Kid-Safe Drugs
U of L Kosair Charities Pediatric Clinical Research Unit Leads the Chase
By Kevin Hyde
“Leery.”
That’s the word Louisville resident Fran Hughes carefully chooses when describing how she felt when her daughter was first diagnosed with hypertension. “Hypertension? But she’s only 12 years old!”
Hughes didn’t know much about the disorder, which is characterized by abnormally high blood pressure. If left untreated it can injure organs such as the kidneys and heart. Hughes also was uncomfortable with Shae-mon possibly having to take medication the rest of her life.
“Nobody in our family had ever had this,” Hughes says. “All of a sudden, these doctors are telling us that she has this thing that was thought to be an adult’s disease. “I wanted—together with my daughter—to learn more about it.”
 Seventy-five percent of all medications marketed today in the U.S. do not carry FDA approved labeling for use in children. Only five of the 80 drugs most frequently given to newborns and infants are labeled for pediatric use. |
So do Dr. Janice Sullivan, Mary Jayne Kennedy, collaborating physicians and the ther nine members of University of Louisville Kosair Charities Pediatric Clinical Research Unit at Kosair Children’s Hospital. In 2003, Hughes agreed to have Shaemon participate in a yearlong clinical study with the unit.
Hughes’ feeling “leery” might apply to most parents when they learn that 75 percent of all medications marketed today in the United States do not carry Food and Drug Administr-ation (FDA) approved labeling for use in children. “Shock” might be the more suitable word when they find out that only five of the 80 drugs most frequently given to newborns and infants are labeled for pediatric use.
“About 75 percent of the medications that are prescribed for children haven’t been studied in children,” says Sullivan, a member of the U of L medical faculty since 1995 and the Pediatric Clinical Research Unit’s director. The unit was established in 2002 to generate scientific data that can lead to the correct labeling of therapeutic drugs for children. “Historically, there have been some significant adverse events with medications in children,” Sullivan adds.
The federal government originally tried to fix that by passing a variety of regulations. Unfortunately, those regulations led drug companies to label countless medications as not approved for children—even ones that could potentially help ailing kids. Even as recently as 10 years ago the medical community didn’t realize the dangers of giving adult medicine to children, adds Kennedy, a pharmacist and the unit’s associate director.
“They thought taking an adult dose and scaling it down based on the size of the child was OK. But the more we’ve learned about how the body handles and responds to medications during growth and development, we have found better ways to choose the right dose for a child. Through scientific advances, we have learned that there are many variables, previously unrecognized by physicians and pharmaceutical companies, that we now must consider.”
‘Every Child Is Different’
Not only are researchers in the pediatric research unit looking at how normal growth and development affects the way the body handles certain medications, they’re also studying the normal effects of genetics and the environment, says Kennedy, who supervises the unit’s lab work while Sullivan works with the patients.
“The way the body handles medications is continually changing during the process of growth, making children a moving target from birth to adulthood,” Kennedy says. “At the same time, genetics, environment and disease also affect the way the body handles and responds to a drug. One of our goals is to determine how all of these variables interact to determine how much medication the child is exposed to following a given dose.”
With a better understanding of how these variables interact, “We will ultimately get a better understanding of how to dose the medication in children of different ages,” Sullivan adds. The researchers must consider that a 2-day-old newborn is different from a 2-year-old toddler—and very different from an adolescent, she explains.
The research unit has anywhere from 12 to 20 trials in progress at all times. Investigators within the unit have studied medications for asthma, botulism, high blood pressure, infections, septic shock, blood-clotting abnormalities and many more conditions. And having these trials taking place in Louisville benefits the region.
“Sometimes participation in clinical trials is the only way patients can have access to certain medication,” Kennedy says. “At that point, you don’t know if the results will benefit the patient, but there are certain things they can’t get otherwise.” Joe Hullihan, 15, is a student at Eastern High School in Louisville. He recently participated in a study evaluating the use of a medication used in adults to treat acid reflux disease, which can cause painful heartburn.
“I’ve had it since I was a baby,” says Hullihan, whose mother found out about the trial through a U of L publication. Every day for a week he visited the research unit where he was given a dose of the drug, underwent a blood test and was asked several questions about how the medication was working. “They were testing out an adult medication to see if it worked in younger people,” he notes.
Did it?
“Oh yes!” Hullihan says. “It helped it a lot. It really decreased the amount of heartburn I have.”
