is a wide range of diseases where treatment might benefit from cord blood in the future, however this is not yet part of regular clinical practice


4.5 Cost

In this sub-section, the cost of cord blood collection, storage and use is discussed. The majority of calculations are based on estimated costs, which were provided by the organisations involved.

4.5.1 Figures on cost

The overview of cost comprises the cost of public and private banking. Public cord blood collection is free of charge for the public. Figure 7, shows the actual cost for NHSBT for the collection and storage of cord blood.

For NHSBT collection and storage related cost are indicated; calculating from the current number of samples in the bank (12,000) and the number added each year (1,800), these costs amount to almost £3.5 million per year to sustain and expand the bank according to plan. Should government policy opt for a cord blood bank of 44,000 samples, the actual collection cost would amount to £140 million pounds, and an additional storage cost of £3.4 million per year. This does not include the initial start up cost of a cord blood bank.

The costs per unit imported and tested in preparation for transplantation (the UK imported approximately 85 units this year) is double the amount that is received as revenue from exporting cord blood samples abroad (exported approximately 35 units this year). Here we have used the figure of £17,000 per transplantation, but other prices have also been suggested. If an increase in use continues, as well as an increase in storage, the public cost will rise further.

The cost for related cord blood banking is even higher, £2,680 per collection as this includes liaison, and local issuing costs. The cost of related banking can be compared to the autologous cord blood banking of private cord blood banks. Private cord blood banks charge their clients between £1,300 and £1,500 for collection and storage of samples for 20 years. We were not able to obtain an estimate of the actual cost to the private cord blood banks.

Figure 7 Cost of cord blood collection and banking

Costs in UK Prices Number of samples x price

NHS-CBB Related collection: £2,680 Unrelated collection: £1,400 Storage/y: £77 Import: £17,000 Issue: £ 350 Total revenue/y : £595,000

Storage unrelated: x 12,000 = £924,000/y Collection unrelated: x 1,800 = £2,520,000/y Importing: ~10 = £170,000/y Issuing cost: ~75 = £26,250/ y Total cost/y: ~£3,650,000

ANT Importing and testing samples: £17,000 per sample

Import: ~80 = £1,360,000/y

Virgin Health Bank £1,500 for collection and storage for 20 years

400 x = £600.000

Future health Technologies £200 (registration) + £795 collection + £300 (storage/20 years) = £1,295

16,000 x = £20,000,000



4.5.2 Issues regarding cost

• The annual cost of sustaining and expanding the public cord blood bank according to existing plans is at least £3.5 million. Increasing the bank to the size needed would cost an additional £140 million and a further £3.5 million per year to sustain it

• The high cost of importing samples and the small revenue generated from issuing samples, would suggest that it is economically favourable to have a bigger public bank and therefore reduce the need to import samples from abroad. This suggestion requires further health economics analysis to quantify the efficiency gains that would be made

• The high cost of publicly funded cord blood banking raises the question as to whether this is a sustainable option. Other, public-private models of cord blood banking should be investigated/reviewed in more detail, given that private cord blood banking is prominent in some countries

4.6 Summary of UK review

4.6.1 Summary of UK issues regarding collection, storage, use and cost

1. Collection of cord blood requires cooperation with obstetric professionals and NHS Trusts. The position paper of the RCOG is generally used as the most recent policy in this area. Few NHS Trusts are officially involved in cord blood collection; the others are not very explicit in their cord blood policy and practices, but they are generally negative about private cord blood collection. There is limited opportunity for altruistic cord blood donation, explaining a donation rate of 0.13% in the UK. Regular communication between all stakeholders may improve the attrition rate of 55% between admission and collection. More evidence on issues of safety in connection with early clamping and collection is warranted; in general more research is needed into routine procedures around birth

2. It will take another 6 years at the current collection rate to reach the NHS-CBB target of 20,000 samples in the public cord blood bank. However, recently presented research from the Anthony Nolan Trust suggests the minimum thresholds for banks needs to be higher and that the UK requires a bank of 44,472 stored samples. The research has not been published yet, however if this new perspective is substantiated, it will have implications for many. In the UK, it might suggest the need to double the NHS target! However, there would be major implications for collection too, as with current collection and attrition rates, it would take several decades to reach this number of stored samples

3. There is a steep increase in the use of cord blood stem cells for allogeneic haematological transplantation in the last 2.5 years, although the numbers remain small. Also the number of double cord blood transplants (i.e. in adults) has increased significantly since 2005. A strong argument to increase the number of publicly available cord blood samples is that the outcome of 4/6 and 5/6 matched cord blood transplantation is comparable to fully matched bone marrow transplantation, which is beneficial to groups currently underrepresented by bone marrow registries. 70% of UK samples are imported from abroad. Given the cost of importing samples this highlights the question of a national view on cord blood collection. Furthermore, it is important to ensure the quality of the cord blood samples. This needs to be secured, due to direct effects on the outcome of transplantation

4. Although autologous transplants have a very limited role in the treatment of haematological diseases, there is a wide range of diseases where treatment may benefit from autologous or related cord blood in the future

5. All the evidence gathered so far would suggest there is a definite need for further, detailed analysis of cord blood collection and use. This analysis should encompass


all the aspects covered in this report including: the practice and ethics of umbilical cord clamping; the methods of collection, population targeting and health benefit return; future need and use and the health economics of any expanded collection/donation system.


5. International comparison of UK policy and practice

5.1 Benchmarking UK with selected comparator countries

5.1.1 Introduction

This chapter deals with the headline observations from the six benchmark country case studies Technopolis carried out for the UK Department of Health that served as input to the review workshop on cord blood banking on 28 May in London. The full country case reports are included in the Annex report.

The organisation of collection, storage and use in the UK is broadly in line with the international practice as this benchmark study shows, and the practice has been reasonably stable during the past five years. A growing number of UK stakeholders are pressing to increase future collection and use, encouraged by international trends and wider social issues, however several challenges have to be faced.

In general we see that the scale of cord blood banking in the US, China and Japan shows their early commitment to this type of stem cell collection and use. France is seeking to catch up by re-opening old and constructing new cord blood banking facilities. Canada is planning a new national facility to complement its smaller provincial facilities, although it expects to continue to make significant use of US banks in the medium term (which provides the critical mass needed). The UK might be said to be at a crossroads, reflecting on the need for increased collection use and practicable options at its disposal. International practice suggests public-private partnerships serving public banks might be an option through which to achieve a step change in collection and use, which is affordable and sustainable, however the UK has little direct experience of this model. A wider discussion with stakeholders and international partners might be a productive means by which to identify and appraise the more promising options.

