As healthcare moves towards personalised and precision medicine,[2] cell and gene therapies (CGTs) have emerged as cutting-edge and paradigm-shifting tools that offer the potential to not only manage but cure life-threatening diseases, in some cases with just a single dose. 

Gene therapy involves the transfer of genetic material, usually in a carrier or vector, and the uptake of the gene into the appropriate cells of the body. Cell therapy involves the transfer of cells with the relevant function into the patient[3]. Some therapies combine both cell and gene technologies, such as CAR-T immunotherapy, which is a cell-based gene therapy revolutionising how we treat various cancers. 

The CGT landscape is rapidly evolving and allowing us to treat an increasing range of diseases, thanks to continual advancements in science and technology. The Alliance for Regenerative Medicine's August 2024 Sector Snapshot highlights significant milestones in CGTs during the last year[4]. Notable recent marketing authorisations include the world’s first CRISPR-Cas9 gene-editing therapy for sickle cell disease and beta-thalassemia (exagamglogene autotemcel), approved by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) in November 2023[5], and the second gene therapy for haemophilia B (fidanacogene elaparvovec-dzkt), approved by the US Food and Drug Administration (FDA) in April 2024 – the latest CGT to enter the market. Seventy-six CGTs have been launched globally as at the end of 2023, more than double the number ten years ago[6].

While CGTs benefit from increasing R&D investment and accelerated regulatory approvals to help get them to the patients who need them the most, these innovations challenge existing regulatory and market access frameworks, creating hurdles to timely patient access. Are the regulatory frameworks able to evolve quickly enough to keep pace with CGT advancements? 

Development: regulatory framework and clinical trials

Medicines using substances of human origin

CGTs use living cells and genetic material, which introduces unique complexities in their development. Both in the EU and in the UK, specific regulations apply to the use of human tissues or cells as starting materials for medicinal products.

In the EU

In the EU, the donation, procurement, and testing of substances of human origin are primarily governed by Directive 2004/23/EC (Tissues and Cells Directive) and Directive 2002/98/EC (Blood Directive), both of which will be replaced by Regulation (EU) 2024/1938 (SoHO Regulation) starting from 7 August 2027. 

Medicines for human use based on genes, tissues, or cells, are classified as ‘advanced therapy medicinal products’ (ATMPs). Regulation 1394/2007 (ATMP Regulation) establishes specific rules concerning the authorisation, supervision, and pharmacovigilance of ATMPs, which fall into three main categories:

• Gene therapy medicines;
• Somatic-cell therapy medicines; and
• Tissue-engineered medicines.

Companies developing an ATMP can request scientific advice from the European Medicines Agency (EMA), which provides recommendations within 60 days. This process is critical for determining whether a medicine qualifies as an ATMP and, if so, identifying the applicable regulatory requirements and quality standards.

In the UK

In the UK, the use of human tissues or cells as starting materials for medicinal products is governed by the Human Tissue (Quality and Safety for Human Application) Regulations 2007 (HTR 2007). Two authorities oversee compliance: (i) the Human Fertilisation and Embryology Authority (HFEA) for gametes and embryos, and (ii) the Human Tissue Authority (HTA) for other tissues and cells. If a human embryonic stem cell line is derived, a sample must be deposited in the UK Stem Cell Bank.

Among other things, the HTR 2007 establishes a licensing regime requiring that procurement and testing of human tissues or cells for ATMP manufacture can only be done by licensed establishments or individuals/organisations under a third-party agreement with a licensed establishment.

Testing cell and gene therapies (CGT)

In the EU

As for all medicines, the testing and manufacturing of CGTs must meet strict regulatory standards in the EU: 

• Non-clinical safety studies must adhere to Good Laboratory Practice (GLP) and are subject to local regulations;
• Clinical trials must adhere to Good Clinical Practice (GCP) and are governed by Regulation (EU) 536/2014 (Clinical Trial Regulation); 
• Manufacturing must meet Good Manufacturing Practice (GMP) standards to ensure consistent quality and is subject to Directive 2001/83/EC (Medicines Directive).

