The following article is adapted from Nice Insight’s Messenger Ribonucleic Acid (mRNA) Market Insight, CDMO Pricing, and Competitor Benchmarking report and provides an in-depth examination of the current regulatory environment, key guidance documents, and anticipated changes that will shape the future of mRNA drug development.
The regulatory landscape for mRNA therapeutics and vaccines is undergoing significant discussion within the industry and is expected to evolve going forward. One key question has to do with whether mRNA products should be considered gene therapies.
Some experts believe that, on the basis of the mechanism of action of mRNA vaccines and therapeutics, they should absolutely be considered gene therapies.1 Others argue adamantly that, because mRNA products do not alter the genome, they should not be classified as gene therapies.
Unlike in vivo gene therapies that integrate new genes into the genome to replace missing or faulty ones, mRNA directs cells via temporary transgene expression to produce proteins to fight viruses or cancer or facilitate some desired biochemical reaction that addresses a particular disease mechanism. In addition, mRNA is rapidly degraded in the body.
For this reason, the term “genetic medicine” is now frequently applied to mRNA therapeutics and vaccines.1 Neither the United States nor the European Union has published regulatory guidance specific to mRNA drug and vaccine development. There is a World Health Organization (WHO) guidance covering mRNA vaccines that discusses “regulatory considerations regarding key aspects of the manufacture and quality control, and nonclinical and clinical evaluation, of preventive mRNA vaccines against infectious disease for human use.”2
Regulations are different in different parts of the world, further complicating the issue.3,4 No mRNA-specific regulations have been issued in the United States or Europe. In the United States, the two mRNA COVID-19 vaccines were approved by the Center for Biologics Evaluation and Research (CBER), which is responsible for evaluating biologics, vaccines and cell and gene therapies. They are not included in the agency’s list of approved gene therapies. Neither are any of the other three RNA-based therapeutics (not mRNA) approved by the agency. In Europe, RNA vaccines are regulated as vaccines, while mRNA therapeutics are classified as gene therapies.3
Therapeutics are classified as a biologic based on how they are manufactured. For this reason, mRNA and any other RNA made by in vitro transcription (IVT) are considered biologics and therefore regulated by CBER. CBER was created to regulate therapies that are produced by biological processes and therefore known to have complex drug substance profiles. An antibody therapeutic, for example, will have numerous glycosylation isoforms in addition to a low level of chemical modification to the residues, such as oxidation and deamidation. CBER has established a regulatory strategy to evaluate these therapies for safety and efficacy, while allowing for variation within the therapeutic.
Synthetically manufactured RNAs, such as small interfering rNA (siRNA), microRNA (miRNA), antisense oligos (ASOs), and aptamers, are regulated by the Center for Drug Evaluation and Research (CDER) because they are synthetically produced. CDER requires that every impurity in a product sample be identified and characterized. With peptides and oligonucleotides, these impurities can number in the thousands, and therefore cannot be characterized by the standards of traditional small molecules. It has yet to be determined how these synthetic RNAs can be evaluated along the same logic as biologics, which are known to have a range of modifications.
There are some regulations from the WHO and the U.S. Food and Drug Administration (FDA) on plasmid DNA vaccines, liposome drug products, and drugs and biologics that contain nanomaterials.3 ISO is reported to be developing a guidance on methods of analyzing mRNA–LNPs (lipid nanoparticles).
There are two general but very different guidance documents that can provide some assistance to mRNA developers. One was issued by the WHO and specifically covers mRNA vaccines delivered as LNPs (i.e., excluding therapeutics),2 and the other is a draft guideline (second edition) from the USP on analytical procedures, again specifically for mRNA vaccines.5 It has been suggested this document will be expanded to include therapeutics as well.3
In light of the success of the COVID-19 vaccines and the explosion of mRNA vaccines and therapeutics entering clinical development, the WHO issued some general guidance regarding the development and manufacture of mRNA vaccines (including self-amplifying RNA (saRNA) products) in December 2021.2 The guidance is purposefully designed to be flexible due to the fact that most processes, analytical methods, and control strategies remain proprietary. The guidance therefore emphasizes the need for developers to speak with relevant regulatory authorities regarding how their specific approaches may impact the quality, safety, and efficacy of mRNA vaccines.
The WHO guidance covers “regulatory considerations regarding key aspects of the manufacture and quality control, and nonclinical and clinical evaluation, of preventive mRNA vaccines against infectious disease for human use.” Detailed information must be provided on the mRNA drug substance and the mRNA–LNP drug product, including the relevant biological characteristics; rationale for selection of target antigen(s) and any encoded proteins, such as cytokines; and reasons for the addition of any coding and noncoding sequences. The full formulation must be described, and rationales for its composition and target dosing regimen provided. Examples of analytical methods are provided for different in-process and product-release applications. The guidance also directs developers to refer to other relevant WHO guidelines, particularly those relating to GMP compliance.
The second version of the U.S. Pharmacopeia (USP) guideline on procedures for mRNA vaccine quality determination was published in April 2023 (the first was published in February 2022) and includes both changes based on feedback and some additional donated methods.5 USP is also evaluating several methods that, if applicable to a broad range of mRNA products, may be advanced as documentary standards.
