Over the past few decades, children’s health has arguably made some of the greatest gains. Infant mortality in most developed countries has fallen dramatically from an estimated 30 per cent to less than one per cent. Infectious diseases, the primary cause of infant mortality, have been addressed with better sanitation and water quality, and the development of vaccines and innovative new therapies. Parents need only consider penicillin or vaccines for polio, whooping cough, meningitis, and chicken pox to get a sense of the stress that parents would have had just a few decades ago.
Why is it important that we do research in infants and children?
The only way to safely dose medicine for children is to study the medicine in children. When it comes to how the body handles a medication, we have to remember that children are not small adults and infants are not even small children. Fortunately, we now have the technology to measure medication concentrations in just a few drops of blood and can coordinate the timing of a blood draw with one already being done for clinical care. By doing so, we can determine how to dose these medications in infants and children while minimizing any risks posed to study participants.
What safeguards are in place to protect the safety of patients enrolled in PTN studies?
Many safeguards are in place to protect the safety of patients enrolled in all research studies. All research studies are voluntary, all procedures involved in research are fully disclosed during the informed consent process (see below), and all studies adhere to a strict confidentiality policy. Children will receive the same care whether or not they are participating in research. All children are monitored for any safety and adverse events, and these events are reviewed by a monitoring committee that will stop a study if harm is detected.
In fact, clinical trial programs have been shown to have public health benefits not only for trial participants, but also for patients in hospitals with infrastructure to conduct clinical trials and for those who subsequently benefit from the insights gained through the research (see Joffe S, Arch Pediatr Adolesc Med 2010;164:293–4).
Regarding the PTN specifically, all drugs being studied by the network are currently being prescribed to children; our research is aimed at finding the most effective and safe dose of medications already in use.
Tell us a little about the informed consent process for pediatric trials and why it exists?
The informed consent process is a personal discussion between a parent/guardian and a specially trained person working on the study. Children ages 7 and older are invited to assent to participate in studies. Parents/guardians are informed of why they are being approached, why the research is being done, and what procedures will occur for research purposes. The risks and possible benefits of such research are disclosed. Families are also given information about how to withdraw from research studies and who to contact if concerns arise. Families must acknowledge with a signature that they understand that their participation is fully voluntary. Research cannot begin prior to informed consent being obtained so that researchers can be certain that families know exactly what to expect from the study and what is expected of them.
What effect do you see the work of the PTN having on everyday clinical practice?
Data from PTN trials will provide evidence for proper dosing of commonly used medications, improving everyday medicine for children in both hospital and outpatient settings. Ultimately, we will make health care safer and more effective for babies and kids.
A study to determine the safety and pharmacokinetics of lisinopril in children and adolescents receiving kidney transplants will begin enrolling participants in April 2012.
Lisinopril is approved by the U.S. Food and Drug Administration for the treatment of children aged 6 years and older and adults with high blood pressure, heart failure, and heart attack. High blood pressure is also common among children and adolescents who have received a kidney transplant, but the appropriate dose of lisinopril in this group is not well known.
In this PTN study, lisinopril will be given to children and adolescents who have received a kidney transplant and have high blood pressure. The levels of lisinopril in each participant will be measured, thereby helping to determine the best dose of the drug to reduce high blood pressure in this unique group. Up to 28 children and adolescents between 2 and 17 years of age with a successful kidney transplant will be enrolled at 8 sites across the United States.
On January 27, 2012, the first patient was successfully enrolled into the PTN’s hydroxyurea (HU) study.
Hydroxyurea is the only major drug breakthrough for the treatment of sickle cell disease within the past 20 years. It is the only drug approved by the FDA to treat adults with sickle cell anemia, and so it is a part of the standard of care for those with severe sickle cell disease in the United States.
Few studies have been done with HU in children to tell us how it is absorbed and expelled. The PTN study will measure how much HU gets into the bloodstream at different time points in children, and how fast it is removed. The study will enroll eligible children ages 2–17 with a confirmed diagnosis of sickle cell anemia. For the children ages 5–17, the study will also explore whether the body handles HU differently in liquid versus pill form.
Study enrollment for all ages will take place during regularly scheduled clinic visits. Children will take their usual dose of HU, and small blood samples will be obtained over the course of a day. Study results will provide information to help the FDA in considering approval of HU for use in infants and children with sickle cell anemia.
