What would Goldilocks do?

When it comes to medicine for kids, finding a dose that's just right is largely a matter of luck

Leslie Williamson
  Anesthesiologist Greg Hammer, MD, is studying whether one drug already commonly used in kids is safe and effective.


Five years ago pediatric endocrinologist Laura Bachrach, MD, faced an unpleasant decision. An 11-year-old girl with inflammatory bowel disease had started experiencing severe backaches and difficulty sleeping. The steroids she had been taking to alleviate her stomach pain had weakened her bones and caused two of her vertebrae to collapse. 

“Clearly this young patient needed a drug to increase her bone density,” says Bachrach. “I felt backed into a corner. At the time there was no drug that I could give her that had been approved in pediatric patients.”

There still isn’t.

Bachrach, a Stanford professor of pediatrics at Lucile Packard Children’s Hospital, was struggling with a dilemma all too common to pediatricians nationwide. About 70 percent of all drugs prescribed to kids have never been tested in children, either for safety or efficacy. Bachrach was forced to do what most pediatricians do — she prescribed a medication normally used in adults, adjusting the dose down to what seemed appropriate for her young patient. Although the girl did well, Bachrach continued to harbor doubts about the one-size-fits-all treatment.

“Can we assume that a drug that’s really great for post-menopausal women would be the right cure for kids?” says Bachrach. “If we simply prescribe it because it works in grandma, it may not be sufficient.”

So how did this happen? Bachrach’s hospital is kid-centric to the umpteenth degree. Kid-created art lines the walls, and a model train toots its way along a track in the hallway. It has kid-sized chairs, examination tables and surgical tools. How is it that about the only thing that’s not just for kids is the medicine that’s prescribed and administered to the hospital’s patients?

The answer lies in a complicated brew of financial, ethical and physiological hurdles that has traditionally relegated kids to second-class citizens when it comes to drug development and testing. But now doctors and researchers are taking action, and they’ve gained government backing. Two legislative acts first cajole and then mandate drug safety and efficacy testing for children. Although opponents worry that the new laws will increase the costs of all prescription medications and delay the arrival of new drugs on the market, most pediatricians think it’s about time.

“The lack of testing of most pediatric drugs is a horrendous problem,” says neonatologist William Benitz, MD. As a medical intern at Stanford Hospital in 1978, Bentiz found that none of his standard references — the pharmacy books, the Physicians’ Desk Reference or even the labels of the drugs he was prescribing to children every day — carried any dosing recommendation for kids. He was troubled enough by this paucity of data that he took matters into his own hands.

“It was a team of one to begin with,” says Benitz. “I did the research the old-fashioned way, going to the library to dredge the scientific literature, fleshing out dosing information on a couple hundred drugs.” As his pocket-sized handbook — intended as a personal reference — grew, he eventually joined forces with clinical pharmacist David Tatro who worked at the Drug Information Center at Stanford Hospital.

“We decided to include only information from studies that had been published in peer-reviewed literature,” says Benitz, “which was a pretty sketchy database. But that was all we had to guide us to the appropriate doses for children of about 500 products.” Their work attracted the attention of colleagues, and was first published in 1981. It has since been through three revisions, and was the standard reference for drugs used in pediatric patients for about 15 years.

Properly testing medications in children is a tricky business. Even healthy children must be categorized by relatively narrow age ranges to account for differences in body

composition, hormone levels and maturation of organ systems that can affect how they will react to the drug. And finding enough children with a particular disease or condition to generate a study with acceptable statistical power can be difficult.

“Kids are basically pretty healthy people,” says Benitz. “If you want to study renal failure or lupus in children under 5 years of age, it really has to be done as part of a national consortium.”

Small payoff

Leslie Williamson
  Laura Bachrach, MD, sometimes has no choice but to prescribe kids drugs that have only been tested in adults.

Benitz’s point about kids’ health highlights yet another problem: The number of children who need an effective bone-strengthening medication, for example, is far lower than the pool of post-menopausal women who might benefit from such a treatment. And those children tend to need much smaller doses. Couple the above difficulties with some very valid questions about the ethics of conducting clinical trials in children [see “Ask the Bioethicist,” page 23] and you’re left with major disincentives for pharmaceutical companies to pursue U.S. Food and Drug Administration approval of their drugs for use in kids.

