Like just about every pediatrician, Danny Benjamin, MD, PhD, is accustomed to going “off-label” with drug prescriptions for children — that is, using educated calculations about how much and how often to give a child a drug that has been approved only for adults and has thus no dosage guidelines for youngsters. The absurdity of the practice literally hit home when he had to sit in his kitchen cutting adult pills with a knife to give the right dose to his 10-year-old son, who took several medications daily for a chronic condition.
“As a parent, you’re left with making the decision when the doctor says, ‘Your son or daughter needs this medicine’” but the medicine hasn’t been approved as safe and effective for children, says Benjamin, a professor of pediatrics at Duke University School of Medicine in Durham, North Carolina. Prescribing off-label “is not something we should be doing every day. But we do that every day.”
Numerous studies have confirmed the routine practice of doctors writing off-label prescriptions for children, including a recent meta-analysis, led by the University of Oklahoma College of Medicine, estimating that they account for up to 38% of all pediatric prescriptions. In some age groups the rates of off-label use are far higher, including 90% of prescriptions for newborn babies, says Gary Noel, MD, chief medical officer at the Institute for Advanced Clinical Trials for Children (I-ACT), a nonprofit that collaborates with pediatric organizations to accelerate pediatric drug development.
“In pediatrics, off-label prescribing is the rule, not the exception,” says Cindy Jackson, DO, a pediatrician and chief operating officer at I-ACT, based in Rockville, Maryland.
The dearth of pediatric labeling information poses two dichotomous risks for children: That they won’t get medications that might help them, or that they’ll suffer side effects from drugs prescribed by their doctors but authorized only for adults. The information on each label approved by the Food and Drug Administration (FDA) includes the drug’s active ingredients, the illnesses for which it is approved, the correct dosage and frequency, how the drug should be administered, and possible side effects, among other things.
Jackson and Benjamin are among a growing number of doctors who are working to reduce off-label prescribing by increasing the enrollment of children in clinical trials for drugs that lack sufficient information about child safety and efficacy. Thanks largely to such efforts, federally authorized information about pediatric use has been added to more than 800 labels since 2004, according to the FDA. Those include drugs to treat asthma, diabetes, high blood pressure, hepatitis, HIV, and much more.
But there’s a long way to go.
“The lag time between adult approval and pediatric approval [of a drug] can be upwards of a decade,” Jackson said in a recent podcast about the challenge. “I find this statistic really sad.”
The pediatric research delay
There are several reasons for the lag time that Jackson laments. While it’s logical for researchers to try developing medications for children based on medications that have been proven safe and effective in adults, studying the reaction to drugs in children is more complicated. Children’s bodies react to medications differently than do the bodies of adults and of children in different age groups.
“As they age, children go through changes in how they metabolize drugs,” says Benjamin, the principal investigator at the Pediatric Trials Network (PTN). He notes that the changes include the acidity of their stomachs, how fast they excrete drugs through digestion, and the size of their organs relative to the surface area of their bodies.
“That’s why it’s critical to assess the effect of drugs across the developmental spectrum,” Jackson says.
The difference between adult and child reactions to drugs was tragically driven home by the use of several additives to medications, such as intravenous solutions, that caused severe adverse reactions and even deaths. One of them, benzyl alcohol, was cited in the early 1980s in 16 infant fatalities.
While such incidents point to the need to study the safety of commonly used drugs in children, some researchers have been wary because of the medical risks and ethical concerns.
“There has been this concept that we had to protect children from research” on new drugs, says Edward Connor, MD, emeritus professor of pediatrics, microbiology, immunology, and tropical medicine at George Washington University School of Medicine and Health Sciences in Washington, D.C. “But we need to protect children through research as well.”
Researchers who do set out to run clinical trials with children often have difficulty finding enough participants, because children are far less likely than adults to suffer from chronic conditions. The children in clinical trials almost always have the illness that’s being studied, and sometimes “there just aren’t enough pediatric patients” to build a statistically valid classical trial, Connor says.
Adding to that challenge is that trials are often designed with requirements that make it difficult or even impossible for many patients to participate. “This is why innovation in trial design is so important,” Connor says.
The relatively small population of child patients also means that drug manufacturers stand to make little or no profit by developing pediatric products for many illnesses. “The return on investment may be limited for a pharmaceutical company,” says Perdita Taylor-Zapata, MD, program lead for the Best Pharmaceuticals for Children Act Clinical Program at the National Institute of Child Health and Human Development in Rockville, Maryland.
