FDA at Warp Speed

Updated FDA Guidance Document (February 22, 2021)

Since the original SARS-CoV-2 virus was identified in Wuhan, China, the virus has continued to evolve and many variants of the original virus have been found around the world. The most common of these are the United Kingdom variant (B.1.1.7), the South African variant (B.1.351), and the Brazilian variant (P.1). There is emerging evidence that the first generation COVID-19 vaccines (Pfizer/BioNTech: BTN-162b2, Moderna: mRNA-1273; Janssen/Johnson & Johnson: JNJ-7836735) may be less effective against some variants of the SARS-CoV-2 virus compared to the original virus. To date, the South African variant has caused the greatest concern. In a press release issued on February 22, 2021, the FDA stressed: “At this time, available information suggests that the FDA-authorized vaccines remain effective in protecting the American public against currently circulating strains of SARS-CoV-2. However, if there is an emergence of SARS-CoV-2 variant(s) in the U.S. that are moderately or fully resistant to the antibody response elicited by the current generation of COVID-19 vaccines, it may be necessary to tailor the vaccines to the variant(s).”

In response to this potential need, the FDA updated the Guidance document, Emergency Use Authorization for Vaccines to Prevent COVID-19, by adding recommendations concerning the development of modified vaccines specifically tailored to enhance efficacy against emerging SARS-CoV-2 variants. As described in Appendix 2 of the Guidance document, vaccine manufacturers may request authorization for emergency use of a modified vaccine by submitting an amendment to their original EUA request. The FDA will not require modified vaccines to be evaluated in a large Phase 3 trial, as long as they are developed by the original vaccine developer and manufactured using the same processes as the original vaccine. Instead, the FDA recommends that vaccine developers conduct immunogenicity studies to compare the immune response (e.g., development of antibodies in the blood that can be measured by laboratory tests) stimulated by the modified vaccine to that stimulated by the original vaccine. The FDA recommends that these types of studies should be conducted in people who have not had COVID-19 or received a COVID-19 vaccine as well as in people who have already received one of the original COVID-19 vaccines. The updated Guidance document also describes the type of safety data required for emergency use authorization. Potentially, these studies would only take a few months to complete.

FDA Press Release (January 4, 2021)

On January 4, 2021, the FDA made it clear that they it can go fast (working overtime, cutting red tape as much as possible, giving high priority to the review of vaccines to prevent COVID-19), but that they will not be rushed. Over the past couple of weeks, there has been a lot in the news about the possibility of “tinkering” with the dosage regimen for the Pfizer and Moderna vaccines to make the vaccines available to more people. This includes: cutting the dose in half, only giving people the first shot (both vaccines require 2 shots separated by at 3-4 week period), and increasing the length of time between doses. In their press release, the FDA makes it clear that none of these modified dosage regimens have been tested and that substantial harm could be done by “tinkering” with the regimens without any evidence of safety and effectiveness. The press release makes it clear that FDA actions are being guided by science and public health concerns. The press release is definitely worth reading in its entirety!

Advisory Committee Meeting (December 17, 2020)

The FDA Vaccines and Related Biological Products Advisory Committee met on December 17, 2020 to provide expert advice to the FDA concerning issuance of an Emergency Use Authorization for the Moderna COVID-19 vaccine, mRNA-1273. Before the meeting, members of this committee were given a three documents, one briefing document prepared by Moderna, an addendum to this briefing document also prepared by Moderna, and a briefing document prepared by the FDA. The meeting can be viewed on the FDA YouTube channel. The table below shows the list of speakers. For those who wish to watch parts of the meeting on YouTube, the first column shows the time when each presentation started. If you would just like to see the slides used during each presentation, click on the title of the presentation.

Advisory Committee Meeting (December 10, 2020)

The FDA Vaccines and Related Biological Products Advisory Committee met on December 10, 2020 to provide expert advice to the FDA concerning issuance of an Emergency Use Authorization for the Pfizer-BioNTech COVID-19 vaccine, BTN162b2. Before the meeting, members of this committee were given a two briefing documents, one prepared by Pfizer and one prepared by the FDA. A transcript of the meeting can be found here. The meeting can be viewed on the FDA YouTube channel. The table below shows the list of speakers. For those who wish to watch parts of the meeting on YouTube, the first column shows the time when each presentation started. If you would just like to see the slides used during each presentation, click on the title of the presentation.

Advisory Committee Meeting (October 22, 2020)

The FDA Vaccines and Related Biological Products Advisory Committee met on October 22, 2020 to provide expert advice to the FDA on the following questions.

