On 3 February 2025, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) launched a consultation asking for stakeholders’ views on  draft guideline in relation to the regulation of individualised mRNA cancer immunotherapies (Draft Guideline).

The aim of the proposed guideline is to establish a clear and streamlined regulatory pathway to authorisation so that these highly innovative products can be made available to patients quickly, without compromising any assessment of safety. While the primary focus of the Draft Guideline is individualised messenger Ribonucleic Acid (mRNA) cancer immunotherapies, MHRA suggests that the regulatory and scientific principles considered might be broadly applicable to other disease indications (including rare diseases) or technologies that could benefit from personalisation or individualisation. It also states that the Draft Guideline will be updated when experience of other technologies (peptides, non-integrative DNA and polymer deliver systems) is available.  

In terms of regulatory assessment of individualised mRNA cancer immunotherapies, the Draft Guideline provides clarification of the data which should be included in marketing authorisation (MA) applications and, importantly, confirms that an individualised medicine may, in some circumstances, be granted an MA under the Human Medicines Regulations 2012 (HMRs), even where the product includes an individualised component tailored to the requirements of a specific patient.

There is currently substantial interest in the use of mRNA technology to develop individualised treatments for cancer. The current consultation is therefore of interest to companies focussing on this and other individualised therapies.

What are individualised mRNA cancer immunotherapies and how do they work?

mRNA is a strand of RNA that directs cells to produce copies of a specific protein (antigen).  Individualised mRNA cancer immunotherapies are medicinal products which utilise mRNA technology to develop a treatment directed towards specific antigens (neoantigens) present in  an individual patient’s tumour. The “personalised” mRNA therapy therefore primes the patient’s immune system to target and destroy their tumour cells, whilst leaving the patient’s healthy cells intact.

The mechanism of action takes advantage of the immune system’s ability to distinguish between “self” and “foreign” proteins. Cells constantly present proteins on their surfaces and the proteins presented on a cancer cell will differ from those on a healthy cell. Administering mRNA that codes for proteins only expressed by cancer cells and recognised by the immune system as “foreign”, will then trigger an immune response targeting only cancer cells. The mRNA is delivered to cells by a drug delivery system such as lipid nanoparticles.

As each product is tailored to an individual’s tumour and is therefore different, this poses questions for how such products should be regulated to maintain high standards of quality, efficacy and safety.

Overview of the Draft Guideline

The Draft Guideline covers most stages of drug development, as well as some post authorisation matters and is designed to assist developers in their MA applications. There are sections covering: (i) regulatory classification; (ii) product design; (iii) product manufacturing; (iv) non-clinical testing; (v) clinical studies; (vi) post-approval safety monitoring; and (vii) information for patients and the public. In view of the novel scientific and regulatory aspects of individualised medicines, developers are strongly advised to seek advice from MHRA in relation to their products.

A summary of the key points is set out below.

1. Regulatory classification

Regulatory classification should be agreed with the MHRA but in general:

• All individualised mRNA cancer immunotherapies, which include both a fixed component and a variable component (tailored to the patient’s unique tumour neoantigen profile), will be regulated as medicines under the HMRs;
• Although colloquially these products are often referred to as “personalised cancer vaccines”, the MHRA confirms that from a regulatory perspective, individual mRNA cancer immunotherapies do not meet the definition of a “vaccine” as set out in the HMRs.
• MHRA currently classifies all individualised mRNA cancer immunotherapies as  “gene therapy medicinal products” within the broader category of Advanced Therapy Medicinal Products (ATMPs).

The MHRA indicates that a single MA covering the use of an individualised medicine across the target population may be issued as long as production processes, strength, pharmaceutical form and method of administration are identical between patient-specific batches. Predefined controls need to be in place to ensure safety and efficacy of the products.

The MHRA is also considering (a) introducing a new-subclassification of ATMP for nucleic acids that do not edit the genome and (b) how to classify chemically synthesised products that do not the definition of a biological medicinal product, and are consequently not a gene therapy medicinal product, or any other form of ATMP. The latter might include an individualised peptide-based immunotherapy where the relevant peptide is synthesised.

2. Product design

The design and manufacture of individualised mRNA cancer immunotherapies is a complex process, including patient sample collection and storage, as well as genetic sequencing and analysis, and neoantigen identification and selection, involving artificial intelligence/machine learning (AI/ML). These steps are subject to various regulatory frameworks, including the Human Tissue Act 2004, the Medical Devices Regulations 2002[1], as well as Data Privacy legislation and requirements for patient consent and ethical approval.

The Draft Guideline emphasises the importance of traceability to ensure the patient sample, genetic sequence and analysis, and resultant mRNA selection are linked throughout the process. It envisages that tumour samples (rather than circulating tumour DNA) will be required to identify specific tumour mutations for the purposes of preparing an individualised medicine, whereas whole blood samples may be used for germline genetic testing.  Standard pathology practices and robust quality control procedures must be applied to collection, storage and transport of samples. 

