Chapter 4: Translation |
56. A theme which permeated much of our inquiry
was that of uncertainty. Without greater certainty of a return
on their investment, namely that the science would be translated
into a clinical treatment, which could be commercially viable,
investors would remain reluctant to invest in regenerative medicine.
The route to market for drugs is well established and, although
costly, an investor can be reasonably certain of a return on investment.
For a regenerative medicine industry to flourish in the UK,
steps must be taken to clear the path "from bench to bedside"
as part of building investor confidence.
57. A reputation for proportionate regulation
is important for the UK both in terms of inspiring confidence
in potential patients and encouraging investment,
and there was general agreement that the current system was sufficiently
robust to protect patients. GE Healthcare, for example, described
the regulatory environment as "positive yet controlled",
OSCI called the system "rigorous, yet broadly permissive",
Lawford Davies Denoon (a life science law firm) viewed the system
as "mature", and the University of Manchester and Cytori
held the UK up as a model for other countries to follow.
Many companies told us about positive interactions with regulators,
including Azellon, Cytori and Shire.
58. The current complexity of the regulatory
system governing regenerative medicine was, however, a source
of great frustration to various witnesses. Many argued that the
system was overly difficult to navigate. Julian Hitchcock, a life
science lawyer, described how international investors were deterred
from investing in regenerative medicine because of this complexity,
and Lawford Davies Denoon said that numerous researchers and companies
choose not to base themselves in the UK because of this complex
framework and associated uncertainty.
A researcher or company could encounter up to 11 UK or European
regulators when developing a regenerative medicine product. Table
8 (overleaf) outlines their roles and remits.
Regulators with jurisdiction over regenerative
medicine in the UK
|European Medicines Agency (EMA)
||Responsible for the scientific evaluation of applications for European marketing authorisation for medicinal products (a centralised procedure).
|EMA Committee for Advanced Therapies (CAT)
||A multidisciplinary expert committee of the EMA to assess the quality, safety and efficacy of ATMPs and follow scientific developments in the field.
|Gene Therapy Advisory Committee (GTAC)
||Reviews applications to conduct clinical trials of investigational medicinal products (IMP) for gene therapy (although GTAC may transfer an application to another research ethics committee where the trial is of low risk). GTAC also has responsibility for ethical review of clinical trials involving other ATMPs or cell therapies derived from stem cell lines. Now part of the HRA.
|Health and Safety Executive
||Operates and enforces legislation in Great Britain that aims to control the risks to human health and the environment arising from activities involving GMOs in containment under the Genetically Modified Organisms (Contained Use) Regulations 2000.
|Home Office Animal Procedures Licensing Inspectorate
||Considers applications for new animal procedures licences and certificates; authorises amendments to existing authorities; and revokes or varies licences and certificates as necessary.
|Human Fertilisation and Embryology Authority (HFEA)
||Oversees the use of gametes and embryos in fertility treatment and research.
|Human Tissue Authority (HTA)
||Licenses establishments which procure (obtain through donation), store, test, process, distribute and import or export human tissues and cells that will be used to treat patients (including the use of cell lines grown outside the human body for patient treatment).
|Medicines and Healthcare Products Regulatory Agency (MHRA)
||Statutory agency charged with ensuring that medicines and medical devices work and are acceptably safe.
|NHS Research and Development Offices
||Offices in NHS organisations which carry out checks and grant written permissions related to the Department of Health's Research Governance Framework for Health and Social Care.
|Research Ethics Committee(s)
||These local Committees, overseen by the National Research Ethics Service, review ethics of clinical trial applications with the purpose of safeguarding the rights, dignity and welfare of people participating in research in the NHS. Now part of the HRA.
|UK Stem Cell Bank||All UK derived embryonic stem cell lines must be offered for deposit in the Bank and for the use of stem cells as a condition of the HFEA license.
59. The UCL applied regenerative science group
described regulatory pathways in the UK as "labyrinthine
and off-putting for overseas investigators, whilst demoralising
for home investigators", and the BIA called the regulatory
environment "overly complex and repetitive". The Association
of British Neurologists (ABN) called for a more streamlined framework,
and the British Society for Blood and Marrow Transplantation (BSBMT),
the British Society for Haematology and the Royal College of Pathologists
argued that the sheer number of regulatory bodies stifled innovation.
60. As well as considerable evidence of a complex
system, we heard that there was significant overlap between the
functions of regulators. The Cell Therapy Catapult explained that
this overlap existed because for many of the bodies "their
role in this regulatory process
is an adaption from their
primary purpose, introduced to fill gaps as the field started
to emerge". The consequences of this overlap were delays
and increased costs for users.
ReNeuron agreed that there was significant overlap in functions,
and Julian Hitchcock and Lawford Davies Denoon pointed to lack
of co-ordination between regulators and, in some cases, inconsistency
in advice. Arthritis
Research UK suggested that the system was particularly confusing
for products containing multiple materials, such as scaffolds
61. As shown by Figure 9, the UK has the joint
second highest number of competent authorities (an authority having
jurisdiction) covering medicines, medical devices, organ transplantation,
tissues and cells, reproduction and blood in the EU.
