ATMP clinical trials in the UK

ABSTRACT

Aims

The UK advanced therapy medicinal product (ATMP) clinical trials database, produced annually by CGT Catapult, aims to assess the progress and state of the UK ATMP clinical development landscape. The aim of this article is to highlight key findings from the database and put them into context within the global landscape and various initiatives intended to attract ATMP developers to the UK.

Method

A targeted search of GlobalData’s clinical trial database was performed, followed by refinement so that only trials investigating products meeting ATMP definitions were included, and that each trial was only counted once in the analysis.

Results

The 2023 data show that the number of ongoing ATMP clinical trials in the UK has remained approximately static, in contrast to a 10% reduction reported globally. Approximately 80% of these trials were commercially sponsored. Although most ATMP clinical trials are early phase, there is evidence indicating progression to later phase studies.

Conclusion

The data indicate that the UK remains an attractive region for ATMP clinical trials. Factors including UK government investment in research, regulatory support offered by MHRA, and the Advanced Therapy Treatment Centre (ATTC) network of clinical sites, may contribute to the positive ecosystem available to developers of ATMPs.

1. Introduction

As with all investigational medicinal products, clinical trials for advanced therapy medicinal products (ATMPs) in the UK are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA), within the framework of the Medicines for Human Use (Clinical Trials) Regulations 2004. As of 1 January 2022, all new applications for clinical trial authorization (CTA) must be submitted through the combined review procedure [1]. The combined review offers a single application submission and coordinated regulatory and ethics review leading to a single UK decision for CTA. The overall statutory timeframe for receiving a decision on a clinical trial application for an ATMP, including regulatory and ethics reviews, and time for the Applicant to respond to questions, is up to 90 days. Although there was previously a large backlog in clinical trial applications leading to increased review times, improvements were put in place, and this was cleared [2]. As of October 2024, MHRA are completing CTA reviews more quickly than the statutory timelines, with an average of 49 days compared to the statutory timeline of 60 days for non-ATMPs [3]. In comparison, the overall timeline for the review of an ATMP clinical trial application in the EU submitted via the Clinical Trials Information System (CTIS) is up to 156 days, including validation, parallel review of Parts I and II (regulatory and ethics submissions), and time for responding to questions [4]. In the US, the review timeline for an initial Investigational New Drug (IND) application is 30 days, but any questions not resolved within that time may result in a clinical hold which will prevent the initiation of the clinical trial in the US until addressed [5,6].

ATMPs in Europe are classified as either gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (SCTMPs) or tissue engineered products (TEPs), each of which has a precise legal definition as laid out in Directive 2001/83/EC and Regulation (EC) No.1394/2007 (Table 1) [7]. Although some products previously approved have been withdrawn, as of October 2024, there are currently 20 ATMPs with regulatory approval in the EU [8] and 19 in the UK [8], including the first gene-edited therapy, Casgevy, which was approved in the UK before any other region. The European Commission awarded conditional marketing authorization to the gene therapy, Durveqtix for treatment of hemophilia B in July 2024 but this was not accompanied by approval in the UK. In contrast to the UK and EU, excluding non-manipulated cell therapies (Lantidra, Rethymic, and all cord blood therapies) which would not be considered ATMPs in Europe, there are 28 approved cell and gene therapy products in the US [9].

Table 1.

Definitions of ATMP categories EMA and MHRA [7].

Gene therapy medicinal product	Gene therapy medicinal product means a biological medicinal product which has the following characteristics: it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence, and its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.
Somatic cell therapy medicinal product	Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics: contains or consists 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, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor, and Is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.
Tissue engineered product	Tissue engineered products, according to Article 2(1)(b) of Regulation (EC) No. 1394/2007, means a product that: contains 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.

Following the UK’s exit from the EU, ATMPs in the UK, encompassing GTMPs, SCTMPs and TEPs, continue to be defined in accordance with Regulation (EC) 1394/2007 amending Directive 2001/83/EC on the community code relating to medicinal products for human use [10]. However, all regulatory procedures, including clinical trials and marketing authorization applications are now reviewed and approved by the UK MHRA separately from the European Medicines Agency (EMA) and EU national regulatory agencies. Therefore, although there was concern that this would negatively impact patient access to innovative medicines [11], there is now an opportunity for the UK to close the gap with the US with regards to patient access to these cutting-edge therapies.