The benchmark study shows the differences and similarities between the comparator countries. The data and statements presented below served as input to the discussion during the workshop on the UK situation.

5.1.2 Policy

The UK and comparator countries have not formulated direct policies on cord blood banking, neither as part of health or science policy, nor as part of blood bank policies. An exception to this is Spain, where a recent Royal Decree was published to set the norms of quality and security for the donation of cells and human tissue. Following this, the ‘National Cord Blood Plan’ was published and a committee was established to implement it. In the other countries some improvements have been made and practical guidelines, license agreements and accreditation schemes have been set up on a national and European level. The UK, together with Spain, is at the forefront of complying with EU regulation. The main objectives behind the promotion of cord blood banking are to increase current number of cord blood units and be able to respond to the national demand, taking into account ethnic differences. The drivers are that cord blood storage and transplantation is regarded as a good alternative for bone marrow transplantation and increasing research material. The main obstacle in reaching these objectives is the funding of cord blood collection. Funding for stem cell research and cord blood activities is not easy to quantify in the comparator countries, due to the fact that it comes from different sources (i.e. USA). In China and France purely private banks (or for-profiting cord blood collection) are either forbidden by law or simply non-existent. Japan, Canada and the USA have looser policies concerning the private blood banking industry, however in the USA many states have their own specific legislation on cord blood collection. Spain actively supports the


private banks, although they need to be accredited and follow all quality standards that public banks have to comply with. In most of the comparator countries the Ministry of Health is responsible for ‘policy making’ concerning cord blood banking. China and Japan have been very active in cooperating with other Asian countries in establishing networks to exchange knowledge, experiences and practices concerning the collection, storage and use of cord blood units. Within the USA, France, Spain and Japan comparable ‘networks’ have been set up amongst the public banks.

5.1.3 Practice

The following table shows the number of public cord blood banks found in the comparator countries.

Figure 8 Cord blood banks in comparator countries

Country # Public banks

UK 2

Canada 3

China 10

France 5

Japan 11

Spain 7

USA 21

(14 within NMDP)


In Japan, the cord blood banks organised themselves within the Japan Cord Blood Bank Network (JCBBN) and almost all of them receive financial support from the Ministry of Health and Welfare and many from the Red Cross Blood Programme. The Network is independent from the Bone Marrow Organization. Three of the French cord blood banks are supervised by the EFS (Etablissement Francais du Sang), while two other banks closed in 2003, but will be reopened in 2008. These banks also work as a network. In the USA, the Centre for Cord Blood within the National Marrow Donor Program is a leader in cord blood banking with 24 cord blood banks, of which 14 are located in the USA. In Spain, the cord blood banks also closely work together with the Spanish Bone Marrow Registry.

5.1.4 Collection

Collection and storage rates differ greatly in each country. The NHS in the UK collected 2,426 samples in 2007/08, which is about 0.13% of the births in the country. Only 55% of all planned donations are actually collected due to external factors such as health complications during pregnancy or at birth, or due to capacity problems at the hospital.

The donation rate in four of the other benchmark countries is higher than in the UK and is typically around 0.3%. The two exceptions are Canada and Spain, which are both below the UK benchmark. In France, 0.34% of the births donate blood samples, which is comparable to the USA, with 0.325% donating cord blood samples. Since it is uncertain how many samples are being stored yearly in Japan, it is not clear what percentage of births donates to blood banks. However, taking into account the increase in the last few years in blood collections, we can be sure that the banks have collected at least 3,000 samples yearly over the last few years. With a birth growth of


1.1 million in 2007, we can estimate that a minimum of 0.3% of the births donated blood to the Japanese cord blood bank network. In Spain the rate is about 0.1%.

In Canada, the public banks collect about 400 samples per year. In China, both public and private collection leads to over 50,000 collected and stored blood samples. In France and Japan, about 3,000 samples were collected in 2007. In the USA, 13,000 samples are being collected annually, in addition the yearly number of collected samples is increasing. It is not clear how many samples are being collected in Spain yearly, but the ambition is to collect 5,000 samples per year.

There is a high level of attrition between collection and storage. Cord blood banks collect 400% of samples stored, since only 25-30% of the collected samples prove to be acceptable for storage. This holds for most of the countries, except for the UK where it is 75%. It would be interesting to further explore this discrepancy since it is not clear whether the difference between the UK and the comparator countries is caused by variability of local definitions of ‘the number of samples collected’ or by real differences in efficiency. It is not clear whether the local attrition rates include or exclude the number of failed collections due to problems before or during birth in the comparator countries.

Collection of cord blood ideally requires cooperation between obstetricians and midwives. In the UK expanding collection faces several challenges; the workload of professionals is already high and there is a natural wariness as to the feasibility of significant extension and increases in collection. Furthermore, the capacity in the public system is under pressure from professionals’ dual roles within public and private delivery systems and hospitals and professionals express concern over the issue of legal liability. So far, only a few hospitals have made an institution-level commitment to collect the cord blood samples. Finally, the private sector involvement in the UK has been restricted to private hospitals and has had limited access to UK NHS Trusts or collaborations with public banks.

In most comparator countries we have not found specific information on the challenges imposed on the professionals while delivering the baby and taking care of the collection of blood. The Spanish National Cord Blood Plan however does describe in detail the different procedures, necessary tools and knowledge, and educational needs to be able to build a stable and well-trained network of professionals in this field.

Practically all cord blood banks in the UK and comparator countries follow a set of strict rules and guidelines regarding the collection of the cord blood. In theory, women first have to fill in a consent form for the blood bank, in public banks this is supported by the hospital and it is anonymous. In this form the parent(s) consent that the cells are collected from the leftover blood in the umbilical cord and/or the placenta after the birth of a child and the cutting of the umbilical cord. There are some doubts whether this informed consent is always asked for in all countries. Officially however, the banks in China do require any informed consent to be signed. In the private banks, the woman/family has the responsibility to inform the cord blood bank about the hospital in which she will deliver the baby and the collection kit should be at that time in the hands of the physician or nurses. After the collection, the family or the hospital should notify the bank, which will then collect the blood from the hospital and process it. Within a few weeks, the test results will be released. In some practices, the mother and child are visited after a few months, to check upon their health status.

