Harnessing Public Interest To Improve Pediatric Off-Label Drug Use At Long Last

The path toward Food and Drug Administration (FDA) approval for medications in modern US medicine is a long, rigorous, and expensive journey. Innovation and regulation are costly steps toward the official seal of approval that Americans expect when they purchase a medication via prescription from their provider to remedy or mitigate an illness. For many, there is an implicit belief that if the prescriber and pharmacist have issued the medication with specific instructions, the choice and instructions must be the result of provider education, accepted medical practice, and an arduous FDA approval process. The specifics of the drug approval process were largely ignored by most lay people in the past; however, public interest has increased dramatically because of the COVID-19 pandemic.

Many people who never before paid attention to the activities of the FDA have anxiously followed the news of the process of vaccine approval. As of June 2022, it had been 26 months since the World Health Organization declared COVID-19 a global pandemic. It took that full time for the youngest group of people, those six months of age to younger than five years old, to have the FDA approve a vaccine for their use. As of late May 2022, Pfizer announced that it had achieved a satisfactory immune response and safety profile in children ages six months to four years after adjusting the dose and frequency used to accommodate this unique group. It was welcome news after an earlier announcement from Pfizer in December 2021 had revealed that a two-dose regimen, like the original series for adults and those 12 years and older, was proven insufficient in the younger age group. The FDA’s Vaccines and Related Biological Products Advisory Committee met in June, and on June 17, 2022, announced it had authorized the Moderna and Pfizer vaccines for use in this age group under amendments to their prior Emergency Use Authorization.

It is only through the strictly regulated clinical trial process that the need to adjust the dose and frequency of doses became apparent to Pfizer. These data have been more publicized than most other prescription biologic or drug trial data given the public interest and have been helpful in highlighting a fact that pediatricians have long known: Pediatric patients are physiologically unique and cannot simply be treated as smaller humans. As younger humans grow and develop there are changes happening internally that impact how a body processes a drug, its pharmacokinetics, and these are evolving over time as the child matures. Recent studies have confirmed that even when accounting for differences in body weight, various age groups process and respond to medications differently as they move through the body. The body of scientific evidence of this has been growing since the 1990s in response to congressional action, after having no pediatric pharmacodynamic or pharmacokinetic studies prior to the 1970s. Despite that, it is concerning that still today there are a disproportionate number of medications on the market, needed by pediatric patients, that may never go through a similar level of scrutiny during the FDA approval process as the COVID-19 vaccine. Instead, too often, pediatricians are left to rely on experience alone to determine if, when, and how much of an adult-approved medication may be appropriate to treat their patients. The ethical and financial issues that prevent proper FDA approval for pediatric use of many medications are not going to change any time soon. Therefore, it is up to policy makers to think outside the box to improve the body of knowledge about medications in pediatric patients.

Background Of Off-Label Use In Pediatrics

Using medications in any way that is not consistent with FDA-approved uses and labeling is considered “off-label” and has been associated with increased risk of adverse drug reactions. This practice has been done commonly by those who provide medical care to patients for whom there simply is not enough research evidence to allow for the full FDA approval process. There are many different reasons why many medications lack pediatric-specific approval including risks and ethical concerns surrounding conducting clinical research trials in children and a lack of financial incentive for pharmaceutical companies to pursue further costly testing.

Congress has tried in a variety of ways over the past several decades to incentivize the pharmaceutical industry to pursue proper pediatric trials and subsequent approvals. This began with the Food and Drug Modernization Act in 1997 by offering six months of patent exclusivity to those who conducted pediatric trials. More recently, the Food and Drug Administration Safety and Administration Act of 2012 made two earlier acts, the Best Pharmaceuticals Act for Children and Pediatric Research Equality Act permanent. Together these resulted in the authorization of the FDA to request pediatric studies with New Drug Applications (NDAs), required the National Institutes of Health to publish a list of needed pediatric studies, allowed for modifications to existing indications, required pediatric assessment and creation of a pediatric safety plan with NDAs, and stipulated that a pediatric plan needed to be established before adult authorization of a drug. As of 2019, these efforts had resulted in more than 500 labeling changes for pediatrics, but the majority of medications in use still do not have pediatric label information. Furthermore, of those that do, many are for medications that do not meet the greatest pediatric needs.

Current Practices

Despite these legislative efforts to create carrots and sticks directed at the pharmaceutical industry to increase in pediatric-specific labeling from scientific evidence, off-label use of medications continues to be quite common. In outpatient practices, a study published in October 2019 demonstrated that at least one or more off-label drugs were prescribed at 18.5 percent of office visits for patients younger than 18 years old. The majority of these were for unauthorized indications, while less common reasons included being off-label by age, weight, or some combination of these factors. Off-label drug use was also proportionally more common for neonates than any other age group. In raw numbers, there were more off-label prescriptions given for adolescents. Importantly in this study, which reviewed evidence from 2006 to 2015, the research revealed that rates of off-label drug use were overall increasing over time despite being stable or slightly decreasing for some antibiotics. In comparison, a 2007 study evaluating the use of off-label medications in hospitalized patients showed that 78.7 percent of patients had been administered at least one medication with an off-label use.

