Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Paediatric clinical trials: redressing the imbalance

Nature Reviews Drug Discovery volume 2, pages 949–961 (2003)Cite this article

Key Points

  • Only a minority of drugs receive labelling for paediatric use; even fewer receive labelling for use by neonates and infants.

  • With so few medications containing adequate labelling information to guide use, off-label prescribing — including use for unapproved indications, or a different age group, dosage, frequency or route of administration — has been an accepted practice.

  • Off-label use is not just a theoretical problem, but equates to an increase risk of harm. Children receive ineffective doses of potentially effective medications and are harmed by medications that might not be effective for their conditions.

  • This article discusses the key issues in paediatric drug development, and the impact of initiatives to encourage clinical trials that provide information sufficient to guide the use of drugs in children, which have resulted in considerable progress in the past five years.

Abstract

Compared with the quantity and quality of information available for adults, the data guiding the dosing, efficacy and safety of medications for children have lagged substantially. This is ironic, because tragedies that primarily involved children spurred the passage of the major pieces of legislation that govern the development of drug products. Clinicians faced with the prospect of confining their practice to medications with adequate information have frequently resorted to prescribing drugs for unapproved uses (different dose, frequency, age group, route, indication or formulation). Although a long time in coming, the past six years, particularly in the United States, have witnessed a new era in drug development for children — an era that is still in its infancy, but which is now showing signs of maturation. This paper will review some of the history and current progress in paediatric drug development, with an emphasis on the developments in the United States, and will examine some of the current controversies and prospects for future progress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. The Federal Food, Drug and Cosmetic Act of 1938: 52 Stat. 1040 et seq. Vol as amended (21 U.S.C. 301–392) (1939).

  2. Harris-Kefauver Amendments. 21 USC 301–394780 (1962).

  3. Shirkey, H. C. Therapeutic orphans. J. Pediatrics 72, 119–120 (1968).

    Article  CAS  Google Scholar 

  4. Wilson, J. T. in Basic and Therapeutic Aspects of Perinatal Pharmacology (eds Morselli, P., Garattini, M. & Sereni, F.) 411–421 (Raven, New York, 1975).

    Google Scholar 

  5. Gilman, J. & Gal, P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. A quiet frontier. Clin. Pharmacokinet. 23, 1–9 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Wilson, J. T., Kearns, G. L., Murphy, D. & Yaffe, S. J. Paediatric labeling requirements: implications for further studies. Clin. Pharmacokinet. 26, 308–325 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. The Pediatric Exclusivity Provision. January 2001 Status Report to Congress: US Food and Drug Administration (2001).

  8. 21 CFR Parts 201, 312, 314 and 601. Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients. Final Rule. Federal Register 63, 66632–66672 (1998).

  9. Henney, J. in Rational Therapeutics for Children. (ed. Yaffe, S. J.) 8–13 (National Academy Press, Washington, 1999).

    Google Scholar 

  10. Collier, J. Paediatric prescribing: using unlicensed drugs and medicines outside their licensed indications. Br. J. Clin. Pharmacol. 48, 5–8 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berlin, C. et al. Uses of drugs not described in the package insert (off-label uses). Pediatrics 110, 181–183 (2002).

    Article  Google Scholar 

  12. Conroy, S. et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ 320, 79–82 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 't Jong, G. W. et al. Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands. Eur. J. Clin. Pharmacol. 58, 293–297 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Coté, C. J. et al. Comparison of three doses of a commercially prepared oral midazolam syrup in children. Anesth. Analg. 94, 37–43 (2001).

    Article  Google Scholar 

  15. Schreiner, M. S. & Greeley, W. J. Pediatric clinical trials: shall we take a lead? Anesth. Analg. 94, 1–3 (2002).

    PubMed  Google Scholar 

  16. 't Jong, G. W. et al. A survey of the use of off-label and unlicensed drugs in a Dutch children's hospital. Pediatrics 108, 1089–1093 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. O'Donnell, C. P., Stone, R. J. & Morley, C. J. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics 110, e52 (2002).

    Article  PubMed  Google Scholar 

  18. Lifshitz, M. et al. Unapproved prescription practices in primary care clinics in Israel: a prospective analysis. Curr. Ther. Res. 63, 830–837 (2002).