The samples are always tested for relevant assays of infectious diseases, such as for example Hepatitis B, Hepatitis C, human immunodeficiency viruses HIV-1 and HIV-2, human T-lymphotropic viruses HTLV-I and HTLV-II, West Nile virus and syphilis (Canada). In France, blood samples are at least tested on HLA and progenitors CFU-GM. In Japan, tests are performed on haematological problems, blood group, HLA, infectious organs and bacterial organs. In Spain, samples are also being tested on Babesiosis, Kala Azar, and Chagas Disease. No information was found on the types of


tests performed in China and the USA. The standards for quality in the UK and comparator countries are not very transparent.

The results of the assays are used to determine whether the cord blood unit can enter the blood bank. In the private banks, the collection and storage needs to be paid for.

5.1.5 Storage

National public banks hold widely differing numbers of samples, from less than 2,000 to more than 200,000. China, Japan and the USA lead in absolute numbers, but differences are less significant when adjusted for population size. Canada, France and the UK do not meet the often-mentioned ‘critical’ size of 20,000 samples in public storage. Figure 9 shows the blood sample units stored in the different countries.

Figure 9 Blood sample units stored in the different countries

UK Canada China France Japan Spain USA

Public 11,270 1,650 ±250.000 6,358 29,359 31,766 123,012

% of total population

0.019 0.005 0.019 0.010 0.023 0,071 0.041

Private >16,400 ±40,000 > 500,000


In France, 40% of the donations are refused due to inadequate volume (minimum is 70 ml). 10% is refused because of the low quality of the stem cells, 2% due to biological anomalies, 4% due to bacterial infection and 6% due to other issues such as a technical incident. The two quality criteria are volume and cell count. For the other countries no such figures have been found.

The minimum amount of blood to be collected seems to be between 50 and 150 ml. The minimum total nucleated cell (TNC) necessary for post processing and storage differs as well in the comparator countries; the minimum amount is 60 x 107 in Canada. In France this is more than 2 x 106, in China this is 1.2 x 109 while it is 1 x 109 in Spain. In Japan, the minimum dose derived from blood units is 27-197 x 107 from 50-141 ml of blood.

Most cord blood banks store the haematopoietic stem cells in liquid nitrogen (cryo-preservation) and keep the information in a database. Some banks have implemented systems to trace the units throughout testing, storage and use process.

Despite this, there is no national or international agreement on the minimum conditions of the samples and storage techniques.

5.1.6 Use

The number of cord blood samples used for transplantation is rapidly increasing. In most countries, this increase in cord blood transplants has not only resulted in a replacement of bone marrow transplants for cord blood transplants, but also in an increase in the total number of transplants being performed. In the USA, Canada, France, Spain and Japan about 15-18% of the recipients of (unrelated) stem cell transplants have received umbilical cord blood stem cells.

In the UK, NHS-CBB issued a total of 210 cord blood samples for transplantation. In terms of the export and import of cord blood units, more of the NHSBT units are exported to other countries than to the UK. Around one-fourth is issued in the UK and the remainder has been issued to 22 other countries (North America 27%, Europe 36%). In terms of import of samples, NHSBT also imported 26 units from non-UK registries, 24 of which were issued. In addition, The Anthony Nolan Trust has


imported a total of 112 cord blood units since September 2005. According to Eurocord, 123 cord blood transplantations have been carried out in the UK since 1996.

The biggest user of cord blood in Canada, the Ste Justine Hospital, has performed 100 cord blood transplantations since 2006. It is estimated that in total the Chinese cord blood banks have provided stem cells from cord blood for over 400 transplantations in the past years. In France, a total of 1,379 transplants took place in 2007, 211 of which were cord blood transplants (6 unrelated). Spain performed over 500 UCB transplantations in the last few years. Japan has performed 4,447 transplantations with UCB over the past years but despite this high number, the number of operations mediated by the bone marrow bank in Japan is still much higher. In the USA about 650 transplants with UCB were performed in 2007. The transplantations are being performed to treat diseases such as leukaemia, benign blood diseases such as anaemia and immune deficiency, SCID, Wiskott-Aldrich syndrome, and Chediak-Higashi syndrome.

In all countries, stem cells from cord blood are also being used for research and other therapeutic needs (such as platelet replacement therapy, red blood cell replacement therapy and cell therapy in China or examining possibilities for non-haematopoietic stem cells such as endothelial cells, cornea, retinoblasts, hepatocytes and mesenchymal stem cells in France). In France, approximately 28% of units collected are registered for therapeutic use, 25% to 33% are used for research and the remaining units are destroyed.

Figure 10 Cord blood use of all HPC transplants


Cord blood use of all HPC transplants

210 cumu-lative + 112

imported

18% 400

cumu-lative

15% 15% 16% 18%


Blood is used for both allogeneic and autologous use in those banks that have both private and public services. In private banks the use is almost totally autologous, however allogeneic transplants dominate, very few autologous cases are known and the success rate of the latter is unclear. The use of cord blood stem cells is increasing with double and triple cord blood transplants being used to extend transplantations to adults.

5.1.7 Costs

The following table shows the different costs related to cord blood collection and storage in the benchmark countries in pounds sterling. Most public banks provide free donation, or charge a relatively small amount. On the other hand, the private banks charge for both the collection (including tests) and yearly storage, mostly up to 10-20 years. In some cases, the public banking activities are subsidised by private banking activities, this is the case in China and the USA.

Collection and storage of cord blood samples is rather expensive in the UK, Japan and the USA, compared to the other countries. Costs in China are lowest, reflecting the national price advantages. £500 seems to be a typical price for private collection, £60 for annual private storage.


Figure 11 Costs of collection and storage

Costs (£)


Public 40 0-100 65 Testing: 36

No costs for donors

but real costs

amount up to 1,034

Private >1,500 Collection: 400-600 Storage:

55-65

Collection: 215-430 Storage:

35-60

Collection: 1,000

Collection: 1100

Storage: 70

Collection: 303-1035 Storage:

75


The Spanish Cord Blood Plan gives a detailed overview of the costs involved in cord blood collection. They have calculated the yearly costs for the maintenance of different stock amounts related to varying percent of stock wasted. For example, the costs of storing a cord blood unit are €1,300 (£1,034) plus an annual amount of €40 (£32), when 50% of collected units are disposed as waste. If 65% of collected samples are waste, the costs per unit stored will become €1,600, and with 80% waste, this will increase to €1,900.

