On March 15, Moderna began enrolling 6,750 children from 6 months to 12 years of age in a study of its mRNA-1273 vaccine (NCT04796896). The study in children launched eight months after the launch of the pivotal Phase III study in adults (NCT04470427). Pfizer started enrollment of their mRNA vaccine, BNT162b2, last April (NCT04368728). As of today (March 21, 2021), Pfizer has not registered a study of the BNT162b2 in young children. The third EUA-approved vaccine in the United States, Johnson & Johnson's Ad26.COV2.S, began enrollment in September (NCT04505722). Johnson & Johnson has not registered a study of their vaccine in children.
Why are children always last?
Most children are only mildly symptomatic from SARS-CoV-2 (Sci Rep 2021;11:5760). However, some children get very ill, particularly if they develop multisystem inflammatory disease (MIS-C) (BMJ 2021;372:n385). The CDC summarizes the evidence succinctly. “Most children with COVID-19 have mild symptoms or have no symptoms at all. However, some children can get severely ill from COVID-19. They might require hospitalization, intensive care, or a ventilator to help them breathe. In rare cases, they might die.” (asamonitor.pub/319zkCS) Black and Hispanic children are at demonstrably higher risk of complications then White children (Morb Mortal Wkly Rep 2020;69:1081-1088). The CDC guidance also notes that the risks are elevated in babies and children with underlying medical conditions (asamonitor.pub/319zkCS).
There are strong ethical and practical reasons to develop COVID vaccines for children (Pediatr Res 2021:1-5). However, the studies are only starting now for the same reason that studies of new drugs are always delayed, if they are done at all: labeling drugs for children is a low-return proposition for pharmaceutical companies: Pharma recognizes that the expense of large, controlled trials in children is high, the commercial market for their products in children small, and, most cynically, they recognize their products will be prescribed for children whether they conduct trials in kids or not. Furthermore, this practice enables their use of the package insert, which states the product is “not approved for patients under the age of 18 years,” as a shield from product liability should a child be injured.
As noted by the FDA:
“Most drugs prescribed for children have not been tested in children. Before the Food and Drug Administration initiated a pediatric program, only about 20 percent of drugs approved by the FDA were labeled for pediatric use. By necessity, doctors have routinely given drugs to children ‘off label,’ which means the drug has not been approved for use in children based on the demonstration of safety and efficacy in adequate, well-controlled clinical trials” (asamonitor.pub/2NMgRJK).
It's not only vaccines that have been slow to be studied in children. In 2006, Joseph Tobin, Peter Davis, and this author (SLS) called out the FDA for the lack of pediatric dosing guidelines for most anesthetic drugs and analgesics in children (Anesth Analg 2006;103:43-8). Schultheis and colleagues responded on behalf of the FDA, noting the success of FDA programs such as the Newborn Drug Development Initiative sponsored by the NIH and FDA (Anesth Analg 2006;103:49-51). Yet in spite of regulations in the 1990s by the FDA to compel Pharma to test new drugs in children – which was successfully challenged by Big Pharma and ultimately struck down by the Supreme Court – and in spite of statutory authority given by Congress to the FDA to require pre-approval pediatric studies, only a very small minority of new drugs are approved for pediatric use, and fewer are approved with efficacy data. That this holds true for immunizations even during a national crisis in which children have been shown to be common vectors of the novel coronavirus and to be at risk of death and disability from COVID-19 is, to say the least, scandalous.
Despite past initiatives, children still come last. The gap between regulatory approval and labeling and the unmet medical needs of young children continues to be funded privately and by federal agencies, and fulfilled by physicians and their health care colleagues who collectively perform research, publish data, and develop guidelines for our youngest and most vulnerable patients, or assume all liability for prescription in the absence of pharmacological data. This issue of the ASA Monitor reviews a particularly vulnerable, refractory, and frankly heart-wrenching population: children with chronic pain.
Drs. Suleman, Torbey, and Slifer emphasize the importance of multidisciplinary approaches in children with chronic pain (ASA Monitor May 2021). This includes psychological and psychiatric assessment. Multidisciplinary programs aim to decrease the focus on pain, disability, and negative thoughts, and refocus the patient on health, wellness, and positive affirmations. Many of these techniques are borrowed from cognitive behavioral therapy.
Drs. Torbey, Rached, Fiani, and Suleman dive into greater detail on the psychiatric considerations for children with chronic pain (ASA Monitor May 2021). They note the association of anxiety and chronic pain, particularly in girls. Although the evidence is inconclusive, several studies also suggest an association between chronic pain, depression, and suicide. And, to hammer home the discussion above, of modern SSRI and SNRI anti-depressants, only fluoxetine (Prozac) is approved for use in children.
Drs. Goeller, Beethe, Spitznagel, and Manning talk about providing multimodal analgesia in children without incorporating opioids (ASA Monitor May 2021). The approach borrows extensively from Enhanced Recovery After Surgery (ERAS) protocols, utilizing NSAIDS, acetaminophen, regional anesthesia, and adjuncts such as gabapentin, ketamine, dexmedetomidine, and dexamethasone. The authors note that there often is a role for opioids, particularly acutely (during and immediately after surgery), but that the emphasis is on switching away from opioids (opioid cessation) as quickly as possible.
Drs. Ali and Edala follow up with an overview of regional anesthesia in children (ASA Monitor May 2021). As they note, children are not small adults, and the differences are important (e.g., the lower level of the conus medullaris and dural sac, the sensitivity of infants to local anesthetic systemic toxicity, the pharmacokinetics of local anesthetics, and the pharmacodynamic insensitivity of children and teens to local anesthetic effect). The use of regional anesthesia in children is increasing. The authors review blocks by anatomy: head and neck, upper and lower extremities, trunk, neuraxial, and peripheral nerve blocks. Because of the lack of regulatory guidance, much of the guidance for regional anesthesia comes from large and very active registries.
Finally, Drs. Lin and Wang describe the evolving use of acupuncture in children, a practice that dates back more than 2,000 years (ASA Monitor May 2021). The authors offer multiple studies and meta-analyses, finding support for acupuncture in treating multiple types of pain and anxiety in children, including postoperative pain and other types of chronic pain like colic, headache, pelvic pain, and chronic low back pain. The authors conclude that “Although there is still paucity of pediatric acupuncture clinical trials in various pain conditions, acupuncture is becoming an increasingly integral part of pediatric health care.”
Children are always last when it comes to new drugs, therapeutic interventions, and (now) vaccines. This is partly the consequence of appropriate caution when introducing experimental or new therapies, partly out of ethical issues that arise because children cannot give informed consent, partly out of caution by regulators, but is largely the consequence of the exceptionally cautious fiduciary risk-benefit assessment of pediatric labeling by the medical drug and device industries. Despite the lack of regulatory review and approval, clinicians continue to address unmet medical needs using the one tool that is available: off-label prescribing and, when possible but infrequently, independently funded research. As highlighted in this issue of the ASA Monitor, as clinicians it is our ethical obligation to see that the medical needs of our most vulnerable patients always come first.