Advisory committee will set the bar for acceptable evidence for vaccine EUA

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) is convening a virtual meeting October 22 to discuss the development, authorization, and licensure of future Covid-19 vaccines.

The meeting will take place in a highly charged atmosphere as 2 companies — AstraZeneca and Johnson & Johnson — competing in the race to develop a Covid-19 vaccine have paused their trials due to safety concerns, and a day after Astra Zeneca announced plans to resume their U.S. trial at the end of October, Reuters reported the death of a participant enrolled in the company’s Oxford trial. Adding to the tension is the constant drumbeat from the Trump administration to roll out a vaccine post haste, as well as the pushback from the FDA, which is requiring 2 months of safety data for its review before approval.

Against that backdrop, the FDA advisors are not slated to review any specific vaccines, but they will discuss studies that will need to be conducted pre- and post-licensure to evaluate the safety and efficacy of potential vaccines — including in specific populations such as children and pregnant women — and further evaluate vaccine immunogenicity and duration of effect. The committee will also discuss requirements for safety follow-up following an emergency use authorization and the need for post-marketing safety studies following approval of a biologics license application for a vaccine.

In a briefing document published in advance of the meeting, the FDA’s Center for Biologics Evaluation and Research (CBER) outlined a number of notable points regarding vaccine approval:

  • “For FDA licensure, a single set of regulatory requirements applies to all vaccines, regardless of the technology used to produce them.”
  • Understanding of SARS-CoV-2 immunology, and, specifically, vaccine immune responses that might predict protection against Covid-19, “is currently limited and evolving.”
  • “FDA is committed to providing a level playing field for sponsors on regulatory issues.”
  • Within 60 days after the current public health emergency ends, the FDA intends to revise and replace its current guidance with updated guidance.

Vaccine Development

In its briefing document, the FDA noted that, while immunogenicity is an important part of vaccine development, “the goal of development programs should be to pursue traditional approval via direct evidence of vaccine efficacy in protecting humans from SARS-CoV-2 infection and/or disease,” adding that vaccine development may be accelerated “based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible.”

The agency also pointed out additional concerns for vaccine development, stressing that vaccine trials must assure the safety of participants, maintain compliance with good clinical practice, and minimize risks to trial integrity, a difficult task given the operational challenges inherent to conducting trials during a public health emergency.

Regarding testing vaccine efficacy and safety among specific populations, the FDA recommended that trial sponsors conduct developmental and reproductive toxicology (DART) studies prior to enrolling pregnant women or women of childbearing potential. And, while the agency “encourages” the inclusion of diverse populations in clinical trials, it is not required.

As for potential endpoints in vaccine trials, the agency noted the following:

  • The primary efficacy endpoint estimate for a placebo-controlled trial should be ≥50%.
  • Either laboratory confirmed Covid-19 or laboratory SARS-CoV-2 infection is an acceptable endpoint for a Covid-19 vaccine efficacy trial.
  • The agency argued for the standardization of efficacy endpoints, recommending that trial authors define either the primary or a secondary endpoint as virologically confirmed SARS-CoV-2 infection with one or more symptoms (fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle/body aches, headache, new loss of taste or smell, sore throat, congestion/runny nose, nausea/vomiting, and diarrhea).
  • Sponsors should consider powering trials with severe Covid-19 as an endpoint — defined as confirmed SARS-CoV-2 infection with clinical signs of severe illness at rest; respiratory failure; shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit (ICU); or death — as either a primary or a secondary endpoint.

The FDA also stressed that in addition to demonstrating safety and efficacy, only Covid vaccines that can be manufactured in a consistent manner will be licensed, and earning an EUA will require adequate manufacturing information to ensure quality and consistency on top of standard trial data.

For a vaccine to be licensed, the stability and expiry date of the vaccine in its final container should be demonstrated “using final containers from at least three final lots made from different vaccine bulks,” the agency wrote, and manufacturers will need to prove that the product maintains its potency by providing postmarketing shelf-life data.

EUAs and ERD

The FDA intends to convene an open session of the VRBPAC before issuing any EUA for a Covid-19 vaccine in order to determine whether or not the benefits of a particular vaccine outweigh any known or potential safety concerns. And a key safety concern for any Covid-19 vaccine is enhanced respiratory disease (ERD), the agency noted.

Exposure to any Covid-19 vaccines opens up “potential for vaccine-induced enhanced respiratory disease (ERD) when vaccine recipients are subsequently exposed to wild-type SARS-CoV-2…[though] ERD associated with human coronavirus vaccines (SARS and MERS vaccines) has thus far been demonstrated only in animal models of SARS-CoV-1 and MERS-CoV and has been characterized by a Th2-biased immune response,” the FDA explained.

“Issuance of an EUA for a Covid-19 vaccine prior to the completion of large randomized clinical efficacy trials could reduce the ability to demonstrate effectiveness of the investigational vaccine in a clinical disease endpoint efficacy trial to support licensure, and such… trials may be needed to investigate the potential for vaccine-associated ERD,” the agency continued. “Thus, for a vaccine for which there is adequate manufacturing information, issuance of an EUA may be appropriate once studies have demonstrated the safety and effectiveness of the vaccine but before the manufacturer has submitted and/or FDA has completed its formal review of the biologics license application.”

A Flaw in the Trial Designs

As the RVBPAC prepares to evaluate vaccine efficacy and safety data coming down the pipeline, Peter Doshi, PhD, assistant professor of pharmaceutical health services research at the University of Maryland School of Pharmacy in Baltimore and associate editor of The BMJ, raised the question of whether current vaccine trials can actually provide enough information to prove that Covid-19 vaccines will save lives.

In a feature published in The BMJ, Doshi cited Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who noted that a Covid-19 vaccine should both reduce the likelihood that you will get severely ill and go to the hospital and prevent infection/interrupt disease transmission. “Yet the current phase III trials are not actually set up to prove either,” Doshi wrote. “None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.”

Doshi noted that, while public-facing information suggests that vaccine trials are assessing patients with severe Covid-19, laboratory confirmed infections with only mild symptoms qualify as meeting the primary endpoint definitions in all ongoing phase III trials for which details have been released: “In Pfizer and Moderna’s trials, for example, people with only a cough and positive laboratory test would bring those trials one event closer to their completion. (If AstraZeneca’s ongoing UK trial is designed similarly to its ’paused’ US trial for which the company has released details, a cough and fever with positive PCR test would suffice).”

He also pointed out that, while Moderna’s phase III trial has hospital admissions as a key secondary endpoint, Moderna’s chief medical officer Tal Zaks, MD, PhD, told The BMJ that the trial doesn’t have the statistical power to assess that outcome. And, Zaks added, their trial will not demonstrate prevention of transmission, “because in order to do that you have to swab people twice a week for very long periods, and that becomes operationally untenable.”

“Hospital admissions and deaths from Covid-19 are simply too uncommon in the population being studied for an effective vaccine to demonstrate statistically significant differences in a trial of 30,000 people,” Doshi wrote. “The same is true of its ability to save lives or prevent transmission: the trials are not designed to find out.”

This article includes original reporting from Lynne Peterson and Diana Quinn of Trends-in-Medicine.

John McKenna, Production Editor, BreakingMED™

Additional reporting by Lynne Peterson, Diana Quinn, Trends-in-Medicine

Doshi co-wrote an op-ed on this topic with Eric Topol, who is quoted in his article, and he co-signed an open letter to the FDA calling for independence and transparency in Covid-19 vaccine related decision making. Doshi had no other relavant relationships to disclose.


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Topic ID: 88,725,730,933,190,31,926,561,927,725,928,925,934