The result? Pediatricians have been forced to make educated guesses about when and how much of a drug to use. But the tide might be shifting. As a result of steady pressure from such physicians as Philip Pizzo, MD, dean of the Stanford School of Medicine, and Charles Prober, MD, a Stanford pediatrics professor who serves as scientific director of the Glaser Pediatric Research Network, Congress has gotten in on the act. Two of them, in fact. The Best Pharmaceuticals for Children Act, signed into law in early 2002, asks manufacturers of existing drugs to go back and test them in kids, and the Pediatric Research Equity Act, passed in late 2003, requires the makers of some drugs in development to prove they are safe and effective in kids. Together the two measures aim to bring all pediatric medications into the fold of FDA approval.

These acts aren’t the first time that the government has tried to rectify the situation. In 1997, Congress passed the Food and Drug Administration Modernization Act, which, among other things, provided an additional six months of exclusive marketing rights to manufacturers that chose to test their drugs in children. This incentive came to be known as the pediatric exclusivity provision, and sparked the first significant wave of pediatric drug testing: Over 50 new studies were conducted during the first three years of the provision, and 25 drugs were granted extended exclusive marketing rights.

The 1997 exclusivity provision wasn’t fail-safe, however. Manufacturers had no incentive to conduct the studies if their exclusive marketing rights had already expired. And certain very important yet little-used drugs didn’t sell enough to warrant spending the extra money on additional testing. Finally, the provision applied to only a small proportion of biological compounds, like vaccines and blood products.

To bridge some of these gaps, in 1998 the FDA issued a new regulation known as the pediatric rule. The rule gave the FDA the authority to require studies of new drugs and biological products that might be useful in children as well as some that were already on the market. Although the courts struck down the rule in October 2002, it was responsible for 67 pediatric studies that would not have been completed under the exclusivity provision. 

The apparent successes of both the exclusivity provision and the pediatric rule sparked the current follow-up legislation. The Best Pharmaceuticals for Children Act became law in January 2002, slipping neatly into place just as the pediatric exclusivity provision was sunsetting. Like its parent, the new version attempts to get pharmaceutical companies to study their products in children by offering a six-month extension to their exclusive right to market, and profit, from their product. However, the new act also provides a mechanism to fund studies on commonly used or therapeutically important generic drugs.

Closing the gap

The Pediatric Research Equity Act, which mimics the pediatric rule by requiring studies of certain drugs to be conducted in children, involved a more contentious legislative effort. Passed in December 2003, the act closed the loophole that had been opened when the previous rule was struck down a year earlier. Although in the interim more than 100 drugs and biological products had been brought to market without pediatric testing, according to the American Academy of Pediatrics, the new act, for which both Prober and Pizzo actively lobbied for several years, is retroactive to any drug application submitted on or after April 1, 1999. The FDA grants waivers only for select cases: for example, if a drug treats a condition, like prostate or breast cancer, that does not occur in children, or if there is strong evidence that the drug would be unsafe for children.

Together the two acts aim to close the testing gap for pediatric drugs. Under the Best Pharmaceuticals for Children Act, the FDA asks the drug’s manufacturer to test the drug. If the company declines, the agency informs the National Institutes of Health, which offers grants, supported by congressional funds and charitable contributions, to researchers willing to conduct the necessary studies on the drug. The FDA decides which to test first according to the likely size of the pediatric market and the degree of potential therapeutic benefit.

A trickle of funding

One of the first grants to be awarded through the NIH landed at Lucile Packard Children’s Hospital just a few months ago. Pediatric anesthesiologist and intensive care specialist Greg Hammer, MD, and colleague David Drover, MD, were awarded a $4.3 million contract to conduct a randomized clinical trial of how children metabolize sodium nitroprusside, a medication commonly used to lower blood pressure in pediatric patients. The drug is frequently used during surgery to reduce blood loss and after neurosurgery to prevent brain hemorrhage. But until now, the amount of active drug that makes it into a child’s bloodstream has been unknown. “Sodium nitroprusside is very commonly used and very potent,” says Hammer, “which is why we need to establish the relationship between the dose and the blood concentration during surgery. We’re also planning to investigate longer-term use of the drug in the intensive care unit. Does tolerance develop? Is there a rebound in the child’s blood pressure after the drug is withdrawn?” 

