The analysis determined that the cost to manufacture autologous therapy (£2260–3040 or US$3630–4890 per dose) will be more
than double that to produce allogeneic therapy (£930–1140 or US$1490–1830 per dose) because current expert opinion is that
with the former each patient will be required to undergo donor screening and testing and their final product will be subject
to release testing. For allogeneic therapy, however, only a small number of donors will need to be screened and tested to
find a high-quality stem-cell sample to produce a cell-bank system, which will provide treatments for around a decade, and
release testing will be limited to each batch of the final product, which will provide approximately 100 doses of therapy.
Neither autologous nor allogeneic therapy will be able to compete with small molecule or biological drugs on retail price.
To maximize their possibility of reimbursement from healthcare payers, stem-cell therapies will need to differentiate themselves
by demonstrating good efficacy and safety in diseases that have significant mortality or morbidity (such as cardiac and neurological
illnesses), where no satisfactory treatments exist or where the standard of care is particularly expensive over the duration
of the illness (in terms of the cost of drugs, hospitalizations, primary care visits, nursing home care, physiotherapy). To
justify their high price, stem-cell therapies will almost certainly need to modify disease progression or help restore normal
physiological function rather than merely provide short-term symptomatic control.
Two fundamental factors will need to be met for cell-based therapies to be commercially successful, regardless of whether
they are allogeneic or autologous. First, automated cell culturing will be required to achieve commercial-scale manufacturing,
to deliver economies of scale, to produce a more consistent product each time, and to reduce the risk of microbial contamination
(manual culturing carries a higher risk of pathogen contamination because of the need for an operator to be at close proximity
to the samples). Second, it will be essential to control the cost of media components and growth factors used in automated
cell culturing, as they will account for a significant portion of manufacturing costs.
The business models used to commercialize allogeneic and autologous therapy will differ substantially (see Table I). Allogeneic
therapy is expected to follow an "off-the-shelf" business model, so could be used in both acute and chronic disease settings,
which will maximize its commercial potential. The manufacturing of allogeneic therapy will be standardized because all doses
will be produced from a cell-bank system, which will also mean that allogeneic therapy is relatively straightforward to scale
up on demand.
Table I: Comparison of autologous and allogeneic stem-cell therapy.
For allogeneic therapy, immune rejection of administered donor stem-cells by the recipient remains a key concern. Mesenchymal
stem-cells (MSCs) will almost certainly become a leading source of stem-cells in allogeneic therapy because they are considered
immunoprivileged and so unlikely to invoke an immune response in the recipient (7). The hope is that using MSCs will abate
the need for immunosuppressive drugs. Another fear is the possibility of transferring pathogens from the donor to recipients,
but this risk will need to be completely excluded via meticulous safety testing when establishing a cell bank system.
In contrast, autologous therapy is anticipated to be commercialized using a "service-based" business model, a much more challenging
business proposition for a number of reasons. The variation in stem-cells from different patients may mean that donor material
from large numbers of patients does not yield therapy after culture expansion for the selected time period, particularly given
that MSCs most probably culture expand less well with advancing age (8), which is precisely the age group at highest risk
of being inflicted with medical conditions. In cases where donor material does not produce therapy after culture expansion
for a specified duration, should culturing be continued? If yes, this would mean that therapies under production for different
patients would be at different stages of the manufacturing process at a given point in time, causing logistical difficulties,
increasing the risk of errors, and adding further to media and growth factor costs. Due to such issues, a considerable degree
of flexibility would need to be built into any manufacturing process for autologous therapy and production would be more difficult
to scale up on demand.
The length of time required to manufacture autologous therapy will prevent it from being used in acute patient care, which
will reduce its commercial opportunity. There is also the fear that if an automated cell culturing machine runs cell lines
from multiple patients simultaneously cross contamination could occur. This risk will need to be ruled out using GMP. Finally,
patients will need to undergo two procedures for autologous therapy, one to extract stem-cells and the other to reintroduce
them a few weeks later after culture expansion, which may raise medical and ethical considerations.
The assumptions for autologous therapy underlying the analysis probably represent the best-case scenario in terms of it being
producible for all patients in the same time frame as allogeneic therapy using automated cell culturing. Therefore, manufacturing
costs for autologous therapy may be much higher, if these assumptions are found to not hold true as our knowledge of stem-cell
science and manufacturing increases.
The analysis undertaken has several key limitations: It assumes that it will actually be possible to manufacture both autologous
and allogeneic therapy for a given medical illness and that both therapy types will have equivalent efficacy and safety. Both
of these assumptions are unlikely to hold true with diseases in reality. It is also quite possible that for certain acute
medical conditions, such as stroke or myocardial infarction, stem-cell therapy may need to be given within a finite window
post-event, say 24–48 h, to achieve optimal results, which would rule out autologous therapy usage. Finally, it may be unwise
to administer autologous therapy to patients with a personal or family history of cancerous, genetic or other pertinent disease.
It is important to highlight that this analysis assumed that each patient would need only one dose of therapy, but in practice
multiple doses may be required to treat a medical condition. Additional doses of autologous therapy could be produced for
a patient at no additional donor and release testing cost, if manufactured at the same time as the first dose and stored until
required. Additional doses of allogeneic therapy could be produced from the established cell bank system, which in practice
would be capable of generating much more than 2500 doses annually for ten years. The cost of release testing would, however,
double in allogeneic therapy, if patients needed two doses as release testing is required for every batch consisting of 100
doses. Donor and release testing (along with cell banking for allogeneic therapy) essentially cost £1290–1820 (US$2070–2920)
for the first dose of autologous therapy and £13–25 (US$21–40) for the first dose of allogeneic therapy, so the cost to manufacture
additional doses of allogeneic therapy for a patient would remain approximately the same as the first dose, but the cost to
produce additional doses of autologous therapy would drastically fall to ~40% of the first dose (from £2260–3040, US$3620–4870
to £960–1200, US$1540–1920) and become comparable to that for allogeneic therapy.