Document(s): 

regenerative medicine project funded by EC

final report with important conclusions

Italian Regenerative Medicine Infrastructure project in Italian and English

Canadian strategy for Regenerative Medicine

Japan new regulatory path for regenerative medicine products

UK House of Lords evaluation on regenerative medicine national strategy

German strategy for national regenerative medicine

New bipartisan USA regulatory proposal for regenerative medicine products

Japan international plan for regenerative medicine

External link: 

http://www.irmi.eu

Author(s): 

ITALIAN REGENERATIVE MEDICINE INFRASTRUCTURE

Year of publication: 

2016

FET Consultation - template FET Flagships

This proposal is submitted by Italian Regenerative Medicine Infrastructure (IRMI), an infrastructure organised by 9 Italian Universities (Turin Politecnico and University, Milan, Trieste, Genova, Modena, Bologna, Pisa and La Sapienza Rome), 5 Research Organisations (IOR Bologna, CNR Rome, CNR Naples, ISMETT and RiMED Foundation Palermo) and 7 private societies (GVM, ABMedica, ABTremila, Genomnia, Igea, Chiesi Farmaceutici and UPMC Italy).The strategic goal of IRMI is to create an infrastructure that will facilitate the exchange of knowledge between the different disciplines that underlie regenerative medicine products. Thank to this strategy, will be encouraged the development of new products on the territory for the advanced therapies, consequently increasing the international competitiveness of Italian Biotechnology sector for products derived from human tissues and cells.

More specifically, the IRMI is supporting the growth in the scientific-industrial sector producing:

1. the development of existing biobanking structures, offering new opportunities for storage of both autologous and allogeneic cells and tissues;
2. the strengthening and rationalization of cell manipulation structures, working in a coordinated and collaborative organisation, following the example of the PACT created in the USA by National Lung, Heart and Blood Institute, also providing all the necessary services for the organization, management and analysis of clinical trials and the interface with authorities, both for clinical trials and for the marketing authorization of drugs.
3. the development of bioprinting through collaboration with Italian Digital Biomanufacturing Network (IDBN), a scientific network with European diffusion. 
4. the creation of support structures for research and industrial development of advanced therapy products, including translational clinical research;
5. research and development of new human tissues derivatives, 3D printed electro-spun biological membranes, biomatrices and biocompatible polymers, cellular products based on progenitors with high differentiation capabilities derived from iPS and active molecules able to regulate the proliferation and differentiation of stem cells, advanced therapies medicinal product based on autologous corneal epithelium
6. new professional figures for biobanking, the manipulation of cells and tissues, the research and development of biomaterials, the application of converging technologies, the bioprinting, the management of clinical trials and regulatory aspects of advanced therapies.

What is the challenge and the vision?

Regenerative medicine

Regenerative Medicine is considered a novel frontier of medical research. The regeneration of body parts is a rather common phenomenon in nature; a salamander can regenerate an amputated limb in several days. Humans have this ability as well, but they lose it over the years: a severed fingertip can regenerate until 11 years of age. The human regeneration potential was well-known also in ancient times, as demonstrated by the myth of Prometheus.

Some European countries have developed a national strategy on regenerative medicine and, first of all, UK has published documents (part of this proposal derives from them), built a Catapult Center and defined UK as leader country in this field.

There are substantially three approaches: cell-based therapy, use of engineered scaffolds and the implantation of scaffolds seeded with cells. diseases Therefore, medicine is facing with pressing problems which require an evolution of medical treatments and the regeneration of damaged tissues, “the fourthR”, could revolutionize modern medicine, offering the way to cure, rather than merely treat symptoms.

Regenerative medicine is not one discipline, but covers a number of emerging and sometimes related fields. At its simplest it can be defined as a therapeutic intervention which “replaces or regenerates human cells, tissues or organs, to restore or establish normal function”.

Regenerative medicine deploys small molecule drugs, biologics, medical devices and cell-based therapies. However, the term is more colloquially used to mean advanced therapies based on cells, tissue engineering, developmental and stem cell biology, gene therapy, cellular therapeutics and new biomaterials (scaffolds and matrices).

Although not “regenerative”, there are also promising associated cell-based technologies such as the use of cells for non-regenerative therapies, stem cells for drug discovery and toxicity testing and other associated tools and technologies.

There are a number of key trends in healthcare today that will impact on the development of regenerative medicine, and provide an indication of the significant role the field could play in the future of healthcare:

· There are strong pricing pressures from public healthcare payers globally as Governments try to reduce budget deficits. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the European economy as a whole.

· While pharma companies remain attracted to the “blockbuster model” where products are developed to work across the broad patient population they are also beginning to develop medicines for much smaller groups of patients (e.g. stratified medicines and targeted therapies) where their genetic predisposition makes it highly likely that the medicine will be effective.

· The expected ageing of the European population will continue to boost market opportunities for regenerative medicine products as well as increase cost pressures on healthcare providers. There are also large and growing unmet medical needs for example neurodegenerative diseases (including Parkinson’s disease), stroke and heart failure that currently have no significant therapeutic options and are therefore only managed palliatively.