Due to the unique nature of CGTs, which involve the use of cells or tissues of human origin, additional requirements (particularly in GCP and GMP) apply to address specific safety concerns. For allogeneic CGTs (i.e., CGTs which utilise donor cells as opposed to the concerned patient’s cells), ensuring full traceability from donor to recipient is especially critical to ensure safety and accountability throughout the process.

Starting in January 2025, Regulation (EU) 2021/2282 on health technology assessment (HTA Regulation) will introduce harmonised methods for evaluating health technologies, including CGTs. This regulation aims to promote collaboration across member states and with the EMA by introducing AU-wide mandatory processes for joint clinical assessments and scientific consultations on medicinal products, ensuring high-quality evaluations of innovative therapies. From 2025, all oncology medicines and ATMPs (including CGTs) will be subject to common assessments. 

In the UK

In the UK, once the starting materials are available, the Human Medicines Regulations 2012 apply. Clinical trials for ATMPs must follow the Medicines for Human Use (Clinical Trials) Regulations 2004, with applications submitted to the MHRA. As of January 2022, all new trial applications must use the combined review service, offering a single application route and coordinated review by MHRA and the ethics committee.  All regulatory inquiries about ATMPs should be directed to the MHRA’s Innovation Office, which coordinates with other relevant bodies (HTA, HFEA, HRA). 

Once a trial plan and design has been completed, ATMP trials must be registered in a public database, such as ISRCTN or ClinicalTrials.gov. UK-only trials may use international registers, while EU/EEA trials must be listed on the Clinical Trials Information System (CTIS).

ATMP developers must apply to the MHRA for various licences throughout the product development process. A manufacturer’s licence for investigational medicinal products is required before starting clinical trials. Later, they must apply for a Manufacturer Authorisation (product manufacturer/importer licence) before submitting a Marketing Authorisation application. The MHRA may conduct a site inspection to ensure compliance with GMP as part of the licence approval.

Emerging challenges in the EU and the UK 

Scaling-up development and manufacturing: autologous versus allogeneic CGTs

One of the ongoing challenges of developing CGTs, particularly as they move toward commercialisation, is scaling up manufacturing processes while ensuring consistent quality and regulatory compliance. 

With respect to Autologous CGTs, which rely on cells obtained from the individual who will receive therapy, the development process is time and resource intensive and places a greater burden on the patient and developing teams. One of the key challenges is the complexity of designing and conducting clinical trials, as the individualised nature of the treatment complicates patient recruitment and protocol standardisation. Finding enough suitable patients, particularly for rare or geographically dispersed populations, can be difficult, which increases costs and may limit the ability to generate robust clinical data for marketing authorisation applications. These personalised protocols, while promising, require significant investment in patient screening and trial execution, which makes scaling up and broad accessibility difficult.

Allogeneic CGTs, in contrast, use donor cells, which provide the advantage of superior scalability, reduced time to treatment, potentially broader accessibility and lower manufacturing costs. In December 2022, the world’s first allogeneic CAR-T therapy (tabelecleucel) was approved by the European Commission[7]. While autologous CGTs currently offer a more favourable risk-benefit profile for each patient due to their more personalised nature, allogeneic CGTs offer the benefits of “off-the-shelf" availability and therefore a potential solution to the challenges of many of today’s CGTs. However, despite these benefits, allogeneic therapies face regulatory challenges, particularly in ensuring strict traceability requirements. Regulatory authorities demand bidirectional tracking from donor to patient and vice versa, which can add layers of complexity to the development and commercialisation process.  

Navigating multi-authority regulatory frameworks

The development of CGTs (qualifying as ATMPs) faces several regulatory challenges, including the need to engage with multiple regulatory authorities (including within a single jurisdiction). This complexity is compounded by the fact that regulatory bodies often seek expert guidance when evaluating applications, which can slow the approval process, as well as the requirement for additional regulatory steps if the therapy is to be marketed as a drug/device combination product (see further below). To mitigate these challenges, various initiatives have been introduced to streamline regulatory pathways, such as, in the UK, the combined review process and the Innovation Office, which provides a “one-stop shop” for regulatory advice. In the EU, EMA offers an early dialogue amongst developers of ATMPs and the Agency's Innovation Task Force, a robust scientific advice procedure and significant fee reductions for both scientific advice and classification phases for ATMPs.

