Regenerative medicine - Science and Technology Committee Contents


23 October 2012

Members of the Committee present were Lord Broers, Lord Cunningham of Felling, Lord Dixon-Smith, Baroness Hilton of Eggardon, Lord Krebs (Chairman), Lord O'Neill of Clackmannan, Lord Patel, Earl of Selborne, Baroness Sharp of Guildford, Lord Wade of Chorlton, Lord Willis of Knaresborough and Lord Winston.

A seminar was held at the Guy's Campus of King's College London to provide the Committee with an opportunity to discuss the Regenerative Medicine inquiry with academic experts, industry representatives, funding organisations, and representatives of the Department of Health, the Department for Business, Innovation and Skills (BIS), and the Technology Strategy Board (TSB).

In attendance:

Professor Fiona Watt (Specialist Adviser to the Committee), Chris Atkinson (Clerk), Cerise Burnett-Stuart (Committee Assistant), Rachel Maze (Policy Analyst), and James Tobin (Policy Analyst).

Presentation speakers: Dr Rob Buckle (MRC); Dr Rupert Lewis and Dr David Griffiths-Johnson (Department for Business, Innovation and Skills); Dr Mark Bale (Department of Health); Dr Zahid Latif (Technology Strategy Board), Michael Hunt (ReNeuron).

Roundtable participants: Professor Charles ffrench-Constant (University of Edinburgh); Professor David Williams (EPSRC Centre for Innovative Manufacturing); Robin Lovell-Badge (National Institute for Medical Research, London); Professor Amanda Fisher (Imperial College London); Anthony Hollander (University of Bristol); Professor Chris Mason (UCL); Steve Bates (BIA); Becky Purvis (AMRC); Priya Umachandran (Wellcome Trust); Alex Denoon, (Lawford, Davies and Denoon); and Tim Allsop (Pfizer).

Overview of UK Research Excellence in Regenerative Medicine—Rob Buckle, Medical Research Council

Rob Buckle opened by providing a definition of Regenerative Medicine treatments, including the approaches and timescale for delivery. Concentrating on cell therapy, a number of approaches were identified. The first, autologous cell therapies, employ cell matter taken from an individual to treat that individual (so called "self to self" treatments). There are currently numerous clinical trials under way in this area, including for the treatment of bone/joint, cardiovascular, eye, liver and neurological disorders. In most cases, stem cells are removed from the patient, often minimally processed, and then reintroduced as part of treatment in the same area or bodily system. Results in heterologous systems—taking stem cells from one area such as the bone marrow, and using it to repair neurological issues for example—have so far proven unconvincing.

In contrast, allogeneic cell therapies where the donor and recipient are different (so called "one-to-many" treatments) have potentially broader potential. However, their use is dependent upon the use of immune suppression or donor matching (as in bone-marrow transplants). There are currently clinical trials underway in this area on skin conditions, stroke, Parkinson's Disease, corneal repair, and Advanced Macular Degeneration (AMD). There is also notable future potential in induced Pluripotent Stem Cell (iPS)-based, and directly-differentiated cell-based, treatments. Finally, a range of activity was being undertaken on endogenous repair, which involves the use of growth factors and small molecules to stimulate repair processes. The MRC, for example, was funding such research in the areas of heart repair and multiple sclerosis.

An examination of the therapeutic pipeline across these areas revealed that there were currently 36 studies at the preclinical-early stage of development (33 academic-led, and three commercially-led.) Six studies were at the preclinical-late stage (five academic-led, and one commercial). Finally, 19 studies were at clinical phases I/II (14 academic-led, and five commercial). When viewed by disease area, the largest number of studies—and, indeed, in many cases the most developed—were muscloskeletal and eye-related conditions.

With regard to the strength of the science base, of the top five research nations (US, China, UK, Japan and Germany) UK researchers generated more articles per researcher, more citations per researcher, and more usage per article authored.[336] The UK's share of the top one percent of most highly cited papers was 13.8% in 2010, second only to the USA. The UK citation impact in regenerative medicine is also higher than for the UK science base more generally.[337] The UK is also a leading collaborator for others, including the USA and Germany.

