The Regulatory Pathway To A Vaccine For COVID-19

By John Fuson, Anne Li and Mena Gaballah
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Law360 (May 22, 2020, 3:05 PM EDT) --
John Fuson
John Fuson
Anne Li
Anne Li
Mena Gaballah
Mena Gaballah
In the ever-changing landscape of COVID-19, the long-term goal remains constant: the need for a safe, effective vaccine that can be produced on a massive scale quickly. Vaccine development is difficult, however, both technically and procedurally. Nonetheless, it remains the key to controlling — or eradicating — the current pandemic.

To expedite vaccine development, the U.S. government has launched Operation Warp Speed. The details of the operation are still unclear, but the federal government will pick promising vaccine candidates, offer funding and resources, fast-track trial and aid in manufacturing efforts. The ultimate goal is to have 300 million vaccine doses ready by January 2021. Details of Operation Warp Speed are expected to be shared before the end of the month.

Pathways for Approval

The average vaccine takes about 10.7 years to develop and has a market entry probability of about 6%.[1] In other words, more than nine out of every 10 vaccines fail, and the successful candidates take over a decade to enter the market.

Vaccine development and approval, which in the U.S. is overseen by the U.S. Food and Drug Administration, can be broken down into four major stages: (1) exploratory, (2) preclinical, (3) clinical development, and (4) review and approval.

In an effort to expedite the response to COVID-19, exploratory steps that usually are taken sequentially are being done simultaneously. Researchers are still learning about the disease and its pathogen while at the same time trying to create and test vaccines. This means that new information that comes to light during exploration could have far-reaching impacts in better understanding the nature of the pathogen and the best way to develop an effective vaccine.

Exploration is followed by preclinical development research that is usually conducted in lab assays and on animal models. Relying on preclinical data, a manufacturer may then submit an investigational new drug, or IND, application to the FDA, which describes the vaccine and summarizes its method of manufacture and quality control. The IND also describes the vaccine's safety profile, immune response in animal testing, as well as the proposed clinical protocol for human studies.

Premarket vaccine clinical trials are typically conducted in three phases.

Phase I consists of safety and immunogenicity studies on a small number of participants to assess whether the vaccine and its adjuvants are safe for human-use and what kind of immune response is provoked.

Phase II may enroll hundreds of patients and considers the immunization schedule, dose-ranges, and method of delivery.

Phase III enrolls hundreds or thousands of participants and examines efficacy and safety on a large-scale. Researchers may notice rare adverse effects during Phase III due to the larger sample size of participants.

If after the first three phases the vaccine appears to be safe and effective, a developer may submit a biologics license application, or BLA. The FDA will review a BLA for safety and efficacy to determine whether the expected benefits of a vaccine outweigh the potential risks and, if so, approve the application. Then, the product may enter the market.

All potential adverse events cannot be known from limited Phase I through Phase III studies, particularly with an accelerated timeline. Manufacturers may therefore conduct Phase IV studies after product launch to collect data from the general population. Manufacturers and the government also rely on the Vaccine Adverse Events Reporting System to identify vaccine-related side effects and problems.

With Operation Warp Speed, the FDA may skip some steps and use an emergency use authorization to allow promising vaccines to enter the market before completing all phases of clinical trials. U.S. Health and Human Services Secretary Alex Azar declared a public health emergency on Jan. 31, which gave the FDA discretion to authorize the emergency use of an unapproved product or an unapproved use of an approved product, provided that other statutory criteria are met. These criteria include:

  • The agent referred to in the declaration can cause serious or life-threatening disease or condition;

  • Evidence of effectiveness based on the totality of scientific evidence available;

  • The known and potential benefits outweigh the known and potential risks; and

  • There is no adequate, approved and available alternative.

It is clear that the SARS-CoV-2 virus is an agent that can cause life-threatening disease and that no adequate, approved and available alternatives exist. Thus, in deciding whether to issue an EUA, the FDA will have to determine whether the risk posed by a particular vaccine or vaccines is outweighed by the potential benefit to public health.

Another process the FDA may rely on is its fast track process. The agency may grant fast track designation to expedite the review of a drug necessary to treat a serious condition and fill an unmet medical need. The FDA may grant a drug fast track review for various reasons, but the most likely one is because a new vaccine will address an emerging public health need. After receiving this designation, a manufacturer is eligible for more frequent meetings with the FDA, accelerated approval and priority review.

Vaccine Front-Runners

Although hundreds of COVID-19 vaccine trials are being conducted around the world, a few classes of vaccine are among the most common. The first category is nucleic acid vaccines in the form of deoxyribonucleic acid or ribonucleic acid. Another promising category is protein-based vaccines. A third major category is attenuated or inactivated viral vaccines which rely on a weakened or uninfectious form of the virus to prompt the immune system's response. This third category is the most common, used to make vaccines for the flu and polio.

Moderna's mRNA-1273 vaccine has garnered attention as a promising messenger RNA candidate. The vaccine has been cleared by the FDA to enter into a Phase II trial comprising of 600 participants. The Phase II trial will assess safety and immune response to a two-vaccine course dosed 28 days apart.

Last month, the Biomedical Advanced Research and Development Authority committed up to $483 million in funding for mRNA-1273. On May 12, Moderna Inc. announced that it received FDA fast track designation for its vaccine candidate and planned to begin a Phase III study early this summer. Moderna's vaccine works by causing the body to partially manufacture proteins that SARS-CoV-2 uses to infect humans. The body's immune system is then trained to recognize the virus by looking for these proteins.

Oxford University's Jenner Institute also appears to be moving quickly and is expected to launch a 6,000 participant Phase II study this month. If the trial demonstrates that the vaccine is both safe and effective, the Jenner Institute, in collaboration with AstraZeneca PLC, plans to have millions of doses available by September.

Researchers at the institute benefited from having already acquired safety data on a similar vaccine that was being tested for Middle East Respiratory Syndrome — a different species in the coronavirus family. The Oxford vaccine uses a virus that has been genetically modified to be unable to replicate in the body.

Novavax Inc. received a $384 million grant from the Coalition for Epidemic Preparedness Innovations on May 12. The company is developing NVX-COV2373, a vaccine currently in Phase I of testing with results due in July. Novavax is relying on nanoparticle technology that is showing promise in influenza vaccine development.

Other current candidates include Inovio Pharmaceuticals Inc., Johnson & Johnson, CanSino Biologics Inc., and the GlaskoSmithKline/Sanofi collaboration.

All of these vaccines are being fast tracked by the FDA in the hope that at least one will prove safe and effective. If that threshold can be met, approval or a more limited EUA would follow.



John Fuson and Anne Li are partners, and Mena Gaballah is an associate, at Crowell & Moring LLP.

The opinions expressed are those of the author(s) and do not necessarily reflect the views of the firm, its clients, or Portfolio Media Inc., or any of its or their respective affiliates. This article is for general information purposes and is not intended to be and should not be taken as legal advice.


[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603987/.

For a reprint of this article, please contact reprints@law360.com.

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