Over the past two years, the Food and Drug Administration (FDA) has approved or issued emergency use authorizations (EUAs) for several interventions intended to prevent or treat COVID-19, including vaccines, monoclonal antibodies, and antiviral medications. These approvals and EUAs are for specific indications, in specific populations, at specific doses, and on specific dosing schedules. However, individuals, clinicians, and state and local governments have often expressed interest in using these COVID-19 interventions outside the parameters specifically approved or authorized by the FDA.
Although it is generally legally permissible for clinicians to prescribe and administer approved products for “off-label” uses, such flexibility for COVID-19 interventions, whether approved or distributed under an EUA, is not so straightforward. Ambiguity in relevant statutory provisions, federal agreements, and guidance has left open important questions about the legality of certain off-label uses of approved COVID-19 products and unauthorized uses of COVID-19 products under EUA, the availability of liability protection for health care professionals who offer such uses, and access to compensation for patients injured by such uses. Additionally, where the Department of Health and Human Services (HHS) has offered clarification, it has often expressed restrictive positions even while failing to enforce those positions in the face of open violations.
Taken together, the current landscape has led to a variety of challenges for public health officials, medical professionals, and patients, including confusion, furtive violations of legal requirements, and deception by individuals seeking interventions outside the scope of current approvals and authorizations. Unlike scientific uncertainty, which must be tolerated during a pandemic, this sort of legal uncertainty is not inevitable and should be remedied quickly where it has been allowed to persist.
Current Legal Structure
The FDA has granted full approval to several COVID-19 interventions, including Veklury (remdesivir) via a New Drug Application (NDA) and both mRNA vaccines via Biologics License Applications (BLA). Once products have marketing approval under these traditional pathways, clinicians can typically offer them off-label for any use they deem reasonable as a matter of professional judgment without violating the federal Food, Drug, and Cosmetic Act (FDCA). In contrast, COVID-19 interventions that remain available exclusively through EUAs, such as the antiviral pill paxlovid (nirmatrelvir/ritonavir), several monoclonal antibodies for treatment or prevention, and the Janssen COVID-19 vaccine are more tightly controlled by the terms of their authorizations, which precisely specify the number of authorized doses, dosing schedule, and eligible population. Unauthorized use outside these EUA parameters may violate the FDCA as provision of an unapproved—rather than off-label—product.
In the context of COVID-19, the Public Readiness and Emergency Preparedness (PREP) Act protects manufacturers, distributors, and health care professionals from liability for injury caused by “covered countermeasures,” while the Countermeasures Injury Compensation Program (CICP) compensates recipients injured by covered countermeasures. COVID-19 interventions are covered countermeasures under these laws only if used pursuant to a BLA or NDA, an EUA, or under an Investigational New Drug application while “the object of research.” An HHS advisory opinion additionally explains that PREP Act liability protection is available to someone who reasonably, but incorrectly, believes they are providing a covered countermeasure. In contrast, those who knowingly provide and those who receive COVID-19 interventions beyond the scope of their EUAs—rendering them unapproved products—likely lose relevant protections and compensation for injury. In addition, it is unclear whether off-label use of a product with full FDA approval will transform a covered countermeasure into a noncovered one.
Clinicians and organizations receiving federally procured COVID-19 vaccines are additionally constrained by the Centers for Disease Control and Prevention’s (CDC’s) provider agreements, which require that providers “administer COVID-19 vaccine in accordance with all requirements and recommendations of CDC and CDC’s Advisory Committee on Immunization Practices (ACIP),” “comply with all applicable requirements as set forth by the U.S. Food and Drug Administration, including but not limited to requirements in any EUA that covers COVID-19 vaccine,” and “administer COVID-19 vaccine in compliance with all applicable state and territorial vaccination law.” The agreement goes on to state that violations “may result in suspension or termination from the CDC COVID-19 Vaccination Program and criminal and civil penalties under federal law.”