An updated review published in 2019 revealed that this number had decreased to 53.9 percent for pediatric inpatients, but across all settings there was still at least one off-label use of medication during more than 25 percent of patient encounters. The high rates of off-label use are in part due to the common use of pain medications morphine and codeine, both of which lack appropriate pediatric information to qualify as on-label use at all in patients younger than 18 years old. For medications such as these, already approved for adult use and readily available as generics, there is no financial incentive for pharmaceutical companies to invest in pediatric trials or the costs associated with filing a supplemental drug application. In light of these limitations, the American Academy of Pediatrics (AAP) Committee on Drugs published an updated policy statement in 2014 indicating that while clinicians should continue to advocate for more pediatric-specific research on all medications, individual clinicians are ultimately responsible for determining the most appropriate available treatment for their patients. They further clarify that these decisions should be based on “the drug’s labeling (when available) or … sound scientific evidence, expert medical judgement, or published literature whenever possible” and that as long as these recommendations are followed, the off-label use of a drug is not wrong and should not be considered investigational.

Public Opinion And The Influence Of COVID-19

While the AAP has issued this guidance on off-label drug use, the lay public has demonstrated that they are not aware of or comfortable with current off-label practices. A broad 2006 poll regarding off-label drug use found that about half of respondents wrongly thought prescribers were not allowed to write prescriptions for any use other than that approved by the FDA and that the practice of off-label prescribing by physicians should not be allowed. Even more, two-thirds, felt that other than in clinical trials, the practice should be banned all together.

More recently, the COVID-19 pandemic has served as a reminder that patients make their own determinations regarding risk-tolerance. Indeed, there were many Americans who were comfortable interacting in public without a face mask but felt that the newly developed vaccines were too risky. Likewise, despite the earlier policy statement from the AAP regarding off-label drug use, there was still professional debate in journals and elsewhere about allowing younger children to receive the COVID-19 vaccine prior to the FDA approval for the younger age groups. In many ways, this would not have been much different than what has been done for a long time with other medications and yet, in the environment of intense public interest, many determined that off-label use of the biologic was inappropriate.

Recommendations

The silver lining to the current situation is that practitioners can use this moment of public interest and understanding of the FDA approval process and the need for testing in children to pursue alternative means of pediatric FDA authorization and improve the database of pediatric drug information. Below are just a few suggestions for consideration by policy makers:

• The high frequency off-label use of medications provides ample opportunity to gather observational data about dose, response, and any adverse reactions. The fact that this occurs so regularly in the United States without capturing the data is a huge, missed opportunity. The FDA’s Adverse Event Reporting System exists to capture data on already-approved drugs. A similar entity, if not a simple extension of this one, should be developed to capture the data on off-label use of medications. Policy makers could even consider requiring practitioners to report their use and experience with off-label medications as a mandatory part of the dispensing process. Every prescription would prompt the pharmacist to initiate an encounter in the system that the provider would have to go back and complete following use of the medication. There would be incentives or penalties for not completing the encounter in the system.
• When ethical concerns make clinical trials in at-risk populations such as pediatrics inappropriate, alternative means to FDA-authorized labeling and use need to be available. While blinded experimental evidence is the strongest, it is not absolute in its ability to offer meaningful contributions to medical knowledge. The FDA should consider guidelines for special circumstances that would allow observational evidence to be considered for FDA review. Even if this review leads to an alternative type of approval wherein the authorization is noted as being different from a standard authorization, it would still be better than the current system that relies on academic journals selectively publishing the experience of those practitioners who choose to write up their experiences for publication. Publishing in a journal is a time-consuming practice and restricts many from sharing their experiences that could otherwise add to a body of evidence that would allow for proper scrutiny of a medication when used alternatively.
• As a consequence of allowing a new form of FDA authorization, pharmaceutical companies could be incentivized to financially support collection of evidence for their products. Currently, the FDA prohibits the promotion of off-label uses by drug companies, and multiple pharmaceutical companies have settled court cases regarding improper off-label marketing for billions of dollars. If an alternative form of authorization was permitted, then policy makers could consider allowing the pharmaceutical industry to advertise this new authorization without fear of penalty. The money saved and earnings potential would likely motivate the investment in proper after-market data collection.

Conclusion

Clinical trials for every medication in every patient type are an ideal gold standard when the FDA considers NDAs, but this is not a realistic expectation. It is past time that all stakeholders involved consider creative alternatives to improve patient safety and public trust. The public should know that what pediatric practitioners do is evidence-based even when ethical or financial concerns prevent the clinical trials required for full FDA approval.