1. Please discuss FDA’s approach to safety and effectiveness data as outlined in the respective guidance documents.
2. Please discuss considerations for continuation of blinded Phase 3 clinical trials if an EUA has been issued for an investigational COVID-19 vaccine.
3. Please discuss studies following licensure and/or issuance of an EUA for COVID-19 vaccines to:
   1. Further evaluate safety, effectiveness and immune markers of protection
   2. Evaluate the safety and effectiveness in specific populations

Before the meeting, members of this committee were given a briefing document with the title, Development, authorization and licensure of vaccines to prevent COVID-19. A summary of the meeting minutes can be found here. The entire meeting can be viewed on the FDA YouTube channel. The table below shows the list of speakers. For those who wish to watch parts of the meeting on YouTube, the first column shows the time when each presentation started. If you would just like to see the slides used during each presentation, click on the title of the presentation.

Guidance Document (October 2020)

The FDA issued a guidance document for vaccine developers who are planning to submit a request for an Emergency Use Authorization (EUA). The document contains recommendations concerning the types of information EUA requests should include.

In November, the FDA created a webpage that highlights major points in this guidance document in user-friendly language. It is about a 10-minute read and answers questions like:

• What is a EUA?
• How are COVID-19 vaccines being tested?
• What kinds of safety and efficacy data are required before a EUA will be issued?
• What are the plans for monitoring vaccine safety after a EUA is granted?

Guidance Document (June 2020)

To reduce the time needed to obtain FDA approval for a COVID-19 vaccine, the FDA published a guidance document (Development and Licensure of Vaccines to Prevent COVID-19) describing the kinds of things it will look at when deciding whether to approve a vaccine.  Key points from this document are outlined below.

Participants in Phase 3 Studies

• Thousands of people will probably need to be enrolled in these studies
• Studies designed to assess protection against severe COVID-19 should include people with chronic health problems that increase the risk of severe disease
• Studies should exclude people who currently have COVID-19, but they do NOT need to exclude people who have had COVID-19 in the past
• Studies should recruit people with diversity in mind
  • Racial and ethnic minorities should be well represented because they have been most affected by COVID-19
  • Elderly people and people with chronic health problems should be included
  • Safety for pregnant women and women who may become pregnant needs to be considered
  • Safety for children needs to be considered

Trial Design

• Phase 3 studies should randomize participants to receive either the experimental vaccine or a placebo vaccine
• Study participants should not know if they received the experimental vaccine
• People interacting with study participants should not know who received the experimental vaccine
• Study participants should be followed as long as possible, “ideally at least one to two years”. This would allow investigators to determine how long protection against COVID-19 lasts and if there is a risk of serious side effects if protection decreases over time. (This paper from the magazine Science explains some of the potential risks that researchers need to learn more about.)

Examining Efficacy

• Studies should determine if the experimental vaccine protects people from SARS-CoV-2 infection and/or COVID-19. [SARS-CoV-2 is the coronavirus that causes the disease COVID-19.]
• The FDA recommends that studies include an endpoint defined as laboratory confirmed SARS-CoV-2 infection plus one or more of the following symptoms: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea. This will make it easier to compare findings across studies.
  
• Studies should also assess whether the experimental vaccine prevents cases of severe COVID-19. The FDA recommends that severe COVID-19 be defined as laboratory confirmed SARS-CoV-2 infection plus any of the following: clinical signs indicating severe illness; respiratory failure; evidence of shock; significant acute problems involving the kidney, liver, or nervous system; admission to an intensive care unit in a hospital; or death.
• To be considered effective, the vaccine should reduce the risk of COVID-19 by at least 50% compared to placebo.
  

Examining Safety

• Information about vaccine safety should be available for at least 3,000 people in each defined group (for example, 3,000 young adults and 3,000 older adults). This is similar to what is required for other vaccines.
  
• ALL study participants should have a way to report vaccine side effects for at least 3 to 4 weeks after each vaccination.
• Investigators should have a way to determine if any study participants have any serious side effects during the 6 month period after their last vaccination.
• If pregnant women are included in a study, or a study participant becomes pregnant within 30 days after getting a vaccine, they should be followed to assess pregnancy and baby outcomes (such as stillbirth or birth defects).
• Studies should regularly monitor for differences in COVID-19 disease outcomes (such as severe COVID-19) that might indicate vaccine-associated enhanced respiratory disease (VAERD, which is discussed in this paper from Science).

Need for Safety Evaluations after Vaccine Approval

• After getting FDA approval to market a COVID-19 vaccine in the US, drug companies should continue to monitor vaccine safety.
• The FDA often requires companies to develop a plan to monitor the safety of newly approved drugs and vaccines. This is because Phase 3 trials may not include enough people to identify rare side effects or side effects that only affect some people (for example, pregnant women, people with a chronic health problem).
• In addition, a COVID-19 vaccine may be approved for use in the US before all people in the Phase 3 trials complete the full 1 to 2-year follow-up period. Therefore, it will be especially important to be able to determine, as quickly as possible, if a vaccine is causing serious side effects when given to people in the general public.

Emergency Use Authorization

• A COVID-19 vaccine could be approved for use in the US under an Emergency Use Authorization (EUA)
• The FDA must determine that the known and potential benefits of a vaccine outweigh the known and potential risks to issue an EUA.
  
• An EUA may be issued before a drug company submits all the materials required to obtain a license to market the vaccine