Number of competent authorities
62. The NHS Blood and Transplant Service (NHSBTS)
noted that some other EU countries have a single regulator, which
reduces the licensing and inspection cost burden,
as does the USA.
In contrast, Aiden Courtney, Chief Executive Officer of Roslin
Cells, said that the number of regulators was not the issue. Instead,
"the challenge we have in cell therapy is
that ... most of the people coming into developing cell therapy
are likely to be either academics trying to start a company or
new companies who are probably going through that regulatory process
for the first time, and it is very difficult for them to find
someone to give them the guidance to take them through the regime".
63. There have been some efforts to support the
industry and to improve the navigability of the regulatory route.
The regulators and the Department of Health produced a UK Stem
Cell Tool Kit which, most recently, took the form of an interactive
website to assist researchers developing a programme of human
stem cell research and manufacture.
Regulators have also been trying to join-up some of their activities.
For example, the Medicines and Healthcare products Regulatory
Agency (MHRA) and the Human Tissue Authority (HTA) have conducted
combined facility inspections.
The MHRA also runs a series of workshops and seminars to assist
those doing research in the field, and offers advice to researchers
64. In addition, the MHRA has launched an Innovation
Office to allow SMEs, academics and individuals to submit queries
about the regulation of medicines, medical devices and processes
through their website.
This initiative was part of the UK Life Science Strategy, as was
the establishment of an Expert Group on Innovation in the Regulation
of Healthcare products, which is considering adaptive licensing,
early access to medicines, the regulation of advanced manufacturing
and how regulators can improve their response to regulatory innovations
in future. Disappointingly, the strategy update of December 2012
indicated that this group was primarily focused on pharmaceuticals,
rather than regenerative treatments.
65. The European Medicines Agency (EMA) also
offers advice to companies. The first type of advice is informal
briefing meetings to discuss the process and relevant documentation
and is free. The second is fee-based and leads to the agency producing
a formal assessment of a development programme. Dr Hans-Georg
Eichler, Senior Medical Officer, EMA, suggested that this resource
was underused and highlighted that SMEs pay a significantly reduced
fee or attract a fee waiver.
66. The purpose of the newly formed Health Research
Authority (HRA) is to protect and promote the interests of patients
and the public in health research.
The HRA will work closely with other bodies, including the MHRA
and NIHR, to create a unified approval process, and to promote
proportionate standards for compliance and inspection within a
consistent national system of research governance. The HRA is
· "provide a single route through IRAS
(Integrated Research Approval System) for seeking all approvals
· provide clear signposting through the
process, with easy access to advice and support;
· embed principles and standards of review
bodies to ensure tasks are worthwhile, relevant and proportionate;
· co-ordinate the activities of review bodies
to remove unnecessary duplication;
· assign tasks to the relevant organization
at the appropriate time and support the exchange of assurances
across the system; and
· maintain a UK-wide overall approach that
recognises and incorporates individual requirements of the IRAS
67. It is too early to assess the effectiveness
of the HRA, but it has already had some success in beginning to
streamline research application documentation. We are also pleased
to see its feasibility study for a streamlined HRA assessment
for all research in the NHS, which would combine and replace aspects
of the current review by NHS Research and Development offices
and Research Ethics Committees.
68. We asked whether there was sufficient support
for companies and researchers seeking to navigate the system.
Dr Hans-Georg Eichler acknowledged that work in this field
is often done by "very small companies or academic groups
that have no experience in the field and are overwhelmed by the
entire complex regulatory system".
Dr Christopher Bravery (a regulatory consultant) accepted
that "the regulators themselves provide a lot of guidance"
but questioned its accessibility: "all of us find it difficult
to find it, even myself, when I do it for a living".
He also highlighted a shortage in regulatory expertise in the
UK. Peter Thompson,
Chief Executive of the Human Fertilisation and Embryology Authority (HFEA),
recognised the daunting nature of tackling the regulatory system:
"it clearly is a complex pattern of regulation which has
built up over time, and I can well see why anybody embarking on
this would not find it as straightforward as it ought to be".
CIRM supports its researchers by providing advice on navigating
regulatory approval from ex-Food and Drug Administration (FDA)
69. Alistair Kent, Director of Genetic Alliance
UK, argued for greater support for "organisations that have
good ideas, potentially good products, bringing them through the
system in a way that makes it clear what the hurdles are that
they will have to overcome and what the standard of proof is that
will be required of them, in order to satisfactorily negotiate
The Health Knowledge Transfer Network recommended a dual approach
of streamlining the regulatory system and providing support to
enable navigation of the current system.
The Health Protection Agency agreed with the need for support:
"there is a clear and urgent need for companies to have access
to early stage high quality advice on the application of regulation
and regulatory science".
Those calling for increased support included Iva Hauptmannova,
Head of Research and Development, Royal National Orthopaedic Hospital
NHS Trust (who submitted evidence in a personal capacity), and
researchers from King's College London and King's Health Partners.