The first enrolled patient provided the required blood draws over a full day in the clinic at Children’s Memorial Hospital in Chicago, IL, under the direction of Dr. Robert Liem, the study site principal investigator. The HU study plans to enroll 40 patients total over the course of several months.
DCRI investigators have completed the study of metronidazole, an anti-microbial agent frequently administered to infants suffering from necrotizing enterocolitis.
The Duke Clinical Research Institute has completed its first drug trial conducted for the Pediatric Trials Network (PTN).
Late last year (2011), DCRI investigators completed their study of metronidazole, an anti-microbial agent frequently administered to infants suffering from necrotizing enterocolitis (NEC). The disease, which causes the victim’s intestinal lining to die, occurs frequently in premature infants and is often fatal.
Doctors have long prescribed metronidazole to infants suffering from NEC, even though there was no reliable information about dosage amounts for children. Metronidazole was not unique in that regard. Prescription medicines are rarely packaged with information about appropriate doses for children. That began to change in 2002, when Congress passed the Best Pharmaceuticals for Children Act (BPCA), a law designed to promote pediatric drug research. The PTN, an alliance of clinical research institutions working in concert with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, was established shortly thereafter. Its goal is to provide doctors with pediatric dosing guidelines for widely prescribed medicines lacking that information. In September 2010, the National Institutes of Health awarded a $95 million contract to the DCRI’s Daniel Benjamin, MD, MPH, PhD, to oversee the first round of clinical trials under the PTN to determine appropriate dosing regimens for children. The metronidazole study began enrollment in January 2011.
The metronidazole study team, pictured above: Mickey Cohen-Wolkowiez, Jennifer Murphy, Debbe Blackwell, Barrie Harper, Ivra Bunn
The purpose of the metronidazole study was to determine the pharmacokinetics and safety of the drug in young children, and thereby determine an appropriate dosing regimen. The metronidazole trial was the first one to enroll patients and complete its study under the PTN contract. The DCRI’s Michael Cohen-Wolkowiez, MD, served as principal investigator. Barrie Harper, MT, was project leader.
The trial, which was conducted at three study centers, enrolled 24 premature infants with suspected infections. Researchers divided the infants into two groups based on their age. One group comprised infants younger than 14 days, the other included infants 14 days or older. Both groups received an equal dose of metronidazole at age-based frequencies over a period of several days. Researchers took blood samples from the infants during the trial to determine how the drug levels behaved within the infants’ bodies.
After analyzing the data, researchers intend to present their findings to the Food and Drug Administration. They hope to submit new dosing guidelines for metronidazole in infants to agency officials to update the metronidazole package insert.
“The goal of the entire PTN is to potentially modify the package inserts with meaningful dosing information for children, which doesn’t exist yet,” Harper said. “Children aren’t little adults, even though a lot of physicians dose them like little adults.”
Harper and Cohen-Wolkowiez agreed that the PTN aided the speed and efficiency of the metronidazole study. The improved communication and collaboration engendered by the network allows researchers to complete their studies on time and on budget, Harper said. The metronidazole study was finished within 18 months.
“We thought we would need a 12-month period [for enrollment],” Harper said. “We beat that.”
“The time line under which this study was completed was exceptional, and it was reached thanks to the professionalism and dedication of the DCRI team,” Cohen-Wolkowiez said. “This study will become a major player in the renewal of BPCA in 2012.”
Harper also credited the DCRI team and its partners at the Emmes Corporation, the NICHD’s data coordinating center, for the study’s success.
“Our people worked really hard on this project, and they were really excited about it,” she said. “It’s been a very collaborative effort.”
The 2011 BPCA Priority List of Pediatric Therapeutic Needs and the 2011 BPCA Priority List of Pediatric Therapeutic Needs under Consideration was released on April 1, 2011. Please refer to the Federal Register Notice for additional details.
Doctors make educated guesses every day. There’s precious little time to decide what treatment to use, much less how often or how much to prescribe, when there are dozens of patients waiting to be seen.That’s why they rely so much on clinical practice guidelines—statements that describe appropriate treatments based on scientific evidence and broad consensus among physicians. The development of treatment guidelines has been a function of professional societies such as the American Heart Association and the American Academy of Pediatrics for more than 20 years.
But as late as 1998…the FDA did not require drug developers to test new drugs on children, even drugs that would be commonly given to children.
