Clinical trials in the pediatric population and neonates: interview with Professor Robert Ward

In pharmaphorum's pediatric care month, Rebecca Aris interviews Professor Robert Ward on clinical trials in newborns.

There are numerous barriers and challenges to research in the pediatric population, and even more so in newborns.

Neonatologist, Professor Robert Ward consults to the FDA, NIH, USP, and CDC to help design clinical studies in children. He also serves on the FDA Pediatric Advisory Committee.

Up until 2012, Professor Ward had watched many drugs undergoing study in children and even infants, but seldom in neonates. The 2012 law required the FDA to have expertise in neonatology and required all studies to include neonates unless a waiver is granted. This was of importance so that neonates could participate in the advances in drug therapy that were accruing to older children through these studies.

Professor Ward began the Pediatric Pharmacology Program in 1997, but has now turned over its leadership to a younger and very energetic pediatric clinical pharmacologist, Michael Spigarelli, MD, PhD.

Professor Ward currently conducts mostly neonatal studies and shares here with pharmaphorum the challenges associated with such studies and what we have learnt from them so far.

Interview summary

RA: What does the trials process look like in newborns?

Fortunately through the 2012 BPCA provisions, they are increasing. The increase has been slow because these studies are simply harder than studies in older children, which are hard enough as it is. Newborns are a complex population with the increasing survival of very premature newborns who are developmentally quite immature. Both their organs, such as the heart and brain, exhibit immature responses to drugs and their pathways for clearing drugs from the body are just developing as well. Birth can change the rate of change for both. It means, however, that older studies in modestly premature newborns may not predict accurately how a drug will affect an extremely immature newborn. More studies are needed, especially in the hardest to study population. Fortunately, both analytic chemical instrumentation and techniques as well as pharmacokinetic analyses have improved and advanced dramatically in the last 10 years to help with these studies.

"More studies are needed, especially in the hardest to study population."

RA: What do you see to be the biggest challenges in studying drugs for use in newborns?

RW: To label a drug for a newborn requires comparison either to a placebo or to a comparable drug. Few drugs are actually labelled for extremely premature newborns so we often lack comparator drugs.

Studies are not conducted in "healthy volunteer premature newborns" because they can't consent for their own participation and taking a risk. That means that studies are conducted in sick newborns who need treatment. Ethical standards require that studies can involve only a minor increase over minimal risk, indexed to risks typical of a healthy child. When I am caring for a child on a heart lung machine, such as ECMO (extracorporeal membrane oxygenator), this standard doesn't seem relevant. The same applies to a newborn receiving multiple antibiotics, antifungal drugs, vasopressors to raise the blood pressure or bronchodilators to improve lung function. Clinical trial provisions are not a good match to the real world practice of neonatal intensive care, yet it is just this setting that needs the guidance of carefully conducted studies.

RA: What does the current regulatory landscape look like for testing drugs in newborns?

RW: These challenges are being recognized and changes are being considered in the regulatory landscape. Fortunately the requirement for neonates to participate should force the FDA and OHRP to address the ethical and regulatory boundaries of this challenging population.

RA: In what disease areas has the most research been done in newborns?

RW: The best studied areas are antibiotics and surfactant replacement for the Respiratory Distress Syndrome that is caused by primary surfactant deficiency. Yet, even in these therapeutic areas, we still have much to learn. Prevention of chronic lung disease that is associated with long-term morbidity and developmental delay is likely linked to better treatment of neonatal lung disease. Studies in these areas are underway and new studies are being planned.

RA: What are the key considerations for parents of newborns considering a trial?

RW: Parents need to recognize that current newborn medicine is practiced using a few well controlled studies and many patterns of practice handed down from innovators and from tradition, because we have practiced that particular pattern for many years. Participation in clinical studies is probably safer than day to day practice because of its careful regulation by Institutional Review Boards and careful study design protocols. By contrast, in clinical practice we try what we view as a reasonable treatment, but without systematic data collection that allows us to understand whether it really worked or not. Without systematic data collection and analysis, we may not detect adverse effects that occur in less than 25% of patients, which means we would miss most adverse effects.

RA: Are there any particular companies or centres that are making progress in this area?

RW: The National Institute of Child Health and Human Development has funded a pediatric clinical trials network that is directed by Duke. They are doing outstanding clinical studies as well as training a new generation of pediatric investigators to help carry on this important work. I can't short change our program here at the University of Utah. We have several postdoctoral fellows who are learning Pediatric Clinical Pharmacology to help create the new data that will guide future clinical therapeutics for children. Dr. Spigarelli's team is currently coordinating over 100 pediatric studies.

"Studies are not conducted in "healthy volunteer premature newborns" because they can't consent for their own participation and taking a risk. "

There are several companies that take a real interest in pediatric drug therapy. The AAP News list of new drug approvals for children, list some of these. They deserve both our praise and our patronage.

RA: What are the greatest medical advances that have been made as a result of drug trials in newborns?

RW: Probably the biggest step forward has been development of surfactant replacement therapy for primary surfactant deficiency in premature newborns. That caused the death of John F. Kennedy's baby in 1963 and the first surfactants were being tested in the late 1980's. I have had the perspective of practicing neonatology both without them and now with them. Several have been developed and we are still learning about them. They are even being tested as a means to deliver drugs to the lung. With expansion of studies of many medications in newborns we will improve treatment while learning more about their development. I think the future is bright for drug therapy in the newborn.

RA: Thank you for your time.

About the interviewee:

Robert Ward, MD began the Pediatric Pharmacology Program at the University of Utah School of Medicine in 1997 and is an attending neonatologist. He conducts studies of medications in pediatric patients and coordinates a group of clinical coordinators who assist other faculty with medication trials. His current studies involve analgesia in newborns and the Neonatal Abstinence Syndrome as well as airway drug metabolism and its potential impact on asthma treatment in children.

What do you think the future of drug therapy for the newborn looks like?