Talking with Susan K. McCune, M.D., Deputy Director, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA
Most medications administered to neonates lack convincing data to support their safety and efficacy. In addition, there is a lack of new drugs that target the unique medical challenges faced by this patient population. While the challenges are many, solutions are being explored – with the right people and the necessary urgency – to tackle this unmet medical need.
Define neonates, as they relate to drug development. What ages are we talking about?
Neonates are a very unique population. A neonate is a full-term infant – about 38-40 weeks gestation – that is less than 28 days old. For a pre-term infant, the neonatal period is determined a little differently. Instead of calculating 28 days from the date the child is born, you must also add on the remaining time the baby would have needed to reach full gestation. So an infant born at 24 weeks is defined as a neonate for its first 14-16 weeks of life, plus 28 days. While both infants are considered a neonate, an infant born at full-term is not the same as a 16-week-old infant born pre-term at 24 weeks gestation from a drug development standpoint.
Why not? Aren’t they are both technically about the same age?
There are various developmental processes that typically mature at different periods during gestation or after birth. There are also tremendous differences in the maturity of the systems necessary to process pharmacologic agents. For example, absorption, distribution, metabolism and excretion of drugs may all be different in neonates; it’s even more complicated with a pre-term neonate.
So that’s part of the challenge in neonatal drug development.
Yes, part of it. To understand the spectrum of challenges, it’s important to understand the in-utero environment compared to the extra-uterine environment. In-utero, the mother is essentially the baby’s life support system. All of the nutrients and oxygen are provided by the mother; all of the toxins are removed from the baby through the mother. After birth, the baby has to take over all of those activities and become an independent entity.
For pre-term infants, things are different. Many of a pre-term infant’s organs are immature at birth. A lot of maturation that normally would have been done in-utero now has to go on outside the mother. In addition, you have to add on the natural development of a growing infant. And studies in neonates – like in other patient populations – need to be feasible, ethical and sufficient to support labeling of drugs for dosing, safety and efficacy.
It must be difficult to obtain volunteers for these studies.
Yes. Many babies are viewed as being fragile; some pre-term infants weigh less than a pound at birth. The neonatal period can be a very vulnerable time for these patients and their parents – both are going through quite a few unexpected challenges. Although clinical trials have very strict rules and oversight to protect patients, physicians and scientists understandably have difficulties approaching parents about potential neonatal clinical studies. We need to provide clinical researchers with better communication tools to help explain to parents the importance, risks and benefits of these neonatal trials. But there are other issues that hamper drug development for neonates.
What are some of the issues?
Because they can’t take pills or capsules, the neonatal population is often treated with needed drugs intravenously or with a liquid preparation taken by mouth or delivered by a nasogastric tube to the stomach. It can be difficult to make these liquid formulations, so neonates may not have access to approved drugs if the correct formulation is not available. In addition, drugs may be metabolized differently in neonates – it may occur more slowly or more quickly than in an adult, which can also affect dosing. Understanding all of this information in a neonate is critical. It's not just, ‘do we have the right drug’ – it's, do we have the right drug, do we have the right dose, do we have the right interval, do we have the right population, and do we have the right measures of efficacy? All of these are important from a safety and efficacy perspective.
Even with these challenges, there are drugs being given to this population, right?
Yes, a recent article by the Best Pharmaceuticals for Children Act – Pediatric Trials Network documented that between 2005 and 2010, 65 percent of the most commonly prescribed medications in the neonatal intensive care units are used off-label. Use of a drug off-label means that the drug has not been FDA-approved for that particular indication, or has not been approved for use in a particular population. Most of the drugs being used in the neonatal population have been studied and are FDA-approved for use in adults but often haven’t been studied for use in children, much less neonates.
The problem is that every time we use a medication in an off-label manner in a neonate, it is a type of experiment. Currently, we're not able to use any of the data from medication use in neonates in a way that can promote better labeling and optimal use. As a scientific community, we need to work together to design and undertake innovative clinical studies that may provide important data on the safety and effectiveness of drugs used in neonates.
