The UK’s Medicines and Healthcare products Regulatory Agency (“MHRA”) is seeking industry feedback on its new draft guideline on individual messenger ribonucleic acid (“mRNA”) cancer immunotherapies (the “Draft Guidance”). Building on the success of mRNA vaccine technology in response to the Covid-19 pandemic, the technology is now being adapted to target diseases such as cancer. The MHRA aims to provide a streamlined robust regulatory framework for the approval of such personalised mRNA-based cancer vaccines without compromising safety.
The Draft Guidance covers the regulatory classification of these novel cancer treatments, product design and manufacture, non-clinical and clinical development, pharmacovigilance and the distribution of information to the wider public. Notably, the MHRA explicitly acknowledges that the regulatory and scientific principles discussed in the Draft Guidance could broadly apply to other disease indications or technologies that could benefit from personalisation or individualisation. Therefore, industry should be aware that the scope of the Draft Guidance may be extended in the future beyond mRNA cancer immunotherapies that use lipid nanoparticle delivery systems to other delivery systems and disease areas. Manufacturers, developers, patient organisations and other stakeholders have until 31 March 2025 to comment on the Draft Guidance.
We explore some of the interesting regulatory considerations arising from the Draft Guidance below.
Regulatory Classification
The classification of a medicinal product is key to determining what requirements and guidelines apply to the development, manufacture and delivery of that product. For example, advanced therapy medicinal products (“ATMPs”) have specific Good Manufacturing Practice (“GMP”) requirements (see e.g., ‘Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products’), strict traceability requirements and additional pharmacovigilance requirements.
Currently, individual mRNA cancer immunotherapies are classified under the Human Medicines Regulations 2012 (as amended) (“HMRs”) as ATMPs and are sub-classified as gene therapies. However, current mRNA therapies do not fit neatly under the ‘gene therapy’ umbrella because, unlike conventional gene therapies, which are designed to edit a person’s genome to treat or cure a disease, mRNA therapies do not involve integration into the host genome.
The Draft Guidance reveals that “a new ATMP sub-classification for nucleic acids that do not edit the patient’s genome is being considered.” A practical advantage of a new sub-classification would be the opportunity to create bespoke and risk proportionate requirements and guidelines for mRNA therapies. This would avoid overburdensome risk mitigations for these products as compared to similar products such as COVID-19 vaccines.
The Draft Guidance also predicts that mRNA therapies could be chemically synthesised (i.e., not manufactured by biotechnology). Such therapies would fall outside the scope of the current definition of a gene therapy as they would not be a biological product. The MHRA is considering the classification of relevant chemically synthesised mRNA therapies as ATMPs.
Patient Sample Collection, Storage and Analysis
The first step in the process of producing an individual mRNA cancer immunotherapy is the collection of tumour specimens and/or blood samples from a patient.
The Draft Guidance indicates that the collection, storage, transportation and retention of specimens and samples are regulated by the Human Tissues Act 2004 (“HTA”). Under the HTA, patient blood and tissue samples constitute “relevant material”. The HTA only regulates “relevant material” if it is intended for one of the scheduled purposes set out in Schedule 1 of the HTA, which include, amongst other things, research. It is not clear which scheduled purpose listed in the HTA applies to an individual mRNA cancer immunotherapy, unless leftover patient blood and tissue samples are stored for future research use. The MHRA does not explain its position concerning the application of the HTA.
Notably, the Draft Guidance does not refer to the Human Tissue (Quality and Safety for Human Application) Regulations 2007 (“Q&S Regulations”) (which implemented the EU Cells and Tissue Directive 2004/23/EC in the UK) and the requirement for healthcare or clinical facilities to have a license from the Human Tissue Authority to store tissues or cells. This is because the Q&S Regulations only apply to cells and tissues intended for “human application”, which means the use of tissues or cells on or in a human recipient. In an individual mRNA cancer immunotherapy, the initial tumour specimens and/or blood samples collected from a patient do not form part of the final product and are therefore not “used in” the recipient nor are they the “starting material” for the product.
Where the HTA applies, genetic sequencing of a patient’s DNA is subject to qualifying consent, and the resulting bioinformatic data must be used solely for an “excepted purpose” (e.g., the medical diagnosis or treatment of the patient).
Regulatory Considerations for the Use of AI/ML Tools
Mutations in the DNA of cancer cells produce proteins with an altered structure – neoantigens. Neoantigens can be unique to individual patients. This makes them suitable for individualised mRNA cancer immunotherapies, which trigger an immune response by delivering an mRNA insert encoding for each selected neoantigen.
Artificial intelligence/machine learning (“AI/ML”) tools are often used to help identify and select candidate neoantigens from an analysis of the genetic data from a patient’s tumour sample.
AI/ML tools can be regulated under GMP for medicines, or as Software as a Medical Device (“SaMD”), either under general medical device legislation or under in vitro diagnostic legislation. The Draft Guidance provides the example of an AI/ML tool that “analyses genetic data to match a patient to a specific treatment, predicts the suitability of certain treatments, or creates an individualised treatment based on the patient’s biodata” being regulated as SaMD under medical device legislation. An AI/ML tool used to autonomise and accelerate a manufacturing process could be regulated under GMP for medicines.
The regulatory status for the use of AI/ML tools (and separate functionalities within tools) will depend on the “exact techniques and processes used, alongside jurisdictional legislations and interpretations”. This will require careful case-by-case consideration by developers and deployers.
Product Manufacturing
The key question is when does the product manufacturing begin. From this point on, the manufacturing of the product is regulated under GMP.
The Draft Guidance confirms that “[t]he principles of GMP will apply to the manufacture of starting materials for individualised mRNA immunotherapies”. The starting materials will be defined and justified by the manufacturer and are likely to be the nucleotide substrates from which the mRNA is manufactured (e.g., a DNA plasmid and ribonucleotides).
Applicable GMPs include GMP for starting materials (unless the process becomes aseptic/sterile, then GMPs for the manufacture of sterile products may apply) and the specific GMPs for ATMPs. UK manufacturers of starting materials will be expected to hold a manufacturer’s license.
Pharmacovigilance
Individualised mRNA cancer immunotherapies are a personalised medicine and therefore product traceability is essential to ensure the correct patient receives the correct product and to link any adverse reactions to specific products.
The Draft Guidance recommends manufacturers consult EU guidance on good pharmacovigilance practices (“GVP”), such as GVP P. II. The specific GMPs for ATMPs also provide guidance. According to the Draft Guidance, an appropriate traceability system could include bidirectional tracking between patient samples and selected neoantigens, the use of a unique patient identification number, and a clear production batch definition from tissue sampling to the labelling of the final container.
There also additional safety considerations that are specific to novel ATMPs such as individualised mRNA cancer immunotherapies. For example, post-authorisation safety studies, which investigate the long-term safety and effectiveness of the products in a real-world clinical setting, are expected to be included in a product’s risk management plan. Developers will also need to assess how changes to AI/ML tools involved in neoantigen selection may impact the safety and effectiveness of the therapy.
Further risk minimisation measures may include the provision of educational materials to healthcare professionals or product distribution only to accredited healthcare facilities demonstrating appropriate processes and infrastructure. The Draft Guidance does not indicate which accreditation body may be relevant.
Next Steps
Anyone wishing to comment on the Draft Guidance should do so before 31 March 2025 using the survey found here.
If you would like to discuss the Draft Guidance and what it may mean for your company’s operations and pipelines, please contact our specialist UK and EU teams: Grant Castle, Marie Doyle-Rossi, Raj Gathani and Sarah Cowlishaw.