Objective. The International Conference on Harmonisation Steering Committee recommends that appropriate formulations be used in pediatric drug trials. However, a lack of formulation research and/or economic constraints means that appropriate formulations are not always used. It is important for investigators who report the results of pediatric drug trials to provide sufficient information on the formulation and method of administration to ensure that the results can be reproduced in other clinical studies (reliability) and, more important, implemented in clinical practice (validity). The objective of this study was to evaluate whether pediatric formulation information was adequately reported in recent published trials of oral medicines that included children who were younger than 12 years.
Methods. Studies that were published between July 2002 and June 2004 in 10 highly cited journals (5 pediatric and 5 general medicine) were hand-searched and data were extracted independently by 2 reviewers according to a protocol. Papers that reported oral medication studies that included children who were younger than 12 years were classified as containing adequate, some, or no information on drug formulation.
Results. Of 3992 papers reviewed, 76 fulfilled the inclusion criteria. Only 28 (37%) gave adequate information for the study to be reproduced accurately, and 20 (26%) did not state the formulation used. When the formulation was reported, only 37 (49%) studies used a pediatric formulation (liquid, chewable tablet, granules). No significant differences between pediatric and general medical journals were seen, and no single journal consistently met the criteria for adequate information.
Conclusion. Highly cited journals seem to permit inadequate formulation information in pediatric drug trials that they publish, impairing their validity and reliability. Authors should provide full formulation information in all pediatric clinical trial reports.
- clinical trial
- literature review
- child (under 12 years)
- dosage forms
- pharmaceutical preparations
Many children who are younger than 12 years are unable to swallow tablets whole even when given specific training.1 Despite this, children are often given tablets or capsules because of a lack of appropriate pediatric formulations.2 Splitting tablets can cause dose inaccuracies.3,4 Crushing or splitting some tablets, or opening capsules, destroys their release properties3 and can impair bioavailability as a result of chemical instability at varying gastrointestinal pHs. Although the chemical stability of matrix-based tablets may not be affected by crushing,3 the resulting powder is often mixed with food or beverages, potentially affecting drug absorption.5 For dosing accuracy and patient compliance, the International Conference on Harmonisation Steering Committee recommends that appropriate formulations be used in pediatric drug trials.6 Unfortunately, because of a lack of formulation research and/or economic constraints, crushed tablets are often used instead of appropriate liquid formulations in pediatric drug trials. In these situations, subsequent pharmacokinetic studies need to be conducted to demonstrate that this method of administration adequately delivers the drug; otherwise, such trials lack validity and reliability.7 A concept paper entitled “Guidance on Formulations of Choice for the Pediatric Population” produced by the European Medicines Agency suggested that it is necessary to identify the gaps in our knowledge that require additional research on pediatric formulations.8
Published drug trials, particularly in highly cited journals, are important sources of information to inform research and disseminate knowledge to pediatric health professionals.9 For applicability in clinical practice, it is essential that detailed information on drug formulation and administration be provided, especially when the medicine is unlicensed. Systematic review of published drug trials in highly cited journals provides an appropriate starting point to identify evidence gaps in pediatric formulations that are used in clinical trials. Our objective was to evaluate whether pediatric formulation information was reported adequately in recent published trials of oral medicines that included children who were younger than 12 years.
We hypothesized that pediatric clinical drug trials that are reported in highly cited journals would describe full information on the drug formulation used. The 5 most cited journals10 in pediatrics and general and internal medicine categories were chosen; journals that were excluded contained mainly review articles or specialist areas of pediatrics. Included journals were hand-searched to identify papers that were published between July 2002 and June 2004 and reported oral medication studies that included children who were younger than 12 years. The papers were identified and analyzed independently by 2 reviewers (Z.K. and J.S.) according to a protocol. The following data were extracted: drug, formulation, manufacturer, and for tablets/capsules whether there was an account of how the dose was administered. Reports were classified as containing adequate, some, or no information:
Adequate: formulation and manufacturer stated; when formulation was a tablet/capsule, an account of whether children were able to swallow the dose whole or how dose was administered
Some information: formulation or manufacturer stated; when formulation was a tablet/capsule, no account of whether children were able to swallow the dose whole or how dose was administered
No information: no mention of the formulation or the manufacturer
Discrepancies were resolved by both reviewers’ rereading the papers and reaching a consensus. χ2 was used to test the differences between pediatric and general medical journals in the proportion of articles that met the criteria for adequate information.