Is data collection a problem?
Medication use in a few neonatal intensive care units is tracked – this has the potential to provide a robust database of information. We need to develop consistent nomenclature describing the type of data we want to capture about medications and their safety and effectiveness in neonates.
Clearly, using registry information and patient electronic health records are important. However, I compare it to playing with a Lincoln Logs and Lego blocks. While you can play with both sets separately, it is not easy to use them together to build things. We need to be able to collect the neonatal data in a way that all the pieces will fit together easily so that we can build from it in an aggregated way. Developing standards for this data in the neonatal population is a key building block.
The pharmaceutical industry is a major stakeholder here, are they engaged in providing a path forward?
Yes, industry is very engaged and the academic community is also an important partner. In addition, patient advocacy groups, professional societies and other Federal government partners have a stake in drug development for neonates and Congress has provided legislative mandates for considering neonatal studies. All of these groups bring a point of view to the table that is really important in this space.
It is critically important that these stakeholders understand the regulatory rigor associated with studies that are submitted to the Agency for neonatal drug labeling. And I think it's important that U.S. and international regulators understand the unique aspects of studies in neonates. All stakeholders need to leverage their experiences from the rare disease arena of small clinical trials to design quality neonatal studies.
Communication is vital – how are you developing ties to these stakeholders?
Public input is what we want – dialog driven by the neonatal community is what we need. For a long time we have wanted to see clinical studies done for neonates. We are starting to have neonatal studies submitted to the Agency, but, in general, they're not studying the drugs that are really being used in neonatal care units across the country. Also, enough novel therapies haven't been developed – we have in a real sense hit a brick wall. We have to figure out how to move forward – regulators saying ‘you should do the studies’ simply isn't enough. We need to better understand the clinical trial issues and brainstorm together to overcome some of the hurdles, in order to study drugs used in the neonatal population and develop new therapies.
The FDA has much experience collaborating in public-private partnerships which serve to bring together stakeholders to address important drug development challenges. In fact, at the end of October 2014 the FDA is co-sponsoring a neonatal scientific workshop with the Critical Path Institute and the Burroughs Wellcome Trust to discuss many of these neonatal drug development issues and hopefully launch a new partnership to address these unmet needs.
What is the goal of this workshop?
The workshop will serve to initiate stakeholder discussion about neonatal studies and to map out the priorities for a potential new consortium devoted to applying regulatory science to the neonatal population. It will also help highlight the importance of communication among all the stakeholders.
Workshop sessions will be co-chaired by individuals from outside of the agency, in academia, industry, other government agencies, and other international regulatory agencies. Topics will include innovative trial designs, trials that allow for extrapolation, criteria for initiating trials in neonates, pharmacokinetic and pharmacodynamic modeling, clinical outcome measures, biomarkers, and ways to prioritize potential projects for the consortium going forward.
What would you like to see the consortium accomplish during the next few years?
Having all the stakeholders coming together to discuss common issues and goals is the first hurdle. I think it's really important that we take what we learn at the workshop and then prioritize topics and deliverables. Ten years ago, we didn't have consortia, we didn't have clinical trial networks; we didn't have the infrastructure needed to get trials done. Groups are coming together in a way that's much more energized – the timing is right. We can leverage a lot of experience from our previous consortium work. Hopefully, this information will help us optimize drug research and development and help bring new drugs to neonatal patients.
Going forward I’d like to see discussion and implementation of master protocols using adaptive trial designs, and using neonatal trial networks that can efficiently provide the infrastructure needed to do these neonatal clinical trials. I would like for to us develop databases and use standardized data to capture natural history information. Once developed, they can be used across multiple therapeutic areas to understand the pathophysiology of disease, and the normal ontogeny of some of the enzyme systems involved in drug metabolism. I'd like a discussion of potential biomarkers that can be developed in the biomarker qualification program.
And, of course, enhanced discussions among stakeholders in the consortium to identify and prioritize scientific questions and gaps to keep driving future innovation in neonatal drug development.