The best guidelines are backed by evidence coming out of randomized clinical trials. In the case of new drugs, these trials are required. The Food and Drug Administration (FDA) will not approve the distribution of a new drug unless it has been tested in hundreds, if not thousands, of volunteers and deemed reasonably safe and effective. But as late as 1998, this rule applied only to adults: the FDA did not require drug developers to test new drugs on children, even drugs that would be commonly given to children.
Danny Benjamin, MD, PhD, MPH
The result is guesswork. Pediatrician Danny Benjamin’s 10-year-old son takes seven different medicines every day, many of which lack pediatric dosing and proper formulation. Without an age-appropriate formulation (such as a liquid or chew-tablet), Benjamin and other parents rely on rudimentary techniques to give the medicines. “Every day, I use a kitchen knife to cut up Jack’s pills—to give him a ‘ballpark’ dose,” said Benjamin. In addition to the problem related to formulation, the ‘ballpark dose’ assumes a linear relationship between the dose and the patient. It assumes that 10 mL of drug per kilogram of weight will work for a 1 kg baby the same way that it will work for a 10 kg child and a 100 kg adult. “Ballparks are great to communicate budget estimates, but not therapeutics,” Benjamin said.
In reality, normal growth and development in childhood result in often opposing, rarely predictable, effects on drug metabolism, explained Benjamin. The proportions of body weight made up of fat, protein, and water change dramatically in infancy and childhood. In a full-term newborn, for instance, water comprises approximately 70 to 80 percent of body weight. By five months, this decreases to 60 percent. Newborns have lower concentrations of albumin, a protein essential to the proper distribution of fluids between the tissues and blood vessels. They also have little muscle mass. Their body surface area is high relative to body mass. The absorptive surface of their small intestine is greater. Food moves through their digestive system faster. There are corresponding differences in the size of their kidneys and liver. “You just can’t think of children as miniature adults,” Benjamin said.
More than two dozen generic drugs
In 1998, the FDA began requiring drug developers to test specifically in children any of their medications that may be prescribed for children. The resulting trials confirmed that pediatric dosing recommendations are little more than guesstimates. Of the first 200 products tested, the “correct” dose was wrong 40 percent of the time. “We were either under-dosing or there was a dosing or safety surprise, like hostility, aggression, irritability, or insomnia. These may not seem like much unless you think through the consequences of an aggressive, hostile, over-medicated 5-year-old in the house with a 9-month-old younger sibling,” Benjamin said.
In September 2010, the National Institutes of Health moved to close another loophole: the lack of pediatric dosing information in generics—drugs that pharmaceutical companies have no exclusive right to market and thus are not required and have no incentive to test. It awarded a $95 million grant to a team led by Benjamin, professor of pediatrics at Duke University, pediatric director of the Duke Clinical Research Unit, and faculty associate director of the Duke Clinical Research Institute (DCRI), to run the Pediatric Trials Network (PTN) and conduct pediatric clinical trials for 16 generic drugs over the next five years.
“I hope we double that,” said Benjamin. His hope for 32 trials is not far-fetched. The PTN, which functions as an infrastructure for conducting safe and scientifically-rigorous trials, now has FDA approval to study four drugs. It is already recruiting participants for its first study drug: metronidazole, an antibiotic given to babies with necrotizing enterocolitis (NEC). Found in approximately 10 percent of newborns who weigh less than a kilogram, NEC can bore a hole in the intestines, allowing bacteria to leak out into the abdomen. Thousands of newborns receive metronidazole every year, but no one has studied what their bodies do to the drug.
“There’s a lot of variability among premature infants when it comes to drug metabolism. Even within the same gestational age and postnatal age, there’s typically a ten-fold difference,” said Benjamin.
“If you give an ‘average’ dose to two neonates, each of whom delivered after 32 weeks in the womb [a normal pregnancy ranges from 38 to 42 weeks], and both seven days old, one is liable to have a trough level of 2ug/mL [micrograms per milliliter] and the other a trough level of 20 or 25ug/mL. Some babies will be fine, but babies who have low levels: they’re not getting enough antibiotic. This is a big problem when you have a fatal bloodstream infection that often goes to the brain.”
In a massive effort that Benjamin likens to “multiple mini-drug development programs,” the PTN will study product formulation, drug dose and safety, and device development. It will then use data collected from the trials to help inform pediatric drug labeling, and to provide regulators, pediatricians, and researchers with new information on how children respond to medication. The primary goal is to generate the data necessary to produce evidence-based clinical practice guidelines.
