The FDA has denied two citizen petitions filed on behalf of the Informed Consent Action Network (ICAN) requesting the agency revoke its Emergency Use Authorizations (EUAs) for the use of the Pfizer-BioNTech and Moderna COVID-19 vaccines (the Vaccines) for children aged 5-17 years old. In its denials, the Agency amalgamated a detailed body of the bases for its EUA authorities and decisions that is not limited to the individual petitions, but rather provides high value maps of the EUA landscape and FDA’s thought process in navigating it.

Main Takeaways:

• FDA’s authority to revoke or revise an EUA is permissive (“may”), not mandatory (“must”).
• Public health emergency determinations are based on the threat to the U.S. population as a whole, not to specific age groups or any other sub-populations.
• The use of immunobridging in conjunction with direct safety and effectiveness data is well-established precedent in assessing preventive vaccines.
• A determination that the benefits outweigh the risks of the Vaccines for use in individuals 5-17 years of age is properly supported by pre-evaluation of age-specific study plans and protocols, assessment of sufficiently representative trials that follow FDA’s EUA Vaccine Guidance, and a focused review of safety data. Such determination is further supported by ongoing analysis of all reported child and adolescent events showing them to be uncommon, representative of medical events expected, and not suggestive of a causal relationship to the medical product.
• Vaccines are not required to show 100% effectiveness in order to have substantial benefit.
• Studies presented to FDA as scientific evidence should be peer-reviewed and published, demonstrate the claims they are used to support, and should not be cited selectively or ignore key statements contravening those claims.
• Because the Vaccines are the only FDA-approved drugs or biologics indicated to prevent COVID-19 in any population, there are in fact no adequate, approved and available alternatives.

The citizen petitions and FDA’s responses are available at Docket Number FDA-2022-P-1399 and Docket Number FDA-2022-P-0872.

Background

On February 4, 2020, the Secretary of HHS exercised authority granted under section 564(b)(1)(C) of the Food, Drug and Cosmetic Act (FD&C Act) to declare that COVID-19 constituted a public health emergency.  The HHS Secretary found that COVID-19 has a significant potential to affect national security or the health and security of U.S. citizens living abroad, and that involves the virus that causes COVID-19. This determination empowered the HHS Secretary to later declare, on March 27, 2020, that the authorization of emergency use of drugs and biological products during the COVID-19 pandemic was justified (Declaration).

This Declaration triggered section 564(c) of the FD&C Act, which allows FDA to issue an Emergency Use Authorization (EUA) for an unapproved medical product, or for unapproved uses of an approved medical product.  Issuance of an EUA during the COVID-19 pandemic requires FDA to determine:

• The agent referred to in the COVID-19 EUA Declaration by the Secretary (SARS-CoV-2) can cause a serious or life-threatening disease or condition.
• Based on the totality of scientific evidence available, including data from adequate and well-controlled trials, if available, it is reasonable to believe that the product may be effective in diagnosing, treating, or preventing such serious or life-threatening disease or condition that can be caused by SARS-CoV-2.
• The known and potential benefits of the product, when used to diagnose, prevent, or treat the identified serious or life-threatening disease or condition, outweigh the known and potential risks of the product.
• There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the disease or condition.

Once issued, the EUA will remain in effect until the Declaration is terminated or the EUA is revoked.  To that end, under section 564(g)(2) of the FD&C Act, FDA “may revise or revoke an authorization” if:

• the circumstances described in the Declaration no longer exist;
• the criteria under [section 564(c) of the FD&C Act] for issuance of such authorization are no longer met; or
• circumstances make such revision or revocation appropriate to protect the public health or safety.

FDA’s Denial Responses Outline Revocation Standard

In its responses to the Petitions, FDA first explained that the standard for revocation of an EUA uses permissive, not mandatory language (e.g., that it “may” be revised or revoked).  In addition to the well-understood construction of “may” as permissive, particularly where, as here, a statute elsewhere uses the term “shall” to confer a mandatory duty, Congress explicitly provided that all decisions regarding EUAs are committed to agency discretion and nothing in the statute requires FDA to revoke existing EUAs in any circumstance.

Permissive discretion also accords squarely with the statutory purpose of giving FDA flexibility to “permit rapid distribution of promising new drugs and antidotes in the most urgent circumstances” because it allows the Agency to permit continued distribution of EUA products.  This removes the need for manufacturers to limit supply or delay seeking approval to exhaust supplies of authorized product.

Thus, even if one or more of the three conditions under which FDA may revoke an EUA are met, it is up to FDA whether to revoke or revise that EUA. But the Agency is not required to do so.  In the case of the Petitions, FDA found that the none of the three conditions were met.

FDA’s Denial Responses Also Outline Conditions for Revocation

1. The Circumstances Causing the Issuance of the EUA Continue to Exist

In asking FDA to revoke the EUAs for individuals 5-17 years of age, ICAN asserted that there is “no health emergency” for children. However, FDA noted that section 564(b)(1)(C) of the FD&C Act does not contemplate separate public health emergency determinations by age group. Rather, it addresses the threat to the population as a whole.

Thus, in order to show grounds for revocation of the EUA for individuals aged 5-17, the Petitions would have had to demonstrate that the circumstances writ large for the EUA no longer exist. Since the Petitions made no such argument or showing, they failed to meet the first condition. 