The main funders of research in regenerative medicine are the research councils, the Department of Health (particularly through the NIHR), the TSB and research charities. Support is largely provided by competitive, response-mode funding. However, there are also areas where the direct stimulation of activity is needed, and therefore targeted schemes (including translational funding) are also provided. Funding is also directed at research infrastructures, international partnerships, and capacity-building, which receives approximately 10% of MRC funding in this area. Research activity overall is co-ordinated through both the UK Regenerative Medicine Forum and the International Stem Cell Forum.

In 2008, research council funding was approximately £43.5 million which represented around 66% of the total research spend on regenerative medicine. The MRC was the largest contributor of this funding at £37.7 million (52% of the research council total). The BBSRC contributed £12.8 million (18%), the EPSRC £11.3 million (16%) and the TSB £8.8 million. The NIHR and ESRC contributed approximately one percent of research funding respectively. Since 2008, the MRC's financial contribution to research in regenerative medicine has approximately doubled (£72.6 million per annum), with funding for 353 projects. When analysed by "technology readiness level"—a spectrum which begins at underpinning research through to user adoption—the majority of research council spending on regenerative medicine remains at the earlier "underpinning" or "preclinical/breadboard" stages. Relatively small numbers of funded projects are at "early clinical-prototype" or "user adoption" phases. That reflects current understanding of the field, and how difficult it is to translate projects into later stages of development.

In terms of current UK strategic investments, there are a number of Centres of Excellence in regenerative medicine research in the UK which the MRC and other research councils help to fund.[338] The MRC is also engaged in strategic funding partnerships designed to accelerate therapeutic development in this area, including with the British Heart Foundation, and with the California Institute of Regenerative Medicine. In November 2012, a joint £12 million initiative between the Wellcome Trust and the MRC will be announced on Human Induced Pluripotent Stem Cells. There is also the UK Stem Cell Bank, which exists to provide human embryonic stem cell lines in an ethically sourced and quality controlled manner, and industry relationships in the form of Stem Cells for Safer Medicines (SC4SM) public private partnership involving pharmaceutical companies using this technology for drug development. Broader support for the area is also provided through a number of NIHR Biomedical Research Centres, and the Blood Transfusion Services which offer distribution and manufacturing capability.

There remain a number of challenges which need to be addressed in the field, however, as identified in the recent UK strategic review. There is a need for better interdisciplinary working between different groups such as biologists, bioengineers and material scientists, and different regenerative medicine centres. There are also issues with regard to controlling cell phenotype and function, in terms of how they are differentiated to form different tissues, while animal models used to test functionality and safety are also not particularly predictive in this area. Particular challenges also exist with regard to potency, or which cells, how many and what mode of action will be needed for a potential treatment, and immunomodulation, so that risks around transplant rejection can be prevented. New tools and technologies will be required for the development of regenerative medicine treatments. How to meet demand for manufacturing facilities and GMP production will also be an important issue. There is also regulatory uncertainty in this area, including how phase I trials should be designed to meet requirements and the appropriate level of monitoring and follow-up. New business models will also be needed for commercial development.

Looking to the broader strategic approach to these issues and challenges, A Strategy for UK Regenerative Medicine was published in March 2012. The Strategy aimed to detail how this area of fast-moving discovery science could be best exploited, and to drive translational approaches and build on the UK's strong science base. To this end, the Strategy documents an injection of £95 million into new strategic funding over the next five years which will be channelled into specific initiatives such as the UK Regenerative Medicine Platform, the TSB Cell Therapy Catapult Centre and new MRC and Wellcome Trust partnerships.

In response to a question on the comparative spending ratios between the UK and the US on early science through to translational/commercial stages, Dr Buckle said it was difficult to get an accurate picture across American providers. However, he believed that they would be broadly similar. When questioned on whether the relatively low levels of translational funding (in comparison with earlier stage research funding) demonstrated in both countries was the result of a lack of resource or a lack of projects to fund, Dr Buckle said that at the current time there was not a (comparatively) large demand for translational funding. In response to a further question on the funding of translational research, Dr Buckle added that the MRC have a specific budget for translational science in regenerative medicine, which has been set at a level capable of satisfying the level of high quality demand, which had remained steady over the last few years. The deployment of that budget is managed through a funding committee formed four years ago, and which has the capacity for industry partnership. With the TSB, the MRC has also launched the Biomedical Catalyst Fund, which aims to provide funding to bridge the "valley of death" where proof of concept is needed before large scale investment can be attracted, and which can absorb the demands of clinical studies in this area as they emerge. Dr Buckle suggested that the result of these various initiatives was a harmonised funding landscape in this area.