A UK world-first initiative to address the challenges of bringing advanced therapies to patients was the establishment of the Advanced Therapy Treatment Centre (ATTC) network in 2018, initially funded through the UK Research and Innovation Medicines Manufacturing Challenge, now the National Institute for Health and Care Research (NIHR), administered by Innovate UK and coordinated by Cell and Gene Therapy Catapult (CGT Catapult) [12]. The ATTC network forged close partnerships between the NHS and industry to bolster capacity for delivering advanced therapies to patients. Collaborative efforts have notably improved clinical trial infrastructure, offering patients access to potentially life-changing treatments, particularly those with limited options or rare diseases.

The UK ATMP clinical trials database, produced by CGT Catapult, aims to assess the progress and state of the UK ATMP clinical development landscape [13]. The database is updated annually and provides a comprehensive review of the UK ATMP clinical trial landscape. The aim of this article is to highlight key findings from the database and put them into context within the global landscape and various initiatives intended to attract ATMP developers to the UK.

Numerous countries and organizations create reports that outline the current state of clinical trials in the area of “regenerative medicine,” which includes ATMPs as a specific category. However, these reports employ varying methodologies to identify and assess trial activities, often extending beyond ATMPs, which makes global comparisons increasingly challenging. It is crucial to highlight that CGT Catapult data may differ from other databases, which can include cell therapies that do not meet ATMP criteria or may categorize the same trial in multiple ways. To compile our data, we adopted consistent and systematic techniques to analyze and refine automatically generated information from the extensive GlobalData database. This process enabled us to filter out trials investigating products or therapies that do not conform to European ATMP definitions (such as non-homologous use or minimally manipulated products) and ensured that each trial was counted only once in our analysis.

2. Method

ATMP clinical trials conducted in the UK were identified through a focused search of GlobalData’s clinical trial database (https://www.globaldata.com). Trials without a publicly accessible ID (such as a Clinical Trials or EudraCT number) and could not be verified outside of GlobalData were excluded.

The products from the remaining trials were evaluated to determine if they met the ATMP criteria defined in Directive 2001/83/EC and amended by Regulation 1394/2007 (Table 1).

To ensure that each trial was counted only once, products that could fit multiple ATMP categories were classified under a single type. For instance, a product such as chimeric antigen receptor T cell therapy (CAR-T), listed as both a gene and cell therapy in the GlobalData database, was recorded once as an ex vivo gene therapy in this report. Additionally, clinical trials investigating multiple indications were categorized under a single therapeutic area.

Key trial information was verified and confirmed in the public domain using at least one of the following databases:

1. EU Clinical Trials Register

2. ClinicalTrials.gov

3. ISRCTN Registry NIHR CRN Public Dashboard

4. WHO International Clinical Trials Registry Platform

UK ATMP trials for which key trial information was unable to be verified outside of GlobalData, using one of the databases above, were excluded from the analysis.

The clinical trial locations were based on site locations, which may change over time.

3. Results

There was a total of 175 ATMP clinical trials ongoing in the UK as of December 2023, compared to a total of 178 ongoing ATMP trials in 2022 (Figure 1). Of these ongoing trials, 70% are represented at sites within the ATTC network (data not shown). Additionally, commercially sponsored trials accounted for approximately 80% of all UK ATMP clinical trials in 2023.

Figure 1.

Numbers of ongoing academic/nonprofit and commercial ATMP clinical trials from 2018-2023.

The majority of the ATMP clinical trials in the UK in 2023 were GTMPs, both ex vivo and in vivo (76%) followed by SCTMPs (19%). TEPs accounted for approximately 5% of clinical trials (Figure 2).

Figure 2.

Breakdown of UK ATMP clinical trials by ATMP type.

Of the cell-based therapies (incorporating TEPs, SCTMPs and ex vivo GTMPs), 74% were autologous compared to 26% allogeneic. This proportion has remained consistent since we began collecting this data in 2018 (data not shown).