Based on these calculations, if wastage is 70%, the real costs for a processed and stored unit will be €900, whereas the real cost for the unit that becomes waste is €400. The number of units which must be collected each year in order to maintain stock, was also calculated. The assumption here is that of 250 units, there is a probability of 1 match for transplantation. Figure 12 shows the yearly costs in million euros of the Spanish National Cord Blood Programme, depending on a variation of the waste rate and objectives and based on maintenance of the stock.

Figure 12 Spanish Cost Model example

30,000 50,000 75,000 100,000 UCB In Stock/ Waste

# yearly to

collect

yearly costs in

M

# yearly to

collect

yearly costs in

M

# yearly to

collect

yearly costs in

M

# yearly to

collect

yearly costs in

M

50% 3,240 3.31 5,400 5.51 8,100 8.27 10,800 11.02

65% 4,629 3.86 7,714 6.44 11,571 9.65 15,429 12.87

80% 8,100 5.25 13,500 8.75 20,250 13.13 27,000 17.50

Source: Spanish National Cord Blood Plan


5.1.8 Private cord blood banks

Based on the information from the website ‘a parent’s guide to cord blood foundation’4 we have made an overview of the private cord blood banks in each of the comparator countries. France does not allow private banks and in China the private banks either participate in a public consortium, or are located outside of China but perform some of their activities in China.

Figure 13 Private cord blood banks in comparator countries

Country # Private banks

UK 8

Canada 10

China 5

France -

Japan 2

Spain 3

USA 29


5.1.9 Summary in numbers

Figure 14 presents the most relevant figures for the UK and comparator countries.

4 http://www.parentsguidecordblood.org/


Figure 14 Summary in numbers

Total number of

samples collected

per year & % useful

for banking

Total number of

samples stored in

public and private banks

Public stored

samples as % of total

population

Cord blood use of all HPC

trans-plants

cost (public &

private

Total number of samples/

total number of births per

year

UK >2,426 75%

Public: 11,270

Private: >16,400

0.019% 201 cumulative

+ 112 imported

Public: £40 Private: £1,500

>0.13%

Canada ±400

Public: 1,650

Private: ±40,000

0.005% 18% Public: £0-£100

Private: Collection: £400-£600

Storage: £55-£65

±0.12%

China ±50,000 ±250,000 0.019% 400 cumulative

Private: Collection: £215-430 Storage: £35-60

0.3%

France 2,979 25-30%

6,358 0.010% 15% Public: £ 65 0,34%

Japan >3,000 29,359 0.023% 15% Public: £ 36 Private: £ 1,000

>0,3%

Spain Expectation: 5,000

Public: 31,766

0,071 % 500 cumulative

16%

Real costs for

collection and storage are: £1,034 +£32, but

not paid by the donor. Transplan-

tation: £15,912 Private: about £

1,100

0,1

USA ±13,000 25%

Public: 123,012 Private:

>500,000

0.041% 18% Private: Collection: £303-1035

Storage: £75 per year

0,33%


5.2 Benchmark data from international organisations

The World Marrow Donor Association (WMDA) carried out a questionnaire in 2006, which was sent to 47 cord blood banks associated with WMDA. For the UK, only NHS-CBB data was included. According to the 2006 annual report, the total number of cord blood units in cord blood banks world wide on 31 December 2006 is 292,175.


Of these, 41,838 were added in 2006. The total number of searches amount to 57,682 in 2006, of which 72% were unrelated international requests. The total number actually transplanted in 2006 is 1,964, of which 875 were for children under 15 years of age. The majority of samples have been used in a 1 or 2-mismatch transplantation, and 596 (432 in 2005) samples were provided for multicord transplantation.

Figure 15 shows that bigger banks do not necessarily correspond with more units provided. In addition, the number exported does not correlate with the number provided either. For instance Japan exports hardly any samples, as their specific HLA types are endemic to Japan. However Spain and France both provided a relatively large number of units taking into account the size of the bank. Of the samples provided, in Spain two-thirds were exported, and in France one-third is exported. Of the UK samples provided, 80% was exported, which might be due to the high levels of ethnic minority samples in the UK public bank. Note that these WMDA numbers only represent a part of all samples issued as not all banks are members. From the USA data, only the three largest banks are included in the figures. No Chinese cord blood bank is a WMDA member.

Figure 15 Relation between units provided and exported to units present

Units provided Exported Units available All public units

UK (NHS-CBB) 34 27 8,000 11,270

Canada 1 1 1,245 1,650

China - - - >250,000

France 180 60 5,737 6,358

Japan (Tokyo) 132 1 4,820 29,359

Spain 123 82 23,628 31,766

USA 372 (NY) 508 (NMDP) 63 (St-Louis)

148 111 9

32,088 54,352 14,5170

123,012

Source: WMDA, 2006 annual report on cord blood registries


6. Conclusions & recommendations

6.1 Conclusions in the context of the UK & benchmark data

• No explicit national policy has been formulated on cord blood banking in the UK, either as part of health or science policy or as part of blood bank policy

• Professional guidelines do exist and license agreements and accreditation schemes have been set up. The UK, together with Spain, is judged to be at the forefront of complying with EU regulation

• The organisation of collection and storage has been broadly in line with international practice, however practice in use has been changing rapidly in the last 2.5 years

• For the seven countries under review, donation rates (collections per year/births per year) to public cord blood banks split into two clusters, with Canada, Spain and the UK at around 0.1% of births and China, France, Japan and the US at around 0.3%. The UK donation rate of 0.13% is around 40% of the highest donation rate of 0.34% (France)5

• There is a high level of attrition between admission, collection and storage. Generally, ~30% of the collected samples prove to be acceptable for storage. This holds for most of the comparator countries, except the UK where the attrition rate between admission and storage is somewhat higher at 40%. 75% of the collected samples are retained for storage (which is efficient by comparison with other countries), suggesting it is that part of collection cycle involving the hospitals and professionals that is not optimal

• National public banks hold widely differing numbers of cord blood samples, from less than 2,000 to more than 200,000. China, Japan and the US lead in absolute numbers, but differences are less significant when adjusted for population size

• Canada, France and the UK do not yet meet the often-mentioned ‘critical’ size of 20,000 samples in public storage

• There is still no agreement on what should be the optimal figure for a UK cord blood bank. Figures vary from 20,000 – 50,000, however work is being undertaken in England, Scotland and Northern Ireland to increase public cord blood bank units. Notwithstanding progress on the latter point, it is clear that international cooperation will continue to be a central component of UK provision for the foreseeable future

• The scale of cord blood banking in the US, China and Japan reflects their earlier commitment to this type of stem cell collection and use. France is seeking to catch up by re-opening old and constructing new cord blood banking facilities. Canada is planning a new national facility to complement its smaller provincial facilities, although it expects to continue to make significant use of US banks in the medium term (critical mass). Spain is implementing a National Cord Blood Plan, which makes a public commitment to collect another 30,000 units in the next 5-8 years

• The UK might be said to be at crossroads, reflecting on the need for increased collection, use and practicable options at its disposal

5 Note that statistics for China, Japan and UK (Virgin) might be a little over-stated as the data include some samples in private collections, due to public-private overlap.


