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18 November 2020
Chemistry, manufacturing and controls
Safety and effectiveness information
Meeting with advisory committee
Update on Phase 3 clinical trials for COVID-19 vaccines
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.
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):
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.
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.
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:
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:
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:
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.
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:
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.
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 (email@example.com or firstname.lastname@example.org). Alternatively, please contact Shira Sasson at Baker McKenzie's Toronto office by telephone (+1 416 863 1221) or email (email@example.com). The Baker McKenzie website can be accessed at www.bakermckenzie.com.
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