Regulatory authorities also need to ensure they have sufficient expertise and resources to review marketing authorisation applications and oversee the monitoring of ATMPs throughout their life cycle. As the volume of ATMPs in development and on the market continues to grow[8], regulatory bodies will likely need significant additional resources to manage the increasing volume of regulatory work around these innovative therapies. 

Market Access: Authorisation, Pricing & Reimbursement Regulatory Approval Processes 

In the EU

Like all medicinal products, CGTs must obtain a marketing authorisation (MA) before being marketed in the EU. However, pursuant to the ATMP Regulation, CGTs must undergo a centralised procedure at the EU level (i.e. pharmaceutical companies may not pursue local MAs in individual Member States). 

In this process, the EMA’s Committee for Medicinal Products for Human Use (CHMP) is responsible for issuing a scientific opinion on the product within 210 procedural days (excluding any clock-stops). If the CHMP issues a positive opinion, the EC then grants an MA, valid across all EU and EEA member states within 67 days. This results in an optimal timeline of 277 days from submission to approval. 

Throughout this process, the EMA’s Committee for Advanced Therapies (CAT) plays a pivotal role. Established under the ATMP Regulation, the CAT provides recommendations on the classification of ATMPs and a draft opinion onthe quality, safety, and efficacy of ATMPs. Its scientific opinion largely informs the CHMP’s final recommendation regarding authorisation. Based on the CHMP’s assessment, the European Commission (EC) ultimately decides whether to authorise the ATMP for market access. 

If the product is a combination ATMP that incorporates a medical device component, developers must adhere to medical device legislation. This involves collaborating with an EU notified body to certify the compliance of the device component. 

This structured approach ensures that innovative therapies meet rigorous standards while facilitating timely access for patients. MAs are typically granted for 5 years but this may vary, with the renewal date being provided in the MA approval. 

In the UK

In the UK, and consistent with other medicines, ATMPs require an MA in order to be marketed. As with EU MAs, UK MAs are typically granted for an initial 5-year period, but this may vary, with the renewal date being provided in the MA approval. There are various potential routes for MA applications available to ATMP developers, including 150-day assessment, conditional MAs. Rolling Review, International Recognition Procedure (Recognition B), Project Orbis and Access Consortium. In exceptional circumstances, developers may choose to provide their product without a MA through the unlicensed route, consisting of either the “specials” route or “hospital exemption” route respectively. 

Applicants based in Northern Ireland must ensure compliance with EMA processes and apply to the CAT on the quality, safety, and efficacy of the ATMP prior to MA submission (CHMP opinion). 

If the product is a combination ATMP including a medical device component, developers must also ensure compliance with medical device legislation and will likely also need to engage a UK approved body to certify compliance of the device component. In the UK, the medical device legislation is currently in the process of being amended by the government following the MHRA’s consultation on the regulatory framework. ATMP applicants will therefore need to pay close attention to the specific details of the final legislation, as well as any further guidance on process promulgated by the MHRA and other relevant regulatory authorities.   

Accelerated and Derogatory Pathways 

In the EU

In the EU, while many ATMPs follow the standard MA process, alternative pathways exist for products facing challenges in clinical trial data collection, particularly for rare conditions or urgent treatment needs. Key alternatives include:

• Accelerated Assessment Procedure: Reduces the review period from 210 to 150 days for products of major public health interest that offer significant therapeutic innovation.
• Conditional MA: Granted when comprehensive data is not yet available, but the product addresses an unmet medical need and demonstrates a favourable benefit-risk profile. This authorisation is valid for one year and can transition to a standard MA upon submission of complete data.
• MA under Exceptional Circumstances: Applicable when full safety and efficacy data may never be obtainable, usually due to the rarity of the condition. These authorisations are reviewed annually but are unlikely to convert to a standard MA.

