Best practices in pediatric clinical trials expand with help of 13 PPRUs
Goal is to increase drug labeling for children
Only 6% of the 80 drugs most frequently used in newborns and infants are labeled for pediatric use, and three out of four of all medications on the market do not have approved labeling for children.1
Nonetheless, physicians frequently prescribe drugs with adult labels to infants and children, and this occasionally leads to serious problems. For example, the antibiotic erythromycin, labeled for adults, was linked to pyloric stenosis among seven babies in Tennessee in 1999, and about the same time, life-threatening pancreatitis was reported in children and adults receiving valproate, a drug used for epilepsy, manic episodes in manic depression, and as a migraine preventative.2,3
Also, in 1999, a 9-month-old infant’s death was attributed in part to the drug Propulsid (cisapride), used to treat gastroesophageal reflux, which had been approved for adults but not in children and was being tested with a hospital study in 100 children. Cisapride was pulled from the market by Janssen Pharmaceutica of Titusville, NJ, in July 2000.4,5
With a goal of improving the scientific knowledge of how various drugs work in children and also reducing medication errors and problems among pediatric patients, the National Institute of Child Health and Human Development began in 1994 to fund a network of Pediatric Pharmacology Research Units (PPRU). The PPRU network now consists of 13 sites and has conducted studies supporting pediatric labeling, as well as investigations into differences in how children and infants metabolize medication.
The PPRU project helped lead to the FDA Modernization Act (FDAMA), and has responded to increased demand for pediatric clinical studies as a result of FDA’s 1998 Pediatric Rule.
"There has been a lot of progress in the last 10 years as federal regulations have changed, and I think the biggest change is a heightened awareness by the public of the needs of the pediatric population for clinical pharmacology," says Janice E. Sullivan, MD, associate professor in the department of pediatrics at the University of Louisville (KY). The University of Louisville began its work as a PPRU in 2004.
"But I think we’ve hardly touched the tip of the iceberg," she says. "Still, 75% of drugs used for children are not labeled for use in children, so although we’ve made inroads in the last 10 years, we still have some ways to go."
One of the key strengths of PPRU is encouraging translational research projects, notes Ross McKinney, MD, associate professor in pediatrics and vice dean for research at Duke University School of Medicine in Durham, NC.
"We’re trying to understand why drugs do what they do, including metabolism and genetic markers that show clearance of a drug," he says.
Strength in networking
Duke and the University of North Carolina at Chapel Hill have formed a North Carolina collaborative PPRU, which has been active for little more than one year, in which one piece is the school of pharmacy and the other is the department of pediatrics, McKinney says.
The two research institutions combine their strengths in good clinical research design, study management, pediatric clinicians, and laboratory resources, he reports.
"In our perspective, this gives us an unusual amount of depth since we have a lot of people with skills that we can access fairly easily," McKinney says.
Another benefit of PPRU is that it has increased the collaboration of pediatric pharmacology investigators around the country, reports Robert M. Ward, MD, professor of pediatrics and a director of the University of Utah Pediatric Pharmacology Program in Salt Lake City. The University of Utah has been involved with PPRU since 2004.
"It allows us to share ideas about what drugs need to be studied, what ideas need to be investigated, and how to carry out those studies," he says.
"It also shows us how to add science that’s important to understanding pediatric pharmacology to other studies that are about to be done," Ward adds. "We’ve even tried to encourage some sponsors to add certain measurements to their studies so we can better understand how developing children respond to drugs and metabolize drugs and excrete them."
Children’s Mercy Hospitals and Clinics in Kansas City, MO, has one of the older PPRU programs, which has studied more than 50 different compounds in its 10 years of existence, reports Gregory L. Kearns, PharmD, PhD, a Marion Merrell Dow/Missouri Chair in Pediatric Pharmacology and chief of the Division of Pediatric Pharmacology and Medical Toxicology.
"About 98% of all the studies we do are early Phase I, II trials, which is a little different from most of the people around the country doing pediatric studies," he says. "We’ve done a fair amount of work that has characterized the age-specific dose requirements for drugs, and in many cases it’s important information for sponsors to take with them in Phase III trials."
The PPRU network provides research strength in numbers of both subjects and in its access to some of the best clinical pharmacologists in the nation, Sullivan says.
"That’s part of the reason we’re interested in the network," says Mary Jayne Kennedy, PharmD, assistant professor in the department of pediatrics and a co-principal investigator on PPRU for the University of Louisville.
"One of our main goals was to generate some data in populations that would go to labeling drugs in children," she says. "The problem is no one site has the capability to generate that data alone."
Born of necessity
The PPRU network, which was created partially in response to the fact that there was little interest among individual sites in conducting drug trials in pediatric populations, provides the necessary critical mass with its 13 sites, Kennedy adds.
