- The new guidance advises COVID-19 vaccine developers now to pursue traditional licensure using the Biologics License Application (BLA) pathway rather than the Emergency Use Authorization (EUA) pathway.
- The guidance provides detailed manufacturing, nonclinical, and clinical considerations to meet investigational and licensure regulatory submission requirements, as well as post-approval pharmacovigilance requirements, following closely the same considerations set forth in 2020 but removing all references to the EUA pathway.
- The guidance does not provide a streamlined process for approval of updated seasonal COVID-19 vaccines and leaves unchanged its references to the use of well-characterized vaccine platform technology, such as for manufacturing and controls, to accelerate vaccine development.
On October 19, 2023, the Food and Drug Administration (FDA)
released a final guidance document titled Development
and Licensure of Vaccines to Prevent COVID-19: Guidance for
Industry, providing recommendations regarding the agency's
current thinking on the process for licensing COVID-19
The document marks FDA's shift from encouraging the use of the Emergency Use Authorization (EUA) pathway to the use of the traditional Biologics License Application (BLA) pathway for COVID-19 vaccine candidates. Most notably, the guidance states that, "at this time, the goal of new vaccine development programs to prevent COVID-19 should be to pursue traditional approval," as opposed to the EUA pathway.
The new guidance details "key considerations" for compliance with the investigational new drug application (IND) regulations under 21 C.F.R. Part 312, and vaccine licensure requirements under Section 351(a) of the Public Health Service Act. The guidance offers detailed considerations for meeting regulatory requirements in four key areas: chemistry, manufacturing, and controls (CMC); nonclinical data; clinical trials; and post-licensure safety evaluations.
This guidance represents the first formal update FDA has provided on these topics for COVID-19 vaccine manufacturers since a June 2020 guidance that bore the same name. The document also provides insights into what FDA sees as the future of COVID-19 vaccine development: in some cases, higher recommended standards for the product, but also a commitment to and continued interest in supporting the development of next-generation COVID-19 vaccines, including through innovative study approaches. (Such efforts extend outside of FDA: through the Administration for Strategic Preparedness and Response, HHS announced investments in a number of next-generation vaccine candidates and technologies earlier in October.)
FDA began issuing guidance for COVID-19 vaccine development in
the middle of 2020: first a general guidance on development and
manufacturing released in August 2020 (dated June 2020) and then
specific guidance on the Emergency Use Authorization pathway in October 2020. The agency revised the EUA
guidance multiple times until announcing in March 2023 that it
would sunset its EUA guidance on November 7 if it was not otherwise
superseded by new EUA guidance.1 FDA states that
"circumstances have changed since the end of the declared
public health emergency on May 11, 2023" and that the EUA
guidance is no longer needed.2 The new guidance formally
replaces the August 2020 guidance,3 and, per the March
2023 notice, the EUA guidance will no longer be in effect as of
November 7 if there is no further comment from the agency.
According to FDA, the agency has shifted its focus toward
communicating directly with individual manufacturers, so it seems
FDA will not be issuing further EUA guidance and expects new
COVID-19 vaccines to secure full licensure.
FDA issued the October 19 guidance as final guidance, without having published a draft version for comment. Under the FDA's good-guidance practices, the agency has the discretion to issue final guidance without first seeking comment when public participation is not feasible. The October 19 guidance simply notes that authority without explaining why the guidance needed to be published in final form, although there may have been a desire to issue a final version of this guidance before the agency's self-imposed November 7 deadline for superseding the EUA guidance. As the guidance notes, it is still subject to comment from the public, and comments may be submitted through regulations.gov.4
The guidance tracks fairly closely in content and
recommendations to the original August 2020 guidance, with many of
the adjustments made for changing understanding of COVID-19 and the
shift from a public-health-emergency posture.
Significant and notable elements of the document include (in order of appearance):
- No formal seasonal process yet: While the agency has repeatedly stated that it plans to develop an abbreviated process for licensing updated COVID-19 vaccines, similar to the process the agency has for seasonal flu vaccines, this guidance does not discuss such a pathway. (An EUA pathway for "modified" versions of EUA vaccines to protect against new variants was discussed in the agency's most recent EUA guidance, from March 2022.5)
- Potential for leveraging platform technology: Consistent with recommendations made in 2020, the guidance states that, "with appropriate justification, some aspects of manufacture and control may be based on the vaccine platform, and in some instances, reduce the need for product-specific data."6
- CMC and final validation of formulation and filling operation: FDA expects final validation of formulation and filling operations to be conducted before product approval, unlike in the 2020 guidance, in which post-approval validation was permitted if adequately justified.
