PTN investigator to retire at end of 2017


In 2004, Dr. Ram Yogev, Director of the Section on Pediatric, Adolescent and Maternal HIV Infection at the Ann & Robert H. Lurie Children’s Hospital of Chicago, was invited to serve on an FDA advisory committee on anti-retroviral, anti-fungal and anti-tuberculosis drugs. As the only pediatrician on the committee, he was surprised to see that drugs were approved for pediatric usage with minimal supporting data and that information on optimal dosing for pediatric patients was virtually nonexistent.

The lesson stuck with him. In 2012, he became an investigator for the Pediatric Trials Network (PTN), conducting trials related to dosing of commonly used medications in children.

Dr. Ram Yogev (center) and Dr. William Muller (right) with Dr. Ellen Chadwick (left)

“The beauty of PTN research is that it gives us the basis for making better decisions in how we treat our patients,” he said.

For the past 5 years, Dr. Yogev has been an invaluable member of the PTN team. He was involved in several studies related to antibiotics, anti-epileptic drugs, and a measuring tape used to determine an infant’s weight when using a scale is impractical. He also enrolled the highest number of participants of any site in a 2012 trial assessing appropriate dosing for a variety of understudied drugs, and contributed more than 44,500 patient records to the PTN Data Repository, which will be used to inform the design of future PTN studies.

After more than 40 years as a practicing physician, Dr. Yogev is retiring at the end of this year. Taking over Dr. Yogev’s role with PTN will be Dr. William Muller, attending physician for pediatric infectious diseases at Lurie Children’s, who lists Dr. Yogev among his mentors.

Laying the foundation

Dr. Yogev has specialized in pediatric and maternal HIV since 1986, when he treated a young patient who had been infected with HIV during a blood transfusion. He found, to his dismay, that many physicians refused to treat HIV-positive patients.

“For me, it was obvious what I needed to do,” he said. “The essence of medicine is the humanity of it. Medicine is important, but more important to me is how the child and his or her family are coping with the disease socially and emotionally.”

In his quest to find innovative solutions for his most vulnerable patients, Dr. Yogev became a champion of clinical research. Named director of the Experimental Therapeutics Program of Children’s Memorial Research Center in 2005, he is credited with building the hospital’s clinical research program from the ground up.

“I had to develop an infrastructure to support my own studies,” Dr. Yogev said. “It quickly became obvious what the obstacles were, so I began to work to address them.” For example, after finding that transportation was a major challenge for people participating in trials, he acquired a van and a driver. He also hired his own phlebotomist to meet the research PK demands more efficiently and to keep from overburdening the hospital staff.

“Soon we were expanding the clinical research unit, educating physicians on clinical research, and developing a mechanism where people were recognized for their contributions and expertise,” he said. After about 5 years, the unit, now known as Clinical and Translational Research (CTR), was providing critical services to more than 125 physicians conducting clinical research at the hospital.

With funding from the NIH, Dr. Yogev also helped develop clinical research sub-units in Thailand and South Africa. Now independent sites, both are successfully conducting clinical trials on their own.

“There’s nothing more rewarding than seeing a sub-unit performing as well as the main site,” he said. “It’s like the pride a father feels when he sees his son or daughter is getting better than him.”

Taking the reins

Dr. William Muller, who will assume Dr. Yogev’s role of site investigator at the end of this year, has worked closely with Dr. Yogev since joining Lurie Children’s 10 years ago. They also both teach pediatric infectious diseases at Northwestern University’s Feinberg School of Medicine.

Dr. Muller’s area of study relates to the effects of viruses such as herpes simplex, Zika, and HIV on neurocognitive development. His current research explores how to most effectively prevent and treat herpes simplex encephalitis in newborns. He also researches infections in immune-compromised patients.

His ultimate goal is to make sure the results of clinical trials are communicated in the field, where they can be incorporated in decisions made when treating patients.

“You spend a lot of time in the lab trying to tease out why something happens, but that doesn’t necessarily help patients,” Dr. Muller said. “We have to look at how this can lead to better outcomes in the people we’re treating.”

Dr. Yogev credits Dr. Muller and the rest of the dedicated team at Lurie Children’s with his success. “They don’t mind what time of day or night; if something is needed, they are there,” he said. “I’ve truly been standing on the shoulders of giants.”

