RNA-Based Therapeutics: Regulatory Challenges and Safety Considerations

By Alicja Fiedorowicz, MSc, Associate Director, CMC at Allucent

RNA Therapeutics and the European Medicines Agency Framework

RNA-based therapeutics, including mRNA vaccines, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and others, represent a rapidly expanding class of medicines with transformative potential for a range of diseases. However, their regulatory landscape in Europe is complex and still evolving, as highlighted by the European Public Assessment Reports (EPARs) of approved RNA therapies. This article explores the principal regulatory challenges, with particular emphasis on insights gleaned from EPARs and the current European Medicines Agency (EMA) framework. 

Diversity and Classification of RNA-Based Therapeutics 

One of the foremost challenges is the heterogeneity of RNA-based products. According to EU legislation (EMA, 2015), RNA-based therapies are categorized differently based on their structure, mechanism of action, and method of production, rather than therapeutic indication. This includes distinctions between mRNA, ASOs, siRNAs, micro-RNAs, small activating RNAs, RNA aptamers, and RNA guides. Current EU classification principles include: 

• Vaccines are classified based on their target disease type (infectious vs. non-infectious diseases). 

• Non-vaccine RNA drugs are classified based on their method of production – whether the RNA is chemically synthesized or biologically produced. 

The latter comes from the requirements that in order to be classified as an Advanced Therapy Medicinal Product (ATMP), the molecule must be a ‘Biological medicinal product’ as outlined in the EMA reflection paper on ATMP classification and Commission Directive 2009/120/EC. The current EU regulatory framework was established before the advent of most RNA therapeutics, resulting in ambiguities.  

A key inconsistency arises from the fact that chemically synthesized RNAs may not qualify as biological medicines under the existing definition, even when they are functionally identical to biologically produced RNAs. This can result in two RNA products with identical sequences, differing only by production method, being regulated under entirely different legal frameworks, leading to inconsistencies in requirements for clinical trials, quality controls, and pharmacovigilance. This regulatory distinction is not trivial because if RNA therapeutics have Gene Therapy Medicinal Product (GTMP) status, it can have significant implications for regulatory requirements, including the need for long-term safety and efficacy monitoring as well as additional preclinical and clinical studies to assess risks such as germ-line transmission, insertional mutagenesis, and tumorigenicity (EMA, 2025).  

Global Regulatory Guidelines for RNA Therapeutics

There is a lack of harmonization between EU, US, and International Council for Harmonisation (ICH) regulatory definitions and classification approaches. This affects global development and commercialization strategies for RNA-based therapeutics. Differences in classification can result in conflicting data requirements, particularly for Chemistry, Manufacturing, and Controls (CMC), where expectations for product comparability, analytical methods, and release specifications may vary significantly depending on how a product is categorized. (For more information on Chemistry, Manufacturing, and Controls requirements, read our blog Cell Therapy Manufacturing: Analytical Testing, Validation, and Regulatory Considerations.) 

In ICH S12  Nonclinical Biodistribution Considerations for Gene Therapy Products, ICH has proposed a new definition for gene therapy products, which may help harmonize regulations for mRNA-based drugs. In ICH S12, gene therapy products are defined as follows: ‘GT products within the scope of this guideline include products that mediate their effect by the expression (transcription or translation) of transferred genetic matter’ and includes ‘Products that are intended to alter the host cell genome in vivo without specific transcription or translation (i.e., delivery of a nuclease and guide RNA by non-viral methods) are also covered in this guidance’. This definition does not mention the need for a GTMP to be a ‘biological active substance’ as required by EMA and hence is broader than that of the EMA. 

The new European pharma legislation has also proposed an expanded definition of GTMP.  In April 2023, the European Commission proposed new pharmaceutical legislation safeguarding the public health within the European Union. The European Parliament subsequently proposed a draft of amendments to the Commission proposal in 2024. Finally, the European Parliament agreed its position on the new rules in 2025. A summary of the definition of GTMPs are provided in the table below:  

European Commission Proposal (2023)	‘gene therapy medicinal product’ means a medicinal product, except vaccines against infectious diseases, that contains or consists of: (a) a substance or a combination of substances intended to edit the host genome in a sequence-specific manner or that contain or consists of cells subjected to such modification; or (b) a recombinant or synthetic nucleic acid used in or administered to human beings with a view to regulating, replacing or adding a genetic sequence that mediates its effect by transcription or translation of the transferred genetic materials or that contain or consists of cells subjected to these modifications;
European Parliament Reform (2024)	‘gene therapy medicinal product’ means a type 1 or type 2 medicinal product; (29a) “type 1 gene therapy medicinal product” means a medicinal product that contains or consists of a substance or a combination of substances that edit the host genome in a sequence-specific manner or that contain or consists of cells subjected to such modification;   (29b) “type 2 gene therapy medicinal product” means a medicinal product, except a vaccine against infectious disease that contains or consists of a recombinant or synthetic nucleic acid used in or administered to human beings with a view to regulating, replacing or adding a genetic sequence that mediates its effect by transcription or translation of the transferred genetic materials or that contain or consists of cells subjected to these modifications;
European Parliament (2025)	Per the initial European Commission wording (Row 1 above)

Regardless of the final wording that will be adopted, the Parliament, Commission, and Council have dropped the ‘biological medicinal product’ from the draft texts. This raises some intriguing regulatory questions, including for example a classification change of synthetic RNA based products pre- and post-implementation of the new Directive. Under the new EU framework, synthetic RNA therapeutics, including chemically synthesized mRNA, siRNA, and ASOs, could be classified as GTMPs, even when not biologically manufactured. As a result, CMC programs may need to incorporate additional GTMP specific requirements such as enhanced batch comparability data, potency testing, and gene editing safety assessments for RNA components like guide RNAs. 

Clinical Development for RNA Therapeutics 

In an effort to begin planning clinical development for RNA therapeutics, Sponsors should begin to map out key regulatory touch points. This should include an ATMP classification procedure with EMAs Committee for Advanced Therapies (CAT) in cases where there is any regulatory doubt regarding product classification. This is a free procedure, and following submission of the document package to EMA, a decision on classification can be expected by Day 60 if no additional information is required. Sponsors can also check the publicly available register of CAT decisions to understand their current thinking on ATMP product classification.  

Sponsors are advised to understand their product classification as soon as possible, as this will have major implications for the CMC and non-clinical and clinical data package required for their Marketing Authorisation Application. We envision a change in product classification with the incoming pharmaceutical legislation but expect a degree of flexibility from regulators to accommodate Sponsors who are in advanced development when this occurs.  

Conclusion 

The regulatory landscape for RNA-based therapeutics in Europe is complex, with significant challenges arising from the diversity of products, evolving definitions, and inconsistent legal statuses. EPARs of approved RNA therapies underscore the need for clearer, harmonized guidelines that can keep pace with technological advances and ensure consistent safety and efficacy standards. As RNA therapeutics continue to proliferate, ongoing regulatory evolution, guided by real-world experience and international collaboration, will be essential to address these challenges and support innovation while safeguarding public health.

At Allucent, we help sponsors navigate the complexities of RNA-based therapeutics and navigate the regulatory challenges in their programs. To learn more about how we can help, see Chemistry, Manufacturing and Controls | Allucent and Cell and Gene Therapy CRO | Allucent.  Our goal is to support you in meeting regulatory requirements and achieving key milestones with confidence, bringing innovative therapies to patients sooner.