• Turning to use, the number of cord blood samples used for transplantation is rapidly increasing; both in absolute terms and relative to other HPC transplant sources (bone marrow, PBSC). 15-18% of the HPC transplantations use stem cells from cord blood. The use of cord blood stem cells is widening as well in the last 2-3 years, with double and triple cord blood transplants being used to extend transplantation to adults. A strong argument to increase the number of publicly available cord blood samples is that the outcome of 4/6 and 5/6 matched cord blood transplantation is comparable to fully matched bone marrow transplantation, which is beneficial to groups currently underrepresented by the large registries. Allogeneic haematological transplants dominate. There is little evidence justifying haematological autologous use of cord blood; only 3 autologous cases are known

• Generally, tests on samples are performed, different minimum sample and cell amounts are mentioned and storage techniques described. There has been no agreement on the minimum conditions of the samples and storage techniques; recently NETCORD started to set guidelines. Still, the standards for quality are not very transparent and cannot be guaranteed; whereas the outcome of transplantation heavily relies on the quality of the product, most notably cell count and volume

• Internationally, researchers and policy makers view stem cells from cord blood as a promising avenue for developing improved treatments for a wide range of conditions. In comparison with other countries the UK is taking a narrow outlook on the field focusing on treatment for haematological conditions, however many other countries are looking to new developments in cord blood use and increasing collection

• Cord blood stem cells are pluripotent and can differentiate into tissues of all three germ layers. Cord blood stem cells can produce over 20 tissues in vitro, including liver and neural cells. Some 85 disorders are supposed to be treatable or supportable by cord blood cells, including haematological, metabolic and oncology disorders, as well as immune deficiencies. Results have been obtained on treatment of Hurler syndrome, Diabetes type 1 (autologous) and tissue repair, suggesting a role for the naive immune cells and/or mesenchymal stem cells. Expansion of cord blood stem cells is key for future developments. All the applications need more research before entering standard clinical practice

• Collection and storage of cord blood samples is more costly in the UK, Japan and the USA as compared with the other four countries. Costs in China are lowest, reflecting national price advantages

• £500 is a typical price for collection, £60 for annual storage. All countries express concern about the sustainability of the costs of collection and storage

• The estimated cumulative additional costs of reaching 20,000 samples amount to around £17 million, or around £3 million a year, while annual storage costs might increase from around £0.9 million presently to £1.7 million by the end of the six-year period. Expanding the current numbers of UK cord blood units to the numbers indicated by other sources creating a bank of 44,000 samples will require at least another 15 years under current practices. Accelerating this accumulation will increase expenditure rates and will almost certainly require substantial additional investment in new and expanded infrastructure and capacities. We have estimated that this might amount to an additional £140 million. It is questionable whether this is fully feasible given general pressures on health care expenditure, however a staged expansion over 5-10 years might be affordable and of course attention to attrition levels holds out the promise of worthwhile efficiency gains and economies. Spain has done some ‘health economic’ calculations, which could be a useful source of reference data and models that might be adapted and re-used by the UK government for testing various investment options


6.2 Issues discussed at the workshop

Based on the outcomes of the review on the UK situation and the benchmark with comparator countries, a discussion was organised with stakeholders in London on 28 May 2008. The main issues discussed at the workshop are listed below:

• The growing number of UK stakeholders pressing to increase future collection and use, encouraged by trends internationally and wider social issues

• An acknowledgement that expanding collection in the UK will require several challenges to be addressed:

− The workload of professionals is already high, and there is a natural wariness as to the feasibility of significant extension/increases in collection

− Capacity in the public system is also under pressure from professionals’ dual roles within public and private delivery systems

− Hospitals and professionals express concern over the issue of legal liability

− Only a few hospitals have made an institution-level commitment to collect the cord blood samples

− Private sector involvement has been restricted to private hospitals and have had limited access to UK NHS Trusts or collaborations with public banks

− Professionals referring to the issue of safety in relation to early clamping of the umbilical cord, and the theoretical possibility that expansion in collection rates in pursuit of one class of health gains might very well result in increased health risks to another much larger class of citizens (mothers and new born babies)

• International practice suggests public-private partnerships serving public banks might be an option through which to achieve a step change in collection and use, which is affordable and sustainable, however the UK has little direct experience of this model. A wider discussion with stakeholders and international partners might be a productive means by which to identify and appraise the more promising options

The Annex report includes a summary of all expert presentations at the workshop and the issues that were put forward and discussed by the stakeholders that were present. At the end of the workshop, the chair summarised some questions that need further investigation. These questions include:

• What justification would a health economist find for continued public investment in cord blood banking?

• Is a national view too narrow? What role might there be for WHO or other global bodies?

• How to balance the right to donate versus the access to matched cord blood? Or stated otherwise; how to respect the freedom of the individual yet affirm higher priority of the community in the need for sick patients, also in relation to minority matching?

• Obstetric related policies and place for relevant research?

• The role of mesenchymal stem cells in cord blood for regenerative medicine, and Wharton’s Jelly banking for MSC?


