The meetings start, as gatherings at 7 A.M. so often do, with people wandering in clutching their coffees and searching for a seat. Fingers instinctively go to pagers affixed at the hip to check for messages, and then all eyes turn to the stacked folders strewn across the table in a generic conference room at Nationwide Children’s Hospital in Columbus, Ohio—the kind of room with long tables, chairs and a projector at the front.
The mundane scene, repeated in facilities across the country, often once a month, determines something quite crucial. In the absence of actual government approval these meetings dictate how your physician will medicate your sick child or infant. Research is showing legion differences in the way drugs work in adult bodies versus those of youths. But because clinical trials rarely include children, the burden of deciding which medications to use—and at what dose—falls to these small committees that decide on a hospital-by-hospital basis. New approaches or legislation, physicians hope, may make that job easier in the future but for now pediatricians and pharmacists are largely on their own.
Less than half of the drugs used in kids—46 percent—are approved for use on child patients. That shocking figure is actually an improvement from decades past when the figure was as high as 70 percent.
In the absence of federal approval for such drugs stopgap measures are implemented: Doctors scour the peer-reviewed literature. They look to hospitals’ own patient experiences and informal LISTSERVS where physicians and pharmacists swap information about dosage and side effects. Small expert committees deliberate usage at monthly meetings. But that approach certainly does not rise to the same level of scrutiny that one would expect when the U.S. Food and Drug Administration approves a drug for a specific use.
In fact, pediatric pharmaceuticals rely the majority of the time on off-label approaches. And for neonatal intensive care units, where there is an even greater dearth of study and regulatory approval, over 90 percent of drugs are used off-label—often prompting clinicians to ask parents for consent prior to their use, says Justin Cole, a clinical pharmacist at Nationwide.
So-called “off label” use is not inherently problematic. Roughly one fifth of all drug use is actually off-label. Singulair, the asthma drug, is commonly prescribed off-label to instead help with chronic obstructive pulmonary disorder. Meanwhile almost all opioid pain medications are used off-label in kids.
Generally, after the FDA approves a medication licensed doctors are free to use it for any purpose they consider medically appropriate. And when it comes to pediatrics, off-label use is, more often than not, the only option—which could be a problem. “I think it comes down to what is the quality of the data they are using, and that’s going to be variable,” says Robert Nelson, deputy director and senior pediatric ethicist in FDA’s Office of Pediatric Therapeutics. Put simply, children are not just tiny adults. Shrinking the dosage of a medication prescribed for a 70-kilogram adult to a proportional level for a 20-kilogram child does not insure the drug will work the same way—it often won’t.
Indeed, simply extrapolating dosage by weight can lead to disastrous consequences. Bactrim, a popular drug used to help fight infections in adults, is rendered almost useless in newborns. Because their livers are not properly developed at that age their tiny systems do not metabolize the drug; instead the infants may turn yellow from jaundice and suffer brain damage. Another drug, chloramphenicol, which was once quite common in adults to help ward off infection, proves toxic in babies that don’t have the proper enzymes to break the drug down, instead causing respiratory issues and turning the babies’ skin an ashen gray. If untreated, it leads to heart failure.
No incentive for kid trials
The obstacles to getting better clinical trial data among kids are many but solutions are few. A major hurdle is that pharmaceutical companies know that drugs will be used off-label in kids anyway, so there is not much financial incentive to develop such expensive and time-consuming trials. Kids are a relatively small patient population, and setting up trials for rare diseases among children makes the monetary benefit of such efforts even harder to see. “They aren’t foolish. They know we’re going to use the drug anyway, but it’s really an extra burden on the provider” says Sarah Erush, clinical manager in the department of pharmacy at The Children’s Hospital of Philadelphia (CHOP).
Getting consent for kids to participate in trials and devising study protocols that work with a family’s schedule are obstacles, too, because it may mean interrupting school and work days to transport a child to the study. An adult subject may be able to stay at a hospital for a couple days to allow researchers to track how a drug interacts with the body but a child would not be as willing or perhaps able to stay, Neville says.
In the past couple decades two pieces of legislation have been enacted in an attempt to help close this gap—and they are widely hailed as helping drugs get to that 46 percent. One law, the Best Pharmaceuticals for Children Act, provides a carrot, trying to spark clinical research for pediatrics with offerings of exclusive sale rights for a short period of time. The other, called the Pediatric Research Equity Act, provides the stick: the threat that in order to gain approval for a drug, if that drug can also be used in kids to fight the same malady, then child testing must be done as well.
But here's the catch with that latter requirement—kids often get diseases adults don’t, rendering the requirement to also test children useless. “Adults get colon cancer, which kids don’t, but kids do get neuroblastoma. So say a drug is labeled for colon cancer, because neuroblastoma is a different cancer the company is not required to study it in children, so kids are left with not that many drugs coming down the pipeline,” says Kathleen Neville, chair of the Committee on Drugs at the American Academy of Pediatrics. That brings doctors back to square one, forcing them to once again look at off-label approaches. To that end, Neville says, “We need new legislation to fill in the holes. One of the concepts people have talked about within the field is maybe the requirements that go along with labeling should be based on mechanism of action of the drug and not necessarily the disease—then if you have cancer, in some ways, cancer is cancer.”
Modifying animal experiments to provide clues won’t work, either: How a baby rat reacts to something is often not how a child will react. And research or technological fixes are few and far between. In the future some clinicians and researchers wonder if so-called “organs on a chip” will help elucidate some answers for child patients because these advanced microfluidic systems could be used to emulate organs in the body, to see how, for example, the human lung would respond to a certain drug. But that may be a long way off. “I’m optimistic that it could help because a lot of times animal models are terrible, but it would need to be proven in adults first,” Neville says.
In the meantime pediatric patients continue to rely on hospitals and existing studies to make the right choices. Paul Offit, head of the Therapeutic Standards Committee at CHOP, is one such example: The majority of drugs used at his hospital, he says, are not licensed for children. And so pharmacists at his facility and elsewhere continue to gather on a regular basis, discussing what little data they have and how they can shift protocols for their hospitals to ensure they maximize the utility of these drugs but minimize side effects—tweaking the dosage level here or swapping out a drug there.
For now, it seems, following what the doctor orders will just have to do.