FDA's new guidance on emergency use authorisations for COVID-19 vaccines

Introduction
Key takeaways
Guidance overview
Regulatory requirements
Chemistry, manufacturing and controls
Safety and effectiveness information
Meeting with advisory committee
Update on Phase 3 clinical trials for COVID-19 vaccines
Comment


Introduction

The search for a vaccine to prevent COVID-19 has been underway at record pace around the world. In order to accommodate the urgent demand for a COVID-19 vaccine, the Food and Drug Administration (FDA) has been given clearance by the Secretary of Health and Human Services to issue emergency use authorisations (EUAs) for certain unapproved drug products or uses thereof. The FDA has already issued several EUAs for drugs and devices for the treatment and diagnosis of COVID-19. For example, in May 2020, the FDA issued an EUA for the antiviral drug Veklury (remdesivir) for the treatment of hospitalised patients with severe COVID-19. The FDA has since approved Veklury (on 22 October 2020), making it the first drug to receive approval for the treatment of COVID-19. However there has yet to be a vaccine candidate under EUA review. This will soon change, as there are currently 131 registered clinical trials on clinicaltrials.gov for COVID-19 vaccines, 44 of which represent Phase 3 studies.

While the development of, and access to a vaccine is critical, the FDA remains mindful of the safety and effectiveness standards that vaccine candidates must meet before being widely administered. The FDA therefore released new guidance in October 2020 on the issuance of EUAs for COVID-19 vaccines. This guidance follows a recent push from industry to prioritise the review of safety and effectiveness data for vaccine candidates prior to EUA approval. For example, the CEOs of nine leading vaccine companies signed a pledge to, among other things, adhere to high scientific and ethical standards regarding the conduct of clinical trials and to only submit EUA requests with adequate data from Phase 3 clinical studies.

This new guidance describes the FDA's current recommendations on the data required for EUA requests and reflects a more tempered approach to a COVID-19 vaccine approval. It includes information on the chemistry, manufacturing and controls involved in vaccine development, clinical and nonclinical data, as well as administrative and regulatory information. Importantly, the guidance builds off and contextualises prior EUA guidance from 2017 and information released in June 2020 on the development and licensure of COVID-19 vaccines.

Key takeaways

Specific to the review of COVID-19 vaccine candidates, the guidance requires the following data to be included in EUA requests (discussed in more detail below):

• Data from at least one well-designed Phase 3 clinical study. The FDA expects that, following submission of an EUA request, the clinical trial would continue for as long as feasible. The Phase 3 data should include, at the time of the EUA request submission:
  • prescribed statistical thresholds;
  • a median follow-up duration of at least two months after completion of a full vaccination regimen;
  • a high proportion of enrolled subjects (at least 3,000 vaccine recipients); and
  • sufficient information to support a low risk for vaccine-induced respiratory disease.
• Information on the vaccine candidate's approval status – for example, if the vaccine candidate:
• is also being considered under an investigational application;
• has an associated master file number; or
• is approved for another use or in another country.
• Supply chain information that will help the FDA to assess anticipated availability of the vaccine, including surge capabilities and distribution details.

The FDA's Vaccines and Related Biological Products Advisory Committee will review each EUA request in an open meeting with vaccine sponsors or manufacturers present.

Applicants will be required to provide briefing materials for this meeting that will become publicly available two days before the meeting.

If proprietary information is being discussed by the advisory committee, an additional closed meeting will be held to review that material.

Vaccine manufacturers, sponsors and EUA applicants are encouraged to review the entirety of the prior and new guidance before submitting EUA requests.

Guidance overview

An EUA may be issued only after statutory requirements are met under Section 564 of the Federal Food, Drug and Cosmetic Act. Among these requirements is a determination by the FDA that the known and potential benefits of a product used in response to a life-threatening disease outweigh the product's known and potential risks. To make this determination with respect to COVID-19 vaccines, the FDA has released new guidance that introduces high thresholds for vaccine authorisation by way of an EUA. In doing so, the FDA reiterates that these decisions are made purely on a case-by-case basis. The guidance also highlights the need for transparency throughout the EUA decision-making process by the FDA's advisory committee.

The main considerations of the EUA request and decision-making process are highlighted below. However, vaccine manufacturers, sponsors and EUA applicants are encouraged to review the entirety of the prior and new guidance before submitting EUA requests.

Regulatory requirements

An EUA request for a COVID-19 vaccine must include a description of the product and its intended use. This includes details and rationales of proposed use, dosage, method of administration and targeted patient groups. The request should also include a discussion of the risks and benefits associated with the proposed use of the product, not only as they relate directly to the contraction of COVID-19, but also any other contraindications that could affect the vaccine's effectiveness. Consistent with prior guidance, the FDA also requires drafts of facts sheets that would be distributed to vaccine administrators if approved.

In an effort to gather as much relevant information as is feasible in a timely manner, the guidance adds a number of other requirements such as a description of the products' status (eg, if it is subject to an investigational application or being used in a foreign country for either the proposed use or another use). The FDA also requests information on the vaccine's supply chain, to assess anticipated availability of the vaccine and whether storage and distribution conditions would affect the vaccine's safety and effectiveness. This discussion would include:

• details on to whom the product would be supplied (ie, the US government or a vendor-managed inventory);
• surge capabilities of the manufacturing site; and
• details of distribution.

Chemistry, manufacturing and controls

An EUA request must include information on the chemistry, manufacturing and controls associated with vaccine development and production. Specifically, information on each manufacturing site would need to be assessed with respect to current good manufacturing practice requirements including, for example:

• storage facilities;
• sterilisation processes and heating;
• ventilation; and
• air conditioning system specifications.

