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Updated: Jul 20, 2021

Opinion Article | Open Access | Published 15 June 2021


The future of medicine - cell and gene therapy


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Foreword | Introduction | References | Author Information


Foreword


While advanced therapeutic medicinal products (ATMPs) have started to gain momentum in recent years, cell and gene therapy is not new, having undergone decades of trials and regulatory scrutiny.


The success of clinical data and eventual approval of multiple CAR-T therapies in the area of blood cancers, has led to an uptick of interest in the field. This interest has resulted in many large pharmaceutical companies turning their attention to innovations coming from small ATMP producers (academics), buying up patents/inventions as promising candidates for similar applications.


The next expected paradigm is that this success will lead to a trampoline effect for ATMP developments into solid tissue cancers or genetic disease affecting increasingly large organs and human biological systems such as the liver, lungs etc. It has already been shown that gene therapy applications for certain ocular diseases can also be very effective, ut producing a gene therapy for larger organs (at the right strength/volume/presentation) is likely to be the next challenge.


There are also advances in the form of bioinformatics, which mean some of these autologous ‘personalised medicines’ (i.e. same patient cells but transformed with a generic gene therapy) could start becoming ‘personalised-personalised medicines’ (i.e. same patient cells but transformed in a custom way based on bioinformatics dependant on the patient-specific gene mutation). However, for the latter to achieve its potential, a robust regulatory framework around decentralised/point of care manufacture will be key.


Post-Brexit regulation


When the UK voted to exit the EU in 2016, there were fears about what this would mean for the UK life sciences sector, which had become strongly embedded within Europe.


Now, several months post-Brexit, the long-term impact of the break is still unclear.


A positive result has been the localised (MHRA rather than EMA) vaccine applications. Those in the industry will know that localised approval was still possible when UK was part of EU, however the agility shown by UK regulators during the height of the pandemic may not have been the case pre-pandemic.

Nevertheless, Brexit is not without challenges; the importing of finished products into EU and the associated batch testing and QP certification is still a concern.


In general, the supply chain for raw/starting materials has become more cumbersome. This could possibly see companies operating on a ‘just in time’ basis in terms of material holding, adding risk to continuity of supply/ongoing manufacturing.


This is somewhat exacerbated at the moment by the increased demand due to the pressure on the industry from new COVID-19 vaccine/therapies.


Lessons from COVID-19


Looking at the specific impact of the COVID-19 pandemic on ATMPs, for obvious reasons many clinical trials have had to pause recruitment, but it has become very evident that companies invested in ATMP research and production jumped into the fight against COVID-19, diversifying, adapting, collaborating, partnering, acquiring, to switch focus to vaccine production.


A huge amount can be learnt by the industry (and regulators) about the vaccine response, and the truncated timelines for product development of what are being shown to be world-changing medicinal products.


A new precedent has been set and the industry is engaged in serious discussion around how

to make under 12-months development nearer the norm, rather than the often-quoted 12 years

- not just for emergency vaccines, but also for life-changing treatments for smaller populations than a global pandemic.


A ‘lessons learnt’ exercise by all pharmaceutical companies that successfully navigated the pandemic (and regulators) could completely reshape how medicines are (or could be) developed.


With new ground opened for cell and gene therapy in the UK, I am confident ATMPs are the future of medicine and we hope you find this white paper not only insightful but also exciting!


Introduction


While cell and gene therapy (CGT), also known as advanced therapy medicinal products (ATMPs) has been around for decades, advanced therapies were introduced into the EU regulatory framework as a new classification of biological medicinal products in 2003.


The regulatory framework is established principally in Directive 2001/83/EC, and a number of other Directives and Regulations (e.g., on clinical trials, manufacturing, orphan medicinal products, paediatric research, and ATMPs) establish its principles.


In late 2008, Directive 2001/83/EC and Regulation (EC) No. 726/2004 (on procedures for human medicinal product authorisation and supervision within the EU and EEA) were amended by a specific Regulation on ATMPs: Regulation (EC) No. 1394/2007. This regulation (which known as the ATMP regulation) defines ATMPs as three specific types of medicinal products, including gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (SCTMPs), and tissue-engineered products (TEPs).