· The increase in obesity and the accompanying rise in type 2 diabetes means that there are growing markets in related products such as advanced wound-care for diabetic ulcers and cardiovascular devices.

There are seven key areas where progress was expected in regenerative medicine in the next five years:

1. Induced Pluripotent Stem Cells: In the next five years, the efficiency of generating iPS cells and the understanding of the mechanisms of cell programming and reprogramming is likely to improve. However, there are ongoing concerns over safety presenting a significant hurdle before we will see significant progress towards therapies. In the shorter term the use of iPS cell-technology will have highest impact in establishing models of disease for research into pathological mechanisms and drug development and screening.
2. Direct reprogramming of differentiated cells has already been demonstrated, as explained earlier and the ability of certain genetic factors to dominantly specify cell fate has been known for some years. However, recent advances have convinced respondents to our call for evidence that this technology is likely to progress significantly over the next five years. Direct reprogramming has a number of major advantages including the potential to produce therapies based on small molecules/biologics for in vivo reprogramming. This method would also produce cell therapies without the need to use a pluripotent cell stage, thus greatly reducing the risk of rogue cells leading to uncontrolled cell growth or inappropriate differentiation into an unwanted cell type.
3. Ongoing trials of adult stem cells which provide the basis for the majority of current commercial research in stem cell therapies, mostly in the area of bone/cartilage repair and wound healing. Other areas under development include blood-related therapeutic research including T cell immune modulation and cord blood.
4. Gene therapy and especially genetically modified cells as therapies (i.e. vehicles for gene therapy delivery) will gain growing prominence – respondents felt that these technologies, that were previously “stalled” due to the state of the science, could now be progressed due to recent advances in other areas. There is also potential to use cells as vehicles to deliver other interventions such as cellbased cancer vaccines.
5. Safety and efficacy data from stem cell derived therapeutics: in the USA clinical trials using human embryonic stem cells have now started for acute spinal cord injury (Geron), Stargardt’s disease (ACT) and age-related macular degeneration (ACT). Clinical applications using human ES cells will likely be focused on agerelated and ‘orphan’ applications initially.
6. Cord Blood: traditionally used to supplement the supply of bone marrow, umbilical cord blood is increasingly proving to be as good as, and in some cases better, for unrelated donor transplant. This is mainly due to the fact that research has proven that cord blood units do not have to be identically matched to be transplanted into an individual. This means that a wider range of patients can be treated. The relatively easy access to cord blood and its availability make it a valuable resource for regenerative medicine. Also, in the US especially, it is increasingly seen as route to provide blood stocks as a contingency the increasing threat of emergency situations.
7. Translational science and technology: regenerative medicine will require new science and technology to enable successful delivery and application, particularly from physical sciences and engineering. This will include new imaging and diagnostics; regenerative scaffolds for delivery and to support tissue function and cell manipulation; as well as manufacturing monitoring and selection technologies. Related research on translational sciences and technologies is essential if impact and economic benefit is to be realised from stem cell science.

Priorities for achieving widespread therapeutics

As the first isolation of human embryonic stem cells only took place in 1998, it is not surprising that therapies derived from embryonic stem cell lines (or iPS first discovered in man in 2007) are used in widespread clinical trials yet. Therapies derived from embryonic, iPS cell lines or from foetal stem cell lines are likely to develop at different rates depending on the specific medical indication, risk-benefit to patients and the technical hurdles that are likely to be encountered in their manufacture and in the clinic. Although the very first embryonic stem cell trials in patients have commenced (i.e. Geron- spinal cord injury) it is unlikely that stem cell therapies will immediately lead to outright cures. Instead a gradual emergence of efficacy over a few generations of cell-based products is a more realistic expectation. Thus both the discovery science and translational science will be pivotal in making the necessary incremental steps to unlock the full potential of cell therapies.

Regenerative medicine interventions will also require advanced diagnostics and stratified approaches, supported by advanced imaging research. Multidisciplinary work on tissue and cell monitoring, labelling, sorting and signalling is also needed, alongside more research into the regenerative repair processes.

Researchers and companies certainly need to be encouraged to look at these issues early in the development of a therapy.

The field faces challenges in key areas such as:

