On Tuesday, the FDA issued an immediate and effective guidance, called “Vaccine Development and Licensing for Prevention of COVID-19,” to help and facilitate the timely development of safe and effective vaccines involving manufacturing, non-clinical and clinical studies, and post-licensing recommendations and requirements.
The FDA said it wanted sponsors to prove that a vaccine widely used against COVID-19 was at least 50 per cent effective in placebo-controlled trials.
The same day, at a hearing of the Senate Health, Education, Labor, and Pensions Committee, FDA Commissioner Stephen Hahn testified that the AGENCY will maintain its standards and independence in approving any COVID-19 vaccine:
“While the FDA is committed to helping speed up this work, we do not cut corners in our decision-making process, and our guidelines are clear about what data needs to be submitted to meet regulatory standards for approval.”
In a press release from the guidelines, Dr. Peter Marks, director of the FDA’s Center for Biological Evaluation and Research (CBER), responded to Hahn’s statement, saying, “Make no mistake: the FDA will only approve or authorize a COVID-19 vaccine if we are certain it meets high standards.”
Clinical endpoints and emergency authorization
In its guidance, the FDA said that current development plans should aim for traditional approval because “there is currently no recognized alternative endpoint that can reasonably predict clinical benefit from coVID-19 vaccines” to support accelerated approval.
The guide says:
“Once more is known about the immunology of SARS-COV-2 and, in particular, the possible reasonable prediction of a vaccine immune response that can prevent COVID-19, expediting the approval of a COVID-19 vaccine can be considered…”
Note here that the potential alternative endpoints will vary depending on the characteristics of the vaccines discussed.
FDA also allows for COVID – in some cases, 19 vaccine issued an emergency use authorization (EUA), but be warned that “before the large randomized clinical curative effect of test is completed, the EUA, issued for the COVID – 19 vaccine may reduce the end effect in clinical disease experiment proves that experimental vaccine efficacy ability, the ability to support the final authorisation”.
The FDA said it may consider issuing EUA for the COVID-19 vaccine as an interim measure after studies have shown safety and efficacy, but before submitting or formally reviewing a biologic license application (BLA).
“Any evaluation of EUA will be case-by-case based on the target population, characteristics of the target population, preclinical and human clinical study data of the product, and available scientific evidence,” the FDA added.
For clinical development, FDA encourages sponsors to consider adaptive or seamless clinical trial designs that could speed up development.
The FDA added that late-stage trials may need to recruit thousands of participants, including comorbidities, to demonstrate protection against severe COVID-19.
FDA strongly encourages inclusion of a diverse population at all stages of clinical development, including those most affected by COVID-19, particularly racial and ethnic minorities, as well as in older patients and those with comorbidities, and adequate representation in trials.
The FDA emphasized that later trials should be randomized, double-blind, and placebo-controlled.
While the FDA says that “1:1 randomization between the vaccine and placebo groups is generally the most effective study design to demonstrate vaccine efficacy,” other types of randomization are acceptable.
Multiple vaccine candidate studies can also be evaluated using a single placebo group, if properly designed.
The guide also provides detailed advice on trial design, efficacy and statistical considerations, as well as efficacy, statistical and safety issues.
Chemistry, Production and Control (CMC)
Despite the urgent nature of the COVID-19 pandemic, the FDA says that any COVID-19 vaccine “must meet the legal and regulatory requirements (including quality, development, production and control) for vaccine development and approval.”
The FDA explains that vaccines must be properly characterized and manufactured in accordance with current GMP standards, and that sponsors must have clearly defined and properly controlled manufacturing processes to ensure consistency.
The FDA added that “to the extent legally and scientifically permissible, development can be accelerated based on knowledge gained from similar products manufactured using the same mature platform technology.”
In addition, the FDA said it could reduce requirements for product-specific data based on certain manufacturing and control areas on its platform.
The guidelines provide more than a dozen specific recommendations for the production of apis and pharmaceuticals, including those on certifying that raw materials are adequately controlled;
Verification of production process;
And determine stability and validity.
While pre-approval inspections are “part of the review of biologics licensing applications,” the FDA acknowledged that its ability to conduct inspections could be affected by a pandemic, and said it would rely on alternative tools “to determine whether to conduct on-site inspections to support application evaluation.”
The guidelines provide a range of recommendations for the types of non-clinical data that sponsors should collect to support their vaccine development, as well as specific recommendations for assessing the risk of vaccine-related enhancement of respiratory diseases.
The type and extent of non-clinical data required to conduct the first human trials (FIH) vary from vaccine candidate to candidate, the FDA noted.
For new vaccines, the FDA said, non-clinical safety studies are necessary if no non-clinical or clinical data is available.
Non-clinical safety studies may not be necessary for vaccines based on well-defined platforms:
“If the candidate COVID vaccine – 19 vaccine is used for the production license or other previously studied research vaccine made of platform technology, and has enough characteristic, may use the toxicology data (for example, repeated dose toxicity study, study the distribution of biological data) and other products using the same platform for clinical data, to support the FIH clinical trials”.
The FDA allows sponsors to submit unreviewed draft final toxicology reports as data for toxicity studies to speed up the timeline for FIH clinical trials, but says full quality assurance reports should be submitted within 120 days of clinical trials.
The FDA also recommends that the authors conduct a developmental and reproductive toxicity (DART) study before enrolling pregnant women or women of childbearing age who have not actively avoided pregnancy in clinical trials.
The FDA said sponsors may rely on data from DART studies using similar products if the agency considers the data to be scientifically sufficient.