Regenerative medicine - Science and Technology Committee Contents


Chapter 4: Translation

Uncertainty

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.[112] The route to market for drugs is well established and, although costly, an investor can be reasonably certain of a return on investment.[113] 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.

Regulatory environment

57.  A reputation for proportionate regulation is important for the UK both in terms of inspiring confidence in potential patients and encouraging investment,[114] 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.[115] Many companies told us about positive interactions with regulators, including Azellon, Cytori and Shire.[116]

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.[117] 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.

TABLE 8

Regulators with jurisdiction over regenerative medicine in the UK[118]
Regulator Role(s)
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)[119] 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 BankAll 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.[120]

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.[121] 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.[122] Arthritis Research UK suggested that the system was particularly confusing for products containing multiple materials, such as scaffolds and cells.[123]

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.

FIGURE 9

Number of competent authorities[124]


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,[125] as does the USA.[126] In contrast, Aiden Courtney, Chief Executive Officer of Roslin Cells, said that the number of regulators was not the issue. Instead, he argued:

    "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".[127]

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.[128] 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.[129] The MHRA also runs a series of workshops and seminars to assist those doing research in the field, and offers advice to researchers and companies.[130]

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.[131] 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.[132]

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.[133]

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.[134] 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 intended to:

·  "provide a single route through IRAS (Integrated Research Approval System) for seeking all approvals and permissions;

·  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 partners".[135]

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.[136]

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".[137] 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".[138] He also highlighted a shortage in regulatory expertise in the UK.[139] 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".[140] CIRM supports its researchers by providing advice on navigating regulatory approval from ex-Food and Drug Administration (FDA) regulatory consultants.[141]

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 those hurdles".[142] The Health Knowledge Transfer Network recommended a dual approach of streamlining the regulatory system and providing support to enable navigation of the current system.[143] 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".[144] 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.[145]

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.[146] Professor Sir Kent Woods, Chief Executive, MHRA, told us that "the regulation is complex, but the science and the technology are complex".[147] 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 functions.[148] Although 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.[149] 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.[150] On its own, this is not proof that the bank is ineffective; nevertheless, its steering committee must ensure that its full potential is realised.

Clinical trials

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".[151] The Life Science Strategy also recognised the need to improve clinical trial governance in the UK.[152] Clinical trials are a sizeable, long-term investment—the 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.[153]

76.  The UK is a cheaper place to conduct clinical trials than, for example, the USA.[154] Many witnesses pointed out the potential advantages of conducting clinical trials in the NHS, and benefits to the NHS of these trials.[155] 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).[156] A Japanese researcher, Professor Sato, drew a favourable contrast between accessibility of patients in the UK compared to Japan.[157] 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.[158] 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 medicine.

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.[159] 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.[160] 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.

FIGURE 10

Time Taken for the MHRA to assess regenerative medicine clinical
trial applications 2008-12
[161]

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.[162] NHS research and development approval processes were perceived to be slow and,[163] 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).[164] 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 development … increase overall costs and erodes value".[165]

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.[166] 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".[167] We heard of one trial which had involved over 37, 000 pages of documentation.[168] Regener8 argued that the skills to conduct administrative preparations required for clinical trials were "not normally found within academic or small company settings".[169] LLR also identified bureaucracy associated with setting up trials as a block to translation.[170]

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".[171] 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.

FIGURE 11

NIHR Biomedical Research Units and Biomedical Research Centres[172]

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 seeks to:

·  "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 care;

·  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 industry".[173]

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.[174]

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".[175] 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".[176]

84.  In contrast, the UCL applied regenerative science group regarded NIHR support as a UK strength and its provision to be "comprehensive".[177] Miltenyi Biotec spoke favourably of the support the NIHR had provided to the cell therapy landscape.[178] The UK Regenerative Medicine Community (UKRMC) considered changes by the NIHR to be "very positive"[179] and the Wellcome Trust welcomed the NIHR Research Support Services Framework.[180]

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".[181] 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".[182]

86.  Many regenerative medicines treat orphan indications—those conditions occurring in relatively few patients. This causes difficulties amassing data in sufficient patients to prove safety, efficacy and patient benefit.[183] 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 across Scotland.[184] 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 six months.[185]

87.  Another difficulty associated with clinical trials was the identification of doctors who would be interested in supporting a trial.[186] 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 not missed.

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 established—safety, 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.[187] The FDA has produced similar guidance for cancer drug and biologic endpoints for treating terminal disease.[188] 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.[189] We recognise that this is a two-way process and a learning curve—regulators 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 end.[190] Therefore, 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.[191] 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.

TABLE 9

Doses per year drives cell batch size[192]
Doses per year
Doses per lot
50 200 500 1, 000 5, 000 10, 000
10, 000200 5020 102 1
25, 000500 12550 255 2.5
50, 0001, 000 250100 5010 5
100, 0002, 000 500200 10020 10
250, 0005, 000 1, 250500
250
5025
500, 00010, 000 2, 5001, 000 500100 50

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.[193] One example of the difficulties faced is the challenge of producing a large batch of cells to a standard potency and quality.[194] Manufacturing in large quantities will not only be necessary, it will also bring economies of scale.[195] 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".[196]

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 use)[197] compatible 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.[198]

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.[199] 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 development".[200] 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".[201]

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.[202] 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.[203] 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.[204] 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.[205]

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 requires this).

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.[206] France has recently invested $143 million in a major manufacturing cluster.[207] 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.[208] 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.

GMP REQUIREMENTS

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).[209] 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.[210] 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.[211] This criticism was echoed by the Cell Therapy Catapult.[212] 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.[213] 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.[214] 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.

