Written evidence submitted by The Humanimal Trust (REG0010)
1. Introduction
1.1. The Humanimal Trust welcomes the opportunity to respond to the Science and Technology Committee inquiry into regenerative medicine. Our comments will highlight the value of regenerative medicine in veterinary medicine and, in particular, of the untapped potential for using veterinary clinical patients as part of a One Medicine approach to understanding disease and developing new treatments for use in humans and animals.
1.2. The Humanimal Trust is the first UK charity set up to promote the advancement of animal and human healthcare through a One Medicine approach that integrates human and veterinary research. One Medicine embodies the view that both human and veterinary medicine share not only similar biological underpinnings but often also the same scientific and technological challenges. We believe that it makes clear clinical and economic sense that advances in human and veterinary medicine should be made in tandem to the advantage of both humans and animals [1].
1.3. The Trust believes that a One Medicine approach has enormous potential within the field of regenerative medicine, in high impact areas such as cardiovascular disease, arthritis and Alzheimer’s disease. Other key potential impact areas for such an approach include cancer, immune-mediated disorders, infectious disease (especially those that spread between humans and animals), endocrine and neurodegenerative disorders. In all of these areas, we believe that a One Medicine approach is most likely to bring viable, safe treatments to the clinic within the shortest timeframes.
1.4. The strong interdisciplinary basis of a One Medicine approach is a crucial element in accelerating biomedical research discoveries and bringing new treatments to both the human and animal markets. In the US, where the One Medicine concept is more established, human and animal interdisciplinary research programmes are already yielding results.
1.5. The UK is well positioned to deliver on the potential of One Medicine, but the effectiveness of delivery is currently hampered by the absence of an integrated funding strategy and by inefficiencies and a lack of clarity in the oversight of research involving the use of veterinary clinical patients.
1.6. In submitting this response, the Trust hopes to highlight the potential value of One Medicine for regenerative medicine, and to contribute to the development of an integrated funding strategy and research infrastructure to support translational studies in the area of regenerative medicine.
2.1 The Humanimal Trust submission focusses on the following key areas:
2.1.1 Regenerative Medicine should be taken forward within a One Medicine framework, taking full advantage of the opportunities afforded by the strong UK veterinary research and clinical base, working collaboratively with the outstanding human medicine research and clinical base, to the advantage of both humans and animals.
2.1.2 Reciprocity should be a fundamental and essential part of all regenerative medicine research involving animals. The ‘3 Rs’ should be reconceived as the ‘4 Rs’, to include reciprocity. Where animals contribute to research as research participants, then animals as well as humans must benefit from the research outcomes.
2.1.3 Studies of naturally occurring disease in veterinary clinical patients are highly relevant to the development of regenerative medicine treatments for human patients. Companion animals share environment, as well as biology, with humans. Such studies provide crucial information about issues such as dosing, the suitability of novel routes of treatment delivery, co-morbidities and interactions with alternative medications. The use of volunteer animal studies has the potential to significantly enhance the translation pathway for human treatments, getting new treatments into the clinic, and reducing the need for laboratory studies involving large animal models.
2.1.4 There is a strong economic case for the inclusion of studies of naturally occurring disease in animals in the regulation pathway for the development of new regenerative medicine treatments for humans. This is fundamentally important in the context of the currently poor trial success rates, representing both an economic and a moral imperative to take on board this source of opportunity.
2.1.5 A UK Strategy for regenerative medicine must include both veterinary and human clinical science. The Humanimal Trust spans both human and animal medicine, and is uniquely placed to contribute a One Medicine perspective to the development of such a strategy. We would be prepared to lead in relevant work strands, should we be invited to do so.
2.2 Recommendations
Recommendation 1: Regenerative medicine research should be progressed within a One Medicine approach, which provides the best possible framework of opportunity for the UK.
Recommendation 2: The potential for clinical trials in veterinary patients to accelerate research and identify therapies that are more likely to be effective in subsequent human clinical trials should be supported by appropriate resourcing, and embedded within research and innovation practice.
Recommendation 3: Any future strategic re-evaluation of the use of animal models in regenerative medicine research should involve input from specialists within human and veterinary medicine.
Recommendation 4: Existing regulatory processes should be refined to better allow for the contribution of veterinary clinical trials to the study of regenerative medicine treatments for humans.