    Article  Google Scholar 

  19. Bücheler, R. et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ 324, 1311–1312 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lazarou, J., Pomeranz, B. & Corey, P. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. JAMA 279, 1200–1205 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. To Err is Human: Building a Safer Health System (Institute of Medicine, Committee on Quality of Health Care in America, Washington, 1999).

  22. Kaushal, R. et al. Medication errors and adverse drug events in pediatric inpatients. JAMA 285, 2114–2120 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Turner, S., Nunn, A. J., Fielding, K. & Choonara, I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr. 88, 965–968 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Horen, B., Montastruc, J. L. & Lapeyre-Mestre, M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br. J. Clin. Pharmacol. 54, 665–670 (2002). Many recent surveys have documented the extent of off-label drug prescribing for pediatric patients. This paper demonstrated that this practice translates into preventable harms.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Boos, J. Off label use — label off use? Ann. Oncol. 14, 1–5 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. American Academy of Pediatrics Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60, 91–101 (1977).

  27. Food and Drug Administration. Labeling and prescription drug advertising: content and format of labeling for human prescription drugs. Federal Register 44, 37434–37467 (1979).

  28. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; revision of 'pediatric use' subsection in the labeling. Federal Register 59, 64240–64250 (1994).

  29. Guidance for Industry. The Content and Format for Pediatric Use Supplements. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) [online], (cited 20 July 2003) <http://www.fda.gov/cder/pediatric/> (1996).

  30. Food and Drug Modernization Act of 1997. 105th Congress edn. (1997).

  31. Guidance for Industry. Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug and Cosmetics Act. US Department of Health and Human Services, Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/cder/pediatric/> (1996).

  32. 21 CFR Parts 201, 312, and 601 Pediatric Patients; Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of new Drugs and Biological Products; Proposed Rule. Federal Register. 62, 43900–43916 (1997).

  33. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Government Printing Office, Washington, 1979).

  34. Clinical Investigation of Medicinal Products in the Pediatric Population. ICH Harmonised Tripartite Guideline [online], (cited 20 July 2003) <http://www.ich.org/pdfich/e11step4.pdf> (1996).

  35. Association of American Physicians and Surgeons, Inc., et al. v. United States Food and Drug Administration, et al.: United States District Court for the District of Columbia; 2002.

  36. Heinrich, J. Pediatric drug research. substantial increase in studies of drugs for children, but some challenges remain. US General Accounting Office; May 8, 2001. GAO-01–705T.

  37. Finkel, J. C. et al. An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children. Anesth. Analg. 94, 1469–1473 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Rose, J. B. et al. Oral tramadol for the treatment of pain of 7–30 days' duration in children. Anesth. Analg. 96, 78–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Roberts, R., Rodriguez, W., Murphy, D. & Crescenzi, T. Pediatric drug labeling: improving the safety and efficacy of pediatric therapies. JAMA 290, 905–911 (2003). This article underscores the overall success and many important lessons learned from the first several years of experience at the FDA following the passage of the FDAMA and promulgation of the 1998 Final Rule. The data reinforce the need to continue the effort to include prescribing information for paediatric patients on the label.

    Article  PubMed  Google Scholar 

  40. Smith, D., Dempster, C., Glanville, J., Freemantle, N. & Anderson, I. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepresants: a meta-analysis. Br. J. Psychiatry 180, 396–404 (2002).

    Article  PubMed  Google Scholar 

  41. Clinical Review for NDA 20–151. Supplement SE5-024. Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/cder/foi/esum/2003/20151se5-024BPCA.pdf> (2003).

  42. Pediatric exclusivity labeling changes as of June 30, 2003. US Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/cder/pediatric/labelchange.htm> (2003).

  43. GSK discussing Paxil pediatric suicide link with FDA; label change in U. K. The Pink Sheet 65, 23 (2003).

  44. FDA Statement Regarding the anti-depressant Paxil for Pediatric Population. US Food and Drug Adminsitration [online], (cited 24 July 2003) <http://fda.gov/bb/topics/answers/2003/ANS01230.html> (2003).

  45. Braunholtz, D., Edwards, S. & Lilford, R. Are randomized clinical trials good for us (in the short term)? Evidence of a 'trial effect'. J. Clin. Epidemiol. 54, 217–224 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Schmidt, B., Gillie, P., Caco, C., Roberts, J. & Roberts, R. Do sick newborn infants benefit from participation in a randomized clinical trial? J. Pediatr. 134, 151–155 (1999). Although the focus of many papers is on the risks inherent in clinical trials, this is one of several recent papers that provides evidence of a trial benefit for participants. What is unique about this paper is that the participants were neonates.

    Article  CAS  PubMed  Google Scholar 

  47. Lantos, J. D. The 'inclusion benefit' in clinical trials. J. Pediatr. 134, 130–131 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Steinbrook, R. Testing medications in children. N. Engl. J. Med. 347, 1462–1470 (2002). An excellent recent review article of paediatric drug trials.

    Article  PubMed  Google Scholar 

  49. O'Donnell, P. EU pediatric rules 'creeping like snail'. Appl. Clin. Trials 12, 22–26 (2003).

    Google Scholar 

  50. Ceci, A. et al. Medicines for children licensed by the European Agency for the Evaluation of Medicinal Products. Eur. J. Clin. Pharmacol. 58, 495–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Best Pharmaceuticals for Children Act. 107th Congress edn. (2001).

  52. Ackerman, T. F. Balancing moral principles in federal regulations on human research. IRB 14, 1–6 (1992).

    Article  PubMed  Google Scholar 

  53. Huston, P. & Peterson, R. Withholding proven treatment in clinical research. N. Engl. J. Med. 345, 912–913 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Landow, L. Current issues in clinical trial design: superiority versus equivalence studies. Anesthesiology 92, 1814–1820 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Temple, R. & Ellenberg, S. S. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann. Intern. Med. 133, 455–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Bristol, D. Clinical equivalence. J. Biopharm. Stat. 9, 549–561 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Ware, J. & Antman, E. Equivalence trials. N. Engl. J. Med. 337, 1159–1161 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Djulbegovic, B. & Clarke, M. Scientific and ethical issues in equivalence trials. JAMA 285, 1206–1208 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Clinical Review for NDA 20-151. Supplement SE5-024. Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/cder/foi/esum/2003/20151se5-02BPCA.pdf> (2003).

  60. Tramer, M. R., Reynolds, D. J. M., Moore, R. A. & McQuay, H. When placebo controlled trials are essential and equivalence trials are inadequate. BMJ 317, 875–880 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Choice of Control Group in Clinical Trials. ICH Harmonised Tripartite Guideline [online], (cited 29 July 2003) <http://www.ich.org/pdfich/e10step4.pdf> (2000). The choice of control group is often the most contentious issue in paediatric trials and the use of placebo is often frowned upon. This guideline provides an overview of the advantages and disadvantages of various trial designs from a regulatory perspective.

  62. Medical Review for NDA No.:19-915 (S-037). Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/cder/foi/esum/2003/19915s037BPCA.pdf> (2003).

  63. Redmon, R. How can children be respected as 'ends' yet still be used as subjects in non-therapeutic research? J. Med. Ethics. 12, 77–82 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Protection of Human Subjects — Title 45 Code of Federal Regulations Part 46, Revised June 18, 1991 [online], (cited 20 July 2003) <http://www.nih.gov:80/grants/oprr/humansubjects/45cfr46.htm> (1991).

  65. 21 CFR Part 56 — Institutional Review Boards. US Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/oc/ohrt/irbs/appendixc.html> (1998).

  66. 21 CFR Part 50 — Protection of Human Subjects. US Food and Drug Administration [online], (cited 20 July 2003) <http://www.fda.gov/oc/ohrt/irbs/appendixb.html> (1998).

  67. FDA Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee's November 15, 1999 Meeting [online], (cited 20 July 2003) <http://www.fda.gov/cder/pediatric/#advisory> (2000).

  68. Administration FaD. Additional safeguards for children in clinical investigations of FDA-regulated products. Federal Register 66, 20589–20600 (2001).