1. Safety: It must be established that stem cell derivatives are suitably safe in relation to the risk of tumour formation or production of unwanted cell types in the body. As already mentioned, these concerns are thought to be particularly pertinent for induced pluripotent stem cells, where we need a better understanding of reprogramming and the epigenetic read-through from the donor cell’s chromosomes. We also need to know how to ensure genetic stability as human ES cells and iPS cells undergo multiplication and/or differentiation, along with how different culture methods influence this.
2. Regulatory Science and standardisation: scientific methodologies and platforms are needed that assist the community in obtaining the data necessary to meet regulatory requirements and ensure product quality, safety and efficacy. Specifically, regulatory standards need to be developed in an ongoing process alongside, and in communication with, scientific and industrial efforts.
3. Imaging and Monitoring: Dedicated efforts in imaging and other techniques for monitoring cell behaviour is necessary. This was thought to be particularly important given the considerable heterogeneity in the way individual cells respond to behavioural cues. In particular in clinical trials, the variation in cell behaviour must be shown to be within tolerable limits across multiple clinical sites to gain regulatory approval in particular for Phase III trials. For example it will be important to monitor where cells migrate to following administration.
4. Manufacturing: the need to manufacture viable (living) cells for regenerative medicine application poses significant challenges. Achieving a controlled and characterised manufacturing process for cell based therapies requires the development of new technologies, tools and techniques.
5. Biomaterials, scaffolds and matrices Many applications in regenerative medicine require scaffolds and matrices for delivery or to produce a functional regenerative repair, example include organs, tissues which require immediate functionality such as cardiovascular system. Multidisciplinary research which brings together different research communities is needed
6. Animal Models: We were told that there had been little research focused on appropriate animal models, which are necessary for pre-clinical trials and can be predictive of safety and efficacy outcomes. There is a perceived need for improved animal models to allow for the functional assessment of human cells without the risk of rejection.
7. Scale up/manufacture: we would have to bridge the detail of biological science and bioprocess/biochemical engineering/manufacturing technology to deliver scalable production processes that deliver particular therapeutics that are safe, effective and at an appropriate cost that would facilitate their widespread adoption by healthcare providers.
8. Immunogenicity: A key issue for some regenerative therapies is the potential for rejection of cell transplants by the patient. This area needs further research with respect to inducing immune tolerance and developing a new generation of immunesuppression drugs specifically for cell therapies. The length of immune suppression also varies by whether the introduced cells are transient in nature, or become engrafted. The latter would currently require long-term immune suppression.
9. Cell Viability: Cell viability, and what constitutes it in vitro, was highlighted as another area where we are lacking knowledge. Linked to this is whether we are able to maintain unstressed cells with high therapeutic potential, that will not die, or form un-wanted derivatives. These factors will impact the ability to manufacture, store and distribute potential cell therapies. This is one of the critical “associated issues” for translation and commercialisation.

New Japan laws facing Regenerative Medicine innovation

Japan’s new regenerative medicine legislation is actually two separate laws. Law No. 84/2013 amends the Pharmaceutical Affairs Act, renamed the Pharmaceutical and Medical Device (PMD) Act, and pertains to the commercial development of regenerative therapeutics. Law 85/2013, the Safety of Regenerative Medicine Act, deals with clinical and physician-led research.

The PMD Act defines regenerative medicine as cultured or processed human or animal cells, or transgenic cells, used to reconstruct, repair, or form structures or functions in the human body, or to treat or prevent human diseases. Gene therapies also are covered by that act, providing they are at least equivalent to cellular and tissue-based products and meet either the FDA definition of gene therapy or the EU definition of advanced-therapy medicinal products.

This law speeds therapeutics to market by allowing conditional marketing authorization. A 20-person trial that shows safety and is predictive of efficacy is sufficient to get conditional approval for seven years, without needing placebo trials. Efficacy will be determined by the market. The new regulations dramatically change the pathway toward revenue. During the seven-year conditional approval period, companies are expected to continue filing data. By the end of that period, they must either apply for final marketing approval (the equivalent of a BLA [Biologic License Application]) or withdraw the product.

USA Senate is now discussing and Bipartisan approving a new law on regenerative therapies similar to the Japanese one.

Regenerative Medicine: need of an European common approach (European Infrastructure or Flagship)

The EU-funded ʹRegenerative medicine in Europe: Emerging needs and challenges in a global contextʹ (REMEDIE) project examined the economic, political and bioethical implications for Europe of near-term and future global developments in this field.Europe's RM industry was found to be highly diversified, although its largest sector is dedicated to cell therapy firms. These firms are split almost equally between therapies based on stem cells and therapies based on somatic cells. The majority of these firms, however, are small and financially vulnerable.REMEDIE identified diverse regimes regulating the ethical boundaries of biomedical research activity and commercialising biomedical innovation on a global basis. These differences have an impact on the research environment and its financing and translational activity and the use of intellectual property rights in the course of biomedical research.RM is often challenged on moral and political grounds, particularly with regards to the legal provisions surrounding patenting. In fact, the issue of whether cell therapies will be patentable in the EU appears to be an obstacle to investment. The global picture of RM suggests that the United States will rapidly establish an unchallengeable dominance. This is based on higher levels of funding available including venture capital as well as having the single largest market for health technologies.REMEDIE has suggested that dedicated funding, stronger links with health technology assessment agencies and the creation of regionalnetworks to promote scientific and clinical collaboration will aid the competitive position of Europe in the RM bioeconomy. RM forms part of a global value chain of innovation..

The above considerations confirm the need of an European common approach to the new

• scientific field,
• healthcare market,
• patients care.

Various European countries have presented and in act their initiatives in Regenerative Medicine, but a common European initiative is absent.

An European Regenerative Medicine Catapult Initiative needs to be urgently activated, if Europe wishes to be an actor in this emerging field.