Recommendation 5: Reciprocity should be the guiding principle that informs the use of animal subjects in the development of research initiatives in regenerative medicine, so that the outcomes of research have positive impact for both animals and humans at the same time.
3. Response to Questions
3.1 The opportunities for regenerative medicine (advanced therapies) and the UK’s ability to reap those advantages
3.1.1 Similar to other high-income countries, the UK is experiencing a slow but steady increase in the average lifespan. The total number of people aged 65 to 84 is expected to rise by 39% by 2032, while the 85+ population is expected to more than double over the same time period [2]. The ageing population brings many challenges, especially with regard to degenerative conditions, and much of the increase in healthcare cost burden reflects the increased need for long-term care of patients with chronic degenerative, cardiovascular, neurological, oncologic or musculoskeletal conditions [3].
3.1.2 Although procedures such as total hip or knee replacement, organ transplantation or cardiac valve replacement can replace diseased tissues and organs, there is a clear benefit to using regenerative therapies to enhance the repair or regeneration of the patient’s own tissue. For example, research in the field of cartilage regeneration to restore damaged articular cartilage or replace it with an adequate surrogate is advancing annually. The potential benefits in preventing progression of arthritis and the subsequent reduction in need to replace diseased joints has significant implications for both humans and animals.
3.1.3 The opportunities for regenerative medicine are strongly influenced by the economic value of the potential market. There is a compelling economic case for considering human and veterinary regenerative medicine together as this increases the size of the available market, thus making investment in new products more attractive. There are upwards of 140 million dogs and cats in the United States [4], and approximately 16 million in the UK [5]. UK horseracing also contributes more than £3.4 billion to the economy each year, with some of this money already being targeted for research through the Horseracing Betting Levy Board [6].
3.1.4 The potential veterinary market for regenerative medicine products is significant, and further aided by the widespread availability and increased uptake of pet insurance. Pets commonly suffer from similar chronic degenerative diseases to humans, including arthritis, cancer, cardiovascular disease and diabetes. For example osteoarthritis affects 1 in 5 dogs over 1 year old [7]. Several commercial veterinary stem cell companies have been launched in the UK, including Vet Cell Bioscience Ltd and, more recently, Cell Therapy Sciences (www.celltherapysciences.co.uk) and Stemcellvet UK (www.stemcellvet.co.uk).
3.1.5 The increasing need for regenerative medicine products to treat the aging human population, combined with a sizeable veterinary market, makes a compelling economic case for a One Medicine approach to investment in regenerative medicine research and development.
3.1.6 In addition to the clinical market in veterinary patients, studies of naturally occurring disease in animals represent an important research opportunity for regenerative medicine. The inclusion of animal studies greatly increases the potential pool of research subjects in which candidate therapies can be evaluated. Clinical trials of animals with naturally occurring conditions that are similar to human conditions could give crucial insights into novel regenerative medicine therapies [8-10]. For example, the use of mesenchymal stem cells (MSCs) to treat tendon damage in horses has been successfully translated into an ongoing clinical trial on the use of MSCs in human patients with Achilles tendon injuries, a clinical problem that has been notoriously difficult to manage using standard surgical approaches [11].
3.1.7 The rationale for studying natural (or ‘spontaneous’) diseases and disorders in animals is to develop a translational bridge between preclinical data derived from normal laboratory animals and clinical trials in human patients. Veterinary clinical trials cannot replace carefully controlled clinical trials in humans, since efficacy in a human disease setting can only be determined from clinical studies in patients with the disease. However, evaluation of candidate therapies in veterinary clinical patients makes sense from ethical, scientific and financial perspectives [12]. The use of naturally occurring disease eliminates the need to use purpose-bred research animals, and is therefore in line with the concept of “reduction” that is espoused in Russell and Burch’s 3Rs [13].
3.1.8 Veterinary clinical trials can be extremely effective in confirming the suitability of novel routes of treatment delivery and the effectiveness of dosing. They are also extremely valuable in confirming the selectivity and the safety of the proposed treatment, making it possible to identify and mitigate potential unwanted, “off-target” effects. As stated in a recent review on the use of stem cells in veterinary clinical trials [14]:
'It follows that companion animal research offers a preclinical window into the feasibility, safety, and effectiveness of therapies in the context of a naturally complex, if not hostile environment that more accurately reflects the human condition. Companion animal studies can blaze new trails in regenerative medicine. These studies can lead us through novel pilot feasibility (Phase 1), safety and early efficacy (Phase 2), and major efficacy (Phase 3) studies which are too early or too expensive to attempt in human patients. These studies will inform human trials at various levels of comparable development, following the example by which canine cancer treatment trials have effectively done so for several years.’
