A brief review of pediatric off-label prescribing reveals a need for remedial action. Real and presumed impediments to acquisition of clinical trial data in children are examined. Many impediments are found to lack substantive merit and fail to offer cause for not undertaking pediatric clinical trials. Recent legislative, and Food and Drug Administration (FDA) and National Institutes of Health (NIH) actions, offer remedial measures to increase labeling of drugs for children and thus decrease off-label prescribing prevalent for 30 years.
WilsonJTPragmatic assessment of medicines available for young children and pregnant or breast-feeding women. Basic and Theraueptic Aspects of Perinatal Pharmacology. New York: Raven Press; 1975: 411–421.
3.
GilmanJTGalP.Pharmacokinetic and pharmacodynamic data collection in children and neonates. Clin Pharmacokinet. 1992;23:1–9.
4.
CotéCJKauffmanRETroendleGJLambertGHIs the “therapeutic orphan” about to be adopted?Pediatrics. 1996;118–123.
5.
American Academy of Pediatrics, Committee on Drugs, 1994–1995.Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: Subject review. Pediatrics. 1996;98:143–145.
6.
WilsonJTAn update on the therapeutic orphan. Pediatrics. (In press) 1998.
7.
ShirkeyHCClinical pharmacology in pediatrics. Clin Pharmacol Ther. 1972;13:827–830.
8.
YaffeSJProblems of drug testing in children in the United States. Pediatr Pharmacol. 1983;3:339–348.
WilsonJTStrategies for pediatric drug evaluation: A view from the trenches. Drug Inf J.1996;30(4): 1149–1162.
11.
Specific requirements on content and format of labeling for human prescription drugs; Revision of “pediatric use” subsection in the labeling; Final rule.Federal Register. December 13, 1994;59(238): 64240–64250.
12.
PinaLMCenter ID's top 10 drugs used off-label in out-patient setting. News Along the Pike. FDA Newsletter. 1997;3(1):6–7.
13.
OTC Switch Drugs. AMA Board of Governors Report. 1996.
14.
Over-The-Counter human drugs; Proposed labeling requirements; Proposed rule.Federal Register. February 27, 1997;62(39):9024–9062.
15.
FDA Modernization and Accountability Act of 1997; (PL105–115).
16.
Draft List of Approved Drugs for which additional pediatric information may produce health benefits in the pediatric population.Food and Drug Administration. (Docket No. 98N-0056).
17.
FDA Proposed Rule of Pediatric Labeling.Federal Register. August 15, 1997. Final November 27, 1998.
18.
National Institutes of Health, RFA# HD-93–06 Network of Pediatric Pharmacology Research Units.NIH Guide. November 1992.
19.
National Institutes of Health RFA# HD-98–002 Network of Pediatric Pharmacology Research Units.NIH Guide. November 1997.
20.
American Academy of Pediatrics, Committee on Drugs.Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics. 1995;95:229–237.
21.
American Academy of Pediatrics, Committee on Bioethics 1993–1994.Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;314–317.
22.
Protection of human subjects-proposed regulations on research involving children.Federal Register. July 21, 1978;43:786.
23.
Additional protections for children involved as subjects in research.Federal Register. March 8, 1983;48:114–117.
24.
KauffmanREKearnsGLPharmacokinetic studies in pediatric patients: Clinical and ethical considerations. Clin Pharmacokinet. 1992;23(1):10–29.
25.
BaileyBKleinJKorenG.Noninvasive methods for drug measurements in pediatrics. Pediatr Clin North Am.1997;44(1);15–26.
26.
RaneAWilsonJTClinical pharmacokinetics in infants and children. Clin Pharmacokinet. 1976;1: 2–24.
27.
SheinerLBLuddenTMPopulation pharmacokinetic/dynamics. Ann Rev Pharmacol Toxicol. 1992;32:185–209.
28.
OlkolaKTHamunenKMaunukselaELClinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet. 1995;28(5):385–404.
29.
GilmanJTTherapeutic drug monitoring in the neonate and pediatric age group: Problems and clinical pharmacokinetic implications. Clin Pharmacokinet. 1990;19(1):1–10.
30.
BrownRDHelmsRPickeringBDWilsonJTA new APAP-CR (Acetaminophen Controlled Release Sprinkles) vs children's Tylenol® elixir (Immediate release; IR) in febrile children. Clin Pharmacol Ther. 1998;63(2):192.
31.
Prescription drug advertising: Content and format of the label for human prescription drugs.Federal Register, June 26, 1979;44(124):37434–37467.
32.
FDA Proposed Rule on Pediatric Labeling.Federal Register, August 15, 1997.
33.
HolmerAFNew Medicines in Development of Children. 1997 Survey. Washington, DC: Pharmaceutical Research and Manufacturers of America: 1997.
34.
Drug Information for the Health Care Professional.United States Pharmacopeia Drug Information. 18th Edition.Englewood, CO: Micromedex; 1998.
35.
NielsonJRHandbook of Federal Drug Law.Philadelphia, PA: Lea & Febiger; 1986.
36.
SilvermanWAAndersonDABlancWACrozierDNA difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics. 1956;18:614–624.
37.
SutherlandJMFatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. Am J Dis Child. 1959;97:761–767.
38.
BumsLEHodgemanJECassABFatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med.1959;261:1318–1321.
39.
TaussigH.A Study of the outbreak of phocomelia. JAMA. 1962;180:1106.
40.
MartinGFinbergL.Propylene glycol: A potentially toxic vehicle in liquid dosage form. J Pediatr. 1970;77(5):877–878.
41.
GershanikJBoeclerBEnsleyHMcCloskeySGeorgeW.The gasping syndrome and benzyl alcohol poisoning. N Engl J Med.1982;307(22):1384–1388.
42.
BrownWIBuistNRMGipsonHTFatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1:1250–1251.
43.
LovejoyFHFatal benzyl alcohol poisoning in neonatal intensive care units. A new concern for pediatricians. Am J Dis Child. 1982;136:974–975.
44.
GlasgowAMBoeckxRLMillerMKMacDonaldMGGilbertPAGoodmanSIHyperosmolality in small infants due to propylene glycol. Pediatrics. 1983;72:353–355.
45.
MacDonaldMGGetsonPRGlasgowAMMillerMKBoeckxRLJohnsonELPropylene glycol: Increase incidence of seizure in low birth weight infants. Pediatrics. 1987;79:622–625.
46.
Unusual syndromes with fatalities among premature infants: Association with a new intravenous vitamin-E product.MMWR. 1984;33:198.
47.
LorchVMurphyMDHoerstenLRHarrisEFitzgeraldJSinhaSNUnusual syndrome among premature infants: Association with a new intravenous Vitamin-E product. Pediatrics. 1985;75:598–602.
48.
BoveKEKosmetatosNEdigKEFrankDJWhitlatchSVasculopathic hepatotoxicity associated with E-Ferol syndrome in low-birth-weight infants. JAMA. 1985;254:2422–2430.
49.
BalistreriWFFarrellMKBoveKELessons from the E-Ferol tragedy. Pediatrics. 1986;78:503.
50.
RobertsRJKnightMEPharmacology of vitamin-E in the newborn. Clin Perinatol. 1987;14(4):843–855.
51.
KorenGGoreskyGCreanPKleinJMacLeodSMUnexpected alterations in fentanyl pharmacokinetics in pediatric patients undergoing cardiac surgery: Age related or disease related?Dev Pharmacol Ther. 1986;9:183–191.
52.
GauntlettISFisherDMHertzkaREKuklsESpellmanMJRudolphC.Pharmacokinetics of fentanyl in neonatal humans and lambs: Effects of age. Anesthesiology. 1988;69:683–687.
53.
KauffmanREFentanyl, fads, and folly: who will adopt the therapeutic orphans?J Pediatr. 1991;119: 588–589.
54.
McCloskeyJJHaunSEDeshpandeJKBupivacaine toxicity secondary to continuous caudal epidural infusion in pediatric patients. Anesth Analg. 1992;75:287–290.
55.
AgarwalRGutlovePLockhartCHSeizures occurring in pediatric patients receiving continuous infusion of bupivacaine. Anesth Analg. 1992;75:284–286.
56.
MevorachDLPerkinsFMIsaacsonSABupivacaine toxicity secondary to continuous caudal epidural infusion in pediatric patients. Anesth Analg. 1993;77:1305–1306.
57.
HillerAOlkkolaKTIsohanniPSaarnivaaraL.Unconsciousness associated with midazolam and erythromycin. Br J Anesth. 1994;65:826–828.
58.
OskiFA, Ed. Principles and Practice of Pediatrics. 2nd Edition. Philadelphia, PA: J.B. Lippincott Co., 1994; 864.
59.
Lloyd-StillJDEditorial: Cystic fibrosis and colonic strictures. A New “Iatrogenic Disease. J Clin Gastroenterol. 1992;21(1):2–5.
60.
SuchyFJBalistreriWFBuchinoJJBatesSRKearnsGLStullJDAcute hepatic failure associated with the use of sodium valproate. N Engl J Med.1979;300(17):962–966.
61.
KearnsGLPharmacogenetics and development: Are infants and children at increased risk for adverse outcomes?Curr Opin Pediatr. 1995;7:220–233.
62.
TruitEBCarrCJBubertHMKrantzJCDetermination of theophylline blood levels. Pharmacol & Exper Therap. 1947;91:185–193.