Nov. 17 marks World Prematurity Day

Friday, November 17th marks World Prematurity Day. Part of the March of Dimes’ Prematurity Campaign, the event is designed to raise awareness of the problem of premature birth and to support ongoing efforts to reduce rates of premature birth in the United States and around the world.

Rachel Greenberg, MD

According to the March of Dimes, roughly 10 percent of U.S. births each year are premature, meaning that they take place before the 37th week of pregnancy. The World Health Organization identifies complications resulting from premature birth as the leading cause of death for children under the age of 5, and premature infants have a substantially elevated risk for a host of serious medical problems, some of them lifelong.

“With premature babies, pretty much every organ system is immature – everything is still developing. The human body wants a chance to mature for 9 months, and when it doesn’t get that chance, there are challenges,” says Dr. Rachel Greenberg, a neonatologist at the Duke Department of Pediatrics and a researcher with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Pediatric Trials Network. She notes that these challenges are complicated by the fact that some therapies that are vital to sustaining premature infants can cause them additional harm. Worse, many medicines used to treat premature infants are not well-studied in this fragile population.

“We have to make an educated guess on what the dose is, based on the dose in adults,” says Greenberg, whose work with the Pediatric Trials Network is focused on gathering evidence to guide the use of medications in children and infants.

Premature birth also takes a heavy toll on parents, who often endure tremendous emotional stress while their child undergoes treatment—sometimes for weeks or months—in a hospital neonatal intensive care unit. “It can be the happiest day of their lives, and it can be the scariest,” notes Dr. Greenberg. “They’re so excited to have a child, but the baby’s sick.”

While neonatologists like Greenberg seek better treatments for premature infants, World Prematurity Day is part of efforts to prevent premature birth in the first place. This is a particularly urgent issue, as rates of premature birth have been rising around the globe in recent years, including in the United States, whose overall performance earns it a grade of “C” on the March of Dimes’ 2017 Premature Birth Report Card. Although infections and other underlying health issues in the mother are known to play a role, Duke’s Greenberg points out that the chain of events leading to a premature birth is often far from clear.

“Many times, we don’t know what causes it,” she says.

The March of Dimes’ Prematurity Campaign is supporting research into preventing premature birth, with the goal of reducing the U.S. rate of premature birth to 8.1 percent by 2020. The campaign also supports efforts to improve care delivery and foster advocacy and community engagement.

More information on World Prematurity Day activities, as well as ways to get involved, can be found at the March of Dimes website.

PTN determines appropriate TMP/SMX dosing in infants and children

Micky Cohen-Wolkowiez, MD, PhD
Micky Cohen-Wolkowiez, MD, PhD

The Pediatric Trials Network (PTN), with funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), recently completed a multicenter study of trimethoprim/sulfamethoxazole (TMP/SMX) to determine appropriate dosing for infants and children. The results of the study were published in the journal Antimicrobial Agents and Chemotherapy on Oct. 30.

TMP/SMX is a combination antibiotic used to treat various types of bacterial infections in children, including urinary tract infections, bacterial pneumonia, and skin abscesses caused by methicillin-resistant Staphylococcus aureus (MRSA). Although it is one of the most commonly used drugs for treating infections in infants and children, pharmacokinetic data in children are lacking and appropriate dosing information had never been determined for this population.

“It’s common to extrapolate adult doses to treat children,” said Dr. Michael (Micky) Cohen-Wolkowiez, co-principal investigator for the study. “However, developmental changes during childhood play a significant role in drug dosing, and failure to account for these changes often leads to decreased drug efficacy and safety in young patients.”

During the study, investigators analyzed samples from 153 infants and children who had been given TMP/SMX as part of their treatment. The TMP/SMX combination is one of more than 30 drug therapies given as part of standard care that are being evaluated in POPS, a study that began in 2011 and is expected to have enrolled approximately 3000 patients by 2018.

Only a small percentage of drugs and devices approved by the FDA are actually labeled for pediatric use. As a result, pediatricians must frequently prescribe medical therapies according to their best guess based on dosing information from adult studies.

PTN, a network of more than 100 sites in 5 countries, aims to fill this gap by conducting trials primarily with off-patent drugs that lack data to guide their use in pediatric populations. Since its inception in 2011, it has studied 72 drugs to determine appropriate dosing for children and infants.