In response to a question about the role of charitable organisations, Dr Buckle said that they were very much acting as partners with the research councils in translational research. He added that industry interest in this area is largely represented by small and medium sized enterprises rather than "big pharma", with companies involved in both the development of treatments, and the development of tools and technologies. The MRC is explicitly trying to encourage industry partnership with targeted funding.[339]

First Roundtable—What potential does regenerative medicine hold to treat disease in the next 5-10 years?

The discussion began with a short introduction from each external participant providing a brief overview of particular points of interest. The potential impact of small molecule therapies, not least because it is a model that pharmaceutical companies are already very comfortable with, was highlighted. The benefits provided by cell reprogramming—the technology for turning different types of somatic cells back into stem cells—were also explained.

It was argued that any supposition that human iPS or human embryonic stem cells should be used for cell replacement was argued to be potentially naive. One possible alternative focus for research attention might be "directed reprogramming", whereby rather than turning a differentiated cell right back into an embryonic stem cell it is turned into a required material that is perhaps mid-way (or at some other point) in the differentiation process.

Autologous therapies were already being deployed. Whilst such therapies were not perfect, they illustrated that it was possible to remove, manipulate, and then reinsert cells, and provide some demonstrable therapeutic effect. It was felt that there was considerable tractability in this area, which would only increase over the next few years as these therapies continue to develop and improve. Tissue engineering—using cells to create tissues outside the body and then implant them—was also identified as a key area for potential. However, considerably more development in the fundamental science would be required, and developing a suitable business model could be particularly complex.

Niche derived factors—factors made by the local environment where the stem cells exist, and which control the activity of those stem cells—and their small molecule agonists and antagonists could be very important over the next 5-10 years.

The benefits derived in the next 5-10 years were very much going to be governed by what is currently in clinical trials. According to the database, (excluding duplicates) there were around 1, 900 trials ongoing. The overwhelming majority were clinician-sponsored, a mode which, it was suggested, historically has not had good results, principally as a result of issues such as lack of later-stage funding. Public companies, rather than clinicians, tend to be well set up for such later stage trials. There were estimated to be about 45 public companies engaged in around 60 active trials, roughly split between 40% at phase I, 40% at phase II, and 20% in phase III. It was argued that there would only be a very small number of therapies coming through in the next 5-10 years, although there was potential for treatments for very small patient groups to progress faster.

Manufacturing capability was identified as an issue. A large scale therapy which would be distributed widely to a large number of patients was unlikely in the next 10 years, as the processes necessary for the scale-up of such treatments did not currently exist. More positively, the UK does possess considerable strength in the area of gene therapy, and the increasing convergence of gene and cell therapies in particular presents a considerable area of future potential.

It was suggested that the level of translational activity in the UK was low in comparison to other countries with more permissive regulatory regimes, which was of particular concern.

The UK Stem Cell Bank was identified as a key resource, particularly given the presence there of clinical grade stem cell lines for research. It was suggested that commercial actors seldom dealt with the UK Stem Cell Bank, preferring instead to deal directly with those who had deposited lines there. Furthermore, as there is currently no mechanism for the long-term exclusive use of a cell line by a company developing a cell therapy, and no ability for a company to control how deposited cells are used, there exists a barrier to commercial investment.

Second Presentation—Mark Bale, Department of Health; Rupert Lewis and David Griffiths-Johnson, Department of Business, Innovation and Skills: the Policy Environment

Mark Bale outlined that the approach of Government since 2000 had been to take a neutral perspective with regard to the source of stem cells, but to be as supportive and enabling as possible with regard to regulation pertaining to derivation, clinical trials and therapeutic application. That work takes place within the wider constraints imposed at a European level.