CGTs may also qualify for the PRIME scheme, which streamlines development and provides early scientific advice, potentially leading to accelerated assessment during the MA application.

Like other innovative medicines, CGTs may further benefit from early access programs prior to MA approval, subject to local requirements in individual Member States. 

Moreover, a specific exemption from the obligation to obtain an MA may apply to custom-made ATMPs under the so-called "hospital exemption" (i.e. ATMP prepared for an individual patient under the exclusive responsibility of a healthcare professional and used in a hospital of a specific EU member state).  In April 2024, the European Parliament approved a proposal to revise the EU pharmaceutical legislation, currently under the Council’s review[9], that would allow cross-border exchanges of ATMPs in justified medical cases. If enacted, this would represent one of the most significant overhausl of EU pharmaceutical legislation since 2004. 

In the UK

In the UK, developers of ATMPs can leverage several national accelerated or derogatory pathways, including:

• Innovative Licensing and Access Pathway (ILAP): This initiative expedites market entry by providing a comprehensive toolkit to navigate the design, development, and approval processes. Applicants can obtain an Innovation Passport from the MHRA, which includes a tailored Target Development Profile (TDP) and fosters collaboration with regulatory bodies.
• Early Access to Medicines Scheme (EAMS): EAMS allows patients with serious conditions to access unlicensed medicines that address unmet medical needs. This scheme also provides developers with opportunities to generate data within the target population.
• Promising Innovative Medicine (PIM) Designation: This designation indicates potential eligibility for EAMS and is granted after a scientific meeting with the MHRA. It facilitates discussions with NICE and the NHS regarding operational planning and feasibility.
• Project Orbis: For oncology products, developers can apply to Project Orbis, which allows for simultaneous review of marketing authorisation applications across multiple countries. Participation requires an Innovation Passport.
• International Recognition Procedure: Developers can benefit from expedited market access for medicines that have already been approved by trusted regulatory partners, such as the EMA, EU member states’ competent authorities and the US Food and Drug Administration.

This robust regulatory framework is designed to streamline the introduction of innovative therapies while ensuring patient access and safety.

Pricing & Reimbursement 

The decentralised pricing and reimbursement process within the EU and the UK presents significant challenges for cross-border access and pricing consistency for CGTs. 

Reimbursement models for CGTs differ markedly from those for traditional medicines. Conventional treatments typically involve smaller, ongoing payments throughout a patient's lifetime, while CGTs often offer long lasting therapeutic effects from a single administration. This discrepancy requires a re-evaluation of health technology assessments and payment models. CGTs, which involve substantial upfront costs, can deliver significant long-term benefits. This is especially crucial as ATMPs are developed for larger patient populations, including those with conditions such as certain types of dementia and Parkinson's disease. National governments must assess whether the long-term advantages of CGTs, which could reduce overall healthcare burdens, justify their significant initial investments.

To address these challenges, adaptive pricing and reimbursement models, such as outcome-based agreements or annuity payments, could be developed to reflect the long-term value of CGTs rather than focusing solely on immediate costs. These innovative payment approaches align financial interests with patient outcomes, incentivising healthcare providers to adopt these therapies effectively. However, pricing issues still impact patient accessibility, with some laboratories withdrawing from the European market due to failed negotiations, leaving many patients without access to critical therapies.

Balancing the urgent need for life-saving treatments with patient safety presents a challenge, as the push for faster approvals must be tempered by concerns over long-term efficacy and safety. Currently, only a limited number of CGTs have received marketing authorisation in the EU and the UK, and while these treatments showcase innovation, their high prices emphasise the tension between accessibility and sustainability of healthcare systems. Although the EU is well positioned to lead in developing innovative pricing models, the member states’ exclusive competence on pricing decisions, enshrined in the Treaty on the Functioning of the European Union (TFEU),  complicates this process. Nonetheless, the pioneering efforts of smaller EU countries could set a precedent for broader reforms, fostering the sustainable integration of CGTs into healthcare systems across the region[10]. 