“Physicians don’t have a whole lot of time to scour the Web, do a literature search, and then think through pharmacology to maybe get the right dose. You have 80 patients that you have to see at the hospital that day and each one of them is on several different therapeutics,” said Benjamin. “Tack on ventilator management, micromanaging fluids, and talking to parents because seeing their child hospitalized is one of the most stressful things they can ever experience, and it’s a busy day. So physicians rely on treatment guidelines and reference materials. That’s why studying these drugs in children is very important. Either that or we continue to make things up.”
A groundbreaking effort to reduce the risks and dangers faced everyday by millions of children who are prescribed medications that lack definitive data about pediatric dosing, efficacy and safety was created today through an initiative supported by the National Institutes of Health (NIH), totaling up to $95 million over the next seven years.
The network will conduct 16 trials spanning a variety of therapeutic areas, including cardiovascular diseases, cancer, infectious diseases, gastroenterology, respiratory diseases, neonatology, and medical devices.
“It’s staggering to consider that less than 10 percent of licensed therapeutics have been adequately studied in children, so much of pediatric drug use is based on an educated guess by a pediatrician using studies conducted in adults, who often absorb drugs differently or experience different side effects than children,” said Daniel K. Benjamin, Jr., MD, PhD, professor of pediatrics at Duke and associate director of the DCRI, who will lead the PTN.
The PTN was conceived to create a scientific, technical, and administrative infrastructure for conducting pediatric clinical trials in an environment that provides optimal safety for the research participants and sophisticated expertise to determine the balance of benefits and risks of drug and device treatment of medical illnesses in children.
Under an agreement among the organizations, the network will conduct 16 trials spanning a variety of therapeutic areas, including cardiovascular diseases, cancer, infectious diseases, gastroenterology, respiratory diseases, neonatology, and medical devices. The drugs and devices have yet to be determined. The compounds studied will be those which have already been on the market long enough that their patents have expired, otherwise known as generic drugs.
A network steering committee will be established to work alongside the NICHD to oversee the network operations. Program management will be conducted by the DCRI and the leadership team will include investigators from Duke Children’s Hospital, Children’s Mercy Hospital in Kansas City, the University of California, San Diego, Children’s National Medical Center in Washington D.C., The Children’s Hospital of Philadelphia, Wake Forest University Baptist Medical Center in Winston-Salem, NC, and Carilion Clinic Children’s Hospital in conjunction with the Virginia Tech Carilion School of Medicine.
“Pediatric dose formulation and therapeutic and diagnostic pediatric device development are urgent pubic health issues of critical importance,” said Robert Harrington, MD, director of the Duke Clinical Research Institute. “This network brings together an outstanding multi-disciplinary team across the spectrum of translational research to greatly expand upon a currently functioning proof-ofconcept network underway at the DCRI and its sister organization, the Duke Clinical Research Unit (DCRU).”
According to Benjamin, the first trial in this project will likely be conducted to determine optimal dosing of medications used to treat high blood pressure in children. Most of the trials will enroll between 100 to 200 children. Aspects of this network will include product formulation, drug distribution and device development. “In effect, each trial will become a ‘mini’ drug development program,” Benjamin explained.
Another objective for this project is to use the data collected from the PTN to help inform pediatric drug labeling, and to provide regulators, pediatricians, and researchers with new information on medication response in children.
“The Pediatric Trials Network has the potential to correct a problem that continues to surprise people—we have inadequate information about the proper treatment of children, even for commonly used treatments that have been on the market for years,” said Robert M. Califf, MD, director of the Duke Translational Medicine Institute (DTMI) and vice chancellor for clinical research at Duke University. “Considering Duke’s established leadership in translational medicine and the involvement and support of many of the pediatricians and clinical pharmacologists active in clinical trials in the United States, this team composed of the nation’s experts in therapeutics in children should provide information that will be critical to pediatricians and the children they treat.”
Six groups will comprise the PTN:
clinical operations and program management,
managing clinical pharmacology design components of trials,
pharmacokinetic and pharmacodynamic simulations, analysis and modeling,
common safety reporting across trials and an ethics review of each study protocol,
overseeing collaboration in the multi-disciplinary development of devices for use in children, and
training the next generation of clinical pharmacologists and clinical trialists by partnering junior investigators with program leaders and senior investigators.
When appropriate, the research will apply the specialized capabilities and technologies available in the DCRU, which is one of just a handful of state-of-the-art, hospital-based, early-phase research units in the country. Benjamin serves as the program director for pediatrics in the DCRU.
