ANÁLISIS DE LOS RESULTADOS DE CONCRETO ENDURECIDO

The Cost of Stem Cell Transplantation

HSCT is a complex procedure, requiring experienced personnel, well-resourced facilities and several highly specialised drugs to support engraftment. In addition, the full costs of a transplant must include the post- operative management provided to the patient. Table 17 outlines the approximate costs of transplantation, including stem cell procurement and post-HSCT care8_{. This has been calculated by adapting the methodology} used by van Agthoven et al. (2002) and drawing on unit costs provided by the PSSRU Unit Costs of Health and Social Care 2009 database. Where these were not available, costs have been scaled and converted from the original study. The costs of post-operative care have also been weighted to reflect the fact that, with every progressive phase of treatment, a smaller proportion of transplanted patients are alive to receive it. Costs were converted using 1999 pound / euro exchange rates and adjusted for 3% annual inflation in pay and prices. There are a number of caveats. The non-UK data may have only limited applicability, and only includes unrelated adult donor transplants, not cord HSCT. The patients are all adults and therefore paediatric patients are excluded.

Table 17 Summary of transplant costs per patient (extrapolated from van Agthoven et al. (2002)).

Component

Average costs per

living patient % alive

Weighted costs per transplant patient Personnel £31,409 100% £31,409 Transplantation £40,140 100% £40,140 Follow Up 1 £29,713 90% £26,742 Follow Up 2 £18,119 48% £8,697 Follow Up 3 £13,075 31% £4,053 Total Costs £132,456 £111,041

This brings the total cost of transplant per patient to around £110,000.This approximates the current London commissioning price of £101,000 per transplant.

However, this should be set against the often considerable costs of not transplanting a patient, such as ongoing chemotherapy and supportive care. These costs have been estimated at around £20,000 per patient, though this may fluctuate significantly from case to case.

The Current Cost of Providing Stem Cells for Transplantation

A significant proportion of the cost of unrelated donor HSCT is the costs of procuring suitably matched stems for patients. This in turn reflects the accumulated costs of each individual step in the process chain, from recruitment/ collection and registration/storage to shipping / issue.

Registries and cord banks are collective resources with low lifetime utilisation rates: only a fraction of adult volunteers and listed cord blood donations will ever be used for transplantation.The true procurement costs of every stem cell sample used in HSCT must therefore include a share of the total costs associated with the other adult donors or cord units that are recruited or collected, typed, listed and searched without ever being selected by transplant physicians. This means that the true cost of each stem cell donation far exceeds the specific costs of the selected donor or cord unit. Consequently, the overall costs of bone marrow (Table 18) and cord blood (Table 19) are weighted to reflect this.

This results in distinct costing dynamics for the UK’s donor registries and cord blood banks. Though the assumed lifecycles of volunteer donors and cord units are similar, in the region of 20 years, donor registries generally have much lower lifetime utilisation rates than cord blood banks. Compared to NHS-CBB’s current utilisation rate of 0.3% and the >1% utilisation rates of some international banks, the BBMR has an annual utilisation rate of around 0.05%9_{.Consequently, donor registries are generally much larger than cord blood banks. This means that} the processing costs for multiple unselected donors must be factored in to the real cost of every selected donor. These may be one-off costs such as donor typing and testing, with an average of 105 donors processed for every donor selected: this reflects the likely 1% lifetime utilisation rate of an individual donor. Other costs, such as registry maintenance, are continuous and have to be spread out across the entire panel, meaning that a selected donor will carry weighted costs amounting to an average of 2,082 years on the panel: this reflects the proportion of listed donors to every sample issued over the course of a year. Balancing the large volume of donors on the registry, however, is the generally low process costs associated with adult volunteers. The most substantial costs are for extended typing, donor work up and harvesting, but these are only performed once the donor has been identified as a suitable match and therefore involves relatively little weighting (extended typing) or no weighting at all (donor work up and harvest) (Table 18). Overall, the weighted current long term cost for a bone marrow donation is around £36K.