Post-market obligations: monitoring and product liability

Post-market surveillance 

CGTs (qualifying as ATMPs) face specific post-market obligations that are critical for ensuring patient safety and maintaining compliance with regulatory standards. 

In the EU

To address the unique characteristics of ATMPs, the EU has established specific guidelines alongside the general pharmacovigilance regulations that apply to all medicines. In February 2018, the EMA issued a draft revised guideline focused on the safety and efficacy follow-up and risk management of ATMPs (the ATMP Guideline), which is currently under revision. This guideline underscores the distinct aspects of synthetic medicines in line with Article 14(4) of Regulation (EC) No 1394/2007, incorporating lessons learned from past authorisations and scientific advice.

The ATMP Guideline provides recommendations for early risk detection during development and outlines effective risk mitigation strategies, as well as the design of appropriate post-authorisation studies to monitor safety and efficacy. It encourages ATMP developers to engage with the EMA early to facilitate an efficient development process and is part of a joint action plan by the European Commission and EMA aimed at streamlining procedures for ATMP developers.

Although the ATMP Guideline does not explicitly address the long-term follow-up of participants in interventional clinical trials involving ATMPs, it acknowledges that some participants may require extensive or lifelong follow-up. Therefore, when designing a post-authorisation follow-up system, it is crucial to consider existing requirements for the follow-up of clinical trial subjects.

In the UK

Following successful MA applications, MA holders must carefully review any imposed conditions to ensure adherence to post-authorisation obligations and ongoing pharmacovigilance procedures. This includes the submission of Individual Case Safety Reports (ICSRs) from both the UK and non-UK sources, which document adverse events associated with the therapies. Additionally, MA holders are required to submit Periodic Safety Update Reports (PSURs) to provide comprehensive safety data over time, alongside Risk Management Plans (RMPs) that outline strategies for minimising risks associated with the product. Together, these obligations are essential for continuous safety surveillance and for fostering public confidence in the innovative potential of ATMPs.

Emerging challenges in the EU and the UK 

Pharmacovigilance and data measurement

In genomic medicine, individual genetic variations can lead to different responses to the same medicine, complicating the establishment of uniform pharmacovigilance guidelines. This variability makes it challenging to identify generalised side effects, necessitating a more tailored approach to drug safety. Thus, specific regulations for ATMPs are essential to effectively manage these complexities.

The emergence of highly personalised medicine, particularly with ATMPs, presents significant challenges for data measurement and analysis. Given the individualised nature of these treatments, conventional metrics for assessing efficacy and safety may prove inadequate. Additionally, the recent advent of these therapies means there is limited historical data to guide best practices, resulting in a situation characterised by limited hindsight in understanding long-term outcomes and potential adverse effects. This highlights the urgent need for robust data collection frameworks capable of capturing the varied responses of diverse patient populations over time. Establishing these systems will be essential for ensuring the ongoing safety and effectiveness of personalised therapies and facilitating effective pharmacovigilance efforts. 

 Liability issues

Addressing liability in the context of ATMPs is essential for encouraging innovation while safeguarding patients and healthcare systems. The unique characteristics of ATMPs - often involving intricate manufacturing processes and personalised treatment regimens - necessitate the establishment of clear liability frameworks. This includes defining the responsibilities of various stakeholders, such as manufacturers, healthcare providers, and regulatory authorities, to ensure accountability in the event of adverse effects or treatment failures. For example, liability should be clearly articulated in terms of product defects, adverse reactions, and the efficacy of the therapies.

Future Directions for Cell and Gene Therapy Regulation 

As developed in previous sections, CGTs pose unique regulatory challenges due to their complex and individualised nature, which traditional frameworks struggle to accommodate. Recent regulatory updates, such as the upcoming SoHO Regulation (effective as of August 2027) and the HTA Regulation (effective as of January 2025) in the EU, aim to address these gaps by streamlining the approval process and harmonising evaluation methods. 