3.1.9 Similar to ageing humans, naturally occurring diseases in animals are often complicated by co-morbidities, some of which require that the patient receive additional medications. The use of natural disease models to study regenerative medicine therapies could therefore also offer enhanced insights into areas such as potentially deleterious drug interactions, management of common comorbidities, toxicology profiling and dose scheduling, which are so far lacking in standard clinical drug development strategies.
3.1.10 The economics of human clinical trials are now such that failure in pivotal, phase 3 clinical trials can deal a terminal blow to a drug or biologic discovery programme. One of the key drivers for the high overall cost of newly approved therapies is the fact that so many candidate therapies fail to make it to market. Recent data indicate that only around 12% of drugs successfully transition from preclinical trials to an approved clinical product, with an overall average total development cost of over $2.5 billion per approved drug [15]. The most common reasons for failure in late-stage clinical trials are a lack of efficacy or identification of unanticipated side effects in patients. Veterinary clinical trials can save the pharmaceutical industry considerable financial resource by providing a more representative test environment for evaluating therapies, including ‘genetically enhanced stem cells, transdifferentiated (lineage specific) stem cells, induced pluripotent stem cells and derived progeny, organoids, 3D scaffolds impregnated with stem cells, extracellular vesicles and extracellular RNA [14], as well as theranostics and personalised therapies. Potential applications for stem cell therapies include osteoarthritis, intervertebral disc regeneration, inflammatory bowel disease, dilated cardiomyopathy, Lafora’s disease and diseases that resemble Alzheimer’s disease [14]. It is notable, for example, that advances in biological compounds to encourage skin growth onto metal in limb amputation prostheses have already been achieved for several years in clinical veterinary patients, and developments are underway in relation to neural-interface potentially with stem-cell augmentation to propagate neural signals from a limb amputation stump to a fully neurally-integrated bionic limb. Such advances clearly demonstrate the potential benefits of establishing a platform for collaboration between clinical researchers across veterinary and human medicine.
3.1.11 The Humanimal Trust emphasises the importance of the opportunities presented by the study of spontaneous disease in companion animals for both human and animal health. As Hoffman and Dow [14] point out:
“Unleashing companion animal studies onto the field of regenerative medicine is an exciting paradigm that may increase our understanding of the complexity of molecular targets in spontaneous diseases, and bring therapies to humans in a more efficient manner, reducing the cost burden and failure of future human clinical trials using comparable cells and technologies.”
The UK has a very strong research base in veterinary science, led by its eight veterinary schools and government laboratories. The UK schools and their clinical networks of collaborating veterinary practices are ideally positioned to undertake prospective clinical trials on new therapies, including those related to regenerative medicine. In addition to a robust clinical caseload, the schools are equipped with specialist imaging and diagnostic equipment that is needed to monitor clinical outcomes in these patients. To truly address One Medicine effectively, there should be continued and expanded investment in veterinary centres of clinical research excellence in which diagnostic equipment is on a level playing field with those available in the academic medical centres. For example, the evaluation of new cartilage repair strategies requires the use of clinically relevant outcome measures, such as serial MRI evaluations. The investment in equipment and infrastructure would be expensive initially but it would enable researchers to identify and validate clinical outcome measures that could then be used in subsequent human clinical trials. Other key issues that would ideally be aligned across this network of veterinary clinical trials centres include electronic medical records systems and biorepositories for archiving veterinary clinical tissue specimens.
Recommendation 1: Regenerative medicine research should be progressed within a One Medicine approach, which provides the best possible framework of opportunity for the UK.
Recommendation 2: The potential for clinical trials in veterinary patients to accelerate research and identify therapies that are more likely to be effective in subsequent human clinical trials should be supported by appropriate resourcing, and embedded within research and innovation practice.
3.2 The regulatory systems involved, their effectiveness and ease of use
3.2.1 Our response in this section will focus on the regulatory processes that relate to the use of animals in biomedical research.