PTN study contributes to successful treatment of MRSA abscess in preterm infant

Early this summer, Lucas,* a one-month-old infant born 9 weeks prematurely, was receiving routine respiratory support in the neonatal intensive care unit at the University of North Carolina Children’s Hospital when he suddenly developed a dangerous neck abscess. Upon testing, the infection was found to be caused by methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Staphylococcus infections in general can be life-threatening in the NICU, but because MRSA is resistant to many commonly used antibiotic therapies, Lucas’ treatment options were limited from the outset.

Dr. Jackie Patterson
Dr. Jackie Patterson, UNC Children’s Hospital

Neonatologist Jackie Patterson, who was caring for Lucas in the NICU, immediately turned to the medical literature to determine the best course of treatment. During her search, she found an article published in the May 2016 issue of Antimicrobial Agents and Chemotherapy that was directly relevant to Lucas’ case. The article reported results from a trial sponsored by the Pediatric Trials Network (PTN) that explored dosing for antibiotics including clindamycin in infants being treated for staph infections.

Clindamycin was originally approved by the FDA in 1997 and is used to treat bacterial infections when other antibiotics, including penicillin and methicillin, are ineffective. The PTN “Anti-Staph Trio” study, a multicenter trial that evaluated 3 different antibiotic therapies for staph infections, was designed to identify drug dosages appropriate for use in term and pre-term infants—information that was not available in existing product labeling.

By combining their findings with pharmacokinetic and safety data from two other studies, the authors were able to describe a dosing regimen for clindamycin in premature infants based on postmenstrual age and total body weight that would allow physicians to effectively treat the infection while avoiding unwanted side effects.

Dr. Patterson knew, based on lab results, that Lucas’ particular strain of MRSA was sensitive to clindamycin. Thanks to the data published in the PTN study, she was able to choose a dosing strategy that would be most effective for Lucas.

“After only a couple of days, we saw a dramatic improvement with no adverse effects,” she said. Lucas recovered completely by the end of the week-long treatment, and was discharged healthy later in the summer.

Although Lucas’s parents had initial concerns about the treatment, they were reassured when Dr. Patterson referenced the study.

“We were confident about our treatment because of the literature,” she said. “This made the family confident in us.”

However, Dr. Patterson noted that this is not always the case, pointing out that information to guide dosing for infants and premature neonates is often sorely lacking.

“In pediatrics, we’re often extrapolating from adult data,” Dr. Patterson said. “In part because families are reluctant to enroll their children in clinical trials, it’s hard to find data specifically related to infants and children.”

Bridging this gap is a key goal for the PTN, an alliance of more than 100 clinical research sites cooperating in the design and conduct of pediatric clinical trials. Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the PTN works to improve healthcare for the youngest patients by providing much-needed information on optimal dosing of commonly used drugs.

“The work that PTN is doing is critical,” Dr. Patterson said. “Especially when working with life-threatening conditions in the newborn population, the more science behind our medical practices, the more confident we can be that we will deliver the best outcomes for our patients and their families.”

*Name has been changed to protect confidentiality.

DCRI and partners awarded FDA grant to create Global Pediatric Clinical Trials Network

The Duke Clinical Research Institute and its strategic partners have been awarded a grant from the U.S. Food and Drug Administration (FDA) to establish a coordinating center for a Global Pediatric Clinical Trials Network (G-PCTN). The G-PCTN will support efficient pediatric clinical trials worldwide by developing scientific and operational infrastructure, fostering collaborative networks, sharing knowledge, and engaging stakeholders. The principal investigators for this program will be Drs. Danny Benjamin and Michael (Micky) Cohen-Wolkowiez.

“Although we’ve made a lot of progress in recent years, pediatric trials are still hard to complete successfully. There are perennial challenges – enrolling patients, finding access to supporting infrastructure, navigating a complex regulatory environment – that affect everyone working to advance pediatric research, but they can be especially challenging for research sites that don’t have access to resources or experience,” said Benjamin. “We’ve had great success with the Exclusivity Program, and NICHD’s off-patent program; but we need to work through some of the challenges that folks have had in meeting the requirements outlined by the Pediatric Research Equity Act. It’s crucial to have success across new therapeutics for children.”

Although the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) were both implemented to encourage research sponsors to conduct more pediatric clinical trials, many drugs used in children lack sufficient information to guide their safe and effective dosing. Further, 42% of pediatric trials done under BPCA have not successfully supported pediatric indications.