Table 18 Current long run costs of providing unrelated adult stem cells for transplantation

Component Cost/Event Events per

Transplant

Weighted Cost per Transplant

Donor recruitment & sample collection £12.90 105 £1,349 Donor typing & testing £107.15 105 £11,207 Donor registration £1.56 105 £164 Maintenance of donor panel £2.31 2,082 £4,817

Registry search £13.82 51 £701

Ship confirmatory samples £567.18 7 £3,861 Perform extended typing £1,313.86 3.7 £4,814 Donor work up £3,838.13 1.0 £3,838 Donor harvest £5,464.76 1.0 £5,465

Follow up £308.07 0.8 £253

Total current long run cost per issued donation £36,469

Cord blood banks are generally smaller, with much higher utilisation rates: the NHS-CBB currently operates with a 0.3% annual utilisation rate. The weighting for the true cost of an issued cord unit in the UK is therefore much smaller. One-off costs such as typing and testing are performed on around 15 cord blood donations for every selected unit, while continuous costs such as bank maintenance, distributed across the entire inventory, require 298 events for every transplant – a much smaller proportion than is required for donor registries. Nevertheless, these processes generally carry a much higher individual cost for cord than with adult volunteers. Ultimately, this means that the real cost of an issued cord unit is at present higher than an adult donation. Overall, the current long term cost for every cord blood unit issued from the NHS-CBB is circa £45K.

Table 19 Current long run costs of providing cord blood units for transplantation

Component Cost/Event Events per

Transplant

Weighted Cost per Transplant

CB recruitment & sample collection £292.36 21 £6,139

CB evaluation £43.19 21 £907

CB typing & testing £244.23 15 £3,757

CB processing £281.63 15 £4,332

CB registration £160.51 15 £2,469

Maintenance of CB bank £51.94 298 £15,479 Perform extended typing £997.26 4 £4,378 Final product evaluation £6,688.11 1.0 £6,688

CB issue £472.44 1.0 £472

Total current long run cost per issued donation £44,622

Cost-Benefit Analysis – Establishing a Fit Stem Cell Registry Donor Panel

The UK already has a combined panel exceeding 770,000 donors (WMDA, 2010). Further expansion would bring only marginal gains, and at considerable expense. To maximise patient benefits, service providers should concentrate instead on quality improvements. The creation of a ‘fit panel’ of high resolution typed, readily available donors would be an effective strategy to achieve this (Annex 4).

In consultation with clinicians and operational managers through the Review, the following framework was developed as a feasible strategy to implement the fit panel:

•.High.resolution.typing - retrospective high resolution typing would be performed on 36% (75,000) of registered donors aged between 18 and 35 years, over a three year period. This would cost £67.70 per type.

•.Regular.communication - all 750,000 registrants would be contacted at least annually to confirm their willingness to donate, their contact details and current state of health. This would cost £0.30 a contact (i.e. £0.23m per annum), with additional contact online and via e-mail at no additional cost as this is already being practised. Furthermore, in the first three years, it will be necessary to contact those in the target groups by telephone to invite them for high resolution typing and make sure they are still willing to donate. This is estimated to cost £7 per contact, so £0.17m per annum for three years.

•.Graft.Identification.Advisory.Service.(GIAS) - an advisory service on donor/donation suitability would be offered. This is already being piloted by the ANT.

•.Predictive.search.technologies - donor search queries would be facilitated by a computer programme such as Haplogic or Optimatch. The costs this would involve are currently unknown.

Together, these measures introduce an incremental cost on a current baseline of £2.2m per annum for the first three years then £0.3M per annum subsequently. This does not include the associated costs of GIAS and predictive search technologies:these have not yet been quantified and so are not at this stage factored into the calculations.

The benefits of this panel would include:

•.Fewer.unsuccessful.searches - registered donors available to donate will increase from circa 60% to 90%. Based on there currently being 25,781 searches at £18.13 each, and the number of searches being reduced by around 1/3, this should bring savings of £0.14m per annum.

•.Fewer.extended.typings.per.final.donation - almost 4 extended typings are currently undertaken for every transplant, at £373 each. With a fit panel, this should reduce to 1 extended typing per transplant.

•.Shorter.search-to-transplant.times - the average time from search initiation to transplant would reduce by an average 4 to 6 weeks (D. Marks, personal communication to the review).This would result in less patient deterioration, less inpatient and outpatient resource, resulting in cost savings to the NHS (not quantified). Reduced search-to-transplant times would also improve quality of life for patients. This would bring in an estimated 0.4 QALY gain for 300 patients over 4 to 6 weeks, translating to a benefit of £0.55 million per annum.