The Network
Significant legislation since 1994 has pretty much forced drug companies into researching medications in children, Sullivan says. Some of that legislation led to the formation of the Pediatric Pharmacology Research Unit (PPRU) Network, a group formed by the National Insti-tute of Child Health and Human Development (NICHD) in 1994. It includes 13 American pediatric pharmacology research units.
“The acquisition of a pediatric pharmacology research unit designation places our Department of Pediatrics in an elite group,” says Dr. Larry Cook, U of L interim vice president of health affairs. “It also recognizes the wonderful efforts of Dr. Jan Sullivan and the rest of our unit.”
A key moment for the pediatric research unit came last October when Sullivan and Kennedy learned that they were awarded a grant to support their PPRU network participation. At the time, U of L President James Ramsey remarked, “As one of only 13 centers in the United States that meets the high NICHD standards for interdisciplinary pediatric research, I am proud of the role that the University of Louisville will play in the worldwide improvement of health care for kids.”
The five-year renewable grant of $1.8 million supports the infrastructure of the pediatric research unit and the development of an independent pediatric core proteomics laboratory. Proteomics focuses on the products of genes and how changes in specific patterns of proteins affect the body’s functions. That funding was followed by another $3 million in 2005 federal earmarks secured by U.S. Sen. Mitch McConnell.
But Sullivan says the benefits of being in the NICHD network will go beyond new labs, equipment and funding. “It provides an opportunity to interact and collaborate with some of the key pediatric pharmacology units around the nation,” she says. “The units meet on a quarterly basis and have regular conference calls every two weeks.” More importantly, the network allows the pediatric research units to conduct clinical trials across 13 quality sites.
“As an investigator here, if I write a clinical study and I need to get hundreds of patients, I can take it to the network and have people all over the country recruiting patients and collaboratively doing things,” Kennedy says.
The network allows the units to take advantage of each other’s strengths. “We can kind of put ourselves together to do some research that we probably could not have done alone,” Kennedy concludes.
Found in Translation
The first focus of the research unit’s work in the network is on generating information for the FDA to label drugs for use in children. Many of the network trials are pharmaceutical company-sponsored studies that either provide new information about how to dose or about side effects the medicine might cause in children.
The second focus tries to answer the question, “Why?”
“If the results of a clinical trial suggest that children respond to or handle a medication differently than adults or children of other ages, it is important to understand the reasons these differences exist,” Kennedy says. That’s where the university’s new proteomics lab will play a huge role. The pediatric research unit is working with Dr. Jon B. Klein, director of the U of L Core Proteomics Laboratory, in developing such a lab for pediatrics.
Investigators within the PPRU unit will conduct studies evaluating the effects of normal growth, development and genetics on proteins that play an important role in various disease processes and on enzymes responsible for drug metabolism. “We hope to identify proteins that may serve as markers of either a disease in a child or as a response to pharmacologic therapy potentially via a noninvasive technique,” Kennedy says. Proteomics research has been done in adults for several years, Kennedy says, “But not many investigators have applied this tool in children. We are adapting this technology so that it can be readily applied in pediatric drug development and monitoring.”
Big Move Ahead
The success of the Pediatric Clinical Research Unit demonstrates what Kennedy calls “the successful team effort” among U of L, Kosair Charities and Norton Healthcare’s Kosair Children’s Hospital.“They’ve all made a significant commitment to developing pediatric pharmacology research,” she says. “We’ve gotten nothing but support. This is a culmination of everybody coming together.”
Sullivan adds, “Over the next several years, we’ll see more advances in pediatric clinical pharmacology. We still have about 75 percent of medications that are not approved for children. Hopefully, we can make a dent in that over the next 10 years with our heightened understanding of growth and development and genetics, proteomics and their effects on how children handle and respond to medications.”
Fran Hughes appreciates the understanding the Pediatric Clinical Research Unit provided her during Shaemon’s participation in the clinical trial. “The biggest plus side is that she has been allowed to be on the lowest amount of medication that can maintain her hypertension,” Hughes says. “That was a big concern for me.”
And while Sullivan, Kennedy and their staff have learned from Shaemon, she has learned much from them, her mom says. “She’s learned how important it is to accurately take her blood pressure—and that it’s her responsibility,” Hughes says. “She’s 14 now, and she has to live with this. We’ve learned a lot.”