70. We were disappointed by the disparity in
regulators' attitudes: the EMA, HFEA, HRA and HTA all acknowledged
that there was room for improvement, whilst the MHRA was more
focussed on what it was already doing.
Professor Sir Kent Woods, Chief Executive, MHRA, told
us that "the regulation is complex, but the science and the
technology are complex".
We consider this view to be overly simplistic. Regulation must
be robust and fit for purpose, but that does not justify the complex
regulatory environment in the UK. Although there has been some
progress, it is clear that there is still considerable room for
improvement. The end users (in this case academics and companies)
have expressed concern that the system is still overly complex
and that there is insufficient support. This, at best perceived,
lack of support must be addressed and the underlying issue of
a complex regulatory system also considered. The twin challenges
of improving perceptions of the regulatory system and streamlining
it are so great that both immediate and long-term action are needed.
71. We recommend that, as a matter of urgency,
the HRA establish a regulatory advice service. This would build
on the expertise of the Office for Life Science toolkit, the newly
established MHRA Innovation Office and the experience of regulators.
Researchers and companies require more than a web-based service.
They should be assigned a single point of contact to support them
in navigating the regulatory system, directing their queries to
others where appropriate, but retaining ownership and oversight
of the advice process. Such a service would be of short-term value
to this (and the broad healthcare) sector until such a time as
the regulatory environment is rationalised.
72. During the course of our inquiry, the Department
of Health published the result of its consultation on the transfer
of functions from the HFEA and HTA. Both organisations have retained
their functions for now, but will undergo an independent review
of how they carry them out. They were also referred to the Shared
Services programme, with a view to streamlining their non-specialist
we welcome this review we consider it too narrow in scope.
73. The Health Research Authority (HRA) has
made some positive first steps and it must now demonstrate its
effectiveness by streamlining the macro regulatory environment.
We recommend that the HRA commission an independent advisory group,
made up of national and international experts in regulation, to
develop a designed-for-purpose regulatory system. The UK rightly
has a good reputation for its robust regulatory system; it is
vital that this reputation be maintained. Similarly, we acknowledge
there is significant value in the expertise of some regulators.
But patients, business and the taxpayer deserve a modern, designed-for-purpose,
efficient regulatory system rather than one that has evolved in
a haphazard, piecemeal way. An independent advisory group supporting
the HRA will give it the necessary support to focus and clarify
the functions of regulators. This group should give special consideration
to reducing the overall number of regulators. We recommend that
the group make proposals 18 months from its establishment. We
will revisit this aspect of the inquiry to ensure that progress
has been made. The HRA must simplify the regulatory route so that
the development of regenerative medicine, and other innovative
therapies, is not hindered.
UK STEM CELL BANK
74. The UK Stem Cell Bank was established in
2002 to provide a repository of human embryonic, foetal and adult
stem cell lines.
CIRM recognised the bank as "an important international resource
to support basic research in regenerative medicine" and praised
it as "one of the top sources of stem cell lines for basic
and clinical research". The HPA and CIRM both recognised
the bank's international reputation for expertise in quality assurance
and governance. However, we heard one case of administrative difficulties
with the bank from a CIRM project leader, Professor Larry
Goldstein. He described the bank as "incompetent and intransigent",
and detailed his difficulties accessing two specific cell lines.
On its own, this is not proof that the bank is ineffective; nevertheless,
its steering committee must ensure that its full potential is
75. Much has been written previously about the
difficulties associated with setting up clinical trials in the
UK. For example, the Academy of Medical Sciences published what
was heralded as a seminal report on this topic in January 2011.
It criticised the "complex and bureaucratic regulatory environment"
which was "stifling health research in the UK".
The Life Science Strategy also recognised the need to improve
clinical trial governance in the UK.
Clinical trials are a sizeable, long-term investmentthe
development process for a new therapy, of which they are a key
facet, is estimated to cost up to $1 billion and can take between
12 and 15 years.
76. The UK is a cheaper place to conduct clinical
trials than, for example, the USA.
Many witnesses pointed out the potential advantages of conducting
clinical trials in the NHS, and benefits to the NHS of these trials.
The primary advantage was access to patients. The NHS, as a single
healthcare system, should, in theory, make it easier to identify
potential patient groups for trials and to access their associated
data (with appropriate permissions).
A Japanese researcher, Professor Sato, drew a favourable
contrast between accessibility of patients in the UK compared
to Japan. The
Association of Medical Research Charities (AMRC) reported that
between 2000 and 2006 the proportion of all the world's clinical
trials conducted in the UK fell from six percent to two percent,
in part because of more attractive regulation and incentives elsewhere.
The Government must therefore identify how the UK can become
a more attractive venue for clinical trials as, currently, the
number of trials does not reflect its significant benefits.
77. We heard three primary causes for concern:
the slowness of trial set-up; the lack of adequate support to
set-up trials; and the design and scale of trials for regenerative
78. Several witnesses identified delays setting
up clinical trials as a serious issue. The Cell Therapy Catapult
said that delays to the start of clinical trials were a major
obstacle to conducting clinical research in the UK.