Speaking directly to the issue of regulation, Dr Bale said that the Government are conscious of the perception that there is a multiplicity of regulators. However, there were very good reasons for the established system. Responding to a question on why the Government had chosen not to locate the regulation of all research functions within the Human Research Authority (HRA), as it had originally intended, Dr Bale said that the Government had undertaken consultation on this issue. He added that in his view, stem cells and other regenerative medicine treatments constituted a very small proportion of the responsibilities of the HFEA and HFA—it was not their core business. Therefore, to remove these functions from those bodies and to place them in the HRA, for example, might in fact increase the resource necessary to deal with them. There might be a need to take on new staff for example, where this expertise already exists in the existing structure.

Dr Bale continued by outlining which regenerative medicine treatments and processes, and at what stage, were currently within the remit of which regulator. Dr Bale acknowledged that the regulatory structure may appear complicated, but said that there had been considerable efforts to raise awareness and increase understanding through initiatives such as the Stem Cell Toolkit, alongside workshops and further guidance materials.

Rupert Lewis outlined the recent steps that BIS had taken to support the development of regenerative medicine, including the creation of the Cell Therapy Catapult. He also pointed to the work undertaken by the British Standards Institute, which had published a number of standards and guides on issue areas such as the use of human cells for clinical application. Measures were also available to improve access to finance, such as the use of tax credits and the TSB's Regenerative Medicine Programme. Dr Lewis added that there were particular programmes which aimed to address the problem of the "valley of death", including Enterprise Capital Funds which seek to leverage private sector investment and demonstrate potential to venture capital. The Enterprise Investment Scheme also exists to provide tax relief for investors.

Dr Lewis then highlighted the potential implications of the recent European Court of Justice ruling in Brüstle v Greenpeace. Dr Lewis said that the Government was concerned about the potential impact of this decision for research using human embryonic stem cells, and had made representations to the European Commission on this issue. The Intellectual Property Office had also issued a revised practice note in light of this ruling. Dr Lewis said that reaction to the decision across the research community had been mixed. He noted that, whilst there was concern if an invention could not be patented, the complexity and expertise needed to develop a regenerative medicine treatment could still provide commercial protection and exclusivity in the absence of a patent.

Dr Lewis noted the wide recognition of the potential of regenerative medicine as a growth opportunity internationally. A number of countries were currently investing in regenerative medicine, particularly in the area of translational research. While some countries such as Japan had chosen to focus on particular areas (iPS cells), the UK had retained a broad approach, preferring to be led by the science. The UK has particular areas of strength in research impact and collaboration, and on the number of companies operating in the area.

Zahid Latif then outlined the role of the Technology Strategy Board in supporting regenerative medicine. As a funder, a key challenge for the TSB was to go to business and find out what was necessary to secure investment into regenerative medicine. Clinical studies proving efficacy was identified as a key requirement, as was the need to invest in the underpinning tools and technologies necessary to develop regenerative medicine, as well as the treatments themselves. Dr Latif said the final area that the TSB needed to examine and "unpack" was value systems and impact modelling—i.e. what is regenerative medicine, is it a product or a service? How should the reimbursement challenges be addressed as a result? The TSB ran a series of competitions for funding from 2009-11 to focus on these areas.

Dr Latif continued by highlighting that the business and operating models present in the regenerative medicine sector differed significantly from traditional pharmaceutical models. As a result, funding programmes had to be designed in a particularly bespoke way in order to address key concerns, including, for example, access to finance. Dr Latif identified a number of success stories, where companies had benefitted from such an approach. Further work, including the creation of the Biomedical Research Catalyst, is currently being undertaken in order to overcome issues such as the "valley of death". Finally, Dr Latif highlighted the work of the Call Therapy Catapult, which provides access to knowledge and expertise as well as access to the finance which companies need.

Members of the Committee raised the question of whether the current regulatory environment facilitated the development of regenerative medicine, or presented a potential barrier to that development. A discussion about access to finance, an unclear and complex regulatory system, and uncertainties about reimbursement followed. It was pointed out that the regulatory rules are the same across Europe. What may be different is the UK is the presence of multiple regulators, and the need to work with different regulators depending in the stage and type of treatment under development. The outreach work that was being done by the regulators to industry in order to overcome any uncertainties or apprehension was outlined. However, it was pointed out that whilst the regulatory environment in the UK was well-regarded, the multiplicity of regulators in the UK created an environment where inconsistent and occasionally contradictory advice was given, and there was no mechanism to resolve such inconsistency.