Prior to approval of vaccine BLAs and expansion of vaccine EUAs to allow for booster doses, at least two localities openly provided COVID-19 vaccines as boosters beyond the scope of their EUAs. Although this seemingly violated both the FDCA and the CDC’s provider agreement, neither the FDA nor the CDC took action. In addition, at least one million recipients received third doses that were unauthorized at the time, typically by misrepresenting themselves as unvaccinated first-dose recipients.
After issuance of the BLA for the Pfizer vaccine, some localities began providing off-label vaccine doses, such as boosters, in circumstances not recommended by the CDC or the FDA. San Francisco, for instance, claimed that “FDA approval of the vaccine provides leeway for off-label prescribing, in contrast to FDA emergency authorization.” However, notwithstanding FDA approval, off-label prescribing that has not been endorsed by ACIP still violates the CDC’s provider agreements—as the CDC has emphasized when warning providers not to offer vaccines off-label to pediatric patients. Perhaps for this reason, other localities asked the CDC for permission before providing fourth doses to non-immunocompromised adults (prior to the recent authorization of second boosters for adults older than age 50, which will also likely lead some younger individuals to lie about their age in hopes of securing additional protection). Nevertheless, we are aware of no action that has been taken against those providing COVID-19 vaccines off-label to adults.
In addition, pediatric patients continue to be legally excluded from access to many COVID-19 interventions based on age cutoffs. For instance, children younger than age 12 may not receive the antibody therapy bebtelovimab or the antiviral paxlovid. Because these therapies are only available under an EUA, their provision to a 10- or 11-year-old—even if weighing over 40 kg and otherwise at high risk of progression to severe COVID-19—could be a violation of the FDCA. The same is true for Evusheld, which has an EUA for pre-exposure prophylaxis. The only treatment legally available for these patients is remdesivir, given that drug’s approval for patients 12 and older and its EUA covering younger/smaller children.
Even for fully approved COVID-19 vaccines, the CDC provider agreements bar children who are currently ineligible for their primary course (children younger than age five) or booster doses (children 5–11) from receiving those doses because they are not yet included in the relevant EUAs and ACIP has not recommended their use off-label. One pharmacy that sought reimbursement for vaccinating ineligible pediatric patients at a time when the Pfizer vaccine remained exclusively under EUA faced federal action. However, thousands of children have received off-label doses either because their parents have misrepresented their age or taken them abroad for vaccination—a practice sometimes referred to as “circumvention tourism.”
The current situation presents serious legal and ethical problems. For example, prior to the CDC’s recent amendment to allow extended dosing intervals between vaccines, providers may have hesitated to recommend this approach even to patients who might prioritize the possibility of achieving longer duration of protection over speed in achieving immunity. In addition, receiving vaccines or therapies through deception makes it difficult to accurately forecast demand and, more importantly, to monitor effectiveness and adverse events. It also creates some risk that rare injuries stemming from unauthorized or off-label uses may not be compensated, depending on how countermeasure coverage is interpreted for purposes of the CICP. Receipt through circumvention tourism is a barrier for those who lack the wealth, health, or governmental authorization to travel overseas. Similarly, the ability to identify a provider who is willing to “bend the rules” to provide unauthorized or off-label interventions creates issues of both equity and professionalism. The open flouting of the FDA and the CDC rules by certain localities introduces arbitrariness and may sow confusion.
One efficient solution to these problems would be an announcement that the government will exercise “enforcement discretion” in limited, medically appropriate circumstances, as was done for certain COVID-19 tests performed beyond the scope of their EUAs. This would entail announcing that regulators do not intend to take action against certain violations of EUA terms or of provider agreement restrictions. (Alternatively, provider agreements could be amended to be less restrictive.) In practical terms, this would be fairly close to the government’s current, but unstated, position—after all, it has seemingly declined to take action against public flouting of EUA and provider agreement terms in most circumstances. However, a clear, public announcement, coupled with the government’s reasoning about why it would exercise enforcement discretion for certain off-label and unauthorized uses and not others, would bring transparency to the current regulatory environment. This could help promote more equitable, less arbitrary, and less furtive access.
