US FDA Issues COVID-19 Vaccine Guidance, Setting 50% Effectiveness Threshold

Maryland, 30 June 2020:

In an immediately effective guidance issued Tuesday, the US Food and Drug Administration (FDA) sets its expectations for the development and licensure of vaccines to prevent coronavirus disease (COVID-19), including considerations for manufacturing, nonclinical and clinical studies and post-licensure requirements.

For a vaccine that would be widely deployed against COVID-19, FDA says it expects sponsors to demonstrate that the vaccine is at least 50% effective in a placebo-controlled trial.

At a Senate Health, Education, Labor and Pensions committee hearing the same day, FDA Commissioner Stephen Hahn, MD, testified that FDA would maintain its standards and independence in its decision to approve any vaccines for COVID-19.

“While the FDA is committed to help expedite this work, we will not cut corners in our decision making and we are making clear in our guidance what are the data we need that should be submitted to meet our regulatory standards for approval,” Hahn told the committee.

In a press release issued alongside the guidance, Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research (CBER), echoed Hahn’s statements, saying, “Make no mistake: the FDA will only approve or make available a COVID-19 vaccine if we determine that it meets the high standards that people have come to expect of the agency.”

Guidance

In its guidance, FDA says that for now development programs should be aimed at obtaining traditional approval, as there are “currently no accepted surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19 vaccine,” that could be used to support accelerated approval.

“Once additional understanding of SARS-CoV-2 immunology, and specifically vaccine immune responses that might be reasonably likely to predict protection against COVID-19, is acquired, accelerated approval of a COVID-19 vaccine … may be considered,” FDA writes, noting that potential surrogate endpoints will vary based on the characteristics of the vaccine in question.

The agency also leaves the door open to issuing emergency use authorizations (EUA) for COVID-19 vaccines in certain circumstances, but cautions that, “Issuance of an EUA for a COVID-19 vaccine prior to the completion of large randomized clinical efficacy trials could reduce the ability to demonstrate effectiveness of the investigational vaccine in a clinical disease endpoint efficacy trial to support licensure.”

FDA says it may consider issuing an EUA for a COVID-19 vaccine as an interim measure after studies have demonstrated safety and effectiveness, but before a biologics license application (BLA) has been submitted or formally reviewed. The agency adds that, “Any assessment regarding an EUA would be made on a case by case basis considering the target population, the characteristics of the product, the preclinical and human clinical study data on the product, and the totality of the available scientific evidence relevant to the product.”

Clinical development

For clinical development, FDA encourages sponsors to consider adaptive or seamless clinical trial designs, which it says could expedite development. The agency adds that late phase trials will likely need to enroll “many thousands of participants, including those with comorbidities, to demonstrate protection against severe COVID-19.

“FDA strongly encourages the inclusion of diverse populations in all phases of clinical development, including populations most affected by COVID-19, specifically racial and ethnic minorities, as well as adequate representation in late phase trials of elderly individuals and those with medical comorbidities,” FDA says.

FDA stresses that later phase trials should be randomized, double-blinded and placebo-controlled. While the agency says that “1:1 randomization between vaccine and placebo groups is usually the most efficient study design for demonstrating vaccine efficacy,” other types of randomization may be acceptable. If adequately designed, a study evaluating multiple vaccine candidates against a single placebo group could be used as well.

The guidance also provides detailed recommendations on trial design, efficacy and statistical considerations, as well as efficacy, statistical and safety issues.

Chemistry, manufacturing and controls

Despite the pressing nature of the COVID-19 pandemic, FDA says that any COVID-19 vaccine, “Must meet the statutory and regulatory requirements for vaccine development and approval, including for quality, development, manufacture, and control.”

FDA explains that vaccines must be adequately characterized and manufactured in compliance with current good manufacturing practice and that sponsors must have well-defined and appropriately controlled production processes in place to ensure consistency.

FDA adds that development may be accelerated, “based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible.” Additionally, FDA says sponsors may be able base some aspects of manufacture and control on their platform, which could reduce the need for product specific data.

The guidance provides a dozen specific recommendations for drug substance and drug product manufacturing, including recommendations for demonstrating that source material is adequately controlled; manufacturing process validation; quality control; and determining stability and expiry.

While pre-license inspections are “considered part of the review of a [biologics license application] BLA,” FDA acknowledges that its ability to conduct inspections may be impacted due to the pandemic and says it will rely on alternative tools, “To determine the need for an on-site inspection and to support the application assessment.”

Nonclinical data

The guidance provides a range of recommendations for the types of nonclinical data sponsors should gather to support the development of their vaccines and provides specific recommendations for assessing the risk of vaccine-associated enhanced respiratory disease.

FDA notes that the type and extent of nonclinical data required to advance to first-in-human (FIH) trials will vary from candidate to candidate.

FDA says that nonclinical safety studies are necessary for novel types of vaccines where there are no prior nonclinical or clinical data to rely on, though vaccines based on well-characterized platforms may be able to proceed without conducting nonclinical safety studies.

“If the COVID-19 vaccine candidate is made using a platform technology utilized to manufacture a licensed vaccine or other previously studied investigational vaccines and is sufficiently characterized, it may be possible to use toxicology data (e.g., data from repeat dose toxicity studies, biodistribution studies) and clinical data accrued with other products using the same platform to support FIH clinical trials,” FDA says.

FDA allows for sponsors to submit data from toxicity studies “as unaudited final draft toxicologic reports to accelerate proceeding to FIH clinical trials,” but says that full quality-assured reports should be submitted within 120 days of the clinical trial.

FDA also recommends that sponsors conduct developmental and reproductive toxicity (DART) studies before enrolling pregnant women or women of childbearing age who are not actively avoiding pregnancy in clinical trials. FDA says that sponsors may rely on “data from DART studies with a similar product using comparable platform technology if … the agency agrees those data are scientifically sufficient.”

The guidance also provides recommendations for when to conduct biodistribution studies and for characterizing immune response in animal models. Regulatory Focus