It’s only in recent times that it has gained momentum for having the power to revolutionise the future of medicine and how we treat various chronic and life shortening illnesses that had previous been seen as incurable.


ATMPs are a fast growing field of novel therapies that are based on genes, tissues or cells that hold promise as treatments for a variety of previously untreatable and high- burden diseases. The main ATMP therapeutic areas are oncology and regenerative medicine, particularly in the field of cardiovascular conditions and haematology. ATMPs offer revolutionary new prospects for the treatment of diseases or injuries, such as skin in burns victims, Alzheimer’s, Parkinson’s disease and cancer or muscular dystrophy. This offers huge potential for the future of medicine, which will allow healthcare providers globally to shift from a paradigm of illness management to one of cure.


Research from 2019, revealed that there were over 930 companies making advancements within the CGT arena¹ and projections by BIS Research has estimated the value of the global industry to be worth over $12 billion by 2021².


ATMPs are considered the therapies of the future but there are a myriad of not only legal but also ethical obstacles on the pathway from lab to patient, from; clinical trials and recruitment of patients, lack of investment, to the obscure regulations that have potential to slow the commercialisation of these products.


There are many different players in the CGT arena, most research and development of ATMPs is conducted by academics, academic spin-offs, not-for-profit organisations, and SMEs. Until recently, only a few larger pharmaceutical companies have engaged in the investigational phases of ATMP development, due to the perception that the early investigational phases of the development of ATMPs is a high-risk activity³.

Typically, SME’s focus on production to the larger pharmaceutical and biotechnology companies, but with many players in the market including investors and the outsourcing partners with sometimes differing goals, harmonisation across regulatory aspects of the industry landscape is needed.

In this paper, we focus on the opportunities inherent in Europe, highlighting the landscape in the jurisdictions where Fieldfisher are leaders in supporting clients in this area – UK, Ireland, France, Italy

and Spain. We also take a multifaceted view at the different areas of law that come into play, focusing on regulatory and commercialisation.

We are on the cusp of the future of medicine and research shows that those companies that made strides to pivot their business focus to gene and cell therapy are reaping the rewards. Fortunately, the industry still has an abundance of space for new players to position themselves to enter and Fieldfisher are well equipped to help businesses at all stages to unlock this opportunity.


What are ATMPs?


ATMPs are medicinal products that are prepared industrially or manufactured by a method involving an industrial process.


Over time, ATMPs have shifted the traditional strategy of “one-size fits all” to a more personalised medicinal approach as cell therapies, for example, can be allogeneic (universal) therapies where the therapy is dependent on a single source of cells (donor) to treat several patients.


To date many of the approved cell therapies have been autologous, where the cells are derived from the patient, modified, expanded and used to treat the same patient⁴.


There are three main types of ATMP:


1. Somatic cell therapy products consist of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered. Somatic Cell therapies include the use in humans of autologous (coming from the patient their self), allogeneic (coming from another human being) or xenogeneic (coming from animals) somatic living cells, the biological characteristics of which have been substantially altered as a result of their manipulation to obtain a therapeutic, diagnostic or preventive effect through metabolic, pharmacological and immunological means.


2. Gene therapy medicinal products contain an active substance consisting of a recombinant nucleic acid used in, or administered to humans to regulate, repair, replace, add or delete a genetic sequence, with the therapeutic, prophylactic or diagnostic effect relating directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.


3. 3. Tissue engineered products contain or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue. A tissue- engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or non-viable. It may also contain additional substances, such as cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or matrices.


In addition, some ATMPs can be referred to as Combination ATMPs. Combination ATMPs incorporates as an integral part of the product, one or more medical devices or implantable medical devices as well as a cells or tissue component. The cells or tissue component of the product must contain viable cells or the non-viable cell or tissue component of the product must be liable to act on the human body

with action that can be considered as primary to that of the device.


The European landscape


Unsurprisingly, the CGT market is dominated by North America, with 60% market share⁵; Europe follows but has a steep hill to climb. So why the disparity between North America and Europe?