6.3 Recommendations

Based on the results from the UK review, in comparison with the benchmark countries and having heard the discussions on the several issues at stake at the workshop in London, we recommended that the UK consider:

• Developing an explicit national policy on cord blood, which amongst other things aims at increasing future rates of collection of cord blood for public banks

• Creating a high-level advisory committee to provide the minister and policy teams with advice on the detail of such a policy. The high-level group should consist of representatives of all parties in the chain of cord blood collection (inclusive of private parties), storage and use, to continue discussion on issues presented in this report and as a follow up to the workshop. A multi-stakeholder committee will ensure the advice is practicable and should facilitate implementation and generally improve communication between all stakeholders in the community

• Requesting the advisory committee to address each of the questions that were raised at the end of the workshop

• Commissioning further research to obtain detailed information on public-private banking models, from a variety of perspectives and with fully worked through costed examples of various international practices

• Developing marketing guidelines for private cord blood companies, in order to prevent misleading information to the public

• Developing further insight into the place of cord blood stem cell research in relation to other stem cell research (cf. UKSCI’s recommendation)

• Investigating the perceptions of British citizens on the issue of altruistic donation as opposed to private donation of cord blood


Appendix A Cord Blood Review workshop

A.1. Agenda


A.2. Speaker presentations

Professor P Braude, Fellow of the Royal College of Obstetricians and Gynaecologists

Professor Braude addressed the question of why the RCOG needed to produce a new position document from the Scientific Advisory Committee to the College on cord blood collection. A number of obstetricians, midwives and patients had received promotional literature from commercial companies offering to store umbilical cord blood. Professionals were uncertain of the need and the implications of acceding to collect cord blood, and patients wished for up to date non-commercial information about whether there was a need for them to access this fee-paying service. Much of the literature they had received suggested that collection was entirely safe for both mother and child. Also private companies put pressure on parents not to do a disservice to their children. In response the RCOG set up an expert panel in 2005 consisting of a variety of stakeholders to review the need and use of umbilical cord blood banking. They examined the haematological and non-haematological uses, ethical and legal issues, consent procedures, the burden on staff and risks during the third stage of labour. The information provided by the RCOG for both professionals and patients does not recommend commercial directed collection of cord blood for low risk families, but does support directed donations for at-risk families, and non-directed donations through established public sector cord blood banks. Where collection is undertaken, the RCOG position paper recommends ex-utero collection by a trained third party according to HTA regulations.

Dr S Bewley, Fellow of the Royal College of Obstetricians and Gynaecologists

Dr Bewley spoke on the lack of knowledge and research regarding the routine procedure of umbilical cord clamping at birth.

Maternal haemorrhage during parturition is a common cause of death and postnatal morbidity worldwide. The rate of haemorrhage is still high in the UK. This may be due to poor management of the third stage of labour and/or the rising rate of caesarean sections. During a physiological third stage of labour the baby receives a transfusion of blood from the placenta while it makes a transition from foetal to neonatal life and specifically from one cardiovascular system to another. The common practice of active management, which involves giving oxytocin to the mother and clamping the umbilical cord was devised to protect mothers. However, studies show that immediate clamping of the cord can result in a 30-50% reduction in blood volume of the newborn. The placental transfusion is affected by gravity, breathing, and clamping amongst other factors. There is an inverse relationship between the timing of clamping and amount of remnant of placental blood available for collection. There are worrying suggestions of harm from immediate clamping in randomised trials, both in term and preterm babies. Thus, despite the rhetoric of those who offer blood banking, the safety of cord blood collection is not assured, and depends on third stage management. The main issue is that, despite the widespread routine use of clamping, good research about the immediate and long-term effects on the baby is lacking. Indeed, the timing of clamping is not even regularly documented. Why do we choose to perform an intervention that has the sole proven advantage of removing the baby from the mother? Pressure on midwives and obstetricians to clamp the umbilical cord comes from convention, lawyers, neonatologists, parents and cord blood banks. Further research is required and evidence used to inform best practice regarding umbilical cord clamping.


Dr S Watt, Head of Stem Cell and Immunotherapies, National Health Service Blood and Transplant (NHSBT)

NHSBT collect cord blood for three purposes: research, related/directed collection, non-directed donation.

Directed collection to treat siblings with haematological disorders has been performed since 1995 and occurs at several hospitals around the country. The rate of collection has increased in recent years and the number of units issued has doubled in the last two years. In total 412 units have been collected. Collection for research has taken place since 2004 in Oxford.

Non-directed collection started in 1996 with the aim to bank 20,000 units by 2013. This takes place in four hospitals in London. The NHSBT currently holds 11,279 units in the non-directed bank, 70-80% of collection attempts are banked with 20-30% of units lost. Rates of issue increased significantly when the bank reached 8000 units. If the current rate of collection and issue continues the NHSBT expect to issue 70 units in the coming year. Approximately 41% of the units banked are from ethnic minority donors, whereas 30% of units issued are for ethnic minority patients. Around 28% of units issued went to patients in the UK, the rest went to patients abroad with 27% going to the USA.

The NHSBT imported 26 units in the last 2.5 years and the Anthony Nolan Trust has imported just over 100 units. In summary, half of the units issued have been issued in the last 2 years; the number of collected units has doubled in this period in comparison to the previous 10 years. The costs of collection and issue are hard to predict.

Dr C V Navarette, Director of the British Bone Marrow Registry (BBMR) and Scientific Director of the NHS-Cord Blood Bank, National Health Service Blood and Transplant

Dr Navarrete addressed the contribution of cord blood banks to hematopoietic stem cell (HSC) transplantation using unrelated donors.

The most influential factor affecting the outcome of HSC transplantation is the degree of Human Leukocyte Antigen (HLA) matching between the patient and the donor. However only 30% of patients have an HLA identical sibling and the rest need to search for a donor in the national and international registries of bone marrow donor volunteers or cord blood banks. The UK has three registries: the Welsh Bone Marrow Registry, the Anthony Nolan Trust and the British Bone Marrow Registry (BBMR). The BBMR is managed by NHSBT and contains bone marrow donors from England, Northern Ireland and Scotland and it also contains cord blood units collected by the NHS Cord Blood Bank and the Northern Ireland CBB. In total these registries offer 750,000 potential donors.

Besides the UK registries, the Bone Marrow Donors Worldwide (BMDW) registry has over 12 million potential donors and NETCORD has over 130,000 cord blood units. The vast majority of these donors are from European Caucasoid ethnic background and therefore some patients, particularly those from ethnic minorities are at a particular disadvantage when looking for a donor.