As the regulatory landscape evolves and multiple regulatory authorities in the EU and the UK are involved, it is, however, becoming increasingly complex and adds layers of challenges for stakeholders to navigate. Striking a balance between necessary oversight and creating clear, efficient routes to market is crucial for ensuring that CGTs can be developed and ultimately reach patients. Innovative pricing and reimbursement models are further needed to accommodate the specific financial challenges posed by these therapies, whose high upfront costs often conflict with traditional healthcare funding models.

Collaboration between regulators, regulatory authorities, researchers, and industry leaders is crucial to overcoming the regulatory hurdles that currently impede the development and approval of CGTs. In this rapidly evolving field, better coordination can not only reduce delays but also promote more consistent and harmonised evaluations across different jurisdictions, ensuring that promising therapies reach patients sooner while enhancing overall quality and regulatory confidence. Engaging with patient advocacy groups is equally important, to foster transparency, build public trust, and ensures that patient perspectives are integrated into decision-making processes.

Despite the UK's departure from the EU, its regulatory framework for CGTs still mirrors many EU principles, although specific EU regulations no longer apply in Great Britain. The newly formed Labour Government has indicated a willingness to strengthen ties with the EU, but the extent of future alignment with EU laws remains uncertain. While the UK aims to attract investment in innovative technologies by potentially easing certain EU-derived regulations, the pharmaceutical industry is likely to advocate for minimal divergence to avoid the costs and complexities of dual compliance. 

Harmonized and streamlined regulatory pathways will be crucial for sustaining the momentum of CGT development across the EU and UK. While minimizing divergence between frameworks is essential to avoid unnecessary duplication and complexities, it is equally important to ensure that the rules governing CGTs remain clear, user-friendly, and competitive, while prioritizing patient safety and access.

Next week in our DLA Piper Genomics Series

Don’t miss next week’s feature, where Kokularajah Paheenthararajah, Pia Riemenschneider, and Mikael Kurki explore the evolving use of gene-editing in plants and the regulatory challenges surrounding genetically modified organisms (GMOs) in the EU. With recent debates over outdated legal frameworks and the European Commission's proposal for new genomic regulations, this article unpacks the legal complexities at play. It also examines the potential of gene drives, their applications, and the future direction of genetic engineering legislation. Stay tuned for an insightful analysis that could shape the future of gene-editing and gene-drive!

[1] The authors would like to extend their thanks to Stefano Marino, senior consultant at DLA Piper, for his very insightful comments and contributions to this article, and Karla Depenne, intern at DLA Piper (France), for her valuable review of this article.

[2] For an overview of latest innovations in personalised and precision medicine, Cf. Life Sciences Index 2024: A study of innovation and growth for the world’s largest biopharma and medtech companies | DLA Piper 

[3] Cf. Gene & Cell Therapy FAQs | ASGCT - American Society of Gene & Cell Therapy | ASGCT - American Society of Gene & Cell Therapy 

[4] Cf. The Sector Snapshot: August 2024 - Alliance for Regenerative Medicine

[5] This product was granted a conditional marketing authorisation (CMA) because it fulfils an unmet need but comprehensive clinical data are not yet complete. It is judged that such data will become available soon, Cf. https://mhraproducts4853.blob.core.windows.net/docs/9e1d2748cccfee159b5761cadbeea47e07ec6463.

[6] Cf. Strengthening Pathways for Cell and Gene Therapies: Current State and Future Scenarios - IQVIA 

[7] Ebvallo™ given world’s first approval of an allogeneic T-cell therapy, Cf. europeanpharmaceuticalreview.com

[8] By way of illustration, according to the ABPI report Unlocking access to future ATMPs in the UK, the number of ATMP approvals in the UK is expected to grow from around two per year to 10-15 per year by 2030.

[9] Cf. Reform of the EU pharmaceutical legislation - European Commission

[10] Cf. Imagining new pricing models for cell and gene therapies in the EU, Marco de Morpurgo