The Draft Guideline contains a section on genetic sequencing, which covers the steps required to transform mixtures of nucleic acids from biological samples into different types of libraries suitable for sequencing. Nucleic acid extraction procedures, as defined by the manufacturer of the relevant sequencing instrument, should be followed, and contaminants avoided. Commercial kits should be used, where possible, for sequence analysis, and the development of own-proprietary sequencing libraries should be avoided. Sequence analysis software should be computer systems validated to meet GMP requirements for software.

There is also a detailed section on bioinformatic analysis and the need to implement thorough quality control assessments and maintain an optimised and validated bioinformatics data analysis pipeline in order to obtain statistically significant and reproducible results. Raw data obtained from genetic sequencing should initially be subject to quality evaluation prior to identification and ranking of potential neoantigen candidates. This latter stage is likely to involve use of AI/ML to filter and select neoantigens. The Draft Guideline notes that bioinformatics data are subject to patient consent and the results of analysis may be used solely for a specific intended purpose, in accordance with the Human Tissue Act 2004. As the output is used for a medical purpose, software generating predictions or absolute results will be regulated as Software as a Medical Device (SaMD) and various standards need to be complied with to minimise risks of bias and unreliability.  The Draft Guideline refers to Good Machine Learning Practice (GMLP) guiding principles from MHRA, FDA and Health Canada and lists key considerations when AI/ML is assessed including performance, generalisability, performance drift, bias and transparency.

3. Product manufacturing

As with more conventional medicines, all manufacturing steps should be carried out in accordance with GMP. The Draft Guideline states that there should be clearly defined and detailed descriptions of how the mRNA is transcribed in vitro or synthesised and purified, and how the mRNA active substance is incorporated within the drug delivery system (considered an excipient) to form the finished product. Furthermore, as the mRNA sequence elements encoding the neoantigens will differ in sequence, structure and length between patients, adequate studies, controls and risk assessments will need to be put in place at all stages of development. Developers are expected to carry out thorough characterisation studies and release testing (wherever possible) for both the mRNA drug substance, as well as the final drug product.

4. Non-clinical testing

The Draft Guideline states that, in principle, any individualised mRNA cancer immunotherapy will be based on a construct, namely an mRNA insert coding for each neoantigen selected from the analysis of the patient’s tumour sample, in a fixed mRNA backbone. Where lipid nanoparticles are used, these will be consistent across products. Subject to minor justified changes in the proportions of the constituents, any alteration in the mRNA backbone or the nanoparticle element will result in a new product with the associated requirement for testing.

Initial in vitro testing is required to demonstrate that the mRNA construct produces a specific anti-tumour immune response. The Draft Guideline does not specify the experimental method to be used and indicates that it is acceptable to cross-refer to other relevant mRNA constructs. 

5. Clinical evidence demonstrating safety and effectiveness

Clinical studies are expected to investigate a list of fairly standard factors (pharmacodynamic activity, optimal dosing, timing etc.) on a fixed set of product design steps; otherwise, any changes would need to be justified to avoid the relevance of such data being questioned. Special consideration needs to be given to the design of randomised placebo-controlled trials as a result of variable manufacturing time of individualised products, to ensure that participants assigned to the placebo arm remain blinded.

6. Post-approval safety monitoring

Standard pharmacovigilance processes should be followed, with additional consideration given to safety concerns applicable to ATMPs and individualised therapies. For example, developers should consider the existence of links between suspected adverse drug reactions and genomic data, and whether safety signals are related to a specific neoantigen.

The Draft Guideline anticipates that post-authorisation safety studies (PASS) will be included in the risk management plan submitted with the MA application for individualised mRNA cancer immunotherapies. It states that an important consideration in the design of pharmacovigilance systems is how the safety and effectiveness profile of the therapy may be impacted by changes to the AI/ML at the neoantigen selection stage. It suggests that developers should record which version of the AI/ML performed neoantigen selection for each batch of the product.

The importance of traceability is emphasised as a key pharmacovigilance requirement for these products.

7. Information for patients, healthcare professionals and the public

The Draft Guideline states that patients, healthcare professionals and the wider public should have prompt access to clear information in relation to individualised mRNA cancer immunotherapies. The MHRA considers that there may be challenges in conveying relevant information on individualised medicines within the current format of the summary of product characteristics and patient information leaflet. It therefore suggests that the appropriate location for information relating to the product design process, how the products are personalised to an individual patient and timeframes from tumour sampling to therapy administration is the public assessment report (PAR). Instead of the 120 day target to publish a PAR after MA approval, the MHRA commits to a 30 day timeline. Educational materials for healthcare professionals and patients may also be appropriate as a risk minimisation measure.

Next steps

Stakeholders are invited to provide their comments on the Draft Guideline by 31 March 2025. The MHRA will then review the comments and update the proposals as necessary.  

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Arnold & Porter would be happy to advise companies on how to bring a novel individualised mRNA cancer immunotherapy to the UK market, including under a named patient basis and by taking advantage of early access programmes.

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[1] In Northern Ireland, it is necessary to comply with the Medical Devices Regulation (EU) 2017/745 and the In-Vitro Diagnostic Devices Regulation (EU) 2017/746.