One advantage of the acts is that they will spur pharmaceutical companies to formulate their drugs in kid-friendly packages such as liquids or chewable tablets. The importance of such forms was underscored during the early days of the AIDS epidemic, says Pizzo.

“It became acutely apparent in the early days of AIDS that drugs available to treat adults with HIV/AIDS were not being developed for use in children,” says Pizzo. Even testing anti-HIV drugs in children was impossible because the pre-packaged pills made it difficult to adjust the dose to a child’s body weight or size. Pizzo had some success by going directly to the major pharmaceutical companies and asking them to develop formulations that could be tested in children.

“Although it took a lot of time and effort, our group was eventually able to do the critical testing on four agents that were subsequently approved by the FDA for use in HIV-infected children,” says Pizzo. “The problem was that each instance required considerable advocacy and time, and I was very concerned that this was not sustainable or predictable.”

In the early 1990s Pizzo began working with the Pediatric AIDS Foundation, which became the Elizabeth Glaser Pediatric AIDS Foundation in 1997. The Glaser Pediatric Research Network headed by Prober was envisioned and created as a vehicle to test new agents in children, says Pizzo.

Not everyone agrees that requiring pediatric testing of drugs is a good thing. Extending exclusive marketing rights delays the introduction of cheaper generic versions and increases the overall cost of prescription drugs for the consumer. A 2001 status report to Congress from the FDA estimated that the pediatric exclusivity provision would increase the nation’s annual pharmaceutical bill by about 0.5 percent. While not a huge increase, it would likely weigh most heavily on lower-income families lacking adequate health insurance.

A question of ethics 

Supporters argue that the required studies will give pediatricians the information they need to treat kids more effectively, and will save money in the long run by keeping them out of hospitals and doctors’ offices. Many believe there’s a moral issue, too. 

“Look at the way pediatricians practice on a day-to-day basis,” says Prober. “One could argue that using an untested drug in a child is an experiment. All you need is a medical license and a drug that’s been approved by the FDA for some purpose.

“Contrast this situation,” says Prober, “with a clinical trial in which you assign a good drug to one patient and an alternate good drug to another for the purpose of learning which is better. It’s a much more rigorous structure, but I believe it is more ethical to treat children within a clinical trial, where you’re going to learn something and share that knowledge with other physicians.”

Benitz adds: “We’re doing something that we hope will turn out OK because it does most of the time. Most of us get through our days pretending it’s not a big issue. You have to.” But sometimes it is. Despite his intense efforts to develop appropriate dosing schedules for children, Benitz found himself uncomfortably close to disaster recently.

“We had sedated a baby who was critically ill with respiratory failure with what seemed to be the appropriate doses of short-acting benzodiazepine,” says Benitz. “This is a drug that is supposed to quickly leave the central nervous system by being redistributed into the fatty tissues.” When the baby’s lung function improved, the physicians stopped the treatment to allow the child to wake up. But the baby had built up levels that were so high it took an additional five days for him to become alert enough to take him off the ventilator.

“Looking back on it, we were clearly shooting in the dark when deciding how much sedative to use with this baby,” says Benitz. “Our lack of understanding led to an additional five days in the intensive care unit. If we had known this would be a problem, we would have titrated the dose for this infant.”

Many pediatricians believe that the current legislation will go a long way toward preventing situations like this one. And they might be right. The Congressional Budget Office estimated in 2003 that about 50 new pediatric studies will be conducted each year as the result of the Pediatric Research Equity Act alone. By spring of 2005, 88 products had new pediatric indications on their labels. However, because both acts expire in 2007, the battle is not yet fully won; drug makers that drag their feet may be able to skip  testing if the laws are not extended. Some think that would be a shame.

“These laws are so important,” says Bachrach. “We know that these drugs are being prescribed right now in doctor’s offices and academic centers all over the country. At least now we can test what’s out there and ensure that new drugs are developed with children in mind.”

Comments? Contact Stanford Medicine at

 Back To Contents