Some of the factors influencing the identification of a donor include:

• The size of the donor panel

• The ethnic composition & compatibility between the patient and the donor panel

• The frequency of the HLA haplotype of the patient in question

• The degree of HLA matching required

• The resolution of the HLA typing of the panel


The aim of the NHS cord blood bank is to maximise the collection of units for ethnic minority groups and we have so far been successful in collecting units/donors from ethnic minorities and in this way adding new HLA types to the donor pool. The cord blood units registered with the BBMR are more genetically diverse than the bone marrow donors and therefore the BBMR UK registry has made a significant contribution to the international donor pool in terms of providing varied or unique haplotypes. In Europe, Spain, Italy and Belgium store the largest numbers of samples.

Professor A N Békássy, Director, Paediatric Blood and Marrow Transplantation, Lund University

Thousands of patients worldwide have received umbilical cord blood transplants. A number of conditions can be treated with cord blood including: blood disorders, malignancies, metabolic storage disorders, and metabolic immune deficiencies. Children and adults with these conditions can benefit from transplantation. Approximately a third of patients find a related donor, another third find an unrelated donor and for the remaining third alternatives are needed. In Sweden about a third of children have a non-Caucasian parent therefore there is an increase in the number of people with unusual HLA types. This issue was one of the driving factors for Sweden to develop an own cord blood bank. For similar reasons, Finland started their own cord blood bank because their HLA profile is very different from the one in other Nordic countries.

There are several advantages to cord blood banking including: no risk to the donor, no donor attrition, immediate availability of the donation and lower incidence and severity of GvHD. Disadvantages include the finite existing resources; it is not possible to “top up” the patient with additional cells after the transplant. Furthermore, it is not known what the viability of cells will be before the transplant takes place. Multi-cord transplants have opened up cord blood transplants to treat adults; in this case the cells from more than one unit are infused to augment the cell dose. Quality management and accreditation of cord blood procuring centres are of major interest.

The Swedish government prevented private cord blood banking by prohibiting the export of a private sample outside of the country. The issue of cord blood banking was discussed in public and after a parliamentary hearing the Minister for Health allocated €1.5 million to form a public bank in Sweden.

Dr A Pagliuca, Clinical Director, Specialist Medicine, King’s College Hospital, President elect British Society of Blood and Marrow Transplantation

There has been a very slow uptake of adult cord transplantation in the UK with only 22 adult cord blood transplants performed from 2001 - 2006 compared to around 500 unrelated stem cell transplants performed annually. This is significantly less than the number of cord blood transplants performed in other European countries, USA and Japan. Mortality rates are improving across the world due to a number of factors, including stem cell dose, larger cell inventories to choose from (many of the current stored cords are inadequate for adult usage), double cord procedures, better infection management and supportive care. There is certainly a learning experience compared to standard unrelated transplants. Stem cell dose, HLA matching and viral infections are therefore critical to outcomes.

There is growing interest in performing UCB transplants in adults in the UK and worldwide. Younger patients demonstrate better outcome data however we have to be aware that the median age for haematological malignancies is around 65 years so offering cord transplantation may not be an option for all patients. Interestingly Japan, which has significant experience in the area, has good outcome data for the patient population over the age of 55 years, even up to age 75. The transplant related


mortality is high and numerous groups are developing ways to reduce this further, such as intra-osseous injection of the cells, double procedures and cellular therapy procedures to speed up immune recovery.

The UK will try and follow a limited number of protocols. At King's, as well as within the BSBMT, we are using the Minnesota (US) protocol for reduced intensity procedures and the Valencia (Spain) protocol for ablative procedures. This will allow us to collect all the necessary clinical and scientific data. The program must be appropriately supported to ensure we do not fall further behind.

Colin McGuckin, Professor of Regenerative Medicine, Newcastle University

At Newcastle University research is being performed on embryonic stem cells, umbilical cord blood stem cells, and adult stem cells. Research is performed using the placenta, Wharton’s jelly, and umbilical cord blood. Twenty tissues have been produced from umbilical cord blood stem cells. The aim of this research is to treat patients. The majority of existing treatment using umbilical cord blood is for haematology and Immunology transplants. However, the list of treatable disorders has grown, up to 85 conditions are treatable or supportable with umbilical cord blood today, with an increasing number of autologous therapies. Promising evidence is seen from the Florida case of children with type I Diabetes Mellitus. Despite this some practitioners are reluctant to investigate the use of new therapies. Furthermore, more cord blood collection should be taking place, worldwide, in order to maximise its potential use and further research. Currently, there is not enough cord blood stored in the world to cover existing needs. Some countries are reluctant to undertake public private initiatives, but these may provide an answer to the costs. Also, you can make tissue from cord blood stem cells that may be used for drug testing. Drug development could profit, and one could earn back some of the money spent on cord blood banking. Cord blood is not only about stem cells, but also other useful cells not least immune cells and some developments are closer to the clinic than others.

Professor Alejandro Madrigal, the Anthony Nolan Trust (ANT)

Professor Madrigal presents the ANT’s UK national cord blood programme. Public health is a driving force for this to provide equity in the access to a timely stem cell therapy in haematology for 20-40% of indications.

In the UK 30% of patients requiring a haematological transplant do not find a donor from the UK or international registries for a 5/6 HLA match. The aim of this programme is to provide 80% of patients with a 5/6 match: for the UK it implies 44,472 samples stored, which in turn would require 111,180 collections needed. Having calculated that a registry large enough to accommodate the remaining 20% would result in reduced cost-effectiveness. This leads to a need for international collaboration of registries to maximise the potential of finding a match for the remaining 20%.


A.3. Points arising from workshop discussion

Autologous versus allogeneic

• For many of the suggested autologous clinical uses of cord blood it would be necessary to expand the mesenchymal stem cells, which show an immune suppressive effect. But mesenchymal stem cell expansion is not as easy with cord blood stem cells as it is with bone marrow stem cells and it is difficult to predict the fraction of samples from which it will be possible to expand cells. In addition, allogeneic mesenchymal cells might work as well in immune suppression as autologous mesenchymal cells. Storing cord blood for treating autoimmune disease may be seen in the near future: e.g. clinical trials for the treatment of Crohne’s disease

Collection

• It is important to consider the parent’s rights in comparison to the child’s rights, and to whom the cord blood belongs

• There is a lack of information and research into clamping the umbilical cord, despite this being a routine practice. It is not well evidenced, whether the cord should be clamped and if it should, after what time period in terms of what is best for the baby. Therefore, is it safe to collect cord blood?