Delivery

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)[215] 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".[216]

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.[217] 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).[218] 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.[219] 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.[220] NHSBTS acknowledges that its infrastructure is pivotal to the effective manufacture and delivery of regenerative medicines.[221] 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".[222]

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.[223]

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.

  1. 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

113   Appendix 5. Back

114   Human Tissue Authority, OSCI. Back

115   GE Healthcare, OSCI, Lawford Davies Denoon, University of Manchester, Cytori. Back

116   Azellon, Cytori, Shire. Back

117   Julian Hitchcock, Lawford Davies Denoon. Back

118   Based upon information about purpose and role from each organisation's website. Back

119   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 form." Back

120   UCL applied regenerative science group, BIA, ABN, BSBMT, BSH, RCPath. Back

121   Cell Therapy Catapult. Back

122   ReNeuron, Julian Hitchcock, Lawford Davies Denoon. Back

123   Arthritis Research UK. Back

124   Consulting on Advanced Biologicals Ltd. Data on Luxembourg and The Netherlands were not available. Back

125   NHSBTS. Back

126   CIRM. Back

127   Q 249. Back

128   Government. Back

129   Supplementary evidence from UK regulators, Human Tissue Authority (HTA), Government. Back

130   Q 300. Back

131   Supplementary evidence from UK regulators. Back

132   HM Government: Strategy for UK Life Sciences One Year On, December 2012. Back

133   Q 301, Q 305. Back

134   HRA: Protecting and promoting the interests of patients and the public in health research, March 2012. Back

135   HRA: IRAS four years on-celebrating and building on success, 2012. Back

136   Q 300, Government, supplementary evidence from UK regulators. Back

137   Q 296. Back

138   Q 335. Back

139   Q 332. Back

140   Q 318. Back

141   Appendix 5. Back

142   Q 331. Back

143   Health Knowledge Transfer Network (KTN). Back

144   HPA. Back

145   Iva Hauptmannova, King's College London (KCL) and King's Health Partners (KHP). Back

146   Q 314, Q 296, Q 318. Back

147   Q 300. Back

148   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

149   Government. Back

150   CIRM, HPA, Appendix 5. Back

151   Academy of Medical Sciences: A new pathway for the regulation and governance of health research, January 2011. Back

152   Op. cit. Life Sciences Strategy. Back

153   AAT. Back

154   Appendix 5. Back

155   Alliance for Regenerative Medicine, UCL applied regenerative science group, BIA, LLR. Back

156   UCL applied regenerative science group, Professor Charles Craddock, Health KTN, KCL, Miltenyi Biotec, ReNeuron. Back

157   Professor Chiaki Sato. Back

158   AMRC. Back

159   Cell Therapy Catapult. Back

160   UK Stem Cell Foundation. Back

161   Supplementary written evidence from the MHRA. Back

162   UKSCF. Back

163   BSBMT, BSH, RCPath, Cell Therapy Catapult, LLR. Back

164   UKSCF. Back

165   Alliance for Regenerative Medicine. Back

166   Q 64. Back

167   Q 65. Back

168   Q 40. Back

169   Regener8. Back

170   LLR. Back

171   Tissue Regenix Group plc. Back

172   Based on information from the NIHR website: www.nihr.ac.uk.  Back

173   NIHR: Clinical Research Network, 2013. Back

174   IbidBack

175   Tissue Regenix. Back

176   BSBMT, BSH, RCPath. Back

177   UCL applied regenerative science group. Back

178   Miltenyi Biotec. Back

179   UKRMC. Back

180   The Wellcome Trust. Back

181   Professor Charles Craddock. Back

182   Regener8. Back

183   Scottish Enterprise. Back

184   Scottish Government. Back

185   LLR, Professor Charles Craddock. Back

186   Pfizer. Back

187   ABPI, AMRC, BIA, RCUK, Welsh Government. Back

188   FDA: Guidance for Industry; clinical trial endpoints for the approval of cancer drugs and biologics, 2007. Back

189   Appendix 5. Back

190   Ibid. Back

191   ABPI, British Society for Oral and Dental Research, EPSRC Centre for Innovative Manufacturing in Regenerative Medicine, Health KTN. Back

192   Presentation made at CIRM by Lonza. Used with permission. Back

193   Q 251. Back

194   RCUK, Appendix 5. Back

195   LGC. Back

196   Q 284. Back

197   European Commission: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, 2008. Back

198   Supplementary written evidence from the Government. Back

199   EPSRC Centre for Innovative Manufacturing in Regenerative Medicine: Annual report, 2011. Back

200   Ibid. Back

201   Ibid. Back

202   ABPI. Back

203   LGC. Back

204   Appendix 5. Back

205   CIRM. Back

206   Q 273, Q 251. Back

207   Q 175. Back

208   Q 245, Q 253, Q 275, Cell Therapy Catapult. Back

209   Op. cit. EU GMP GuidelinesBack

210   Mastroeni, M., Mittra, J., and Tait, J.: TSB Regenerative Medicine Programme: Value Systems and Business Models, the REALISE project, May 2012. Back

211   Arthritis Research UK. Back

212   Cell Therapy Catapult. Back

213   Ibid. Back

214   Q 276. Back

215   Op. cit. PAS 84. Back

216   UCL applied regenerative science group. Back

217   Op. cit. Taking stock, Government. Back

218   SNBTS. Back

219   Op. cit. Taking stock. Back

220   Azellon. Back

221   NHSBTS. Back

222   Azellon. Back

223   Q 335. Back


 
previous page contents next page


© Parliamentary copyright 2013