There are currently only 10 ATMPs available within the European Union⁶, despite there being in excess of 386 current clinical trials being conducted across the EU. So, why with all the early stage activity are

approved treatments so low?


In an article by Labiotech.eu, the journalist alludes to the youth of the European market⁷. In another article, the same publication asserts that EU regulations are what has stagnated the CGT market in Europe⁸.


Once a drug is granted marketing authorisation within the EU, it is then approved across the EU for use.


However reimbursement - which is arguably the determining factor in the commercialisation of CGT - is still decided at a national level⁹.

Additional practical challenges are the limitations in the application of existing regulation and GMP guidelines to smaller scale batch manufacturing.


Many of the current regulations/GMP guidelines in place are still tailored to large volume/batch manufacture of conventional small molecules. This can be restrictive for some ATMPs where a batch is for a one patient dose.

This presents a conundrum in that while the move to decentralised or point of care manufacturing may be productive, overcoming these more dated GMP guidance lines is likely to be a challenge.


For example, Qualified Person (QP) certification of an autologous, one unit batch within a hospital setting, could prove cost prohibiting.


Below we look at some of the key CGT hotspots across Europe.


United Kingdom


The number of ATMP clinical trials in the UK continues to increase year-on-year, with 154 trials reported as ongoing in 2020, indicating more than a 20% increase from 2019. This is representative of approximately 12% of all ATMP trials in progress globally.


Gene therapy trials currently account for 70% of the ATMP clinical trials in the UK, somatic-cell therapies account for approximately 20% of trials, whilst tissue engineered therapies make up the remaining 10%.


In 2020, there were 26 UK GMP manufacturing facilities and nine licenced ATMP products approved for use. Total financing for UK ATMP companies between the years 2018-2020 was £1.7bn contributing to over 3,000 people employed in the sector¹⁰.


Alongside France, the UK leads in Europe for CGT but its potential has not been completely untapped. There is a real need to streamline the authorities that oversee CGT, for instance both the Medicines

and Healthcare products Regulatory Agency (MHRA) and the Human Tissues Authority (HTA) are competent authorities in the process.

Multiple regulatory authorities for CGT is a theme that can be seen across Europe.


However, there was a significant breakthrough for CGT in May 2021, when the UK’s first patient received gene therapy treatment Zolgensma®, reimbursed by the NHS. As highlighted earlier reimbursement is a critical issue in getting product to market.


In this particular case, Novartis, producers of Zolgensma® struck a deal with the NHS, offering a discounted price, becoming only the second medical treatment for children with SMA to be available on the NHS, since Spinraza® became available in May 2019. This is a good indicator to those in the CGT space that the pathway to market for innovative treatments is getting clearer.

Regulations and Licenses in the UK


In the UK, the MHRA is the competent authority for clinical trial authorisation for all medicinal products, including ATMPs and for UK manufacturers or importers of ATMPs whilst the HTA is responsible for regulating human tissues and cells intended for human application.


Establishments which import, export or store tissues and cells intended to be used as the starting material in the manufacture may require an HTA licence for these activities. A licence for processing may also be needed if the tissues or cells are processed prior to the commencement of manufacturing.


Examples of where this could apply would be the derivation of early cell lines or banks prior to establishing a Master Cell Bank (MCB), or the banking of tissue where the future use is unknown but could include the manufacture of an ATMP.


Moreover, to undertake a research study involving gene therapy, embryonic stem cell therapy, the therapeutic use of genetically modified stem cells, or therapeutic xenotransplantation, researchers may also need to apply to an NHS Research Ethics Committee (REC) for approval prior to commencing studies. The Gene Therapy Advisory Committee (GTAC) is the UK national REC for gene therapy clinical research according to regulation 14(5) of The Medicines for Human Use (Clinical Trials) Regulations 2004.


There are two ways in which unlicensed ATMPs can be made available in the UK

- namely under the Hospital Exemption or the ‘Specials’ schemes. Manufacturers need authorisation from the MHRA in order to use either scheme.