- Concern around specific adverse events: In the original 2020 guidance,7 FDA noted that sponsors should use animal trials to assess any potential for vaccine-associated enhanced respiratory disease (ERD) before proceeding to larger human clinical trials, and maintains this recommendation in the 2023 guidance, given the still "limited" understanding of this risk that COVID-19 vaccines may present.8 The new guidance also includes a mention of myocarditis/pericarditis, stating that, in developing pharmacovigilance plans, "studies or other actions to evaluate specific safety concerns such as myocarditis and pericarditis should be considered."
- Scale of late-stage trials: The agency continues to expect, as in the 2020 guidance that late-stage clinical trials "will likely need to enroll many thousands of participants."9 Previous FDA vaccine guidance has noted the importance of sufficiently large sample sizes for, e.g., detecting rare adverse events in vaccines that will be administered to the general population, but not in such specific terms.
- Clinical study exclusions: The new guidance no longer advises sponsors to exclude participants at high risk of SARS-CoV-2 exposure (e.g., healthcare workers) from early phase studies, but continues to recommend that early phase studies focus on enrolling participants who are at low risk of severe COVID-19.
- Trial diversity: As in the 2020 guidance10 and in line with FDA's general priority to increase diversity and representation in clinical trials, the agency "strongly encourages the enrollment of populations most affected by COVID-19, specifically racial and ethnic minorities," while also noting the importance of representation and inclusion of elderly individuals, individuals with multiple co-morbidities, and pregnant women.11
- Standardizing endpoints: Similar to the 2020 guidance,12 FDA recommends that sponsors standardize their primary endpoint, or a secondary endpoint, as virologically confirmed SARS-CoV-2 infection with one of a list of 11 symptoms provided, and also provides a recommended secondary endpoint for severe COVID-19.13
- Statistical considerations for measures of efficacy: In the 2020 guidance, the agency stated that the expected degree of efficacy would be 50 percent or more on a pivotal trial's primary endpoint, with a lower bound confidence interval of >30 percent, which has now been replaced with a general statement that "the primary efficacy endpoint point estimate for placebo controlled clinical disease efficacy trial and the lower bound confidence interval should be "appropriately justified."14 FDA also removed the possibility that a lower bound of less than 30 percent but greater than 0 percent may be acceptable as a statistical success criterion for a secondary efficacy endpoint (which the agency had said "may be acceptable" if the secondary endpoint hypothesis testing is dependent on success of primary endpoint).
- Maintaining standards on safety: In the 2020 guidance document, the agency noted that "the number of subjects receiving a COVID-19 vaccine in pre-licensure clinical studies may not be adequate to detect some adverse reactions that may occur infrequently," while safety data on some subpopulations, such as pregnant women, "may be limited at the time of licensure" (a concern that FDA notes can exist with all licensed vaccines). In the 2023 document, potentially reflecting the agency's continued desire to accelerate clinical development and licensure, the agency repeats this acknowledgment that safety data may be limited.15
- Accelerated Approval a possibility in the future: As in the 2020 guidance, the agency states that, once scientific understanding of COVID-19 immunology advances to where a surrogate endpoint may be reasonably likely to predict clinical efficacy, it would be open to considering COVID-19 vaccines under the Accelerated Approval process.16
- Human challenge studies: The guidance repeats its stance from the 2020 guidance17 that, "If it is no longer possible to demonstrate vaccine effectiveness by way of conducting clinical disease endpoint efficacy studies, the use of a controlled human infection model to obtain evidence to support vaccine efficacy may be considered. However, many issues, including logistical, human subject protection, ethical, and scientific issues, would need to be satisfactorily addressed."18 FDA has traditionally not endorsed the use of such "human challenge" trials and the continued inclusion of this point, even outside of the context of a public health emergency, may be expressing somewhat greater openness to the concept.
FDA's new guidance reflects the agency's continued interest in supporting the development of new and next-generation vaccines for COVID-19, even as the agency has shifted away from an emergency footing. At the same time, a number of issues for the future of COVID-19 vaccines are not covered by the guidance, and it remains to be seen whether the agency will develop a framework for annual updates to the vaccines that already have or will be granted full licensure
1. 88 Fed. Reg. 15,417.
2. 88 Fed. Reg. 72,489, 72,491.
3. 88 Fed. Reg. 72,489.
5. 2022 Guidance, p. 19.
6. 2023 Guidance, p. 3.
7. 2020 Guidance, p. 8.
8. 2023 Guidance, p. 8.
9. 2023 Guidance, p. 10.
10. 2020 Guidance, p. 11.
11. 2023 Guidance, p. 11.
12. 2020 Guidance, p. 13.
13. 2023 Guidance, p. 13.
14. 2020 Guidance, p. 10; 2023 Guidance, p. 14.
15. 2020 Guidance p. 16; 2023 Guidance p. 16.
16. 2023 Guidance, p. 18.
17. 2020 Guidance, p. 18.
18. 2023 Guidance, p. 18.
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