On 22 October 2020, the FDA approved the anti-viral drug Veklury (remdesivir) for hospitalized COVID-19 patients, making it the first drug to receive approval for the treatment of COVID-19. Before approving this drug, the FDA issued an Emergency Use Authorization for the use of Veklury in COVID-19 treatment. We will continue to monitor such major developments in the response to this pandemic.
Introduction and Executive Summary
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 Authorizations (EUA) 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 hospitalized 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 – as of the date of this alert – 127 registered clinical trials on clinicaltrials.gov for COVID-19 vaccines, 41 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 on the issuance of EUA for COVID-19 vaccines (the ‘Guidance‘). This Guidance follows a recent push from industry to prioritize 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 contextualizes prior EUA guidance from 2017, and information released in June on the development and licensure of COVID-19 vaccines.
Specific to the review of COVID-19 vaccine candidates, the Guidance requires the following data to be included in EUA requests (to be 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
- 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 and/or in another country.
- Supply chain information that will help the FDA assess anticipated availability of the vaccine, including surge capabilities and distribution details.
In reviewing the EUA requests, the FDA’s Vaccines and Related Biological Products Advisory Committee (the ‘Advisory Committee‘) will review each EUA request in an open meeting with vaccine sponsors and/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.
An EUA may only be issued 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 known and potential risks of the product. To make this determination with respect to COVID-19 vaccines, the FDA has released new Guidance that introduces high thresholds for vaccine authorization by way of 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 here. However, vaccine manufacturers, sponsors, and EUA applicants are encouraged to review the entirety of the prior and new Guidance before submitting EUA requests.
A request for EUA 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 impact the effectiveness of the vaccine. 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 (for example, if it is subject to an investigational application, or being used in a foreign country for either the proposed use or another use, etc). 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 who the product would be supplied to (i.e., the US Government, or a vendor-managed inventory), surge capabilities of the manufacturing site, and details of distribution.
Chemistry, Manufacturing, and Controls
The 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, sterilization processes, and HVAC 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 re-submitted for the FDA’s EUA review at least one month before the submission of the request.
However, the FDA recognizes that some of this information will not be available 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. Additionally, 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 (i.e., whether the severe COVID-19 cases split between vaccine and placebo groups supports a favorable or concerning benefit-risk profile)
The FDA recognizes 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, hospitalizations, and other serious adverse events).
Meeting with the 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 summarizing 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 only 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 – as of the date of this alert – 127 registered clinical trials on clinicaltrials.gov for COVID-19 vaccines. We may therefore expect 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. They include:
- 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. Phase 3 trials began in July, with its final trial enrolling 30,000 healthy individuals in sites across the U.S. 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 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-American partnership launched their late-stage trial in July of over 30,000 subjects with sites in the US, Germany, Argentina, and Brazil. The companies have also recently requested FDA approval of an expansion to 44,000 subjects in the US. Interim results from August showed that participants receiving the first dose reported mostly mild symptoms like fatigue and headache. So far, the European Union, 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, and after promising results, it entered into Phase 3 in late September, 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, Johnson & Johnson announced a pause to all vaccine trials due to an unexplained illness in a study participant. The trial is set to resume soon 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 the coronavirus, and the vaccine candidate went on to Phase 3 testing in late August. Shortly after, however, AstraZeneca announced that it was halting trials globally due to a serious neurological condition in one patient. The trial has since resumed in most countries, and is expected to resume in the US soon. 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. The trial is currently limited to 10,000 subjects and only in the United Kingdom, but Novavax has indicated that it will begin a larger trial in the US in November. 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 while also being mindful of their proprietary information and applicable privacy laws.
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 very 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.
Baker McKenzie’s North America FDA Practice Group
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