Of the total 175 ongoing UK ATMP clinical trials recruiting patients in 2023, the majority were Phase I/II trials (37), followed by Phase III (22), and Phase II trials (20). There were 25 Phase I/II trials in follow-up, 14 Phase II trials, and 14 Phase III trials (Figure 3). Most of the trials initiated in 2023 were recruiting (76%), with the rest in planning/set-up. The majority of these newly initiated trials were Phase II, with five newly initiated trials, while three of these initiated trials were Phase I/II, and three were Phase trials III (data not shown).

Figure 3.

Ongoing UK ATMP clinical trial numbers grouped by clinical phase in 2023.

The division of therapeutic indications among the total ongoing UK ATMP trials remained largely unchanged from previous years. Oncology, which includes hematological malignancies and solid tumors, remained the dominant therapeutic area accounting for 41% of ATMP clinical trials, followed by hematological (10%), ophthalmology (9%), and metabolic (8%) (Figure 4(a)). When only ongoing Phase III trials are considered, the dominant therapeutic areas remain the same (Figure 4(b)).

Figure 4.

Distribution of UK ATMP clinical trials by therapeutic area. (a) all ongoing UK ATMP trials; (b) ongoing Phase III UK ATMP trials.

4. Discussion

The data reported here show that the number of ongoing ATMP clinical trials in the UK has remained more or less static, with 175 clinical trials in 2023 compared to 178 in 2022. This number is potentially an underestimate due to the methods employed whereby trials that did not have a publicly available ID or couldn’t be verified outside of GlobalData were excluded. However, as the majority of trials did not meet these criteria, it is expected that the impact on the data is low. In contrast, the Alliance for Regenerative Medicine (ARM) have reported a total of 1,894 active cell and gene therapy clinical trials worldwide in 2023 [14], representing a greater than 10% reduction from the 2022 total of 2,220 clinical trials [15]. The ARM data also specifically highlights the reduction in cell and gene clinical trials in Europe from 403 in 2022 to 358 in 2023. Alternative data on the number of ATMP clinical trials in 2022 is discussed by Wilkins et al [16]. This study, based on the (Medicines INnovation Database (MInD) developed by the NIHR reports 616 records pertaining to 482 unique ATMPs associated with 583 clinical trials across the UK, EU and North America. The reason for the discrepancy between 2022 data from MInD and ARM is not clear, but possible explanations include an overestimate from ARM due to the inclusion of therapies that would not be defined as ATMPs in Europe and potential duplication in records due to, for example, an ex vivo gene therapy being counted twice as a cell therapy as well a gene therapy. However, assuming that the same method was utilized by ARM to produce the 2022 and 2023 data, the trend in overall reduction in cell and gene therapy clinical trials, particularly in Europe, is clear. Within this context, the results reported here are indicative of the UK as a favorable option for ATMP clinical trials. Factors such as UK government investment in research, the regulatory support offered by MHRA to ATMP developers, and the ATTC network of clinical sites, may contribute to the positive ecosystem available to developers of ATMPs.

The MHRA Innovation Office is available to developers of early stage, innovative products for free regulatory advice. By seeking input at an early stage, developers can ensure that early studies are planned and conducted with the appropriate regulatory considerations in mind. This can potentially accelerate the route to clinical development and increase the likelihood of regulatory approval of a clinical trial application. Similarly, MHRA has developed the Innovative Licensing and Access Pathway (ILAP) to support innovative approaches to the safe, timely and efficient development of medicines to improve patient access. MHRA encourages developers to apply to ILAP during early product development. Successful applicants get the opportunity to work collaboratively with the multi-stakeholder consortium to obtain harmonized clinical, regulatory, and health technology appraisal (HTA) advice. In addition, the ILAP gives developers access to the target development profile (TDP) toolkit which includes support with patient recruitment and increasing patient engagement, as well as pre-assessment of draft clinical trial documentation before the clinical trial application is formally submitted.

Over time, the UK has increased its capacity for advanced therapy clinical trials, with support from the ATTC network enabling numerous NHS centers to host their first trials [17]. This is demonstrated by our finding that 70% of the ongoing trials in 2023 were conducted at ATTC sites either solely or in addition to other sites not within the network. Additionally, this is consistent with the results from an ATTC survey in 2022 which found that 63% of manufacturers surveyed used the ATTC network or their resources whilst conducting ATMP clinical trials [17]. Between 2024 and 2028, through funding from the NIHR, and in close collaboration with NIHR infrastructure and its counterparts in the UK’s devolved administrations, the ATTC network aims to further build the UK’s advanced clinical trial readiness. The goal being to expand capacity and capability across a broader network to bring more innovative therapies to patients and strengthen the UK’s appeal to industry. This work in ATMP clinical trials increases the reputation of the UK in the research and clinical trial area, making the UK a more attractive place to conduct trials.

