Pediatric Labeling Research Articles

The impact of the written request process on drug development in childhood cancer

The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children. A search of the FDA document archiving, reporting, and regulatory tracking system was performed for January 1, 2000 to December 31, 2010. Drugs were identified and pediatric-specific labeling information was obtained from Drugs@fda.gov and FDA Pediatric Labeling Changes Table. Fifty WRs have been issued for oncology drugs. Pediatric studies have been submitted for 14 drugs. Thirteen received pediatric exclusivity. As of December 31, 2010, labeling changes have been made for 11 drugs. Three drugs were approved for pediatric use. WRs have provided a mechanism to promote the study of drugs in pediatric malignancies. Information from studies resulting from the WRs regarding safety, pharmacokinetics, and tolerability of oncology drugs has been incorporated into pediatric labeling for 11/14 of the drugs. Earlier communication and collaboration between the FDA, National Cancer Institute, clinical investigators, and commercial sponsors are envisioned to facilitate the identification and prioritization of emerging new drugs of interest for WR consideration. Since this is the only regulatory mechanism, resulting from specific legislative initiatives relevant to cancer drug development for children, efforts to enhance its impact on increasing drug approval for pediatric cancer indications are warranted.

Changes to Prescription Drug Pediatric Labeling: Awareness by Practicing Pediatricians.

The US Congress and the US Food and Drug Administration encouraged studies in children so that the labeling information about pediatric use could be updated for pharmaceutical products. Pediatricians receive this updated labeling information through many different sources. A pilot survey was conducted to determine what source pediatricians use to learn about this updated information and whether and when they learned of specific changes. It appears that most pediatricians did not know that there had been recent changes in pediatric drug labels, although changes to drugs that were used more commonly in practice were more likely to be known.

Pediatric News

Pediatric News

Benzonatate Toxicity in a Teenager Resulting in Coma, Seizures, and Severe Metabolic Acidosis

We report a benzonatate overdose in a teenager resulting in life-threatening toxicity to increase awareness of this overdose, and discuss recent pediatric warnings and labeling information provided by the US Food and Drug Administration (FDA). After an overdose of benzonatate, a 13-yr-old female presented to our emergency department with coma, seizures, hypotension, prolonged QT interval on electrocardiogram, and metabolic acidosis. Benzonatate is an antitussive medication with sodium channel-blocking properties and local anesthetic effects on the respiratory stretch receptors due to a tetracaine-like metabolite. Overdose is reported to cause coma, seizures, hypotension, tachycardia, ventricular dysrhythmias, and cardiac arrest. The FDA recently issued a Drug Safety Communication warning that accidental benzonatate ingestion in children younger than 10 years of age have increased risk of death and added the new information to the Warnings and Precautions section of benzonatate's label.