"We conduct Phase I to Phase IV clinical trials, and one study we brought to the network had 240 patients at eight out of 13 sites," she says.
Sullivan and Kennedy both have trained in clinical pharmacology, and the University of Louisville has established an inpatient/outpatient clinical research pediatric unit. Receiving the federal grant to become a part of the PPRU network carried the institution’s pediatric research mission to the next level, Sullivan says.
Likewise, the PPRU network has evolved as sites like the Louisville one have been added, she notes.
"With each cycle of the PPRU network, the mission has matured," Sullivan says. "Initially, its mission was primarily for the labeling of medications for children, and now it’s more focused on gaining an understanding of the ways children are different."
For instance, the Louisville PPRU staff work closely with pediatricians and subspecialty physicians, often benefiting from their collaboration in a study, she explains.
"They have an understanding of the need for drugs for the disorders they’re treating, and that’s one of the biggest helps," Sullivan says.
The University of Utah PPRU is one of four PPRU sites with a neonatologist, which will increase the study of drugs in newborns it is hoped, says Ward, who is a neonatologist.
"I trained in clinical pharmacology from 1976 to 1979, and since that time there has been only a limited study of drugs in pediatrics," he says.
With the PPRU network, Ward says he is encouraged that scientists can begin to provide evidence for the practices neonatologists carry out in the newborn intensive care unit.
One potential benefit involves the study of an antimicrobial drug that would help reduce chronic lung disease in newborns, Ward says.
"Chronic lung disease is associated with developmental delay, prolonged hospital stay, and increased mortality," he explains. "If this drug is safe and effective, it could change the way we care for a very small baby."
The PPRU network also brings together different experts, who are scattered geographically across the country, Ward says.
"At the University of Utah, we have an extraordinary strength in drug analysis; and in Kansas City, they have a strong group in analyzing pharmacokinetics, how people metabolize drugs. Other sites around the country have different strengths," he reports. "Some have people extremely skilled in mathematics in how you analyze the data, and so this brings together those strengths from all around the country so that we can now share."
While PPRU holds promise for advancing pediatric drug research, there are some drawbacks, McKinney notes.
"PPRU grants are not huge," he says. "They provide some basic infrastructure, and you use that infrastructure to obtain funding from other projects, but it’s not enough money to do a whole lot of research beyond the core infrastructure."
Also, while some of the PPRU sites have had a great deal of success in attracting sponsors for pediatric drug trials, others like the relatively new Duke/UNC PPRU have not, McKinney says.
"We have not seen greater interest among pharmaceutical companies," he reports. "There’s a certain degree of reluctance among pharmaceutical companies to work with PPRU in general related to the fact that it’s funded through the National Institutes of Health." This is because federal funding comes with strings attached, McKinney explains.
"If federal dollars are used to support development of a new compound, there is the potential that if the drug’s pricing doesn’t fit the desires of the people who authorized federal support, then they have the ability to do a reach-through and change the pricing," he says. "This hasn’t been exercised, but there are several times it’s been discussed."
Also, pharmaceutical companies often want to control the design of a trial, while scientists generally want the clearest answer directly related to clinical care, McKinney says.
Nonetheless, there are some PPRUs that have had successful relationships with pharmaceutical companies, he notes.
Children’s Mercy Hospitals is one example of a PPRU success story in that the site has 28 staff in the pediatric pharmacology program and has averaged 10-15 peer-reviewed publications per year for the past 10 years, Kearns says.
"We don’t touch anything in terms of an industry-sponsored clinical trial that doesn’t make new knowledge and result in publication," he points out. "We’re certainly one of the most productive of the 13 sites; and programmatically, we have a huge investment in pediatric pharmacology."
McKinney expresses optimism for PPRU as a network, even though at present it does not have as many multisite trials as might be expected from a collaborative group.
"Our hope is over time it will function as a network," he says. "It has good scientists doing good work."
References
- Department of Health and Human Services, Food and Drug Administration. Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients. Final Rule: 21 CFR Parts 201, 312, 314, 601. Docket No. 97N-0165.
- Centers for Disease Control and Prevention. Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin — Knoxville, Tennessee, 1999. JAMA. 2000; 283(4):471-472.
- Sinclair DB, Berg M, Breault R. Valproic acid-induced pancreatitis in childhood epilepsy: Case series and review. J Child Neurol 2004; 19(7):498-502.
- FDA Talk Paper. Janssen Pharmaceutica stops marketing Cisapride in the U.S. March 23, 2000, T00-14.
- Letter to the Food and Drug Administration/FDA asking for the immediate withdrawal of Propulsid (cisapride) from the market. HRG Publication #1519. April 11, 2000. www.citizen.org/publications/print_release.cfm?ID=6720.
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