Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies

Office of Counter-Terrorism and Pediatric Drug Development, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Md 20855, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 09/2003; 290(7):905-11. DOI: 10.1001/jama.290.7.905
Source: PubMed

ABSTRACT Approximately 50% to 75% of drugs used in pediatric medicine have not been studied adequately to provide appropriate labeling information. In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA), which encouraged pediatric drug development by providing an incentive in the form of additional marketing exclusivity.
To identify new drug labeling information from pediatric studies submitted to the FDA in response to written requests.
Between July 1998 and April 1, 2002, the FDA requested studies on 242 drugs, and 53 drugs were granted exclusivity. As of January 2003, 49 drugs have new labels. Data from the studies of the first 33 drugs with new pediatric information on the label as of April 2002 are included. Significant labeling information was analyzed along with baseline data and types of studies requested.
Safety data and pediatric information for labeled drugs.
There were 53 studies for 33 drug products, 12 (23%) were evaluated for safety only; 23 (43%), safety and efficacy; and 18 (34%), pharmacokinetics and/or pharmacodynamics. Significant new dosing and/or safety information was identified for 12 (36%) drugs. New dosing information was determined for 7 of these drugs. Safety information was defined for gabapentin, propofol, sevoflurane, the combination of ribavirin and interferon alfa-2b, and various betamethasone-containing dermatologic preparations. There was a higher percentage of deaths reported with patients who received propofol compared with controls in the pediatric intensive care unit. Seizures were seen in patients administered sevoflurane. Patients receiving a combination of ribavirin and interferon alfa-2b experienced an increased incidence of suicidal ideation when compared with adults. An unexpectedly high percentage of those receiving betamethasone-containing dermatologic preparations had documented hypopituitary-adrenal axis suppression.
The FDAMA has stimulated pediatric clinical studies resulting in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine, important dose changes, and improved safety for children taking certain drugs.

Download full-text


Available from: William Rodriguez, Aug 12, 2015
  • Source
    • "The assumption that children respond similarly to adults with respect to disease pathophysiology, medication efficacy, and adverse reactions is often erroneous [1]. It is largely known that the developing central nervous system (CNS) is qualitatively different from the adult nervous system, as the latter represents the final result of a complex ontogenetic process that requires various steps of cellular proliferation, angiogenesis, migration, synaptogenesis, differentiation , and myelination [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood.
    International Journal of Endocrinology 09/2014; 2014:282489. DOI:10.1155/2014/282489 · 1.52 Impact Factor
  • Source
    • "In the interest of safety, conservative dosing is warranted in initial adolescent pharmacotherapy studies (Roberts et al., 2003). Therefore, we undertook this initial double-blinded, outpatient, within-participant study to determine the tolerability of oral THC (0, 2.5, 5, 10 mg) in a group of older adolescents with marijuana use disorders. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The tolerability and effects of oral Delta9-tetrahydrocannabinol (THC) have been previously investigated in adult marijuana abusers. However, no studies have included adolescent participants. This double-blind laboratory study investigated the tolerability and effects of oral THC in a group of older adolescents with marijuana use disorders. Eight participants (ages 16-21 years), smoking an average of 5.2 days/week and 2.5 "joints"/day, completed this four-session study, during which they received one of four oral THC doses (0, 2.5, 5, 10 mg) each session. Administration of oral THC doses was counterbalanced across participants. During each session, participants completed the Digit-Symbol Substitution Task (DSST) and subjective-effect ratings at baseline and 1, 2, and 3 h after oral THC administration. Oral THC (5 mg and 10 mg) increased several "positive" subjective-effect ratings (e.g., "Good Drug Effect"), while producing no significant effects on cardiovascular measures, DSST performance, or "negative" subjective-effect ratings. These results indicate that oral THC was well tolerated and suggest further study of this medication in adolescent marijuana abusers.
    Pharmacology Biochemistry and Behavior 11/2008; 91(1):67-70. DOI:10.1016/j.pbb.2008.06.011 · 2.82 Impact Factor
  • Source
    • "The present off-label use of drugs in hundreds of thousands of children without the knowledge of efficacy and risks involved is worrisome and raises several ethical issues. (Roberts, Rodriguez et al. 2003) The situation poses an even greater risk to neonates in that the off-label use of drugs during this critical period of development also may be associated with a fetal programming effect.(Barker 2004) The question, then, arises: Should society accept randomized clinical trials (RCT) involving drugs used off-label in a finite number of neonates rather than continue the use of drugs in neonates without full knowledge of their safety, pharmacokinetics, or efficacy? "
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of drugs for indications unapproved by the Food and Drug Administration (FDA), often called "off label use, "is widespread in children, including neonates. The widespread off-label use of drugs in neonates presents ethical and safety challenges. Since the passage of the Best Pharmaceuticals for Children Act (BPCA) in 2002, both the FDA and National Institutes of Health (NIH) have taken initiatives to facilitate and encourage research to achieve the necessary labeling for drugs routinely used in infants and children. Federal regulations provide broad rules and guidance for the protection of human subjects in research. However, there are ethical issues that a physician may face when designing clinical trials of drugs in neonates that are routinely used off-label and widely believed to be beneficial. We attempt to describe these ethical challenges and provide recommendations, including alternative study designs, to resolve them in an ethical framework that takes into account the Belmont Report, the statement of the World Medical Association (WMA), and federal regulations.
    Accountability in Research 07/2008; 15(3):168-87. DOI:10.1080/08989620802194392 · 0.72 Impact Factor
Show more