The UK Stem Cell Foundation also viewed stoppages as a major issue,
citing both delays in approval and difficulties in identifying
patient cohorts as problems.
Figure 10 shows the length of time taken by the MHRA to consider
regenerative medicine clinical trial applications. It shows that
there is great variation in how long this process can take and
it is this kind of uncertainty that can put off potential investors.
Time Taken for the MHRA to assess regenerative
trial applications 2008-12
Note: each bar refers to an individual application
progressing through a sequence of stages
79. The identification of suitable patients for
trials was also a cause of delay.
NHS research and development approval processes were perceived
to be slow and,
despite efforts to improve its working, some witnesses were still
critical of the time taken by GTAC to consider applications (even
after its merger into the HRA).
The Alliance for Regenerative Medicine spelled out the consequences
of these delays: "real and/or perceived bottlenecks that
delay or adversely impact the speed and efficiency of clinical
increase overall costs and erodes value".
80. We heard ample evidence that more could be
done to support clinical trial set-up. Professor Robin Ali,
UCL, made the case for additional support for clinicians setting
up clinical trials because of the "huge numbers of forms
and the documentation" required.
He argued that "clinicians and senior academics just do not
have the time to spend filling in huge numbers of forms and the
documentation that is required".
We heard of one trial which had involved over 37, 000 pages of
Regener8 argued that the skills to conduct administrative preparations
required for clinical trials were "not normally found within
academic or small company settings".
LLR also identified bureaucracy associated with setting up trials
as a block to translation.
81. There have already been some efforts to address
this need for support. The NIHR was set up with the expressed
purpose "to create the best possible research environment
in the NHS and build an international reputation for excellence
in translational and applied research".
It has invested in a network of Biomedical Research Units (BRUs)
and Biomedical Research Centres (BRCs). The map below (Figure
11) shows where they are located.
NIHR Biomedical Research Units and Biomedical
These BRUs and BRCs seek to support the translation
of research to patient benefits and to drive innovation in the
prevention, diagnosis and treatment of ill-health. Another NIHR
initiative is the NIHR Clinical Research Network (CRN), which
· "ensure patients and healthcare professionals
from all parts of the country are able to participate in and benefit
from clinical research;
· integrate health research and patient
· improve the quality, speed and co-ordination
of clinical research, and
· increase collaboration with industry partners
and ensure that the NHS can meet the health research needs of
82. The CRN comprises a co-ordinating centre,
six topic specific research networks, a primary care research
network and a comprehensive research network enabling research
to be conducted across the full spectrum of disease and clinical
need. It allocates and manages funding to meet NHS service support
(for example, additional nursing time, pathology sessions, lab
costs, imaging, additional out-patients costs) for eligible studies.
One aspect of this support is the research design service, which
includes expert advice on clinical trials.
83. We heard mixed evidence about the efficacy
of NIHR efforts. Tissue Regenix told us that: "the multifarious
levels of bureaucracy we, as a partner, have to be involved with
is confusing and ultimately unproductive, wasteful of time and
money and this is meant to be a streamlined process".
The BSBMT said these efforts compared unfavourably with other
national models, including that of the USA, because the USA has
central funding available and its clinical trial governance structures
are "less complex and time consuming".
84. In contrast, the UCL applied regenerative
science group regarded NIHR support as a UK strength and its provision
to be "comprehensive".
Miltenyi Biotec spoke favourably of the support the NIHR had provided
to the cell therapy landscape.
The UK Regenerative Medicine Community (UKRMC) considered changes
by the NIHR to be "very positive"
and the Wellcome Trust welcomed the NIHR Research Support Services
85. It is clear that the NIHR's actions to support
clinical trials are welcome, but there are some questions about
their adequacy. Professor Charles Craddock, Queen Elizabeth
Hospital, argued that there was insufficient funding for clinical
trial support: "the major challenge to the United Kingdom
realising its full translational potential primarily relates to
the absence of appropriately funded clinical trials networks in
areas such as regenerative medicine where the United Kingdom already
possesses exceptional strong basic science and clinical teams".
Regener8 called for growth in this support: "specialist knowledge
and the ability to navigate around the approval process are required
and can be a steep learning curve for the novice. Greater provision,
and expansion, of the current support from the NIHR at the local
level would be a benefit in overcoming this difficulty".
86. Many regenerative medicines treat orphan
indicationsthose conditions occurring in relatively few
patients. This causes difficulties amassing data in sufficient
patients to prove safety, efficacy and patient benefit.
Clearly it is not appropriate to consider lowering evidence standards
as patient safety must be a priority. But one way of addressing
this issue would be to improve ease of identifying suitable patients.
The NIHR has already made some progress in this, but other initiatives
show there is further potential to speed up and ease the identification
of potential participants. The Scottish Government have set up
NHS Research Scotland, which helps to address this challenge by
co-ordinating the rapid approval of multi-centre clinical trials
Similarly, the LLR Trial Acceleration Programme (TAP) established
in 2011 has had exceptional results. It funds a central trials
hub in Birmingham and supports research nurses or trial co-ordinators
in 13 leukaemia centres across the United Kingdom to allow rapid
recruitment to early phase studies from a 20 million population.