Pediatric Regional Anesthesia

Two articles in this month’s Anesthesia & Analgesia address safety of regional anesthesia and analgesia in pediatrics.1,2 At first glance, one is very reassuring, the other is frightening. In this Editorial, we will recommend a middle ground. Practitioners of pediatric regional anesthesia should be careful and vigilant but can be confident that many types of complications can be made extremely rare by adopting some recommended practice patterns. Over the past 30 years, pediatric applications of postoperative regional anesthesia and analgesia have expanded rapidly.3 There is now a substantial body of studies regarding techniques, pharmacokinetics, and clinical outcomes. Agerelated trends in local anesthetic pharmacokinetics have been characterized, and safe dosing guidelines have been established.4 Most regional anesthesia in adults is performed awake or with doses of sedatives and analgesics that maintain verbal responsiveness, permitting patient reporting of paresthesias, severe pain with needle movement or injection, immediate symptoms of systemic local anesthetic effect, and progression of sensory and motor blockade over the minutes after injections. Textbooks, review articles, and consensus documents often strongly criticize performing most types of major peripheral or neuraxial blocks in adults under deep sedation or general anesthesia.5 In contrast, most, but not all, regional anesthesia in children is performed under either deep sedation or general anesthesia. Advocates of pediatric regional anesthesia have cited a series of retrospective and prospective safety studies to support their contention that the widespread practice of performing regional anesthesia under general anesthesia is safe.6–8 Polaner et al. report on the first 3 years of prospective registry data from PRAN, the Pediatric Regional Anesthesia Network, a consortium of North American pediatric centers. This report has a number of strengths. The data collection and analysis plan was generally thoughtfully constructed. There is a good degree of detail and new information regarding how procedures are performed and regarding most adverse events. The methodology for data gathering is likely to be fairly complete for intraoperative serious adverse events and for events occurring during patients’ inpatient stay. There are several scenarios that could potentially lead to underreporting of peripheral nerve injuries, most notably partial nerve injuries in nonverbal or nonambulatory children that might evade detection by parents and physicians. For example, a thoracic nerve root or an intercostal nerve injury following thoracic epidural or thoracic paravertebral block might not be detected in a preverbal child. In addition, for a patient in a cast, a deficit might not be apparent until days to weeks postoperatively. The methodology for postoperative surveillance in this registry is likely to omit some cases with delayed detection. Despite these possible sources for underreporting, the PRAN investigators make a good case for the overall very good safety of pediatric neuraxial and peripheral blocks as performed by clinicians in these hospitals. In contrast to the conclusion of the PRAN investigators that “nothing really bad happened,” Meyer et al. showed admirable courage and forthrightness in reporting on 4 cases of neurologic injury following epidural anesthesia in children. All 4 cases involve care by experienced anesthesiologists with extensive experience in pediatric epidural analgesia and acute and chronic pain management. Based on the incomplete information available in this case report, we would tend to agree with the authors’ general contention that there was “absence of proof of medical negligence.” A more important question, which the authors have addressed in their discussion, might be phrased as follows: “Based on these cases and other available knowledge, do we have ways to modify our practice to prevent similar complications in the future?” We consider the 4 cases in this light, taking advantage of “20–20 hindsight.” Among the 4 cases, case 1 was perhaps the most frightening, because the patient was healthy and uncomplicated, the epidural catheter placement proceeded uneventfully at a lumbar level below the terminus of the spinal cord, the duration of general anesthesia was short, and there were no hemodynamic clues intraoperatively to raise concerns. The test dose was appropriate (0.1 mL/kg). E EDITORIAL

Drug Development

Drug Development

Pediatric Drug Labeling

Pediatric Drug Labeling

Use of Analgesic, Anesthetic, and Sedative Medications During Pediatric Hospitalizations in the United States 2008

The wide need for analgesia, anesthesia, and sedation in children and the lack of pediatric labeling leads to widespread off-label use of medications for pain and sedation in children. Any attempt to address the lack of labeling will require national estimates of the numbers of children using each medication, their ages, and other factors, to understand the overall use of these medications. We describe use of analgesics, anesthetics, and sedatives in pediatric inpatients by result of conducting a statistical analysis of medication data from >800,000 pediatric hospitalizations in the United States. The purpose was to provide national estimates for the percentage of hospitalized children receiving specific analgesics, anesthetics, and sedatives and their use by age group. Data from the Premier Database, the largest hospital-based, service-level comparative database in the country, were used. We identified all uses of a given medication, selected the first use for each child, and calculated the prevalence of use of specific medications among hospitalized children in 2008 as the number of hospitalizations in which the drug was used per 100 hospitalizations. Dose and number of doses were not considered in these analyses. The dataset contained records for 877,201 hospitalizations of children younger than 18 years of age at the time of admission. Thirty-three medications and an additional 11 combinations were administered in this population, including nonsteroidal antiinflammatory drugs, local and regional anesthetics, opioids, benzodiazepines, sedative-hypnotics, barbiturates, and others. The 10 most frequently administered analgesic, anesthetic, or sedative medications used in this population were acetaminophen (14.7%), lidocaine (11.0%), fentanyl (6.6%), ibuprofen (6.3%), morphine (6.2%), midazolam (4.5%), propofol (4.1%), lidocaine/prilocaine (2.5%), hydrocodone/acetaminophen (2.1%), and acetaminophen/codeine (2.0%). Use changed with age, and the direction of change (increases and decreases) and the type of change (linear, u-shaped, or other) appeared to be specific to each drug. A variety of drug classes and individual medications were used to manage pain and sedation in hospitalized children. The variation in patterns of use reflects the heterogeneity of the dataset, comprising a wide range of ages and conditions in which analgesia, anesthesia, and sedation might be required. It was not possible to assess whether use of a specific medication was clinically appropriate, except to note use of medications in age subgroups without pediatric labeling.