• There is also the possibility of growing cells from amniotic cells and the Wharton’s jelly. It is important to question if cord blood is what should be banked or the cord itself

• There was discussion of some confusion surrounding new HTA regulations regarding licensing of each hospital to collect or enabling a third party license to cover collection, as would be the case if a collection was made on behalf of a private bank. The Human Tissue Authority: there is moratorium in order to understand what the procurement would mean

• Parents should have freedom of choice. They should be informed of the options of collecting cord blood stem cells and given the option to preserve them if they choose. Future Health is communicating with the NHS and ANT and would like to form collaborations

Current use

• What is the number of people going without treatment in the UK each year, who could be treated with cord blood?

• The NHS, under financial pressure, is reigning in spending on transplantation, which prevents developments to move forward and improve transplant procedures, particularly for adult patients. EBMT data shows that the rate of transplant in an individual country is related to the gross national income

• There is an increased risk of leukaemia in patients that have been transplanted with cord blood. A transplant patient who has suffered from leukaemia may be more susceptible to a relapse

• Cord blood may be more cost effective than other forms of treatment, particularly as an early prevention. For example, in treating late onset leukaemia in over 40 males, which is not an aggressive disorder, but cord blood treatment could potentially prolong the period of healthy life. However, previous evidence of using autologous transplant for leukaemia was found after cost-benefit analysis to be no better than chemotherapy


• The rate of transplants is related to the gross national income: wealthy countries do it more. Minority groups do not reach transplants because of economic reasons. In underdeveloped countries cord blood banking is providing more opportunity for transplantation because these countries are never are able to import the sample. It is cheaper to construct a blood bank

Research and future uses

• The use of spare units, which are not sufficient for transplantation, for research is a potential method of generating income for a cord blood bank

• The NHSBT collect units specifically for research in Oxford. This was questioned due to the clinical need for units, suggesting instead only units too small for transplantation should go to research

• Collection for research is justified when there is a need for clinical research. But it is questioned whether it is ethical to collect specifically for research when there is not enough for transplantation

• Cryo-preservation is not yet well understood and cord blood has not yet been preserved for the life of an individual. Researchers in Newcastle are attempting to replicate protocols on frozen units. If this is not possible it demonstrates that cryo-preservation techniques are not yet sufficient to provide units for research

• The transit time of the cells prior to freezing is a significant factor. It is argued that it should be less than 16 hours

• Units from ethnic minorities are often smaller meaning that smaller units going to research are disproportionately from the ethnic minorities, which are most needed in the bank. Plenty of frozen units are available from NHSBT, but researchers all want fresh units

Public/private banking

• HTA regulations of collection and how this affects public/private banking

• The potential for a private contribution to costs to make up for using NHS resources, one example given was paying for training midwives

• If those who can afford to pay for private collection are the white population there is no mechanism to target ethnic minorities

• The history of a lack of dialogue between private companies and the NHS trusts

• Cord blood Charity. A major problem is that no one has decided how many units should be aimed for that is publicly available. Previously the figure of 20,000 was used, ANT suggests 44,000, Eurocord suggests 50,000 to serve the Caucasian population alone. A consensus is required on this issue

• Continuing to throw public money at the problem is not a long-term solution. A sustainable plan is needed. Virgin charge £1500 to parents to collect the cord blood, they can then chose whether to donate the public part of the unit. Virgin doesn’t have to charge for the units used for transplant to maintain the bank

Questions from the Department of Health

• How does the hybrid model work in practice? Spain and Italy have hybrid models, but these require people to donate to public use if the unit is required, which leads to those who can afford to banking their cord blood abroad. There is a problem with the conflicting statement to parents that they should donate, but also that the


blood could be useful to their family. How do you balance this from a public health perspective?

• Some women who were considering private banking chose to donate to the ANT public bank instead when they found out that the unit can be traced back to them with the ANT registry

• The RCOG position does not prevent cord blood banking. It says that NHS trusts should have a policy on cord blood collection and should recover their costs. It asks for evidence of efficacy for autologous use and evidence and truthfulness in marketing

• Products need to be of high quality. NHS trusts will not pay for units if the quality is too poor for transplant purposes. Quality standards should be transparent regardless of whether banks are public or private

• There are stringent quality standards from FACT/NETCORD. It is important to ensure that imported units are from accredited sources


A.4. Workshop invitation list

Cord Blood Workshop 28 May 2008 Invitees

European Association of Tissue Banking (EATB) Ruth Warwick, Chair

Lund University, Sweden Albert Bekassy

Mark Bale

Colin Pavelin

John Connolly

Department of Health

Zubeda Seedat

Technology Strategy Board Zahid Latif

Douglas Greig

Roma Armstrong

Scottish Government

Catriona Graham

Scottish National Blood Transfusion Service Mark Turner

Robin Buckle MRC

Catriona Crombie

Cristina Navarrete

Suzanne Watt

NHS Cord Blood Bank

Tim Wallington

Alejandro Madrigal Anthony Nolan Trust

Sergio Querol

Antonio Pagliuca Kings College Hospital

Terie Duffy

Oxford University Tariq Enver

Peter Braude RCOG

Susan Bewley

Guys & St Thomas Hospital Belinda Ackerman

Royal College of Midwives Janet Fyle

Human Tissue Authority Hazel Uppington


Cambridge Institute for Medical Research Lidia Duncan

Colin McGuckin Newcastle University

Nico Forraz

UK Stem Cell Network Ben Sykes

Scottish Stem Cell Network Mark Turner

The Cord Blood Charity Lionel Salama

Great Ormond Street Hospital Paul Veys

Imperial College Fabrizio Vianello

Joanna Tilley Virgin Health Bank

Michael LeBrocq

Future Health Technologies Ltd Roger Dainty


List of interviewees

List of interviewees representing UK stakeholders

Peter Garwood

Ruth Warwick

NHSBT

Cristina Navarette

Anthony Nolan Trust Steve McEwan

Royal College of Midwives Janet Fyle

Newcastle University/Novus Sanguis Colin McGuckin

Roger Dainty Future Health Technologies

Stephen Baines

Joanna Tilley Virgin Health Bank

Michael LeBrocq

King’s College Hospital Antonio Pagliuca

Guys and St Thomas’ Hospital Susan Bewley

University College Hospital Rachel Hough

Royal Sussex County Hospital Chief midwife

Documents

Cord blood banking in the UKdata.parliament.uk/DepositedPapers/Files/DEP2009... · The UK national cord blood bank purchased 10 imported samples in 2007, at a cost of £170,000 or