More information on recommended analytical methods and techniques can be found in the April 2023 version of the USP guideline on procedures for mRNA vaccine quality determination.5 The draft guidelines include methods to evaluate the content, identity, purity, mRNA integrity, and safety parameters of mRNA vaccines, some of which, the group says, may also apply to other mRNA therapeutics. Tables of methods for characterization and release testing for plasmid DNA, mRNA drug substance, and mRNA–LNP drug product, as well as a table on methods for mRNA production process and testing, are provided. The group continues to seek input from industry and academia and is also testing assays that could ultimately become compendial methods if they have broad applicability to many different types of mRNA products.
The overall goal is to establish “a set of analytical methods for mRNA quality to support developers, manufacturers, regulatory agencies, and national control laboratories worldwide” and “create a shared understanding of mRNA quality attributes to accelerate product development, guide successful scale-up of manufacturing and fuel regulatory confidence that manufacturers are employing best practices and appropriate quality controls when using this new modality.”
A paper published by a group of three European researchers summarized the regulatory requirements in the United States and Europe regarding preclinical biodistribution studies for mRNA therapeutics and vaccines.6
Like the WHO, the European Medicines Agency (EMA) is also concerned about the lack of specific guidance for mRNA vaccines in the face of the large number of candidates under development. The agency announced publication of a new concept paper in June 2023 describing its plans to issue guidance on the quality requirements for mRNA products, including “specific aspects regarding the manufacturing process, characterization, specifications and analytical control as well as the definition of active substance and finished product.”7
As is the case with the WHO and USP guidances, the EMA guideline will focus solely on mRNA (including saRNA) vaccines for infectious diseases. It will include definitions of all materials, recommendations for control of starting materials, identification and control of impurities, specifications for drug substance and drug product, and potency testing and formulation strategies, among other aspects.
Additional topics to be discussed will include the development and testing of bivalent and multivalent vaccines, specifics related to saRNA–LNP vaccines, non-LNP delivery systems, and the application of platform technologies. Notably, the EMA guideline will take the WHO guidance document on mRNA vaccines “into account.”
The FDA, meanwhile, updated and finalized guidance for the development of COVID-19 vaccines, including mRNA products, in late October 2023.8 The guidance covers considerations for the generation of chemistry, manufacturing, and controls (CMC) and preclinical data, analytical methods, clinical trials, and post-marketing studies.
Even though mRNA products are quite new, the administration of hundreds of millions of doses of COVID-19 mRNA vaccines to people around the world has generated a vast quantity of safety and performance information on a highly disperse population — a unique situation for any class of drug, let alone a new modality.
Despite the existence of these historic data, the approval of future mRNA vaccines and therapeutics is not expected to proceed along the same path as that of the COVID-19 vaccines.9 The pressure of the pandemic is no longer a driver for such accelerated development. In addition, the lack of clarity on the basic definition of mRNA products and the lack of any mRNA-specific guidelines suggests that regulatory compliance will be complex.
On the other hand, the rapid approval of newer versions of the first COVID-19 vaccines targeting one or more new variants raises hopes for a potentially accelerated pathways for products produced using a true platform manufacturing process in which only the mRNA sequence is changed without significantly impacting critical quality attributes (CQAs). Even so, the issuance of mRNA-specific guidelines with stricter characterization and quality requirements is expected.1
1. “Medicine’s Hot New Modality, mRNA, Faces Unclear Regulatory Landscape.” BioSpace. Accessed 28 Jan. 2024.
2. Evaluation of the Quality, Safety and Efficacy of Messenger RNA Vaccines for the Prevention of Infectious Diseases: Regulatory Considerations. Accessed 28 Jan. 2024.
3. Welch, Anna Rose. “Moderna’s Regulatory Journey: 3 Takeaways to Foster The mRNA Renaissance.” Cell & Gene Collaborative. 22 Mar. 2023.
4. Guerriad, Mathieu, and Evelyne Kohli. “RNA-Based Drugs and Regulation: Toward a Necessary Evolution of the Definitions Issued from the European Union Legislation.” Frontiers in Medicine. 17 Oct. 2022.
5. Analytical Procedures for mRNA Vaccine Quality (Draft Guidelines)- 2nd Edition. USP-NF. Accessed 28 Jan. 2024.
6. Vervaeke, P., et al. “Regulatory Guidelines and Preclinical Tools to Study the Biodistribution of RNA Therapeutics.” Advanced Drug Delivery Reviews, vol. 184: 114236 (2022).
7. Development of a Guideline on the Quality Aspects of mRNA Vaccines - Scientific Guideline. European Medicines Agency. Accessed 28 Jan. 2024.
8. Haigney, Susan. “FDA Finalizes Guidance on Development of COVID-19 Vaccines.” BioPharm International. 24 Oct. 2023.
9. Welch, Anna Rose. “Beyond Moderna’s Regulatory Legacy: (Re)Defining The mRNA Regulatory “Norm.”” Cell & Gene Collective. 22 Mar. 2023.