Together, these measures result in an estimated quantified benefit from a fit panel of approximately £1.0m per annum. In summary, this preliminary cost-benefit analysis shows that the fit panel proposals look promising, with an incremental cost of circa £9m balanced against £9m gain over a 10 year horizon. However, other significant costs and benefits remain to be evaluated. These include the costs of GIAS and the search algorithm, as well as the improvement in survival outcomes from shorter search-to-transplant times and reduced chemotherapy toxicity. The results should be verified when the currently ongoing GIAS pilot is completed, and further work is done to evaluate the overall costs and benefits.

An Expanded UK Cord Blood Inventory

When designing a UK inventory, a number of factors should be considered. These include:

•.Size – the size of the inventory. A larger inventory will have higher costs, but may be more efficient in terms of per unit costs as the fixed costs and overheads are shared across a greater number of units.

•.Annual.utilisation – the proportion of an inventory’s stored units issued every year. In principle, utilisation rates may fall as the size of an inventory increases, but in reality this relationship is more complex. Utilisation is one of the key determinants in whether a cord inventory is economically feasible.

•.Ethnicity – the racial composition and diversity of its stored units. Cord blood has a particular role to play in reducing current levels of unmet need. However, considerable Caucasian demand for cord also exists. Size

The optimal size of a cord inventory is one of the central considerations in its design. Clearly, the overall

operational costs of a smaller cord inventory are likely to be less than for an expanded inventory. In theory, in the context of limited patient demand, a smaller bank should issue a higher proportion of its stored units every year, even if the actual number of units is lower. In reality, the relationship between size and utilisation is not so clear cut. This is discussed in more detail below.

Despite incurring greater overall costs, a larger inventory may prove more economic due to the significant portion of fixed overheads in staff, equipment and infrastructure.While many of the costs of adult donations are associated with donor identification and extraction, processes only undertaken once the donor has already been selected for transplantation, with cord blood the majority of the costs such as collection and storage are upfront and carried out regardless of whether or not they are issued. Expanding the size of the UK’s cord inventory could therefore reduce the individual share of that fixed cost per unit, provided a reasonable utilisation rate was maintained.

Secondly, an inventory requires a ‘critical mass’ of cord units to operate effectively as a patient-oriented service and justify its investment. An expanded inventory should have a broader range of HLA types and can therefore provide a greater number of patients with a match. Up to a point, this may raise its number of issued units sufficiently to maintain an acceptable utilisation rate.As its size increases, however, this may be underminedby replication as stored cord blood donations begin to ‘overlap’ with the HLA type of other units in the inventory and increasing number of stored units become redundant.

Expansion therefore needs to be accompanied by well designed, targeted recruitment strategies. This is why utilisation needs to be considered alongside other issues, including the need to reach an appropriate proportion of donors from black and ethnic minority groups.50,000 units has been identified as the optimal size for the UK’s cord blood inventory: fewer units would result in inferior patient outcomes, but more units would bring only limited patient gains (Figure 32) (Querol et al. 2009b).

Figure 32 Matching probability relative to the size of a cord inventory (hypothetical)

0 10 20 30 40 50 60 70 80 90 100 1 10 100 1000 10000 50000 100000150000 % Probability Inventory size 5/6 Match 6/6 Match Utilisation

The current cost of a cord blood unit does not reflect the long-term financial viability of a UK inventory. The utilisation rate of bank, meaning the proportion of its stock selected for HSCT in any given period of time, is a major determinant of its value and sustainability. By increasing the utilisation rates of its cord blood inventory the UK could significantly improve its cost effectiveness and lower the real costs per donor/unit dramatically. However, the utilisation rate of an inventory is also influenced by its size. In theory, in the context of fixed patient demand, the utilisation rate of a bank should reduce as its size expands.

However, the relationship between the overall utilisation rate of a bank and its size is actually more complex and balanced out by other considerations. For example, a larger inventory is likely to have a better ‘brand’ in its own country and internationally, due to the improved HLA range of its stored units and greater associated resources for marketing and outreach.

Drawing on recent international data (Foeken et a., 2010), Figure 33 illustrates the annual utilisation rates of a range of cord banks of varying sizes. It is clear from the graph that the relationship between size and utilisation is ambiguous and complicated by other variables.