A Specials Licence (MS) is needed for the manufacture and supply of unlicensed ATMPs for human use outside of clinical trial whilst cell or gene therapies used in clinical trials must be manufactured under an MIA (IMP) Licence (Manufacturers Authorisation for Investigational Medicinal Products).


Post-Brexit


Now that the UK has left the EU, debate continues around how this will impact the future of CGT in the UK and new ventures in this area.


Since 1st January 2021, ATMPs have been regulated nationally in relation to Great Britain by the MHRA according to the same principles that previously applied. In Northern Ireland ATMPs will continue to be regulated according the European Medicines Agency’s (EMA) Centrally Authorised Procedure. This means that marketing authorisation applications for ATMPs will be assessed in accordance with the general provisions in place for the licensing of medicines, taking the specific requirements for this group of medicines into account¹¹.


Looking to the future at the manufacturing challenges for advanced therapies, the MHRA is developing a framework for point-of-care manufacture in 2021.

Despite the uncertainties that Brexit may have created in the sector, and as mentioned briefly above the Cell and Gene Therapy Catapult’s 2020 ATMP clinical trials database and report indicates that there has been in fact a 20% growth in the number of ATMP clinical trials in the UK since 2019.


One particular feature in the report is the increased number of commercially sponsored trials from 89 to 115 trials since 2019.


These figures suggest that international companies continue to invest in the UK as a location of choice for their ATMP trials, including those in late phase as commercialisation approaches. Businesses that continue to draw their attention to ATMP efforts will be setting themselves up to be ahead of positive change and benefit from inherent opportunities.


Focusing on the recent COVID-19 pandemic and the race to get a vaccine to the market we can see that some much needed agility has been applied to the UK CGT market. This is evidenced by the fact that the MHRA speedily approved the use of multiple COVID-19 vaccines (mRNA and Adeno vectors), whilst in contrast the EMA were arguably slower to act.


Will UK be the crown of Europe?


The UK is a world leader in the development of advanced therapies, contributing to the growth of the life sciences industry. There is a strong academic and commercial early-stage bioscience research base, in addition to access to clinical trial infrastructure and patients via the NHS.


Several UK government initiatives have helped foster innovation in the life sciences sector. For example, the Cell and Gene Therapy Catapult, supported by Innovate UK, was established in 2012 to bridge the translational gap between early stage research and late stage clinical development, and build a world-leading cell therapy industry in the UK. Furthermore, to help address manufacturing challenges, the MHRA is developing a framework for point-of-care manufacture due to be published at some point in 2021.


Challenges


At a meeting in June 2019, NHS England Accelerated Access Collaborative (ACC) identified three main issues in preparing for and securing sustained uptake of approved ATMPs¹²:


(a) Lack of clinical data about patient outcomes;

(b) Limited experience in implementing ATMPs in joint pathways between the NHS and industry; and

(c) Variation in the clinical areas and use of ATMPs.


The ACC has a mandate for accelerating the adoption of promising products, which are early stage (pre-NICE approval), and late-stage (post-NICE approval) and regulatory systems are being put in place for these innovations.


The ACC highlighted that greater clarity and agreement on patient numbers, placement on the patient pathway, diagnostic requirements, and co-location is a recognised requirement in the AMTP sector. The variation of manufacturing and implementation including workforce- training requirements and on-boarding for providers also presents significant challenges and without collaboration ahead of value assessment, there are risks of delay to adoption downstream.

To facilitate the uptake of advanced therapies the UK government has developed a network of Advanced Therapy Treatment Centres (ATTCs). Established in 2018, the ATTC network is a world-first, UK-wide system of Advanced Therapy Treatment Centres (ATTCs) operating within the NHS framework. These centres are supporting the opening of multiple ATMP clinical trials in a range of diseases across the country, and are developing and sharing best practice with other hospitals to increase adoption of ATMPs across the UK.


Collaboration between industry and academia is vitally important in this sector area. For instance, The Advanced Therapy Manufacturing (Good Manufacturing Practice (GMP)) Platform at the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London is a research platform designed the production of ATMP clinical studies, and early phase clinical trials.