In its first 12 months, the TAP launched two early phase clinical
trials and planned to open four further studies in the following
87. Another difficulty associated with clinical
trials was the identification of doctors who would be interested
in supporting a trial.
A further challenge was how to ensure that treatments were developed
in such a way that they were scalable when it came to increased
patient numbers, an issue which we will explore in greater depth
in the next Chapter.
88. The evidence received conveys considerable
demand for greater support in the design and set-up of clinical
trials. There is expertise in clinical trial design and set-up
in the NIHR CRN, its BRUs and BRCs, and amongst academics exploring
innovative trial design. There is also considerable expertise
in NICE, which could help inform trial design to ensure outcomes
meet its evaluation requirements, in the MHRA, which already offers
an advisory service, and amongst manufacturing experts from both
industry and academia, who could provide advice to ensure that
therapies are developed in a scalable fashion. Each of these groups
would benefit from greater two-way interaction: to inform regulation
and guidance making, and product development and trial design.
89. Consequently, we recommend that the NIHR
establish a regenerative medicine stream of its clinical research
network. Such a move would support researchers in addressing the
specific needs of regenerative medicine clinical trial design,
help overcome difficulties in identifying patients and ensure
that doctors interested in such trials could be easily identified.
The network could also facilitate dialogue with regulators on
future regulatory needs and issues encountered with regulation.
The regenerative medicine stream of the network should employ
a hub and spoke model for allogeneic treatments, whereby it has
one or two co-ordinating centres and regional operations. Given
the need for clinical trials of a certain size, this network should
span across the UK and build on existing developed infrastructures
like NHS Research Scotland.
90. The NHS would be a very attractive location
for trials with these improvements, and there are reciprocal benefits
to the UK in the form of inward investment, gaining further experience,
potential for early market adoption and thus availability to NHS
patients. The Government must ensure that this opportunity is
91. Clinical trials in regenerative medicine
have some issues specific to the field. For traditional pharmacological
clinical trials, the endpoints and clinical indications are reasonably
well establishedsafety, efficacy and patient benefit. Designing
clinical trials for regenerative medicines presents some distinct
challenges as there may not, for example, be a comparable therapy
with which to compare efficacy. Some witnesses called for regulator-defined
endpoints, indications and measures.
The FDA has produced similar guidance for cancer drug and biologic
endpoints for treating terminal disease.
For investigators, and their financial backers, to know what they
should be aiming to demonstrate through their trials, they need
to know what evidence requirements regulators will have of them.
We recognise that this is a two-way process and a learning curveregulators
have as much to learn about developments in the science as researchers
do about evolving regulation. CIRM run productive seminars where
the FDA and scientists engage in dialogue to help achieve this
we recommend increased dialogue between regulators and researchers
in the form of regular regenerative medicine workshops, and that
the MHRA produce a series of guidance notes (to be updated bi-annually)
setting out clinical trial endpoint requirements for regenerative
medicine, in consultation with the industry and academic researchers.
UK regulators should learn from the example of FDA-CIRM workshops
and similar efforts in other countries.
92. Ultimately, all of these efforts will be
fruitless unless more is done to allow clinicians time to participate
in research activities, including clinical trials. Providing time,
resources and space for people to innovate was a key recommendation
of Sir David Nicholson's report Innovation, Health and
Wealth, 2011. The inclusion of research in the NHS Constitution
is a positive step and the efforts of the NIHR are laudable. But
the Department of Health must remain vigilant to ensure that research
and development is a priority in the newly structured NHS.
Scale-up and manufacturing
93. Scaling a treatment up from a product for
a handful of people, to service a large sample of people in a
trial and ultimately, potentially, to patients across the nation
provides specific manufacturing challenges for this industry.
Unlike a pharmaceutical treatment where a pharmacy can issue uniform,
mass-produced tablets, regenerative medicines often require the
safe treatment and delivery of living cells. Table 9 gives an
idea of scale of batches of cells required when one considers
the numbers of doses potentially involved in cell therapies if
delivered to sizeable groups. The number of doses of a particular
cell-based treatment required in a given year can be achieved
by increasing the number of doses prepared per batch.
Doses per year drives cell batch size
|Doses per year
||Doses per lot
|50, 000||1, 000
|100, 000||2, 000
|250, 000||5, 000
|500, 000||10, 000
||2, 500||1, 000
94. To deliver at significant scale it will be
necessary to develop closed and automated systems, and for therapies
to be designed in such a way that they can be manufactured in
bulk. One example
of the difficulties faced is the challenge of producing a large
batch of cells to a standard potency and quality.
Manufacturing in large quantities will not only be necessary,
it will also bring economies of scale.
Zahid Latif, Head of Healthcare, TSB, summed up the issue well:
"Typically, what happens with a promising therapy that comes
out of the research sector, or some of the SMEs that are often
undercapitalised, is that the processes are essentially laboratory,
hand-cranked processes. When they come out to be manufactured,
frankly, the processes are not up to it".