Antihypertensive Drug Use By Children: Are the Drugs Labeled and Indicated?

J Clin Hypertens (Greenwich). 2012; 14:388–395. ©2012 Wiley Periodicals, Inc.As a result of the Food and Drug Administration (FDA) Modernization Act and the Best Pharmaceuticals for Children Act, the number of medications with FDA‐approved pediatric labeling has increased. To assess the success of these initiatives, we examined whether antihypertensive drugs used by children with hypertension in 2008 had FDA‐approved pediatric labeling and indications. Using a nationwide commercial insurer database, 2915 children with primary (n=2607) and secondary (n=308) hypertension were identified. Drug user rate and days of supply were calculated from pharmacy claims. Drugs were categorized based on pediatric labeling and indication and whether they were recommended for pediatric use. Antihypertensive drugs were used by 889 (34%) children with primary hypertension and 200 children (65%) with secondary hypertension. User rates were 44.3% in hypertensive children younger than 6 years, 30.9% in those 6 years to older than 12 years, and 38.1% in those 12 years to older than 18 years. Seven percent of drugs were neither labeled for pediatric use nor considered recommended for use in children. In children younger than 6 years, 29% of drugs used were not indicated for use in that age group. Despite recent legislative initiatives, many drugs used by hypertensive children still lack pediatric labeling. Additional efforts are needed to close the gap between the availability of drugs that are labeled and indicated for pediatric use and actual drug usage in children.

Morphine Use in Hospitalized Children in the United States: A Descriptive Analysis of Data From Pediatric Hospitalizations in 2008

BackgroundMorphine is among the top 10 medications given to children in the inpatient setting. It is not labeled for any pediatric indication, making it one of the drugs most widely used off-label in pediatrics. ObjectivesThe aims of this study were to describe the epidemiology of morphine use in pediatric inpatients in the United States and to describe the characteristics of patients and hospitals in hospitalizations with morphine use. MethodsDeidentified data from the Premier Perspective Database (2008) were analyzed. Morphine use was defined as any morphine administration during the hospital stay and estimated by patient age in years, sex, race, and type of insurance; and hospital bedsize, teaching status, setting (urban or rural), and geographic location. Proportions (95% CI) were calculated for the entire population and for individual strata. The estimate was applied to national data to calculate the number of pediatric hospitalizations with morphine use in the United States in 2008. Logistic mixed-effects modeling was used to calculate the probability of morphine use by hospital after controlling for hospital and patient effects. ResultsThe database contained records from 877,201 pediatric hospitalizations and 423 hospitals in the United States. Morphine was administered in 54,613 of pediatric hospitalizations (6.2%). Use was higher in boys than girls (6.4% and 6.1%, respectively) and in blacks compared with whites or other racial groups (7.5%, 6.7%, and 5.0%). Use increased from 1.6% in children aged <2 years to 27.4% in those aged 12 to 17 years. Based on these data, morphine may have been administered in 476,205 pediatric hospitalizations in the United States in 2008. The 2 diagnoses most frequently associated with morphine use were appendicitis (14.4%) and fracture (11.1%). On logistic mixed-effects modeling for patients with appendicitis and for patients with fractures, there was hospital variation in morphine use after controlling for variables in the model. ConclusionsBased on the data from this analysis, morphine was used in hospitalized children in all age groups, despite the lack of pediatric labeling. Common conditions such as appendicitis and fracture were leading diagnoses associated with morphine use.

Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs

In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation. Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.

Pediatric drug development: unmet medical needs and opportunities for collaboration between industry, academia and the US FDA

The needs and advances in pediatric drug development have burgeoned since Shirkey initially referred to children as ‘therapeutic orphans’ [1]. Owing to requirements and incentives to investigate and develop therapeutic classes of molecules in children, drug development involving pediatric patients has risen steadily. The requirements are the result of the Pediatric Research Equity Act and the incentives are from the Best Pharmaceuticals for Children Act, two pieces of legislation that are set to expire in 2012 [101]. Pediatric Research Equity Act and Best Pharmaceuticals for Children Act have resulted in a total of 335 written requests issued (1998–July 2011), 323 marketing applications approved with postmarketing requirements (through May 2011) and 415 labels changed (1998–July 2011). From a global development perspective, ongoing collaborations between the US FDA and the other regulatory agencies, including the European Medicines Agency, facilitate these advances in pediatric product development. The significant role of personnel exchanges (short-term), working groups between both agencies, European Medicines Agency Non-clinical and Formulations Working Groups and expert meetings and workshops (including FDA representatives) and WHO initiatives, are helping to facilitate critical involvement and participation. Other collaborative networks between global regulatory partners include the Pediatric Regulators Network and Essential Medicines for Children Activities, Japan’s Pharmaceuticals & Medical Devices Agency as observers in the FDA’s and European Medicines Agency’s pediatric collaboration and the FDA and NIH collaboration to develop a publicly available framework on pediatric formulations. One important area for further development is the understanding of biomarkers and surrogate markers and their applications to pediatric clinical trials and drug development. The lack of appropriate parameters for pediatric clinical trials in children with gastrointestinal disease has resulted in the lack of appropriate end point identification and delays in pediatric product development. This is an area that would benefit from earlier attention in the overall development process. A renewed commitment to identify appropriate drug candidates and plan a process for approval for children is needed. Of the total products studied and labeled under US pediatric legislation, drugs with pediatric gastroenterology labeling account for only 8.6% (n = 11). Drug classes studied included treatment of hyper cholesterolemia, inflammatory bowel disease, vomiting, obesity and hepatitis B and C and acid blockade

Pediatric Cardiovascular Drug Development and Research: Integration of Modeling and Simulation as One Future Direction

The integration of the needs of children into the legal drug development process since 1997 in the United States and since 2007 in the European Union has improved health and stimulated innovative approaches in the design of clinical trials and will benefit both current and future populations. According to the US Food and Drug Administration, to date, 394 pediatric labels together with safer medicines and better dosing practices have provided a sound basis for the safer and more effective use of drugs in a pediatric population. This may be measurable with fewer medication errors and perhaps shorter hospital stays in the future. Although relevant data have been generated by clinical trials in pediatric populations, challenges, such as nonefficacy and safety issues, have arisen. Heterogeneity in the physiological maturation and growth processes and differences in the etiology and pathogenesis of disease in patients from birth to 18 years of age may explain these results. The use of cutting-edge technology, such as modeling and simulation of "in silico" pediatric populations, may allow the integration of data from previous trials and experiments into the design of future clinical trials and allow exploration in other areas that have the potential to enhance the outcome of clinical trials in children.

Parental Misinterpretations of Over-the-Counter Pediatric Cough and Cold Medication Labels

Parental Misinterpretations of Over-the-Counter Pediatric Cough and Cold Medication Labels

Oral chelation: Should it be used with young children?

Deferasirox, the only oral iron chelator approved in the US and Canada, achieved a pediatric label indication down to 2 years of age. FDA-mandated post-marketing safety surveillance in children under age 6 is ongoing. We wish to raise a non-safety-related concern with deferasirox chelation in very young children (2-5 years old). Specifically, the circumstances required for reliable daily ingestion of deferasirox do not mesh well with the developmental characteristics common in young children, which may limit adherence and cause parental distress. We review developmental challenges associated with oral chelation in this age group and provide suggestions to improve adherence in this population.

Differences in Pediatric Drug Information Sources Used by General Versus Subspecialist Pediatricians

To describe pediatric labeling information needs and sources of general and subspecialist pediatricians. Study design. Self-administered questionnaire of Fellows of the American Academy of Pediatrics (AAP). The response rate was 48%. Top sources used by pediatricians to obtain pediatric labeling information were journals (86%), pediatric dosage books (84%), AAP News (77%), drug representatives (65%), and PDA-based databases (35%). Generalists were more likely than subspecialists to use AAP News (82% vs 60%; P < .001) and drug representatives (72% vs 41%; P < .001) to obtain prescribing information. Both groups reported that it was most important to have additional prescribing information for mental health and cardiovascular medications. Despite differences in the methods used to obtain pediatric labeling information, generalist and subspecialist pediatricians both prioritized mental health and cardiovascular medications as needing additional prescribing information. Interventions to effectively disseminate new or revised pediatric labeling information to pediatricians should consider using methods identified in this study.

Pediatric Drug Trials

It is well known that there has been a lack of safety data on pediatric use of medications. Only about 25% of the drugs used in children have adequate pediatric labeling information.1 The younger the age group, the less likely it is that adequate information exists. Because of this lack of information, many drugs are used off-label in pediatric practice. This lack of research may lead to unintended problems in pediatric patients. The first is risk of unknown adverse effects. The second is risk of the drug being ineffective, possibly as a result of underdosing.

Index of Suspicion

Index of Suspicion| March 01 2010 Index of Suspicion Author DisclosureDrs Bradley, Adger, Splinter, Leggett, Madan, and Marks have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Pediatr Rev (2010) 31 (3): 117–123. https://doi.org/10.1542/pir.31.3.117 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Index of Suspicion. Pediatr Rev March 2010; 31 (3): 117–123. https://doi.org/10.1542/pir.31.3.117 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsPediatrics In ReviewPediatricsHospital PediatricsNeoReviewsAAP Grand RoundsAAP NewsAll AAP Sites Search Advanced Search Subjects: In Memoriam, Letter from the President, Parent Plus, Pediatric Drug Labeling Update, Seen & Heard Topics: chest x-ray, fatigue, fever, hypoglycemia, hypothermia, induced, hypothermia, natural, omental infarction, tuberculosis, weight reduction, omentum You do not currently have access to this content.

Moral responsibility to attain thorough pediatric drug labeling

Many drugs used in children have not been labeled for pediatric use. While this was the standard for many years, recent regulations and incentives have improved the depth and breadth of pediatric drug labeling. Nonetheless, common pediatric drugs have not been adequately labeled, particularly generic and orphaned drugs and drugs that were approved for one age group but never tested in other age groups. Anesthesiologists have a moral responsibility to encourage government, pharmaceutical companies, and researchers to study drugs in children.

Can we get the necessary clinical trials in children and avoid the unnecessary ones?

Clinical trials are necessary to provide data on the safety, efficacy and optimal use of medicines. In children, data are needed to cover all ages, from newborns to adolescents. Getting the necessary clinical trials performed is required to achieve the goals of the U.S., EU and WHO paediatric medicines initiatives [1]. However, as stated in the EU Paediatric Regulation [2], unnecessary trials should be avoided for obvious ethical reasons. For new medicinal products of therapeutic interest for children, the EU requirement of early submission of a Paediatric Investigation Plan (PIP) for approval by the Paediatric Committee (PDCO), and compliance with the PIP to get the substantial reward/incentive are likely to capture most of the necessary trials being [2] performed. So far the majority of the 122 PIPs approved by the PDCO [3] include a deferral for the studies to be performed after more data become available in adults. However, it is already evident that clinical trials of off-patent products will not be performed in children to the same extent as they will be for the new products. Only 13 (4%) of the 313 PIPs submitted were for off-patent products [3]. When we consider that 70–80% of approved medicines are not labelled for children, and about half of the medicines used for children are off-label, the work ahead is substantial before the necessary clinical trials are performed and paediatric data have been appropriately assessed. Prioritising the medicines to be studied on the basis of children’s needs has proven difficult. It is also uncertain whether the way the EU is funding the study of the prioritised medicines will result in necessary or ‘scientifically interesting’ trials. Much paediatric data on medicines used off-label in children exist but have never been submitted for regulatory assessment and are not included in the product information. The recently published paper of Tafuri et al. in this journal [4] demonstrated that for two of the five proton pump inhibitors (PPI) used in the treatment of GERD in children, much of the necessary clinical evidence already exists and is publicly available. Existing data may also fill at least a significant part of the regulatory requirements for paediatric labelling, which is not necessarily surprising as three of the five products studied are already labelled for children in the U.S. Studying the other two PPIs is hardly necessary. However, as the example of SSRI studies in adolescents’ showed [5], important existing data are not always available, particularly not data from industry-sponsored trials that show negative results for safety or efficacy [5]. The provisions of the EU Paediatric Regulation [2] for making information on all paediatric clinical trials, including results, publicly available and the requirement for the marketing authorisation holders to submit all paediatric studies, including those not in the public domain, for assessment to the competent authority should further help reduce unnecessary duplication of trials. Available data are not always as good as for the PPIs but may still contain important information that should be considered before new clinical trials are planned. Old data, modern understandings of developmental pharmacology and modelling methods combined with clinical experience may be substituted for the learning phase of the learningconfirming cycle of trials to attain the necessary data for safety and efficacy. This approach is currently being tested Eur J Clin Pharmacol (2009) 65:747–748 DOI 10.1007/s00228-009-0675-y