Applicants would typically submit this information to their respective investigational applications or cross-referenced master files and, if so, this information should be resubmitted for the FDA's EUA review at least one month before the submission of the request.

However, the FDA recognises that some of this information will be unavailable at the time of the submission and will continue to work with sponsors on the resolution of any gaps or issues in that respect.

Safety and effectiveness information

The guidance outlines the requirements for both clinical and non-clinical data to be included in the EUA request, including all safety data from Phase 1 and 2 studies.

The guidance here reflects a higher threshold set by the FDA in the submission process:

• First, all placebo-controlled trial data must meet certain statistical requirements as prescribed by the FDA.
• Second, the Phase 3 study must – at the time of the request submission – have already endured a minimum follow-up duration of at least two months after completion of the vaccination regimen.
• In addition, at the time of submission, the Phase 3 study should have already enrolled at least 3,000 vaccine recipients and shown sufficient information to support a low risk for vaccine-induced respiratory disease. To show this, the FDA recommends that a total of five or more severe COVID-19 cases among placebo recipients would be sufficient to assess a benefit-risk profile (ie, whether the severe COVID-19 cases split between vaccine and placebo groups supports a favourable or concerning benefit-risk profile).

The FDA recognises that the Phase 3 studies will likely be ongoing at the time of the EUA request submission and therefore requests a plan for ongoing trial activity and active follow up on safety (including death, hospitalisations and other serious adverse events).

Meeting with advisory committee

The guidance expresses the FDA's intention to convene open sessions with the advisory committee and the applicant's representatives. To facilitate this, applicants are asked to provide briefing materials summarising their safety and effectiveness data, with the understanding that these materials will be uploaded to the FDA's webpage to be publicly available, at least two business days before the advisory committee meeting. Closed sessions would be held with regard to any proprietary data that needs to be discussed.

Update on Phase 3 clinical trials for COVID-19 vaccines

There are currently 131 registered clinical trials on clinicaltrials.gov for COVID-19 vaccines. The first of many EUA requests under the new guidance for COVID-19 vaccines from those companies with vaccine candidates already in Phase 3 studies can therefore be expected. They include the following:

• Moderna, along with the National Institutes of Health, had been testing their messenger RNA vaccine candidate (mRNA-1273) in humans since as early as March 2020. Phase 3 trials began in July 2020, with its final trial enrolling 30,000 healthy individuals in sites across the United States. Moderna has since entered into agreements with both the US and Canadian governments for the supply of a collective total of 120 million doses.
• BioNTech and Pfizer are currently in a split-Phase 2/3 trial after having tested a number of their vaccine candidates and narrowing down to one mRNA candidate (BNT162-B2). This German-US partnership launched their late-stage trial in July 2020 of over 43,000 subjects with sites in the United States, Germany, Argentina and Brazil. In early November 2020, Pfizer and BioNTech announced favourable interim results, demonstrating a 90% effectiveness in preventing COVID-19 in participants without evidence of prior COVID-19 infection. So far, the European Union and the Canadian, Japanese and US governments have arranged to purchase over 400 million doses.
• Johnson & Johnson has repurposed its Adenovirus (Ad26) for the development of a COVID-19 vaccine. The company began testing the Ad26 vaccine in humans in July 2020 and after promising results, it entered into Phase 3 in late September 2020, recruiting for up to 60,000 participants. The US government entered into an agreement with Johnson & Johnson for the supply of 100 million doses of the Ad26 vaccine. However, on 12 October 2020 Johnson & Johnson announced a pause to all vaccine trials due to an unexplained illness in a study participant. The trial is set to resume following an investigation by an independent monitoring board.
• AstraZeneca, along with the University of Oxford, has also been working off an adenovirus called ChAdOx1. Phase 1 and 2 trials showed that the vaccine raised antibodies against COVID-19, and the vaccine candidate went on to Phase 3 testing in late August 2020. However, shortly after, AstraZeneca announced that it was halting trials globally due to a serious neurological condition in one patient. The trial has since resumed. The European Union has agreed to purchase 400 million doses of AstraZeneca's vaccine.
• Novavax launched its Phase 3 trial on its protein-based vaccine candidate in September 2020. The trial is currently limited to 15,000 subjects and only in the United Kingdom, but Novavax has indicated that it will begin a larger trial in the United States in November 2020. The US government has already committed to purchase 100 million doses of the protein-based vaccine. Novavax has also reached an agreement with vaccine manufacturer Serum Institute of India to expand their production capabilities.

In furthering the collective and rapid response to COVID-19, some companies have begun publishing their clinical trial protocol information (see for example, publications by Moderna, Pfizer and AstraZeneca). Such transparency is encouraged among vaccine manufacturers and sponsors, but they should also be mindful of their proprietary information and applicable privacy laws.

Comment

The new guidance reflects the FDA's priorities and responsibilities with respect to ensuring the safety and effectiveness of COVID-19 vaccine candidates. Despite the expedited emergency review that the EUA regime accommodates, the concerns around weighing the risks and benefits reliably are real in the face of mass administration to millions of Americans. Any assessment regarding an EUA would therefore be made on a case-by-case basis, with consideration of the totality of the available scientific evidence.

For further information on this topic please contact Veleka Peeples-Dyer or Khelin N Aiken at Baker McKenzie's Washington DC office by telephone (+1 202 452 7000​) or email (veleka.peeples-dyer@bakermckenzie.com or khelin.aiken@bakermckenzie.com). Alternatively, please contact Shira Sasson at Baker McKenzie's Toronto office by telephone (+1 416 863 1221) or email (shira.sasson@bakermckenzie.com). The Baker McKenzie website can be accessed at​ www.bakermckenzie.com.