2. The Criteria for Issuance of the EUA Continue to be Met

a. COVID-19 is a Serious or Life-Threatening Disease or Condition

As with the first condition, the statutory criterion do not require a conclusion that the threatening agent (here, the SARS-CoV-2 virus) can cause a serious or life-threatening disease or condition in a specific age group; as long as the disease or condition (here, COVID-19) is serious or life-threatening, this criterion is met. Thus, variations in statistics between age groups are essentially a difference without a distinction.

FDA concluded nonetheless that SARS-CoV-2 can cause a serious or life-threatening disease or condition in individuals 5-17 years of age. While acknowledging that COVID-19 tends to be less severe in children and adolescents than adults, millions of pediatric cases have been reported, including those that led to hospitalization and death. In addition, the Omicron wave saw more children and adolescents getting sick with the disease and suffering longer term effects, even following initially mild disease. Moreover, as with adults, children and adolescents with underlying conditions are at higher risk than their heathier counterparts for COVID-19-related hospitalization and death.

Interestingly, FDA pointed out that in attempting to distinguish between adult and pediatric rates of serious or life-threatening illness, the Petitions acknowledged the virus can cause a serious or life-threatening disease or condition, including in children and adolescents. For example, in attempting to show COVID-19 is not as great a threat to children and adolescents as it is to adults, the pediatric comparators showed precisely at what rates the SARS-CoV-2 virus can cause them a serious or life-threatening disease or condition. In attempting to show the majority of children are not affected by COVID-19, the Petitions acknowledged that children with underlying conditions are at risk of serious or life-threatening disease; and in attempting to show deaths in children were rare, they cited without disputing the CDC’s conclusion that if COVID-19 associated death rates were compared to leading causes of death in 2019, COVID-19 would have nonetheless been tied for eighth.

Thus, the Petitions failed to show that SARS-CoV-2 cannot cause a serious or life-threatening disease or condition (either writ large or in a specific age group) and therefore failed to meet the first statutory criterion.

b. There is Sufficient Evidence of Effectiveness

Section 564(c)(2)(A) of the FD&C Act requires that for an EUA to be issued for a medical product, FDA must conclude that it is reasonable to believe that the product may be effective in preventing, diagnosing, or treating the identified serious or life-threatening disease or condition that can be caused by the agent identified in the EUA declaration (SARS-CoV-2). This analysis requires consideration of the totality of available scientific evidence, including data from adequate and well-controlled trials (if available). FDA had made such determination when granting the EUAs with regard to 5-17 year-olds.

The Petitions asserted that the testing was inadequate because “it was limited to assessing antibody levels and comparing those levels to adult levels using immunobridging.” However, describing in the studies in detail, FDA noted that they indeed included safety and effectiveness data from children and adolescents. In addition, to the extent they also used immunobridging, FDA noted that it is well-established regulatory precedent with other preventive vaccines. For these reasons, FDA found the Petitions failed to establish the second criterion was no longer met.

c. The Benefits Outweigh the Risks

Section 564(c)(2)(B) of the FD&C Act requires that for an EUA to be issued for a medical product FDA must conclude “the known and potential benefits of the product, when used to diagnose, prevent, or treat [the identified serious or life-threatening disease or condition], outweigh the known and potential risks of the product.” FDA had reached this conclusion before authorizing the Vaccines for emergency use in individuals 5-17 years of age.

ICAN lodged numerous objections to the adequacy of clinical trial safety data for children and adolescents, including trial size and duration, trial population and the existence of adverse events. Regarding trial size and duration, FDA described its detailed, ongoing analysis including that the agency had pre-evaluated study plans and protocols as it commonly does, that the trials followed FDA’s EUA Vaccine Guidance and that FDA’s review focused on the child and adolescent safety data. Regarding trial population, FDA pointed out ICAN’s incorrect math and that the Petitions included no evidence the trials were insufficiently representative. Regarding adverse events, FDA detailed its ongoing review and analysis of all reported events and noted that, while uncommon, they “represented medical events expected to occur among individuals in this age group and with the underlying conditions represented in the study population” and that “available data did not suggest a causal relationship to the Vaccines.”

ICAN further claimed that the existence of breakthrough infections and evidence of lower effectiveness against emerging variants warranted revocation of the EUA for children and adolescents; FDA responded that vaccines need not have 100% effectiveness against current or future viruses in order to have substantial benefit. As to other evidence presented by ICAN regarding post-trial adverse event reports, a “profound impairment in type I interferon signaling”, “increased risk of original antigenic sin and antibody dependent enhancement”, and “natural immunity” FDA detailed that, as applicable, the studies cited were not peer-reviewed and published, did not demonstrate the claims being made by ICAN, or that the Petition cited them selectively and ignored key statements that contravened their claims. Ultimately, FDA determined that none of the concerns undermined the agency’s conclusion that the known and potential benefits of the Vaccines outweigh the known and potential risks when used to prevent COVID-19 in children and adolescents.

d. There Are No Sufficient Alternatives

The Petitions did not assert that there are adequate and approved alternatives to the Vaccines, and thus failed to meet the second condition for revocation. FDA also reconfirmed that, because the Vaccines are the only FDA-approved drugs or biologics indicated to prevent COVID-19 in any population, there are in fact no adequate, approved and available alternatives.

3. There are No Other Circumstances Making Revision or Revocation Appropriate to Protect the Public Health or Safety

The Petitions did not assert other bases for revising or revoking the EUAs for individuals 5-17 years of age and therefore failed to satisfy the third condition for revocation.

Conclusion

FDA ultimately found no basis in either Petition on which to exercise its permissive discretion to revoke the EUAs for use of the Vaccines in children and adolescents ages 5-17. In doing so, the Agency provided fulsome insight into the analysis it applies to that discretion.