Third Presentation—Michael Hunt, ReNeuron

Michael Hunt, Chief Executive of ReNeuron opened his presentation by providing a brief background about the work of ReNeuron, and their work as a small company taking a regenerative medicine treatment through basic research into clinical trials. Mr Hunt then outlined some of the challenges the company faced going forward, including securing finance to develop further avenues of treatment so far unexplored due to those financial constraints, the specific concerns of ensuring purity and potency of cell lines, and broader issues of developing an effective business model and negotiating the regulatory landscape. Speaking in particular to those regulatory burdens, Mr Hunt said that in his experience the processes involved had often proved to be complex, inefficient, and subject to considerable overlap between regulatory agencies. By way of illustration, he said that ReNeuron had been subject to eight different inspections, by three regulatory bodies, in the preceding twelve months. Mr Hunt said if reviews could be implemented to make the regulatory process more timely and proportionate, the UK would be more attractive to those seeking to develop regenerative treatments such as themselves.

Turning to the issue of funding, Mr Hunt said that private investment into UK companies was currently small in comparison to other areas, notably the United States. He said that, despite the progress being made in the field both in the basic science and translationally, investors were still demonstrating reluctance to commit funding. Similarly, with regard to publically provided funding, there were some funds available in the UK for translational research, but again this was a fraction of what small companies in the US were able to access.

Looking at positives in the UK landscape, Mr Hunt said that in general the UK Government had proven to be supportive of regenerative medicine, and there were increasing levels of research council funding available. He also particularly welcomed the establishment of the Cell Therapy Catapult. Finally, Mr Hunt highlighted the benefits presented by the NIHR and the NHS, and the presence of trade bodies particularly focused on regenerative medicine.

Second Roundtable—Where could the Committee's inquiry best add value?

Moving around the table, suggestions were heard regarding the areas where the Committee might be able to add the most value and the key questions that it might seek to address in its inquiry.

It was argued that one of those areas should be the regulatory framework and the creation of an active mechanism to pull products through from basic research, through clinical trials, into commercialisation.

Another view was that it was best to focus on what was achievable in regenerative medicine, in comparison to what was considered aspirational, and how one engaged the full community effectively.

In addition to examining regulatory issues, guidance provided to companies working in the field should be considered. It was suggested that, given the timing of the inquiry, the ongoing discussions on the EU Horizon 2020 programme would be a particularly pertinent issue to consider. The development of effective business models was a key issue, requiring close interaction with regulators, and also dialogue across the regenerative medicine community.

Another area where the Committee might add significant value, where there is currently uncertainty, was the adoption of treatments and technologies in the NHS. It would be important to address the issue of stem cell tourism, not least with regard to unscrupulous providers preying on those desperate for treatment. It was considered vital that the Committee examine adoption and reimbursement, not least in balancing up-front costs with potential long-term savings, with a view to convincing Government to provide more support and assistance in these areas. It was also important to concentrate on the finance and funding gap which currently exists.

Attention should be given to the small and niche products being developed as well as the so-called "blockbuster treatments". Support for the key role of large and small charities in addressing issues such as access to finance and adoption of regenerative treatments by healthcare providers including the NHS could be considered. It was argued that advice and support services need to be significantly improved. The possibility of early-phase reimbursement should be explored.

It was suggested that translation and commercialisation were often confused when in reality they were two very different parts of the development pathway. The UK was very good at basic research, getting better at translation, but extremely poor at commercialisation. In order to develop the UK's regenerative medicine sector, this last issue in particular needed significant focus. Access to finance, and a need for Government support to encourage investment was also highlighted. Finally, the significant challenges in terms of trial design and implementation, and the need for a skilled workforce to meet these challenges, merited attention.

336   According to the findings of BIS: International Comparative Performance of the UK Research Base, 2011. Back

337   Op. cit. Taking stock. Back

338   They include the Stem Cell Institute in Cambridge, with the MRC in partnership with the Welcome Trust; the MRC Centre for Regenerative Medicine in Edinburgh; the EPSRC, BBSRC, TSB Medical Technologies Centre in Leeds; and the ESPRC Centre for Innovative Manufacturing in Loughborough. Back

339   The principle route for this funding would be from the MRC to a university, who would then subcontract to a company. Back

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