95. There have been initiatives to address some
of these issues. The TSB Regenerative Medicine Programme had,
as one tranche of its funding, a tools and technologies programme.
This gave funds to projects including a high throughput platform
for the discovery of GMP (Good Manufacturing Practice: quality
assurance to ensure that medicinal products are consistently produced
and controlled to the standards appropriate to their intended
stem cell manufacturing protocols by Plasticell Limited, Cell
Guidance Systems Limited, LGC Limited and NHS Blood and Transplant
(NHSBT); a closed point-of-care preparation device by Lonza Biologics
PLC, eXmoor Pharma Concepts Limited and Amercare Limited; and
a project to enhance cell stability during manufacture and administration
by Stabilitech Limited and UCL.
96. Furthermore, £5.8 million over 5 years
has been invested by the EPSRC to establish a Centre for Innovative
Manufacturing in Regenerative Medicine which has leveraged £13.4
million of geared funding since October 2011.
The Centre is a partnership between Loughborough, Nottingham and
Keele Universities and industry (they currently have around 20
industry partners) together with other end users. Its vision is
"to form a differentiated translational "go to"
resource for regenerative medicine product developers with a focus
on manufacturing science, and manufacturing system and process
Its core research themes are manufacturing and automation; characterisation;
and delivery and 3D constructs (such as scaffolds). An example
of one of their projects is the testing and validation of a prototype
hydrostatic pressure growth chamber capable of scale-up for manufacturing
for cell therapy applications. The Centre explained: "hydrostatic
force applied to cells in culture leads to an increase in bone
cell growth and mineralisation, two processes highly important
for the regeneration of skeletal tissue. The novel Tissue Growth
Technologies (TGT) bioreactor allows standard format cell culture
plasticware to be used, with additional control over frequency
and amplitude of hydrostatic forces applied. Such a design will
allow large scale-up".
97. The Association of the British Pharmaceutical
Industry (ABPI) recommended that early dialogue with industry
on manufacturing, scalability, transportation and delivery solutions
and consideration of "commercial viability" should be
funding criteria for translational and applied research.
LGC Limited argued that regenerative medicine innovators embarking
on commercial development should outsource the manufacture of
their products to contract pharmaceutical manufacturers that have
established processes, skills and infrastructure to conduct this
work and comply with regulatory requirements.
Despite these differences in approach, these views add weight
to the argument that scalability must be researched, invested
in and must inform the development process for a product at an
early stage. CIRM have a disease team model which brings together
multidisciplinary teams to work on specific disease areas, and
these teams include manufacturing and scale-up experts.
This ensures that researchers are thinking about these issues
together and CIRM bring in expertise to support them in thinking
about commercial issues during development.
98. We recommend that the phase II disease
teams of the TSB regenerative medicine platform, and other regenerative
medicine funding programmes, specifically require researchers
to involve manufacturing and scale-up experts in their development
process to ensure that translational work is scalable and therefore
deliverable to a large number of patients (where the disease area
99. Very few witnesses called for a significant
expansion of UK GMP capacity at present, but rather for more research
to be translated to the point where it was required. Professor Williams,
Professor Marc Turner, Medical Director, SNBTS and Keith
Thompson, Chief Executive, Cell Therapy Catapult, all cautioned
against building "steel palaces" as, they argue, to
invest heavily in clean room capacity now could be short-sighted
should significant breakthroughs in closed and automated systems
be made in the next few years.
France has recently invested $143 million in a major manufacturing
cluster. UK investment
in manufacturing must not fall behind that of its major competitors
in Europe and further afield. In the first instance, greater co-ordination
of UK GMP facilities through a central registry would ensure that
these facilities are used to their maximum capacity.
100. Recognising the importance of capacity
to deliver therapies at scale, both for trials and wider patients
populations, and the fast-moving pace of the manufacturing and
scale-up field, we recommend that the TSB and EPSRC undertake
an annual stock-take of regenerative medicine manufacturing capacity
and make recommendations to BIS about future needs, with the first
survey informing the Government's review of infrastructure investment.
The Cell Therapy Catapult has begun work on such a survey so we
recommend that this work is taken as a starting point. BIS must
then act to ensure that appropriate infrastructure investment
is made to support the field. At the very least, investment should
be made in facilities to support the scale-up of treatments in
mid to late stage clinical development. Money for this, and other
recommendations, should be found by the re-prioritisation of budgets
and innovative funding methods (discussed below).
101. UK capacity to manufacture at scale could
be attractive to companies considering investing in or expanding
operations to this country. We recommend that the UKTI Life Science
Investment Organisation use the results of this survey to advise
foreign companies on UK capacity to manufacture regenerative products.
102. We heard calls for more trained technical
staff in this area. Specifically, there was a need for more technical
staff trained in manufacturing processes and with experience of
the quality requirements.
Without these staff, investment in infrastructure will be wasted.
103. We recommend that the NHS develop a training
programme for technical staff to support the development of cell
therapies and other regenerative therapies at scale.