Cell-based therapies can fall under any of the three classifications, and therefore, including ex vivo gene therapies, the majority of ongoing ATMP trials in the UK are with cell-based therapies, most of which are autologous. Similarly, of the cell-based therapies which are approved in the UK, only 2 are allogeneic (Alofisel and Ebvallo). Although autologous cell therapies avoid issues such as graft vs host disease, they come with additional manufacturing logistics challenges and higher costs per batch. Point of care (POC) manufacturing may address some of the challenges associated with autologous cell therapies by removing the need to transport cells between the clinical site and a central manufacturing facility. This is especially important when patients have life-threatening conditions and may not necessarily survive long enough for their product to be manufactured and transported. Following a public consultation in 2021, MHRA is now developing new legislation to amend the UK’s Human Medicines Regulations and the Clinical Trial Regulations to introduce a regulatory framework for POC manufacturing [18]. The measures proposed by MHRA included the concept of a Control Site which would be a physical site named on CTA or marketing authorization application (MAA) documentation as the primary focus of regulatory controls. Amongst other activities, the Control Site would be responsible for the oversight of each POC site in a ‘hub and spoke’ model [19]. It is expected that the development and implementation of this new framework will support increased patient access to autologous cell-based therapies in the coming years.

Although the majority of ATMP clinical trials are early phase, either Phase I or Phase I/II, there has been some progression to later phase studies over the previous 5 years. This is indicative of the success of early phase trials and continued development. Additionally, the data show a greater increase in Phase I/II trials compared to Phase I trials. In contrast to typical Phase I trials which focus on safety assessments, Phase I/II trials assess both safety and efficacy. In a Phase I/II trial, if dose-finding was conducted in the initial phase, the highest dose tested which was found to be safe (known as the recommended Phase 2 dose) is administered to a larger number of patients and efficacy is assessed. This combined design allows for expedited clinical development. The increase in Phase I/II is indicative of the general trend toward adaptive clinical trials demonstrated by the finding that over 20% of trials supporting marketing authorizations in Europe were Phase I/II trials [20]. It is recognized that the typical paradigm of consecutive Phase I, Phase II, then Phase III trials is not always relevant to ATMPs which commonly target orphan indications and significant unmet needs requiring a more flexible approach [21]. As a result, regulatory agencies are publishing guidance and recommendations related to innovative designs and adaptive approaches [22,23]. Additionally, MHRA are proposing the Clinical Trial Lifecycle Package (CTLP), a new clinical trial approval approach whereby Sponsor would submit a complete application adopting a combined phase approach [24]. This approach would support adaptive trial designs as the primary submission would include all phases with amendments submitted with results from each phase. The proposed framework would also allow for scientific advice to discuss amendments to the clinical development plan as trials progress.

Oncology is the dominant therapeutic area in which ATMPs are being investigated in clinical trials across all phases of development as well as in Phase 3 trials. These comprise both hematological malignancies and solid tumors. The results reported here are aligned with a previous similar study [16], and are indicative of where money is being invested and the likely therapies that will be licensed in the future. Currently, 6 of the 19 approved ATMPs in the UK and EU are for treatment of hematological malignancies. Additionally, FDA has recently approved Tecelra which is the first cell therapy for treatment of a solid tumor [25]. It is therefore anticipated that additional ATMPs for oncology indications will be available to patients in the UK in the future.