  69. Ross, L. R. Do healthy children deserve greater protection in medical research. J. Pediatr. 142, 108–112 (2003).

    Article  PubMed  Google Scholar 

  70. Janofsky, J. & Starfield, B. Assessment of risk in research on children. J. Pediatr. 98, 842–846 (1981).

    Article  CAS  PubMed  Google Scholar 

  71. Kopelman, L. Moral problems in assessing research risk. IRB 22, 3–6 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Miller, P. B. & Weijer, C. Moral solutions in assessing research risk. IRB 22, 6–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Freedman, B., Fuks, A. & Weijer, C. In loco parentis: minimal risk as an ethical threshold for research upon children. Hastings Cent. Rep. 23, 13–19 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. Ethical and Policy Issues in Research Involving Human Participants Vol 1 (National Bioethics Advisory Commission, Bethesda, 2001).

  75. Administration FaD. Protection of human subjects: categories of research that may be reviewed by the Institutional Review Board (IRB) through an expedited review procedure. Federal Register 63, 60353–60356 (1998).

  76. Freedman, B. Equipoise and the ethics of clinical research. N. Engl. J. Med. 317, 141–145 (1987).

    Article  CAS  PubMed  Google Scholar 

  77. Food and Drug Administration: additional safeguards for children in clinical investigation of FDA-regulated products. Federal Register 66, 20589–20600 (2001).

  78. Wendler, D., Shah, S., Whittle, A. & Wilfond, B. Non-beneficial research with individuals who cannot consent: is it ethically better to enroll healthy or affected individuals. IRB 25, 1–4 (2003).

    Article  PubMed  Google Scholar 

  79. Williams, P. C. Ethical principles in federal regulations: the case of children and research risks. J. Med. Philos. 21, 169–186 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. American Academy of Pediatrics Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 95, 286–294 (1995).

  81. Meetings of the Subcommittee. November 15–16, 1999 Transcripts. Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee [online], (cited 29 July 2003) <http://www.fda.gov/ohrms/dockets/ac/cder99t.htm#Anti-InfectiveDrugs> (1999).

  82. Wendler, D., Rackoff, J. E., Emanuel, E. J. & Grady, C. The ethics of paying for children's participation in research. J. Pediatr. 141, 166–171 (2002). The authors' proposal brings rationale and common sense to a difficult topic: payment for paediatric research subjects.

    Article  PubMed  Google Scholar 

  83. Dickert, N. & Grady, C. What's the price of a research subject? Approaches to payment for research participation. N. Engl. J. Med. 341, 198–203 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Fernhoff, P. M. Paying for children to participate in research: a slippery slope or an enlightened stairway? J. Pediatr. 141, 153–154 (2002).

    Article  PubMed  Google Scholar 

  85. Weise, K. L., Smith, M. L., Maschke, K. J. & Copeland, H. L. National practices regarding payment to research subjects for participating in pediatric research. Pediatrics 110, 577–582 (2002).

    Article  PubMed  Google Scholar 

  86. Pediatric Studies Breakdown Report for Issued Written Requests. US Food and Drug Administration [online] (cited 20 July 2003) <http://www.fda.gov/cder/pediatric/breakdown.htm> (2003). These frequently updated statistics are just one of many valuable resources available on the FDA's pediatric page ( http://www.fda.gov/cder/pediatric ). The page also has — among other resources — recent presentations, minutes from meetings and updated guidance documents.

Download references

Author information

Authors and Affiliations

  1. Children's Clinical Research Institute, 3535 Market Street, Suite 1200, Philadelphia, 19104, Pennsylvania, USA

    Mark S. Schreiner

Authors
  1. Mark S. Schreiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Institute of Medicine

Institute of Medicine Meeting on Clinical Research Involving Children

National Institute of Child Health and Human Development

Glossary

DELTA

The difference in response rate or mean response between two treatments beyond which the treatments will be declared not equivalent. Differences of less than delta are consistent with the hypothesis of the equivalence of the two treatments.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schreiner, M. Paediatric clinical trials: redressing the imbalance. Nat Rev Drug Discov 2, 949–961 (2003). https://doi.org/10.1038/nrd1253

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1253

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing