Announcer: From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, welcome to another installment of NICHD Research Perspectives. Your host is the Director of the NICHD, Dr. Alan Guttmacher.
Dr. Alan Guttmacher: Hello, I’m Alan Guttmacher. Thanks for joining us for another in our monthly series of podcasts from the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health.
We will be talking today about research conducted in the Obstetric and Pediatric Pharmacology and Therapeutics Branch here at NICHD. We have as our guests Dr. Perdita Taylor-Zapata and Dr. Zhaoxia Ren [Zow-shah Ren], both medical officers in the Branch. We will talk with them about the role of NICHD in ensuring the safety and efficacy of pharmaceuticals used for infants, children, and pregnant women.
Drugs undergo a several-stage testing process before they make it to the pharmacy shelf. After a company develops a drug, it is first tested in a laboratory. After that, drugs must be tested in clinical studies, which involve human volunteers.
These clinical studies involve three phases, each one designed to answer specific questions about dosage, safety, and efficacy. After these three types of studies have been completed, and assuming no substantial problems have been found, the company then submits an application to the Food and Drug Administration—the FDA—for approval. If, after reviewing the research evidence, the FDA determines that the drug has been shown to be both safe and effective for its intended use, FDA officials will work with the drug company to develop and refine prescribing information. This process is referred to as labeling.
The label of FDA-approved drugs provides information about the drug, including the populations for which it has been studied, the approved doses, common side effects, and how the drug is used to treat the medical condition for which it was approved.
Although all drugs approved by the FDA must go through this process, most of these clinical trials involve testing of drugs only in adults, not children or pregnant women. This means that the majority of drugs prescribed for infants, children, and pregnant women today are used without adequate understanding of appropriate dose, safety, or efficacy for those populations. You might wonder how this is possible. Once the FDA approves a drug, physicians can use their best judgment to prescribe it to their patients—whether or not their patients are similar to those who took part in the clinical trials. Physicians can also prescribe drugs for diseases or conditions other than those for which they were originally tested. This is called off-label prescribing and is quite common.
Before 1998, pharmaceutical companies were not required to test their drugs in infants and children, even if the drugs were commonly given to those populations.
Children, however, may respond differently to a medication from the way that adults respond. The result of such off-label prescribing may be that some children receive drugs that don’t work for them or that they receive too much or too little of a potentially useful drug. Similarly, there may be side effects unique to children.
Because of this, in 2002 Congress enacted the Best Pharmaceuticals for Children Act. The legislation is designed to foster pediatric drug testing through preclinical and clinical drug studies. The Act directed the Secretary of the U.S. Department of Health and Human Services, acting through the Director of the National Institutes of Health, to establish a program for pediatric drug development. This welcome task was given to NICHD, which was directed to establish and conduct pediatric drug testing activities. Implementing the Act is the major role of NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch, where both of today’s guests work.
Since the legislation was first enacted, the NICHD has sponsored numerous projects to obtain the information needed to improve pediatric drug labeling.
Our first guest, Dr. Perdita Taylor-Zapata, will review past projects under the BPCA Program at NICHD and discuss some current projects.
As I mentioned, only a small percentage of drugs and devices approved by the FDA are actually labeled for pediatric use. But, clearly, it’s in the best interest of children to test and label drugs that will be prescribed to children. However, not every drug can be studied at once. Perdita, could you explain for us how you prioritize which drugs need to be studied?
Dr. Perdita Taylor-Zapata: Absolutely, and thank you for this opportunity, Dr. Guttmacher. As you stated, drugs, biologics, and devices; which are called therapeutics, are used in children every day even though a large percentage of these drugs have very limited data available to us, such as if the drug being prescribed is correct and if the drug is truly effective and safe for that child’s age or size or even medical condition. The pediatric medical community, the public health community, and governmental agencies have all recognized that there are multiple gaps in knowledge regarding the use of therapeutics in children. These gaps have frequently resulted in inadequate labeling as you described for pediatric use and ultimately in widespread off-label use of prescription drugs in children. This off-label use of a drug substantially limits the ability to gain important clinical information of the drug product, such as the correct dose of a drug, changes in drug metabolism and response during growth and development, and important short- and long-term effects. The lack of adequately collected safety and efficacy data in children can increase a child’s risk for adverse effects. The mission of our branch is to ensure, through research, that medications given to children and pregnant women are safe, effective, with the appropriate dose and formulation for that affected population.
Under the Best Pharmaceuticals for Children Act, our branch is responsible for the development of a priority list of needs in pediatric therapeutics, and we do this in consultation with the FDA and experts in pediatrics. We are also responsible for sponsorship of relevant pediatric clinical trials; and the submission of the results in clinical trial data to the FDA for pediatric labeling changes.
This list, that we’ll call the BPCA Priority List, is developed in collaboration with our colleagues at the FDA and in consultation with experts across the country in pediatric research and clinical care. The Priority List consists of key therapeutic needs in the medical treatment of children and adolescents; it is organized by therapeutic area, which can be a group of conditions, a subgroup of the population, or a setting of care. Brief examples of therapeutic areas that we have prioritized include the following: the safety of inhaled anesthetics in developing brains; new formulations of drugs for the treatment of cancer in children; and the dosing, safety, and effectiveness of lithium in the treatment of bipolar disease in children. As you can see, the list covers a broad range of therapeutic needs in children.
As you previously stated, Dr. Guttmacher, because of the vast number of gaps, we cannot study them all effectively with limited resources. So over the years, we have developed a well-defined process for prioritization that includes a systematic approach of consultation with working groups of experts in a manageable number of therapeutic areas annually to determine needs in those particular areas. Once the working groups provide us with their recommendations of gaps in their respective areas, the NICHD then incorporates objective measures, such as the level of evidence available in the literature and drug labels, the impact of delivery of care, and consideration of different populations that may benefit from research as key criteria for final prioritization. The first BPCA priority list of off-patent drugs needing further study under the 2002 BPCA legislation was published in January 2003 in the Federal Register. The most recent priority list was published October 26 of 2012; all the Notices and BPCA Priority Lists can be found on the BPCA website:
From the Priority List, then, the Pediatric Trials Network conducts pharmacokinetic, safety, and efficacy trials of drugs that have been prioritized for study.
Dr. Guttmacher: Thank you, Perdita. That really helps understand how the legislation is implemented and how priorities are made. Can you tell us something about the results of some of the specific studies the branch has supported?
Dr. Taylor-Zapata: Absolutely. The Pediatric Trials Network that I mentioned earlier has the capacity to conduct multiple trials in a variety of areas, including areas such as cardiovascular diseases, cancer, infectious diseases, gastroenterology, respiratory diseases, newborn health, and even medical devices.
The Network’s first completed study investigated a drug called metronidazole. It’s an antimicrobial agent frequently given to infants suffering from a disease called necrotizing enterocolitis. The disease, which causes the intestinal lining to die, occurs frequently in premature infants and is often fatal. Metronidazole is an antibiotic that has been approved for adults to treat infections caused by parasites and by certain bacteria. It’s also prescribed for infants with this necrotizing enterocolitis. Other studies in the Pediatric Trials Network are investigating include the use of lisinopril to treat high blood pressure in kidney transplant patients, and the use of hydroxyurea for sickle cell disease in very young children. Lisinopril for example is a drug that’s used and is labeled for use in adults and children greater than 6. Fortunately, the frequency of high blood pressure in children is low. However, there are children who suffer from chronic kidney disease and ultimately require a kidney transplant, and these children need adequate blood pressure control to prevent rejection of their transplant. Because the drug is not labeled for this particular indication, there is no clear information on the proper dose to give children who actually need it. The Pediatric Trials Network has embarked upon a dosing and safety study of this drug in this high-risk group of children.
The hydroxyurea study that I mentioned earlier is a follow-on study to a larger study called BABY HUG study that was conducted in collaboration with the National Heart, Lung, and Blood Institute. The original study evaluated the safety and efficacy of hydroxyurea to prevent complications due to sickle cell disease. One of the difficulties in this trial was the formulation of the drug: it only comes in capsules, and, as you can imagine, it’s very difficult to give a capsule to a 9-month-old to swallow. So we needed to make a special liquid formulation for the research trial. The Pediatric Trials Network is now conducting a study comparing the drug concentrations from the liquid and the capsule formulation of hydroxyurea that is commercially available in children between the ages of 5and 18 years of age in order to determine if the concentrations are similar. These are just a few examples of the research conducted by the PTN.
Dr. Guttmacher: Thank you, Dr. Taylor-Zapata. That is very informative. Our second guest today, Dr. Zhaoxia Ren is a medical officer in the Obstetric-Fetal Pharmacology Research Unit Network within the Branch. The network conducts studies of drugs used during pregnancy and works to develop safe and effective treatments for diseases and conditions in pregnant women. This network also focuses on studying medications that are most commonly used during pregnancy, but as I mentioned have never specifically been tested in pregnant women. Over the last 3 decades, the use of prescription drugs during the first trimester of pregnancy has increased by more than 60 percent. By 2008, approximately 50 percent of women reported taking at least one medication during pregnancy. Women during pregnancy undergo extensive physiological and biochemical changes that may influence how they metabolize certain drugs and how they respond to a drug treatment. Also, of course, various drugs may have important effects on the developing fetus. However as with pediatric populations, very few drugs that are prescribed during pregnancy have been specifically tested in pregnancy. By providing the infrastructure for the necessary studies, the network works to rectify the situation. Dr. Ren, including pregnant women in clinical trials is complex and not without risks of course. However, not treating pregnant women’s health needs is also risky. Can you tell us how the Network approaches its studies of pregnant women to optimize their health and the health of the fetus, while minimizing the risks inherent in testing any drug?
Dr. Zhaoxia Ren: Sure, Dr. Guttmacher. Similar to children, pregnant women are also a special population that is vulnerable to drug toxicity effects. Pregnant women are generally excluded from drug research and new drug development due to technical, ethical, and legal concerns. Currently, the majority of the drugs prescribed by physicians for pregnant women are also used off-label and the usage is largely based on an empirical understanding of drug dosage, safety and efficacy, which may have led to ineffective treatments and unpredictable consequences for both pregnant women and their unborn babies.
To address these concerns and to minimize potential risks for both pregnant women and their unborn babies, the OPRU network has employed a unique approach that combines a group of experts from diverse scientific disciplines working together to determine optimal drug dosing and effectiveness and the safety of medications in pregnant women, and the outcome of their pregnancy. All clinical studies have been carefully designed following regulatory guidelines and the safety of the study participants has been closely monitored by the study team.
Dr. Guttmacher: Zhaoxia, I know that one of the Network studies involve the drug, glyburide, an approved medicine that helps control blood sugar levels for people with type 2 diabetes mellitus. The study tested the drug in pregnant women who have developed gestational diabetes, a form of diabetes that occurs in pregnant women. You found that when given the same dose, the concentration of drug in the blood was lower for pregnant women as compared with non-pregnant women. This might explain why the pregnant women in the study did not respond as well to the oral medication. Can you explain what is happening, why the study found differences in the concentration of the drug in the blood, and what this might mean for treatment?
Dr. Ren: As you, Dr. Guttmacher, mentioned earlier, women during pregnancy undergo many physiological changes such as increased blood volume and changes in drug metabolism by the liver, and elimination by the kidneys. As a consequence, the concentration of the drug within the bloodstream is decreased in pregnant women, so the same dose in non-pregnant patients may be ineffective in pregnant women.
In addition, glyburide is metabolized by two enzymes in the liver. During pregnancy, the activity of those two enzymes are increased, which has led to the glyburide being broken down much faster in pregnant women than that in non-pregnant women. Therefore, to achieve therapeutic effects, there may be a need to increase drug dosage in pregnant women. So, this was the case with glyburide.
Dr. Guttmacher: I see. Dr. Ren, another study involved oseltamivir, the most commonly used prescription medication to treat influenza. Again, this drug hasn’t been tested in pregnant women. You found results similar to those in the glyburide study you just talked about. When treated for influenza with oseltamivir, the pregnant women had significantly lower concentrations of the drug in the blood than non-pregnant women. Again, what does this actually mean for treating patients?
Dr. Ren: This means that using the current dose for treating influenza in pregnant women may not be effective. It also suggests that there may be a need to increase the dose and or dosing frequency to achieve comparable drug concentration and clinical efficacy of the drug in pregnant women.
Dr. Guttmacher: Thank you, Zhaoxia. That brings us to the end of our podcast for this month. I’d like to thank both Dr. Perdita Taylor-Zapata and Dr. Zhaoxia Ren for joining us today and for sharing with us some of their research to improve the safety and efficacy of pharmaceuticals used for infants, children, and pregnant women. I’d also like to thank our podcast listeners for joining us and for your interest in our work here at NICHD.
For more information on any of today’s topics and many related topics, visit www.nichd.nih.gov. That’s www.nichd.nih.gov. I’m Alan Guttmacher, and I hope you will join us for more NICHD podcasts as we post them on our website each month.
Announcer: This has been NICHD Research Perspectives, a monthly podcast series hosted by Dr. Alan Guttmacher. To listen to previous installments, visit nichd.nih.gov/researchperspectives. If you have any questions or comments, please email NICHDInformationResourceCenter@mail.nih.gov.
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