Overall, the data presented here demonstrate that the UK remains a favorable environment for ATMP clinical trials. ATMPs such as Amtagvi and Elevidys are approved in the US, but not yet approved in the UK. However, these products were investigated in clinical trials in the UK, allowing patient access before approval. Additionally, in order to expedite patient access to licensed therapies, MHRA launched the International Recognition Procedure (IRP) in January 2024. This procedure means that products approved initially in the US, EU/EEA, Australia, Canada, Switzerland, Singapore and Japan can undergo an abbreviated review. For ATMPs, the Recognition B 110-day review timeline will apply. In contrast, the target timeline for the review of national applications for high-quality MAAs is 150 days. It is therefore expected that by targeting resources and relying on reviews conducted by the trusted reference regulators, where the UK is not the first region for approval, it will be a fast follower. Furthermore, as HTA assessment is due 90 days after the MHRA approval, IRP could require a 50% reduction in time taken for appraisal from the National Institute for Health and Care Excellence (NICE), from the current timeline of 60 weeks to 32 weeks for products approved under Recognition B of the IRP [26]. As a result, NICE is working with industry stakeholders to identify ways of ensuring timely access with IRP, including submission to NICE before MHRA, focusing external assessment on key decisions, and greater standardization of evidence submission inputs. The aim of these discussions being to support earlier patient access to new medicines in the UK. Additionally, there are several initiatives to create a favorable reimbursement environment in the UK. These include the introduction of the Innovative Medicines Fund in 2022, intended to provide earlier access to innovative therapies under managed access while further data is still being collected [27].

5. Conclusion

Since the end of the Brexit transition period in January 2021, MHRA has become the UK’s standalone medicines and medical devices regulator. Despite concern that this could lead to reduced access to innovative medicines in the UK, the data presented here indicate that the UK remains an attractive region for ATMP clinical trials. As listed in Figure 5, MHRA procedures such as ILAP and the IRP have been introduced to support patient access, and a framework for POC manufacturing is being developed to potentially increase access to autologous cell therapies. In addition, the ATTC network continues to work toward addressing the logistical challenges of bringing ATMPs to patients in the UK.

Figure 5.

Current and proposed UK initiatives to support development and access to innovative therapies.

Funding Statement

This paper was not funded.

Article highlights

Introduction:

• The UK ATMP clinical trials database, produced annually by CGT Catapult, aims to assess the progress and state of the UK ATMP clinical development landscape.

• The aim of this article is to highlight key findings from the database and put them into context within the global landscape and various initiatives intended to attract ATMP developers to the UK.Method:

• ATMP clinical trials conducted in the UK were identified through a targeted search of GlobalData’s clinical trial database.

• Consistent and systematic methods were used to interrogate and refine the automatically generated data from the GlobalData database.

• Trials investigating products/therapies not complying with European ATMP definitions were identified and removed, and each trial was only counted once in the analysis.Results:

• There was a total of 175 ATMP clinical trials ongoing in the UK as of December 2023, compared to a total of 178 ongoing ATMP trials in 2022. Of these, approximately 80% were commercially sponsored.

• The majority of the ATMP clinical trials in the UK in 2023 were GTMPs.

• Of the cell-based therapies, 74% were autologous compared to 26% allogeneic.

• The majority of ongoing trials were Phase I/II trials, with progression to later phase studies over the previous 5 years.

• Oncology, including hematological malignancies and solid tumors, was the dominant therapeutic area investigated in ATMP clinical trials.Discussion:

• In contrast to data generated by ARM which shows a reduction in 2023 from the previous year in cell and gene clinical trials globally, including in Europe, the data reported here shows that the number of ongoing ATMP clinical trials in the UK has remained approximately static.

• Current MHRA procedures such as ILAP and the IRP have been introduced to support patient access, and a framework for POC manufacturing is being developed to potentially increase access to autologous cell therapies.

• The UK has increased its capacity for advanced therapy clinical trials, with support from the ATTC network enabling numerous NHS centers to host their first trials. This is exemplified by our finding that 70% of the ongoing trials in 2023 were conducted at ATTC sites.Conclusion:

• Overall, the data indicate that the UK remains an attractive region for ATMP clinical trials. Factors including UK government investment in research, regulatory support offered by MHRA, and the ATTC network of clinical sites may contribute to the positive ecosystem available to developers of ATMPs.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Author contributions

All authors: Rehma Chandaria, Philippa Rice, Daniel Baston, Finn Willingham, Jacqueline Barry

• – Made a significant contribution to the work reported, whether that’s in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas.

• – Have drafted or written, or substantially revised or critically reviewed the article.

• – Have agreed on the journal to which the article will be submitted.

• – Reviewed and agreed on all versions of the article before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage.

• – Agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460751.2024.2427505.