“Despite how vital it is for children’s health, proper dosing information is still sorely lacking for many important therapies used in children and infants,” Cohen-Wolkowiez said, noting that the relatively small numbers of patients eligible to enroll in pediatric trials of therapies for rare diseases adds an additional layer of difficulty. “This Network will provide a key opportunity to address inefficiencies and build capacity across the globe for conducting more effective pediatric clinical trials, which will help inform the decisions parents and healthcare providers make when caring for our youngest patients.”

The grant will be used to create a coordinating center comprising 3 cores for network operations, patient engagement, and scientific oversight and 5 clinical study groups devoted to study design, dosing, regulatory/pharmacy, network partnerships, and rare diseases. Benjamin, who also serves as Principal Investigator for the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Pediatric Trials Network (PTN) envisions the programs working synergistically: “There are natural interactions, or lessons learned, across the trials conducted in the older, off-patent medicines and the trials conducted for newer therapeutics.”

The creation of the Network reflects consensus findings from a multistakeholder group that included regulators, industry, academia, patient advocacy groups, disease networks, and parents. The group noted that no one set of stakeholders can address these problems in isolation; instead, a global network involving all stakeholders could better ensure successful pediatric trials, especially those being conducted in patients with rare diseases.

The G-PCTN will leverage and extend the extensive infrastructure, networks, and experience already in place via the PTN, whose administrative coordinating center is also located at the DCRI.

POPS Paradigm Explained

PTN studies managed via the POPS paradigm seek to determine the appropriate dosing of understudied drugs in children by using samples collected as part of regular care (for example, blood draws). The data collected provides valuable pharmacokinetic and dosing information for drugs in different pediatric age groups and special pediatric populations (such as obese children).

Dr. Ram Yogev, POPS Investigator at Lurie Children’s Hospital of Chicago, explains, “The current empirically-based dose selection for pediatric patients can be improved by applying evidence-based dosing strategies. POPS studies provide important information about how best to dose medications in children and adolescents, and support dosing strategies that provide the best chance for any given drug to demonstrate both efficacy and acceptable tolerability.”

Since its inception, POPS has investigated 48 understudied drugs with 19 currently enrolling. POPS has a total of 31 active sites, and in March, two UK sites joined the ranks, Southampton General Hospital and Alder Hey Children’s Hospital. As of June 1, POPS sites enrolled 1904 participants of the targeted 3000.

SCAMP Enrollment is Wrapping Up

Two years ago, the study site at the University of Florida–Jacksonville Shands Medical Centerwe enrolled SCAMP’s first patient. With remarkable effort from more than 50 study sites, including 5 in Canada, SCAMP will close enrollment by the end of 2016. Once the enrollment period ends, the study team will analyze the data and submit the clinical study report.

PTN MD, Micky Cohen-Wolkowiez, receives Young Investigator Award

MCW_HeadshotMichael (Micky) Cohen-Wolkowiez, MD, PhD, director of the Duke Clinical Research Unit, has received the 2016 Young Investigator Award from the Pediatric Infectious Diseases Society (PIDS). The award recognizes a young physician whose research has generated outstanding contributions in the field of pediatric infectious diseases.Cohen-Wolkowiez is the author of more than 75 peer-reviewed publications and has led several multicenter pediatric studies, including trials for pediatric labeling. He also spent two years as a scientific advisor to the Office of Pediatric Therapeutics at the U.S. Food and Drug Administration and participated in a series of projects related to pediatric dosing and the ethical aspects of pediatric regulatory submissions.

“This prestigious award could have not gone to a more deserving physician-scientist,” says Coleen Cunningham, MD, professor of pediatrics and chair of the Divisions of Infectious Diseases and Global Health in the Duke Department of Pediatrics.

Cohen-Wolkowiecz received his medical degree from the Central University of Venezuela in 2001. He trained in pediatrics at the Miami Children’s Hospital in Florida and completed a pediatric infectious diseases fellowship at Duke University Medical Center in 2009.

PIDS is the world’s largest organization of professionals dedicated to the treatment, control and eradication of infectious diseases affecting children. Membership is composed of physicians, doctoral scientists, and others who have trained or are in training in infectious diseases or its related disciplines, and who are identified with the field of pediatric infectious diseases through clinical practice, research, teaching, and administrative activities.