Lack of research, drug development detrimental to neonatal patients
It is estimated that more than 65% of drugs given to neonatal patients — and up to 90% of drugs used in neonatal intensive care units — are administered off-label, according to the FDA.
With wide variation in clinical policies and newborn characteristics, the use of off-label drugs continues to be largely dependent on the professional judgment of the physician. Therapeutic decision-making relies on best available evidence, which remains lacking in the neonatal population.
Infectious Diseases in Children spoke with several neonatologists and infectious disease experts regarding the severe lack of research regarding the neonatal population, the risks related to off-label use of medications, and the many challenges that make neonates a difficult, yet paramount focus for medical research and development.
A neglected population
Neonatal patients are a persistently understudied patient population in the field of medical research. Due to an overwhelming lack of study data for all pediatric patients, the Best Pharmaceuticals for Children Act (BPCA) was passed in 1997. This law allowed the FDA to broaden the amount of drugs studied for use in pediatrics, by identifying which drugs would benefit children most from having a pediatric indication. This approach incentivized research geared toward pediatric drugs by offering pharmaceutical companies extensions on their patents and exclusivity in market — which, in turn would allow the manufacturers to increase profitability of a drug that could be marketed to both children and adults.
Source: Duke University
In 2003, the Pediatric Research Equity Act (PREA) was signed into law. PREA took a different approach than the BPCA by requiring that pharmaceutical companies developing any new drug or new drug use indication for an existing drug must have a pediatric research plan in place to market and study the drug.
Despite these efforts, between 1998 and 2006 only 6% of the 365 drug indication changes made that involved pediatric studies pertained to neonatal medicine research, according to a statement from the Institute of Medicine. An additional five products that were studied in neonates, granting pharmaceutical companies extended patents and marketing exclusivity, failed to result in any labeling changes pertinent to the neonatal patient population.
The lack of practical FDA labeling changes that are applicable to neonates results in off-label administration of the majority of neonatal medications, experts say.
“Currently most of the drugs that we use in neonates are off-label, and we use them based on studies that are done in adults and in older children, where we try to extrapolate the information to neonates,” Pia S. Pannaraj, MD, MPH, of Children’s Hospital Los Angeles and the University of Southern California, told Infectious Diseases in Children. “However, neonates are very different, even from older children, making it very difficult to know whether or not we are using the right doses.”
“If you are going to give medicines with all the care of throwing darts, sometimes you miss,” Daniel K. Benjamin Jr., MD, PhD, MPH, of the departments of pediatrics and infectious diseases at Duke University School of Medicine, told Infectious Diseases in Children.
A history of catastrophic adverse events resulting from the use of understudied off-label drugs in neonatal medicine has not done much to increase the amount of drugs with FDA labeling indications for neonates. Research from Matthew M. Laughon, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, and colleagues found that the majority of drugs used in neonates remain insufficiently studied.
“Any time a drug is used off-label — meaning that the use is not endorsed by the FDA, the dose is different than the FDA label, the indication is different than the FDA label or it is not indicated at all in infants or children — this increases the risk of adverse events, particularly adverse drug reactions,” Laughon said in an interview. “Some of these reactions can be really serious, life-threatening or increase the length of hospitalization.”
According to Benjamin, a primary component fueling the use of off-label drugs in the neonatal population is the inability to extrapolate adult research dosing data in order to estimate the dosage needed for neonatal patients.
“If you take the world’s smartest pharmacologists, infectious disease doctors, microbiologists, people from the pharmaceutical company, people from the FDA, people from the NIH, get them into a room and you say, ‘Here’s all the adult data; what should the doses be in children?’ they can come up with an awesome database, and great animal and computer models ... but they are still wrong 40% of the time,” Benjamin said.
Due to the lack of labeling indication research for certain drugs, neonatologists are forced to rely heavily on anecdotal research and experience, resulting in doses that vary widely from the FDA label.
“Caffeine is a good example for off-label usage,” Laughon said. “Most neonatologists use caffeine for weeks and weeks and weeks, sometimes months, but the duration of treatment on the label is for up to 10 days. There is a real disconnect between what is on the FDA label and what neonatologists are doing in the ‘real world.’ ”
According to both Laughon and Benjamin, off-label drug use is a symptom of the many challenges associated with designing and carrying out studies in the neonatal population, including the patients’ complicated physiology, parental reluctance and systematic study design issues.
Neonatal Physiology, a small population
A neonatal patient typically is defined as a newborn aged younger than 28 days beyond the postnatal period, which includes all preterm births. Traditional study methods are often complicated by the small size and weight of neonatal patients.
“The small size of neonates, just to give a sense of perspective, means that a typical level 3 NICU baby who weighs 1 kilogram has a complete blood volume of about two and a half ounces,” James M. Greenberg, MD, director of the division of neonatology at Cincinnati Children’s Hospital, told Infectious Diseases in Children. “Doing studies using traditional methodology puts an undue burden, just from loss of blood, on these babies.”
