mRNA Clinical Trials: Key Regulatory Considerations

Over the past two years, Operation Warp Speed brought mRNA-based vaccines into the spotlight, as organizations like Moderna and Pfizer/BioNTech raced to develop a COVID-19 vaccine. While scientists have worked on messenger ribonucleic acid (mRNA) for years, these successes have enabled researchers to use mRNA technology to develop vaccines against a number of other infectious agents, as well as to develop potential therapeutics for a number of other disease indications.

Curious about mRNA technology and the regulatory requirements for its use in clinical trials? You’re not alone—our biosafety team frequently receives questions from study sponsors, contract research organizations (CROs), and sites. Read on as we respond to our most commonly asked questions.

What is mRNA?

mRNA is a biological molecule used by cells to serve as an intermediary between the genes encoded in DNA and the proteins those genes code for.

According to the Central Dogma of Molecular Biology, cells contain all the instructions for producing proteins in DNA-based genomes, as shown in the figure below. It’s impractical for cells to make protein directly from DNA, so cells use a process called transcription to reproduce the “blueprint” for making a single protein into mRNA. A separate process called translation reads the genetic instructions in the mRNA and uses it to make protein.

Illustration of translation and transcription processes

Making mRNA is akin to photocopying a single page from a standard operating procedure (SOP) manual (i.e., the DNA genome) to carry out a single procedure (i.e., making a specific protein). Cells can make many mRNA “photocopies” of the genetic blueprint, which allows for efficient mass production of the desired protein.  

mRNA contains genetic information (i.e., nucleic acids), and the U.S. Food and Drug Administration (FDA) regulates mRNA technology as a biologic.  

How do mRNA Vaccines Work?

Typically, mRNA-based vaccines are delivered within lipid nanoparticles in oily casings designed to protect the mRNA. The lipid nanoparticles have similar chemical makeup as cell membranes, so once injected into recipients, the lipid nanoparticles merge with the recipient’s cell membranes to allow the mRNA to enter their cells at the injection site.

Once inside a cell, ribosomes read the mRNA and follow the instructions found in the mRNA to make protein – a process called translation. mRNA-based vaccines present that protein to the immune system, stimulating an adaptive immune response against the protein encoded in the mRNA.

mRNA-based vaccines against SARS-CoV-2, the virus that causes COVID-19, encode the virus’ spike protein. This approach is comparable to a subunit vaccine, in the sense that the vaccine only delivers the key target antigen for the immune system to attack, without the added risk associated with utilizing a live attenuated virus or a heat or chemically inactivated dead coronavirus.

Illustration of how an mRNA-based vaccine works against SARS-CoV-2

As successful mRNA-based vaccines helped prevent severe COVID-19, the technology is also actively under study for use against a number of other infectious agents such as Zika virus, respiratory syncytial virus (RSV), influenza, herpes viruses, and others. The vaccine platform is also utilized to develop anti-cancer vaccines.

What are the Regulatory Requirements for Clinical Trials of mRNA Vaccines?

Since FDA regulates products utilizing mRNA as biologics, sponsors must submit an investigational new drug (IND) application through the FDA’s Center for Biologics Evaluation and Research (CBER) and receive a biologics IND number prior to initiating any human clinical trials. Assuming human trials are successful, sponsors can seek approval to market an mRNA-based product through the CBER biological license application (BLA) process.

Due to the public health crisis posed by the COVID-19 pandemic, Pfizer/BioNTech’s and Moderna’s mRNA-based COVID-19 vaccines initially received emergency use authorizations (EUAs). However, later BLAs provided full approvals for both.

Prior to initiating a clinical trial involving human research subjects, a research ethics committee called an institutional review board (IRB) must provide approval. In Canada, the committee is called a research ethics board (REB), and in the EU it’s an ethics committee (EC). The Japanese equivalent is the ethical review committee (ERC).

Do Clinical Trials Involving mRNA Delivery to Human Research Subjects Require IBC Review?

Research involving engineered genetic material may also require an institutional biosafety committee (IBC) to review the research. So, in a word, yes – if there are ties to National Institutes of Health (NIH) support.

NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) Section III-C-2d calls for IBC review of research involving the deliberate transfer of engineered genetic material into human research participants, where the engineered genetic material “can be translated or transcribed.”

mRNA functions within a cell by being translated into a protein. In the case of mRNA-based vaccines, that protein is the antigen used to trigger an immune response.

Why Do Trials Involving mRNA Need IBC Review?

NIH provides the standard for oversight of research involving genetic engineering and gene therapy. The NIH Office of Science Policy (OSP) promulgates the NIH guidelines and calls for local oversight at the research site by an IBC reporting to the NIH OSP.

An IBC is charged with protecting study personnel, the community, and the environment from exposure to engineered genetic material. An IBC may also advise the IRB in assessing risks to the study participants.

For more information on IRB and IBC responsibilities, check out our blog IBC vs IRB: What’s the Difference?

The IBC review requirement applies to research involving engineered genetic material taking place at sites receiving support from the NIH or participating in NIH-supported research. Sponsors or sites receiving any NIH support are obligated to comply with IBC review, regardless of whether the support is associated with the particular gene therapy study in question.

In cases where the agency did not provide monetary support, NIH may still require IBC review if the agency collaborated in the research of the study agent or provided materials for its development, as stated in NIH Guidelines Section I-C-1-a-(2).

Even if there are truly zero NIH funds or collaboration involved, IBC review is considered a best practice: “Individuals, corporations, and institutions not otherwise covered by the NIH Guidelines are encouraged to adhere to the standards and procedures set forth in Sections I through IV” (Section IV-D-1).

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