These factors explain why Taylor-Zapata is struggling to treat a three-year-old patient with asthma.
“Her case is severe enough where I would like to put her on a combination medicine” — which asthma suffers typically take through inhalers — “but combinations medications are limited in her age group. There’s little safety and dosing information for her age.”
That leaves Taylor-Zapata doing what pediatricians routinely do when a patient suffers from an illness for which there is no drug approved for children, or when a patient does not respond well to those that are approved for children: Seek information about adult drugs that have been safely and effectively used off-label for children. Doctors turn to published medical guides like the Harriet Lane Handbook for pediatric diagnosis and treatment, and to colleagues through personal connections, professional organizations, and online networks, such as Sharing Antimicrobial Reports for Pediatric Stewardship.
“We haven’t been shooting blind” when prescribing off-label, notes pediatrician J. Routt Reigart, MD, incoming chair of the American Academy of Pediatrics Committee on Drugs.
Taylor-Zapata referred her three-year-old patient to an allergist to help decide what medicine to use and at what dosage and frequency, “because whatever we put her on is very likely going to be off-label.”
Changes in trials
Several initiatives are encouraging more clinical drug trials for children and making it easier to run them.
In the early 2000s Congress passed two laws of particular note: The Best Pharmaceuticals for Children Act (BPCA), which directs the the National Institutes of Health (through the program that Taylor-Zapata oversees) to prioritize drugs that should be studied for pediatric use and incentivize pharmaceutical companies to study them by extending their exclusive marketing rights for the drugs they subsequently develop; and the Pediatric Research Equity Act (PREA), which allows the FDA to require pediatric studies of adult products that are likely to benefit many children.
The laws have contributed to changes in the way trials are designed and carried out. Here are some of the strategies to increase child enrollment:
Draw blood from current patients: In some trials, blood samples are collected from pediatric patients who are already on off-label medications, so that researchers can study the safety and efficacy of the drugs. The children continue to get the drug in the hospital or doctor’s office, do not have to travel to a separate site for the trial, and are in the trial only as long as their doctor has them on the medication.
“It has very little impact on the life of the child, but the data that we get is very important to understand how the drug is affecting that child,” Taylor-Zapata says.
Let doctors decide on drugs and doses: Under the BPCA Clinical Program, the PTN initiates and oversees trials and analyzes the data. The network establishes protocols to study specific illnesses in certain age groups, giving doctors leeway to choose the drugs, dosage, and frequency.
“We say we’re going to study this infection, and you [the doctor] can choose from any of these 10 medicines to use,” says Benjamin at the PTN, which uses data from blood samples for its analysis.
Expand eligibility: Researchers are working to make more children eligible to participate in trials by reducing the factors (such as various medical conditions) that must be present to include or exclude them.
“I see people do trials where there are 20 inclusion criteria and 15 exclusion criteria, because they want this pure patient population” that meets very specific conditions, Benjamin says. “That is a kiss of death [for enrollment]. There are just not enough children” who meet the criteria for enrollment in the trials.
Build on adult data: More children’s trials are building on data from adult trials that established the effectiveness of certain drugs, then moving on to study the safety and correct doses for children. That helps to reduce the number of participants and the amount of time the trials require.
For some drugs, “you don’t have to do big efficacy trials to show that it already works because you can extrapolate efficacy [from adult trials] to pediatrics if the disease and the expected drug effect are similar in adults and children,” Connor says.
That process was used for some vaccines and treatments for COVID-19, such as remdesivir, Connor notes.
Include adolescents in adult trials: More adult trials are making room to include adolescents either from the start or soon thereafter, as was done with some COVID-19 vaccine trials, based on evidence that older adolescents often react to drugs in ways similar to adults.
“There’s a mindset shift from excluding adolescents from all adult clinical trials to an assumption that we should include adolescents in clinical trials unless there’s a reason not to,” Connor says.
Changes like these have helped researchers produce data for the FDA to add pediatric information to hundreds of drug labels, including for drugs that had not previously be approved for children as well as drugs that had been approved for some age groups but not others. The FDA publishes a database of changes to pediatric prescription labels since 1998. The additions grew from three that year to 73 last year.
Moving forward, doctors see several major areas of need for certain treatments, including anesthesia, drugs that moderate immune responses, and drugs for newborns and young infants. The NIH maintains a Priority List of Needs in Pediatric Therapeutics, which identifies scores of illnesses and the drugs for them that need to be approved.
“We still have a problem,” Jackson says, while noting that “there have been hundreds of label changes, which is terrific.”