3.2.2 The use of purpose-bred animals for research involving ’regulated procedures’ in animals is covered under the Animals (Scientific Procedures) Act 1986. While it is the Trust’s policy not to fund research involving the use of healthy, purpose-bred research animals, we recognise and accept the importance of preclinical animal studies in defining the safety and technical feasibility of new candidate therapies. Decisions as to exactly what animal studies need to be performed rest with the research team and study sponsor, with the guidance of the relevant regulatory agency. As stated by Mittra et al. in their study of regulatory and innovation pathways for cultured red blood cells [16]:
‘Animal testing continues to be held as a fundamental preclinical standard and developers of innovative products must consider early in the development process what regulators are likely to find acceptable as an appropriate animal study.’
Preliminary safety studies are usually performed in rodent models that are relatively inexpensive. For efficacy testing, large animal models may be recommended and these can be very expensive. For small companies, the financial obstacle may be overwhelming:
‘.. if regulators did insist on a large animal study [in addition to safety studies in a small animal model], and more extensive testing protocols for safety and efficacy … the time and cost could escalate substantially and pose a threat to the long term viability of the project…..This raises the question whether there is scope to rethink the role of animal studies in the preclinical requirements for some regenerative medicine therapies, and to give much greater weight to in vitro techniques, to provide innovators with a very clear and unambiguous route to first clinical trials’.
3.2.3 The Humanimal Trust contends that excessive costs are threatening the delivery of treatments to the clinic because regulatory hurdles are too burdensome. We strongly support a move towards the use of spontaneous disease models in the evaluation of the safety and efficacy of new regenerative medicine strategies, as long as it can be shown that the information gleaned from these studies will benefit humans and animals alike. It is the Trust’s position that for research under One Medicine the 3Rs should be expanded to the 4Rs to reflect this reciprocity of knowledge transfer.
3.2.4 The use of veterinary clinical patients in research presents a challenging scenario for regulatory oversight, in part because of the decentralised nature of veterinary clinical work, which is performed in primary care settings, private referral practices and academic centres alike. Additionally, while standard veterinary procedures can be performed under the Veterinary Surgeons Act 1966, procedures that are inconsistent with the prevailing “standard of care” fall outside the purview of the Act and require additional oversight. For example, the administration of a new pharmaceutical or biological product for regenerative medicine may well be consistent with standards of care, but if additional, especially invasive, procedures are required to evaluate the efficacy of the treatment, these would be beyond the overview of the Veterinary Surgeons Act 1966 and would need to be reviewed under the Animals (Scientific Procedures) Act 1986.
3.2.5 In 2015, the Royal College of Veterinary Surgeons and the British Veterinary Association published draft guidance on how to conduct research studies involving veterinary clinical patients [17]. These guidelines recommend the use of a local ethical review process, either within the clinical practice or in collaboration with an academic veterinary medical centre. We see these guidelines as an essential foundation for the oversight of veterinary clinical trials and a core component of an integrated One Medicine strategy. We support investment in the creation of a network of veterinary clinical trials centres to serve as academic leads for studies under One Medicine.
3.2.6 The Humanimal Trust would welcome the opportunity to take part in discussions about the role of animal models, and evidence from studies of naturally occurring disease in animals, in the future of regenerative medicine research. We would be prepared to lead elements of this process.
Recommendation 3: Any future strategic re-evaluation of the use of animal models in regenerative medicine research should involve input from specialists with expertise in both human and veterinary medicine.
Recommendation 4: Existing regulatory processes should be refined to better allow for the contribution of volunteer animal research to trials of regenerative medicine treatments for humans.
Recommendation 5: Reciprocity should be the guiding principle that informs the use of animal subjects in the development of research initiatives in regenerative medicine, so that the outcomes of research have positive impact for both animals and humans at the same time.
3.3 The arrangements for researchers and manufacturers in the remedial medicines/ advance therapies field to be able to innovate and secure innovation funding and support
3.3.1 Although the Trust recognises the importance of developing streamlined and integrated pathways for stimulating, supporting and commercialising innovation, we elect to forego detailed comment on this section in the interests of keeping our submission to a reasonable length.
3.4 The case for a government-approved Regenerative Medicines Strategy
3.4.1 It is our strong view that any UK Strategy for regenerative medicine in the UK must cover research and developments in both human and animal medicine. This is the only way that the full opportunities of available interdisciplinary knowledge and potential market can be realised. The Humanimal Trust spans both human and veterinary medicine, and we are therefore uniquely placed in this respect to contribute to the development of such a Strategy, and would welcome the opportunity to do so.
References
Rev Sci Tech. 33:453-464.