BioRationality: Should mRNA Copies Be Filed as NDAs or Biosimilars?

Biosimilars are only intended for therapeutic proteins, and to establish this, the FDA moved them from Center for Biologics Evaluation and Research to Center for Drug Evaluation and Research, yet they are still approved under the biologics license application (BLA) pathway. There was no rationale except the FDA was unsure how biosimilars would emerge. The determining factor was whether a product could be fully characterized by the amino acid sequence and its secondary and tertiary structures. So far, so good. Now comes a challenge for the FDA.

The FDA classifies messenger RNA (mRNA) therapies under "gene therapy," particularly when the mRNA modifies protein expression to treat or prevent disease. This classification aligns with the FDA’s regulatory framework for gene therapies, which includes products that use nucleic acids to alter cellular functions. The FDA's "Guidance for Industry: Long Term Follow-Up After Administration of Human Gene Therapy Products" (2020) states that gene therapy includes any therapy that uses nucleic acids, such as mRNA, to elicit a therapeutic effect.

The mRNA products are made up of a nucleoside chain that does not undergo any structural transformation to a higher order, and they can be compared with a copy of a chemical molecule no less than a chemical molecule. Again, like biosimilars, there was no vision that this question would arise one day, the FDA decided not to address this question. First, RNA is not a gene; it does not enter the nucleus or have no effect on the genes or the DNA. It is a chemical. So, I asked the FDA why it should not be eligible for abbreviated new drug application (NDA) 505(b)(2) filing or 351(k) filing.

The answer was no. It will be a new BLA if you copy an approved mRNA product, for example, if I copy the Pfizer of Moderna COVID-19 vaccine. No one could tell the difference between my product and the product coming out of Pfizer or Moderna, but it will be subject to extensive testing of gene therapy products. This new and exciting challenge has profound impacts as thousands of mRNA products are expected to land soon, including therapeutic proteins, protein vaccines, and many more. They will be available once their exclusivity and patents expire, but we do not know which legislation will allow them to be.

And then there is another category to be considered: a product approved under 351(a), and upon the expiry of exclusivity if I deliver the same protein using its mRNA, would this be considered a “biosimilar”? We have the same route of administration, but everything else is different and does not comply with biosimilars' qualifications.Can we expect a “hybrid biosimilar” category for such products? It is still a gene therapy product, states the FDA. I disagree.

Regardless of the regulatory pathway for these products, I anticipate a deluge of such possibilities that the FDA will face, and to help the FDA, I have filed a petition with an outline of a new guideline for copies of nucleoside products and another guideline for alternate expression of proteins, such as from recombinant to ribosomes. It will be an exciting future from a scientific and logical perspective. I do not think the FDA is ready.