104. GMP (Good Manufacturing Practice) is quality
assurance to ensure that medicinal products are consistently produced
and controlled to the standards appropriate to their intended
use, and as required by a product's marketing authorisation or
product specification. There are particular technical and regulatory
challenges in developing cell lines and expanding autologous cells
for clinical use. To satisfy these standards, quality standards
must be built into the development process from the start, and
clinical grade GMP maintained throughout the development process
(although research grade facilities may be used for non-clinical
applications). This includes both a GMP compliant quality control
regime (the panel of tests for the cells) and GMP compliant cell
processing facilities (real estate).
As the report of the TSB REALISE project observed, the cost of
meeting regulatory requirements for the development of cells to
clinical grade GMP standard is significant.
Arthritis Research UK argued that the requirements for the expensive
GMP compliant processes imposed by regulation are inflexible,
and based on the traditional needs of drug therapies, and thus
hinder development of novel cellular therapies.
This criticism was echoed by the Cell Therapy Catapult.
It advocated an approach better tailored to the therapy and stage
of development which reflected requirements in areas such as batch
potency, release and comparability testing. This would recognise
the fact that when the product is a living cell, 'batch' sizes
for cell based therapies can be very small and the testing requirements
can become unfeasible both in terms of time and material requirements
as well as prohibitively expensive.
Professor David Williams, Director of the EPSRC Centre, argued
that building stronger links between the regulators and those
who are regulated would be a vital step in overcoming the difficulties
of GMP requirements.
GMP requirements are agreed at an EU level.
105. We recommend that the MHRA canvas views
from industry on the suitability of current GMP requirements and,
if there is significant discontent, take these problems to the
European Commission to seek agreement on overcoming them through
amendments to the GMP Directive and associated guidance.
106. By delivery we mean the process of preparing,
storing, transporting and administering a treatment to a patient.
Different types of treatment require different delivery models.
For example, some autologous cell treatments could be manufactured
using "off the shelf" technologies. Others might require
significant manipulation in specific facilities, which would require
transportation both to and from a specialist centre. Similarly,
allogeneic cell treatments may require preservation, storage and
transportation from donor to recipient. The UCL applied regenerative
science group, gave an example which illustrates the need for
both infrastructure investment and clear delivery routes: the
Moorefield's Eye Hospital / ACT retinal pigment epithelium
cell replacement derived from human embryonic stem cell to treat
Stargardt's disease (described in paragraph 14 above) is an "off-the-shelf"
allogeneic product yet requires thawing from cryopreservation
(maintenance of the viability of cells, tissues and organs by
a process of cooling and storing at very low temperatures)
and dosing within a four hour travelling distance of the patient.
It argued that "if the current clinical trials in the UK
and the US continue to be successful this is an ideal candidate
for commercialisation but only if an infrastructure of hospital-based
"cellular pharmacies" is in place across the UK such
as the three highly specialised, MHRA licensed facilities we have
across UCL to deliver these products close to the patients".
107. Taking Stock argued that the UK possessed
a key advantage in the delivery of cell based products in the
form of the NHSBTS and devolved equivalents. Each of these organisations
is familiar with the challenges in distributing blood products,
stem cells (for bone marrow and cord blood) and organs, as well
as necessary tissue typing services. NHSBTS already delivers a
diverse range of specialist services in human tissue and cells
such as the collection, GMP production, storage and delivery of
viable cell therapies.
In Scotland, SNBTS is already a key part of the regenerative medicine
environment, undertaking clinical development of a pipeline of
new therapies and taking a lead role in several multi-partner
public and private projects (for example, a Wellcome Trust funded
project to create red blood cells).
There is similar potential for the NHSBTS to partner with SMEs
and researchers, either as a purchaser of specialised services
of infrastructure, or as an incubator for a small number of SMEs
in need of GMP production facilities.
Azellon is already partnering with NHSBTS in cell production for
the clinical trial of its platform technology using mesenchymal
stem cells (MSCs) to repair damaged knee tissue.
NHSBTS acknowledges that its infrastructure is pivotal to the
effective manufacture and delivery of regenerative medicines.
Azellon note that as the number of cell products expands, NHSBTS
will need to further develop its capacity to provide a cell production
service at different locations, and argue that "there is
a significant opportunity for NHSBTS to fill this gap using a
semi-commercial approach, but with flexibility and a cost model
that is more attractive for early-stage cell therapy companies".
108. It is clear that the national blood and
transfusion services have the logistical capability to collect,
produce, store and transport components of regenerative treatments.
However, we were concerned to see that the NHS is less ready for
the provision of regenerative therapies. We were surprised
that Sir Bruce Keogh, NHS Medical Director, and James Palmer,
Clinical Director for specialised services, NHS England, could
not point to future infrastructure needs to provide regenerative
treatments on mass to patients.
109. Investors need to see a clear pathway
from development to delivery in the NHS if they are to have the
confidence to invest in regenerative medicine. It is not sufficient
to rely on trail blazing therapies to forge pathways to clinical
delivery. The NHS must shift from reacting to regenerative medicine
to a state of preparedness to deliver new and innovative treatments.