This approach would also need to be coupled with attention to PREP Act liability protection and CICP injury compensation, both for unauthorized uses of EUA products and off-label uses of approved products. Because enforcement discretion does not change the underlying nature of the legal violation, it likely could not support a professional’s claim that they reasonably believed unauthorized use of EUA-only interventions were covered countermeasures, as needed for PREP Act liability protection. In other words, providers would still be taking some legal risk if they chose to offer EUA products beyond the scope of their authorization. Additionally, patients should understand that EUA-only COVID-19 interventions provided outside the terms of their EUAs under enforcement discretion are likely not covered countermeasures for purposes of CICP eligibility, an important issue to disclose during the consent process.
In contrast to unauthorized use of EUA-only interventions, the argument is stronger that fully approved vaccines or therapies remain covered countermeasures for purposes of PREP Act and CICP protection even if used off-label because such use does not alter approval status. However, the statutory language and relevant guidance on this point are not entirely clear, leading to confusion and concern that may inhibit off-label uses for which the benefits are likely to outweigh the risks. HHS should explicitly confirm that PREP Act and CICP protection extend to such uses, and it has strong legal grounds to do so.
Importantly, we do not mean to suggest that off-label or unauthorized uses are universally appropriate, and we acknowledge that scientific uncertainty remains, as demonstrated by the dueling findings recently reported by New York State and the CDC regarding pediatric COVID-19 vaccine efficacy. However, current government restrictions on the use of fully approved COVID-19 interventions deviates from the norm of allowing clinicians to decide whether and how approved products should be offered in their patients’ best interests; this norm is even more pronounced in pediatric populations, where off-label use is typical. Following that preexisting, permissive norm seems especially appropriate during a pandemic, when a wide variety of other regulatory standards have been eased to accommodate the public health emergency, and even more so at the present time when people at high risk of progression to severe COVID-19 and those concerned about the risks and uncertainties of long COVID must face a world with fewer non-vaccine protections. When the off-label uses sought for fully approved COVID-19 products pose low risks of obstructing evidence generation because clinical trials are fully enrolled (or indeed oversubscribed), there is also less reason for concern.
Unlike fully approved interventions, allowing unauthorized uses for products distributed exclusively under EUAs would depart from usual practice. Although permitting clinician discretion about unauthorized uses may occasionally be appropriate, considering the evidence supporting the unauthorized use and the risk that allowing it might undermine evidence generation through clinical trials is crucial. Where unauthorized uses could offer clinical benefit, the government could encourage and support use via the expanded access pathway until EUAs are amended.
We recommend that HHS immediately clarify whether off-label uses of approved COVID-19 interventions retain liability protection and injury compensation and explain when and how the provider agreements for vaccines will be enforced. HHS should also clarify the liability protections and compensation regime for unauthorized uses of interventions that remain under EUA. Uncertainty about the current legal environment may be precluding appropriate off-label or unauthorized uses in individual circumstances, disproportionately harming those with the fewest resources to advocate for themselves, while potentially facilitating inappropriate uses due to the perception that the government is looking the other way. Coordinated policy and clear guidance can replace opacity and confusion with a fair and transparent process.
Professors Lynch and Persad have received grant funding from the Greenwall Foundation. Professor Persad has received personal fees from the ASCO Post and the World Health Organization. Professor Zettler has served as an expert witness in Direct Purchaser Class Plaintiffs in In re Suboxone Antitrust Litigation, No. 2:13-MD-2445 (E.D. Pa) and Direct Purchaser Class, End Payor Class, and Retailer Plaintiffs in In re Opana Antitrust Litigation. Professor Lynch is a member of the NYU Grossman School of Medicine Working Group on Compassionate Use and Preapproval Access.