Figure 33 1-year utilisation rates relative to size of international cord blood banks 0.00% 0.20% 0.40% 0.60% 0.80% 1.00% 1.20% 1.40% 1.60% 1.80% 2.00% 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 U ti li sa ti o n Bank Size 1 Year Utilisation

The cord banks of Mexico, France, Japan, New York and the NMDP together have the highest utilisation rates in the world (Table 20). However, the inventories service specific populations and vary greatly in size. The high rate of utilisation in Mexico is due to the small size of the cord blood bank and the relative genetic homogeneity of the Mexican population.The NMDP, on the other hand, has a large inventory serving an ethnically diverse population: its utilisation rate is sustained by high levels of domestic demand. France provides a closer comparator for the UK; its population has similar levels of ethnic diversity. Importantly, with a 1% annual utilisation rate, it achieves a lifetime utilisation rate of 18.1%, compared to the current rate of 6.5% in the UK.The NMDP, with around 4 times the number of units in its inventory, achieves a similar utilisation rate of 1.1%.

Table 20 Size and utilisation rate of international cord blood banks

Country Bank Size 1 Yr utilisation 20 Yr utilisation

Mexico 2,300 1.8% 30.5%

France 21,000 1.0% 18.1%

Japan 73,000 1.2% 21.0%

New York 77,000 0.5% 9.7%

NMDP* 86,000 1.1% 20.6%

*National Marrow Donor Program, USA

a 1% utilisation rate is therefore a feasible target for a UK cord inventory of 50,000 units to achieve. This will inform the cost calculations below.

Ethnic composition

Annex 3 describes in detail the challenges that ethnic minority patients in particular face in locating a donor. Matching rates for ethnic minority groups on UK and international registries are significantly lower than for Caucasian patients. Mixed race patients in the UK have a 40.7% probability of locating a suitable donor on the BBMR, compared to an 88% probability for Caucasian patients.

This imbalance is the result of a number of factors, including:

•.Underrepresentation.on.donor.registries – only 5.1% of donors on the BBMR belong to ethnic minority groups.

•.Greater.HLA.heterogeneity – certain ethnic minority groups have much broader HLA diversity than

Caucasians. The probability that two randomly selected African Americans have matching types is only around a tenth that of two randomly selected Caucasians (Bergstrom et al, 2008).

•.A.smaller.search.pool – as ethnic minorities only make up a fraction of the UK’s population, searching patients have a smaller donor poll in which to indentify a suitably matched donor.

However, an expanded cord blood inventory offers the possibility of addressing a significant portion of this unmet need. This is due to a number of reasons, including:

•.Targeted.recruitment – cord blood lends itself more readily to targeted collection strategies compared to adult donors. NHS-CBB has 5 collection sites located at hospitals in areas with ethnically diverse populations: as a result, 39.5% of its stored units were sourced from ethnic minority donors.

•.Increased.tolerance.of.HLA.mismatch – one of cord’s positive characteristics as a stem cell source is its ability to tolerate engraftment with a greater degree of mismatch between donor and patient. For patients with rare haplotypes and a very low probability of locating a 10/10 matched adult donor, cord blood may be their only option.

Even so, ethnic minority patients still face lower matching rates than Caucasian patients when searching for a cord unit for transplantation. An inventory of 50,000 units would provide the population as a whole with an 80% probability of locating a suitably matched unit, but only a 49% probability to ethnic minority patients. To provide ethnic minority patients with an equivalent 80% chance of finding a match, the inventory would have to expand to 150,000 units (Querol et al, 2009b). This would results in large numbers of redundant stored units and would not be economic.

Instead of expanding the inventory beyond 50,000 units, a more effective strategy would be to raise the proportion of cord blood donationssourced from ethnic minority donors in the inventory. One option would be to collect cord blood from Black and minority ethnic women exclusively. However, this would mean that the inventory was unable to supply any Caucasian patients with a match. In terms of utilisation, it is clear that Caucasian cord blood donations are also in high demand. While around 40% of NHS-CBB’s inventory is sourced from ethnic minorities, 30% of its issued units are from ethnic minority donors. From these figures it is possible to deduce the respective matching rates of Caucasian and ethnic minority cord blood donations: