A young man is adjusting a baby's protective surgical face mask on the child's face for COVID 19 safety issue.

Bioethics Forum Essay

With Pediatric Hospitalizations Rising, Reconsider Off-Label Covid Vaccination for Young Children

Pfizer recently announced that its trials in children 2 to 5 years old produced a weaker than expected antibody response and that it would hold off requesting authorization from the Food and Drug Administration. It was a clinical disappointment, and also an emotional blow to families (including some of our own) with a child under 5 who will be waiting longer to be vaccinated. Pfizer is testing a three-dose-series in these youngest kids, with results (and hopefully authorization) anticipated in the first half, as opposed to the first months, of the year.

The news from the Pfizer trial creates opportunities – and additional challenges – for off-label use of Covid-19 vaccines in children, which we’ve previously argued should be both ethical and legal. Although off-label vaccination is not a strategy for widespread vaccine access, it ought to be an option for some individual children when the potential benefit of immediate vaccination could outweigh the risks. The news from Pfizer does not change our analysis, but it does provide more information about anticipated risks and benefits.

According to our research, the Centers for Disease Control and Prevention’s prohibition against pediatric off-label use of Covid-19 vaccines in its vaccine provider agreement was ethically and legally unprecedented.  For children under 5 with high-risk medical conditions in particular, pediatricians and parents should be able to make the decision to vaccinate off-label together, as is possible to do for any other off-label use of medications or vaccinations.

To be clear, using vaccines off-label has both risks of unknown or rare side-effects, and logistical obstacles — even if the CDC Covid-19 vaccine provider agreement didn’t stand in the way. The update from the under 5-year-old Pfizer trials further illustrates these challenges. But paired with record pediatric hospitalizations, the news also underscores potential benefits of access to off-label vaccination.

Off-label means using an FDA-approved product for a different indication or population, or at a different dose, than that for which it was approved. The FDA fully approved the Pfizer-BioNTech Covid-19 vaccine as a two-dose series of 30 micrograms each for people ages 16 and older in August. The vaccine for children ages 12 to 15 uses the same dosage but is only authorized for emergency use.

In kids ages 5 to 11, a lower 10 microgram 2-dose series of the same formulation, administered with smaller needles, is FDA-authorized for emergency use. Because the Covid-19 vaccine for 5- to-11-year-olds is not fully approved, pediatricians can’t use it off-label to vaccinate younger kids. But they could modify the dosing of the fully approved version.

In the American Academy of Pediatrics statement against off-label vaccination, Dr. Yvonne Maldonado said, “We do not want individual physicians to be calculating doses and dosing schedules one-by-one for younger children.”

If pediatricians were to engage in off-label vaccination, they would have to determine an appropriate dose. One option could be to follow the ongoing clinical trials using 3 micrograms of vaccine in children under 5. Other options involve relying on clinical judgment and available data to determine an alternate dose. This is what the AAP was trying to avoid. Administering alternate doses outside of clinical trials does not involve the close monitoring and reporting that comes with doing so inside a clinical trial.

For this reason, engaging in variable dosing regimens prior to vaccine authorization might ideally be done in “open-label” trials. However, these trials involve additional time and resources to initiate and may not be accessible to the individuals for whom potential benefits of off-label vaccination might still outweigh risks.

The results of the 2-to-5-year-olds trial suggest that anticipated benefits of off-label vaccination may not be as significant as intended. But they also show that the known risks remain low. According to Pfizer, the trial dosing showed “no safety concerns” and “demonstrated a favorable safety profile in children 6 months to under 5 years of age.” Two reports from the CDC confirmed minimal adverse events in young children who have been vaccinated against Covid-19.

Extending the timeline for completion of clinical trials for children under 5 also extends the risks of remaining unvaccinated –  especially as a new variant circulates and Covid-19 cases continue to climb in kids. CDC projections indicate the Omicron variant will create a peak of infections in the U.S. in January that could extend to April. Current estimates suggest that a vaccine will not be authorized for children under 5 before the spring.

While children are more likely to have mild cases of Covid-19, some do experience severe illness or death. Pediatric hospitalizations have as much as quadrupled in some parts of the country, primarily among unvaccinated children – many without the option to become vaccinated. New York State, for example, reported at the end of December that approximately half of pediatric hospitalizations with Covid-19 are among children under 5. As of early January this trend continues, with CDC data indicating that the “steep rise” in children hospitalized with Covid-19 infections nationwide is among children under 4.

Off-label vaccinations could protect individual children at greatest risk of severe Covid-19 infection this winter and spring. One of the greatest risks of off-label vaccination at the trial dosing is that it might not be as effective as hoped. But for families of high-risk kids and their doctors, this might be a risk they would like to be able to take.

Elizabeth Lanphier, PhD, MS (@EthicsElizabeth), is an assistant professor in the Ethics Center at Cincinnati Children’s Hospital Medical Center and in the departments of pediatrics and philosophy at the University of Cincinnati, as well as a nonresident research fellow in the Institute for Philosophy and Public Policy.  Shannon Fyfe, PhD, JD (@sefyfe), is an assistant professor of philosophy at George Mason University, where she is also a fellow in the Institute for Philosophy and Public Policy and an adjunct professor at the Antonin Scalia Law School.

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  1. Dear Elizabeth and Shanon,
    Thanks for this insightfull essay. I just have a couple of questions. First, what is the probability that off-label use significatively delays or hinders research results from the ongoing clinical trials? Second, do you think a (better and wider) expanded access program (EAP) for the relevant group of children may be an alterantive possibility to the off-label use? If that’s the case, you’ll have independent support for better EAP here (1). Thanks in advance.

    1. Fernandez Lynch, Holly, Arthur Caplan, Patricia Furlong, and Alison Bateman-House. “Helpful Lessons and Cautionary Tales: How Should COVID- 19 Drug Development and Access Inform Approaches to Non-Pandemic Diseases?” American Journal of Bioethics, 2021.

    1. Thanks for these questions. There are a couple reasons why off-label vaccination would not likely impact the current progress of clinical trials. The most pertinent reason related to our analysis is that on our view off-label use is not a strategy for mass vaccination, but would be most ethically justifiable for kids with high-risk conditions, who would also be unlikely to meet inclusion criteria for vaccine trial participation and therefore would not take away from a pool of available study participants (though open-label trials like those discussed by Wolfe and Lantos in a recent Hastings Bioethics Forum essay might be a different story as they could potentially accommodate a wider range of study participants). Regarding expanded access, we discuss this in the full research article, which is linked to in the essay above. Because the restrictions on off-label use come from the CDC provider agreement rules imposed on federally purchased and supplied Covid-19 vaccines, expanded access could be an alternative, though also comes with other limitations and constraints.

      1. Dear Elizabeth,

        Thanks for your prompt and insightfull answers. I found your first reply convincing specially for kids with high-risk conditions. Perhaps, an alternative to Wolfe and Lantos, and closer to your proposal would be a national mandatory registry for off-label use for kids with high-risk conditions with some form of augmented therapeutic consent (inspired in the suggestion of Largent et al (2009) for what they call “suppositional off-label use”). Another alternative beside exapande access of mRNA COVID-19 vaccines under trial -logically possible but I don’t know if practically feasible- would be to use another type of vaccines that already have been used for kids, also under an expande access program (e.g. China, Argentina and other countries have been vaccinating children from 3 to 11 with innactivated virus vaccines, a vaccine platform with better known risk-benefit profile that the mRNA vaccines [disclosure: I’m not an expert in vaccines]). A recent WHO statment do not promote general use in children and adolescents but seems not to discard altogether use for kids with high-risk conditions (personal interpretation of WHO 2021).

        Perhaps, it would be usefull for understanding the current limitations posed to the off-label use of vaccines for children, to put it in the contexts of the recent experience in the US and elsewhere with widespread, unmonitored and uncontrolled off-label use of ivermectine, hydroxicloroquine and other “off-label” uses of proven interventions and completely unproven interventions for COVID-19 (PAHO 2020) and its threats to a .

        Finally, as a side comment, I believe that the affirmation in your paper that “Off-label use is not experimental, but it could be mistakenly interpreted as such” (p. 30) might be clarified because of the multiple meanings of the term “experimental”. I agree with you that it is not experimental if by that you mean that it is not research, that is, the main aim of off-label use is not “to develop generalizable [scientific] knowledge”. However, the term experimental may not only refer to research but also is commonly used as a synonym of “innovation”, “non-validated practice” (National Commission 1978, Beauchamp & Saghai 2012) or “new non-validated practice”, that is “the first or recent use of […] interventions that introduce a significant change, with an insufficient level of evidence of safety or efficacy for regular healthcare, and with the main aim to benefit individual patients” (Mastrole & Holzer 2020). Hence, in this second sense, off-label uses of proven interventions may be experimental or “investigational” (Largent et al 2009) depending on the level of evidence and uncertainty.

        I mention this latter point because I believe that the substantive disscussion regarding off-label use of mRNA vaccines for kids with high-risk conditions is related to the sufficient evidence of safety and efficacy for a widespread use in the health system (being under emergency use authoriaztion or full authorization) and the impact of widespread uncoordinated individual actions in the health of the public, and that should be a consideration that practitioners prescribing off-label use should bear in mind even though they are not engaging with research activities. This does not mean forgetting individual kids with high-risk conditions and their families (that’s why we are thinking about alternatives, isn’t it?).

        Again, thanks for your response, and I hope some of these comments might prove useful for this relevant discussion.

        References

        Beauchamp, T. L., & Saghai, Y. (2012). The historical foundations of the research-practice distinction in bioethics. Theoretical Medicine and Bioethics, 33(1), 45–56. https://doi.org/10.1007/s11017-011-9207-8

        Largent, E. A., Miller, F. G., & Pearson, S. D. (2009). Going Off-label Without Venturing Off-Course: Evidence and Ethical Off-label Prescribing. Archives of Internal Medicine, 169(19), 1745–1747. https://doi.org/10.1001/archinternmed.2009.314

        Mastroleo, I., & Holzer, F. (2020). New non-validated practice: An enhanced definition of innovative practice for medicine. Law, Innovation and Technology, 12(2), 318–346. https://doi.org/10.1080/17579961.2020.1815405

        National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). (1978). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. US Government Printing Office.

        Pan American Health Organization (PAHO). (2020). Emergency use of unproven interventions outside of research Ethics guidance for the COVID-19 pandemic. https://iris.paho.org/handle/10665.2/52429

        World Health Organization (WHO). (2020, March 31). Off-label use of medicines for COVID-19. https://www.who.int/news-room/commentaries/detail/off-label-use-of-medicines-for-covid-19

        World Health Organization (WHO). (2021, November 29). Interim statement on COVID-19 vaccination for children and adolescents. https://www.who.int/news/item/24-11-2021-interim-statement-on-covid-19-vaccination-for-children-and-adolescents

  2. Thank you! I am a parent of an 18 month old and a 4.5 year old. We are trying to avoid omicron but in order to do that I think would have to go into full lockdown mode as we live in a county where there is a public “health” order against enforcing masks. It feel like an impossible choice and I would feel comfortable having both of my kids vaccinated at the 1.5 year old fits into age group that was shown to be safe and effective for the dose tested and I know some other countries are allowing anyone born in 2017 the 5-11 dose. She is months away from turning 5 and I would take my chances with her not being quite 5 at time of vaccination if my pediatrician could do off label use. It feels so hard to wait when there is a reasonable option for my kids and I feel like the red tape in this situation is making us sit with impossible choice of making them live in lockdown for 4 more months (which is exceptionally hard when the world around us acts like there is no more pandemic) or basically except they will get omicron before they are vaccine eligible. I am mostly concerned about long Covid and long term effects of Covid on a developing brain that remain unknown at this time. We know vaccines help with long Covid and find it quite ironic in the world we live in today that allowing this option gives parents and pediatricians the right to choose!

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