- We recommend that the Department of Health
establish a regenerative medicine expert working group to develop
an NHS regenerative medicine delivery readiness strategy and action
plan by December 2014. This group should report to the Secretary
of State for Health directly and have the support of a high-profile,
independent chair. The group must also contain NHS England officials,
NHSBTS and devolved blood and transfusion services, regulators,
researchers and industry representatives. We consider the role
of the chair further in Chapter 5.
112 Alliance for Regenerative Medicine, Azellon, Health
Knowledge Transfer Network, Scottish Enterprise, UKRMC. Back
Appendix 5. Back
Human Tissue Authority, OSCI. Back
GE Healthcare, OSCI, Lawford Davies Denoon, University of Manchester,
Azellon, Cytori, Shire. Back
Julian Hitchcock, Lawford Davies Denoon. Back
Based upon information about purpose and role from each organisation's
Directive 2001/20/EC, Article 2 (d), provides the following definition
for an IMP: "a pharmaceutical form of an active substance
or placebo being tested or used as a reference in a clinical trial,
including products already with a marketing authorization but
used or assembled (formulated or packaged) in a way different
from the authorised form, or when used for an unauthorised indication,
or when used to gain further information about the authorised
UCL applied regenerative science group, BIA, ABN, BSBMT, BSH,
Cell Therapy Catapult. Back
ReNeuron, Julian Hitchcock, Lawford Davies Denoon. Back
Arthritis Research UK. Back
Consulting on Advanced Biologicals Ltd. Data on Luxembourg and
The Netherlands were not available. Back
Q 249. Back
Supplementary evidence from UK regulators, Human Tissue Authority
(HTA), Government. Back
Q 300. Back
Supplementary evidence from UK regulators. Back
HM Government: Strategy for UK Life Sciences One Year On,
December 2012. Back
Q 301, Q 305. Back
HRA: Protecting and promoting the interests of patients and
the public in health research, March 2012. Back
HRA: IRAS four years on-celebrating and building on success,
Q 300, Government, supplementary evidence from UK regulators. Back
Q 296. Back
Q 335. Back
Q 332. Back
Q 318. Back
Appendix 5. Back
Q 331. Back
Health Knowledge Transfer Network (KTN). Back
Iva Hauptmannova, King's College London (KCL) and King's Health
Partners (KHP). Back
Q 314, Q 296, Q 318. Back
Q 300. Back
DH: Government response to the consultation on proposals to
transfer functions from the Human Fertilisation and Embryology
Authority and the Human Tissue Authority, January 2013. Back
CIRM, HPA, Appendix 5. Back
Academy of Medical Sciences: A new pathway for the regulation
and governance of health research, January 2011. Back
Op. cit. Life Sciences Strategy. Back
Appendix 5. Back
Alliance for Regenerative Medicine, UCL applied regenerative science
group, BIA, LLR. Back
UCL applied regenerative science group, Professor Charles Craddock,
Health KTN, KCL, Miltenyi Biotec, ReNeuron. Back
Professor Chiaki Sato. Back
Cell Therapy Catapult. Back
UK Stem Cell Foundation. Back
Supplementary written evidence from the MHRA. Back
BSBMT, BSH, RCPath, Cell Therapy Catapult, LLR. Back
Alliance for Regenerative Medicine. Back
Q 64. Back
Q 65. Back
Q 40. Back
Tissue Regenix Group plc. Back
Based on information from the NIHR website: www.nihr.ac.uk. Back
NIHR: Clinical Research Network, 2013. Back
Tissue Regenix. Back
BSBMT, BSH, RCPath. Back
UCL applied regenerative science group. Back
Miltenyi Biotec. Back
The Wellcome Trust. Back
Professor Charles Craddock. Back
Scottish Enterprise. Back
Scottish Government. Back
LLR, Professor Charles Craddock. Back
ABPI, AMRC, BIA, RCUK, Welsh Government. Back
FDA: Guidance for Industry; clinical trial endpoints for the
approval of cancer drugs and biologics, 2007. Back
Appendix 5. Back
ABPI, British Society for Oral and Dental Research, EPSRC Centre
for Innovative Manufacturing in Regenerative Medicine, Health
Presentation made at CIRM by Lonza. Used with permission. Back
Q 251. Back
RCUK, Appendix 5. Back
Q 284. Back
European Commission: EU Guidelines to Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use, 2008. Back
Supplementary written evidence from the Government. Back
EPSRC Centre for Innovative Manufacturing in Regenerative Medicine:
Annual report, 2011. Back
Appendix 5. Back
Q 273, Q 251. Back
Q 175. Back
Q 245, Q 253, Q 275, Cell Therapy Catapult. Back
Op. cit. EU GMP Guidelines. Back
Mastroeni, M., Mittra, J., and Tait, J.: TSB Regenerative Medicine
Programme: Value Systems and Business Models, the REALISE project,
May 2012. Back
Arthritis Research UK. Back
Cell Therapy Catapult. Back
Q 276. Back
Op. cit. PAS 84. Back
UCL applied regenerative science group. Back
Op. cit. Taking stock, Government. Back
Op. cit. Taking stock. Back
Q 335. Back