According to Laughon, blood volume is not the only barrier associated with drawing blood from neonatal patients. Unduly inflicting pain on neonates, who may already be vulnerable due to the myriad of complications present in NICU patients, presents an ethical dilemma, he noted.
“If we are drawing blood, then that it makes it challenging because families do not want researchers to stick their baby, because it hurts,” Laughon said. “Therefore, we try to avoid sticks, for research-only purposes, and instead collect a little bit of extra blood when babies are getting blood drawn for other reasons.”
Along with neonates being physically small, according to Benjamin, the neonatal population is also restrictively tiny compared with other study populations. That makes gathering study cohorts difficult and an obstacle that must be overcome before research can even begin.
“There is only an estimated 330,000 neonates in America, and ... over 90% of them go home on day 1 of life and don’t come back sick during their first month of life,” Benjamin said. “You don’t have a target population of 330,000; you have a target population from around the country at any one time of about 30,000. Additionally, they don’t have just one problem that is the same problem. They have dozens of different types of problems, requiring dozens of different types of medicines. So, your target patient population for any study at a particular site, might be only one or two infants per year.”
Despite these challenges, technological advances in neonatal medicine that deal with barriers related to the physiology of infant patients are beginning to emerge.
“The most exciting thing happening right now that will inform a lot of our work are the really remarkable advancements in micro-methodology, which will allow us to do pharmacokinetic and pharmacodynamic studies using a thousand times less blood than what has typically been required,” Greenberg said. “These technologies are also point-of-care types that use mass spectrometry technology to do the work and give the information in real-time.”
Another barrier: Parents and doctors
As neonates are innately unable to consent to participate in research studies, this adds yet another barrier to studying the population and limits research and development for studies that may directly benefit these patients. In lieu of individual consent, permission to study neonates must be granted by parents, which, according to Alissa Craft, DO, MBA, director of curricular outcome and improvement at the Western University of Health Sciences, Oregon, can be difficult to obtain.
“For parents, just the concept of someone studying or experimenting on their baby can be very, very difficult for them to understand,” Craft told Infectious Diseases in Children. “It often takes multiple conversations and a lot of time and gentleness. Sometimes, especially in life-threatening situations, there may not be time available to have those conversations with families in a good way, to help them understand the difference between care being done and care being applied for research purposes.”
According to Laughon, neonatologists often are equally hesitant to engage their patients in research studies.
“Neonatologists are also reluctant to enroll participants in studies, because they feel like they know what is right for the infant, even though the evidence suggests otherwise,” Laughon said. “If you try to get neonatologists to use a dose that is different than what they are used to, even though there is no evidence or supporting pharmacology data to support that dose in infants, they do not want to do it. And I don’t understand that.”
Matthew M. Laughon
According to Benjamin, this reluctance to participate in studies is tied to failure as a culture to recognize that in order to advance the understanding of neonatal medicine, engagement in neonatal research and development needs to be significantly expanded.
“The next big hurdle is fundamentally going to be cultural on the part of neonatologists and parents,” Benjamin said. “Only an estimated 20% of NICUs in the United States are really active in high-quality clinical investigation involving therapeutics; the rest are either not doing any research at all, or what they are doing is not going to have any impact on public health. As a community, it is upon us, the pediatricians, to be convinced that this is how child health gets improved in the long run.”
“For parents and clinicians, if they have the opportunity to participate in research studies, I would highly encourage them to seriously consider it,” Laughon said.
High risk, low reward
The lack of neonatal research naturally results in a lack of new drug development for products specific to the neonatal population. Furthermore, a significant portion of drugs studied for use in NICUs are never used to treat those patients. According to study findings by Laughon and colleagues, 13 of the 28 drugs analyzed in a study of NICU drug use were not used at all.
Experts noted that the development of new drugs for the neonatal population is hindered by a perceived lack of financial incentive on the part of pharmaceutical companies to invest in research.
“The pharmacokinetic studies that are done to get a drug approved are typically funded by the drug companies, and they do not have financial incentive due to the small [neonatal] population,” Michael Neely, MD, MSc, FCP, of the Laboratory of Applied Pharmacokinetics and Bioinformatics at Children’s Hospital Los Angeles, told Infectious Diseases in Children. “It’s not only the small population, but also the amount of drug in a dose is extremely tiny compared to older children and adults.”
According to Jay S. Greenspan, MD, MBA, chair of Pediatrics at the Sidney Kimmel Medical College at Thomas Jefferson University/Nemours, the key to getting pharmaceutical companies to invest in neonatal medicine lies in figuring out how to translate the value of lifespan that can be added by neonatal treatments.
“If you can fix something in the first few days of life, you may be able to really change the course of a life that could be 95 to 100 years long,” Greenspan said in an interview. “The return on investment, at least for that person, is huge compared to some of the other trials that may be looking at folks that are older or have a shorter life expectancy. It’s just a matter of finding a way of stimulating the companies to get this research going.”
Jay S. Greenspan
There is a need for neonatal-specific products to treat diseases and complications specific to the neonatal population, including chronic lung disease, bronchopulmonary dysplasia and intraventricular hemorrhaging, according to Benjamin. The need for neonatal specific antiviral and anti-infective products, however, is not so urgent.
“With neonates, you can extrapolate efficacy for most things: meningitis maybe not, invasive candidiasis, probably not, community-acquired pneumonia, probably not,” Benjamin said. “However, you can extrapolate for most things, such as intra-abdominal infections, urinary tract infections and bacteremia. I am not convinced that we need drugs specifically designed for neonates.”
Neonatology could benefit by emulating the enrollment styles other specialized areas of medicine use to perform research studies, according to Pannaraj.
“One of the groups that has studied drugs really well are the oncologists, where almost every child with cancer gets enrolled in a chemotherapeutic study,” Pannaraj said. “They have these huge networks all around the world to study the effects of chemotherapeutic drugs. I think that that is actually a really great model for the study of any drug, including in neonates. If we form networks across all the major NICUs to study these drugs, we could pick out neonates that are all similar. If we could model clinical trials after some of the oncology trials that could be a huge benefit.”
The incorporation of enrollment techniques from other specialties is crucial to informing future policy changes and promoting long-term pediatric health, according to Benjamin.
“The classic examples of improved research enrollment strategies are the pediatric oncology group, the vaccine trials and the HIV trials,” Benjamin said. “Those are three areas where the pediatricians have been extremely persistent at getting the research done and maintaining a culture where almost all children are enrolled. If you have cancer in this country, chances are very good you are going into multiple different clinical trials. If you have pediatric HIV, your chances of getting into a clinical trial are very high. Vaccine groups have made sure that the evidence goes into policy, and they have delivered on multiple very large trials in order to get those vaccines approved.”
The lack of a unified research network of neonatologists has resulted in a standard of care that varies widely from hospital to hospital, according to Benjamin.
“Neonatologists need more systemwide randomization about our practices that we consider standard of care,” Benjamin said. “Very rarely is there a national standard of care as far as the details of the practice of medicine in neonatology. People have a very, very firm idea, almost invariably, on what they think is the standard of care. But I am always impressed by the number of physicians who insist that the way that they practice is the standard of care. Often, they are sitting across from people who have an entirely opposite approach on the same question, who will also insist that their approach is the standard of care.”
According to Laughon, the key to advancements in neonatal medicine lies in convincing parents to enroll their children in studies by emphasizing the importance of pediatric research.
“The knowledge gain is immeasurable,” Laughon said. “There are babies in 2015 that are directly receiving benefit because of the mothers and fathers who consented their babies to research 15 to 20 years ago. The only way we are going to move the field forward is if we do rigorous quantitative evaluation of our drugs and methods, and the only way to do that is through research studies.”
Although neonates are a small study population, their vulnerability makes them a primary focus area for better medical research, according to Greenberg.
“There are a lot of NICUs, and there are a lot of preterm babies,” Greenberg said. “They contribute a tremendous amount of morbidity and mortality to our population, and it’s about time that somebody started paying attention to them.” – by David Costill
- Laughon MM, et al. JAMA Pediatr. 2014;doi:10.1001/jamapediatrics.2013.4208.
- McCune S. Regulatory Science Needs for Neonates: Innovation in Study Design and Drug Development Paradigms. 2013; www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM342992.pdf. Accessed October 13, 2015.
- Nelson R. The Current Challenge: Neonatology – Responding to the Need and Legislation. 2013; www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM343640.pdf. Accessed October 13, 2015.
- For more information:
- Daniel K. Benjamin Jr., MD, PhD, MPH, can be reached at Duke Clinical Research Institute,
- Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705.
- Alissa Craft, DO, MBA, can be reached at the College of Osteopathic Medicine of the Pacific – Northwest, 200 Mullins Dr, Lebanon, OR 97355.
- James M. Greenberg, MD, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229; email: firstname.lastname@example.org.
- Jay S. Greenspan, MD, MBA, can be reached at Jay.Greenspan@nemours.org.
- Matthew M. Laughon, MD, MPH, can be reached at UNC Hospitals, 101 Manning Drive, CB #7596, 4th Floor, Rm N4055, Chapel Hill, NC 27599-7596.
- Michael Neely, MD, MSc, FCP, can be reached at email@example.com.
- Pia Pannaraj, MD, MPH, can be reached at firstname.lastname@example.org.
Disclosure: Benjamin, Craft, Greenberg, Greenspan, Laughon, Neely and Pannaraj report no relevant financial disclosures.