It's the second contract under a federal program established to address the pharmaceutical industry's failure to study certain drugs in infants and children both at the time the drugs were approved for use in adults and specifically after the drugs' patents have expired.
The Stanford researchers will study a hypertension drug commonly used in pediatric surgery and pediatric intensive-care settings. The work is needed because the company that invented the drug some 30 years ago never studied its effects in pediatric patients. And after the drug's patent expired, its price dropped so low that no company will invest further resources studying it.
"We should know as much about the science of how drugs work in children as is known in adults," said Greg Hammer, MD, professor of anesthesia and pediatrics and associate director of the pediatric intensive-care unit at Lucile Packard Children's Hospital at Stanford. "These studies will provide that information." Hammer is principal investigator on the contract.
"Unfortunately, pediatric patients aren't just small adults," said David Drover, assistant professor of anesthesia and co-investigator of the study. Kids respond to drugs differently and also break down and excrete drugs differently from adults. And drugs have different toxicities in neonates, infants, children and adults.
Historically, companies avoided testing in pediatric populations either because they didn't want to risk injuring children or didn't want to risk finding out that drugs deemed safe and effective in adults weren't so safe or effective in kids, said Drover.
"The truth may be that by not studying drugs in children, young patients have been left vulnerable to inappropriate or unsafe treatments," he said. "Clinicians are using trial and error on a case-by-case basis around the world - exposing kids to more risk than if the companies just did the studies in the first place."
After a few drugs approved for adults were shown to be toxic in children, pediatricians pressured the Food and Drug Administration and Congress to mandate drug studies in children. In 2002, Congress passed the Best Pharmaceuticals for Children Act. For drugs still under patent, the law offered companies a patent extension if they would conduct specified studies in kids.
But for drugs with expired patents (so called "off-patent" drugs), another solution was needed. "Drugs that are off-patent have no value for big pharmaceutical companies," said Drover. "The profit margins are extremely low. And that means someone else now has to pay for the investigations that the companies never did in the pediatric population."
Under the 2002 law, that "someone else" is the federal government. Thus far, the FDA has created a list of 25 off-patent drugs needing clinical testing and has issued nine written requests asking pharmaceutical companies if they will do the work. When the companies decline, as they are almost certain to do, the NIH's National Institute of Child Health and Human Development steps in to fund the work. So far research contracts have been granted for just two drugs.
Under the contract awarded to Stanford, Hammer and Drover will spend three years conducting clinical and laboratory tests to determine the safety and effectiveness of sodium nitroprusside. This drug works to control blood pressure during anesthesia and in the intensive-care unit. The FDA listed it for testing because it is known to produce cyanide - the toxin people associate with suicide pills.
"There are early reports from years ago of patients dying of cyanide poisoning," said Drover. "So we know about the risk, but no one has ever really measured the drug's toxic effects in kids." The study will aggressively record cyanide levels in the blood of pediatric patients given nitroprusside.
According to Hammer, "It may be difficult to appreciate whether certain adverse changes are attributable to the drug rather than the underlying illness or another drug being given at the same time. That's why nitroprusside needs to be studied in a systematic fashion."
In addition to testing the drug's toxicity, the study will determine the right starting dose for infants and children of different ages and sizes, how much a particular dose affects blood pressure levels and whether it's safe to use the drug in pediatric patients for more than 12 or 24 hours.
"The competition for this contract was stiff," said Drover. In fact, Stanford wasn't the only winner - Duke University will study nitroprusside as well.
Hammer and Drover plan to write proposals for additional off-patent drug contracts in the future. "It's going to be a long, slow process catching up with these drugs that have been long out of patent," said Drover.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
Lucile Packard Children's Hospital at Stanford is a 264-bed hospital devoted to the care of children and expectant mothers. Providing pediatric and obstetric medical and surgical services and associated with Stanford School of Medicine, LPCH offers patients locally, regionally and nationally the full range of health-care programs and services - from preventive and routine care to the diagnosis and treatment of serious illness and injury. To learn more about Lucile Packard Children's Hospital, please visit our Web site at http://www.lpch.org.