The 5 general medicine journals were New England Journal of Medicine, Journal of the American Medical Association, Lancet, Annals of Internal Medicine, and British Medical Journal. The 5 pediatric journals were Pediatrics, Pediatric Research, Journal of Pediatrics, Archives of Diseases in Childhood, and Acta Paedatrica. A total of 3992 papers were reviewed; 76 fulfilled the inclusion criteria. Reports were classified as containing adequate, some, or no information (Table 1). Only 46 (61%) of the papers stated the manufacturer of the medication used. No significant difference between pediatric and general medical journals was observed (Pearson χ2P = .92), and no single journal consistently met the criteria for adequate information.
Nineteen (25%) studies used tablets or capsules, but only 5 of these reports stated how the drug was administered. Table 2 gives a detailed analysis of the papers that used tablets or capsules, along with the age range of included patients. Only 1 study (on nelfinavir pharmacokinetics) provided an alternative formulation for children who were unable to swallow whole solid dose forms. Six studies used tablets or capsules and included children who were younger than 4 years yet gave no dose administration information. No paper that described tablet crushing/opening capsules provided pharmacokinetic data or references to show that drug absorption was adequate.
Pediatric drug formulation reporting in recent, highly cited, peer-reviewed journals was largely inadequate. Only 28 (37%) publications provided adequate information for the study to be reproduced accurately, and 20 (26%) did not state the formulation used at all. When the formulation was reported, only 37 (49%) studies used a pediatric formulation (liquid, chewable tablet, granules), suggesting that the International Conference on Harmonisation guidelines6 are often overlooked. That there was no significant difference in the use of an appropriate formulation between pediatric and general medical journals and that no single journal consistently met the criteria for adequate information suggest that inadequate formulation information in pediatric drug trial reports is a widespread problem.
One of the core principles in reporting any scientific research is to provide enough information for the experiment to be repeated (reliability) or transferred into clinical practice. The most surprising result of this study was that highly cited journals did not routinely state the form, manufacturer, and administration details of drugs in drug trials that included children. When this information is not provided, the reliability of any findings is brought into question.7
When the formulation was stated, tablets or capsules were often used without giving any administration details (Table 2). If details of how the drug was administered are given, then pediatricians and pediatric pharmacists will know that by repeating this method, similar results can be expected. However, that none of the papers that described tablet crushing gave any supporting pharmacokinetic data suggests that authors are unaware of the potential impact on bioavailability. The outcomes in such studies lack validity unless data are supplied to show that adequate drug levels are achieved.
The use of excipients (ingredients used to promote physical/chemical/microbial stability and palatability) was not addressed specifically in our study, although it is widely recognized that some can be harmful when given to children.11–14 It therefore is important that the manufacturer be stated so that the formulation and its excipients can be identified. This may facilitate the explanation of any unexpected adverse reactions, and pediatric pharmacists will know where to obtain the product that produced the trial results. Obtaining the same formulation is especially important when the medicine is unlicensed, as unlike licensed preparations, unlicensed preparations are not tested for bioequivalence, meaning that bioavailability can and does differ between different formulations of the same drug.5 It therefore is of some concern that fewer than two thirds of analyzed papers gave the drug manufacturer.
Many published drug trials that included children had doubtful reliability and validity because the amount of drug absorbed was neither tested nor reported. When such studies are published in highly cited journals, it perpetuates the myth that children come to no harm when inappropriate formulations are used. This review should prompt authors and journal editors to provide full formulation information in future pediatric drug trials.
Highly cited journals often provide inadequate formulation information in pediatric drug trials that they publish, impairing their validity and reliability. The reporting of formulation information needs to be improved in future drug trials that include children.
- Accepted April 19, 2005.
- Reprint requests to (I.C.K.W.) Centre for Paediatric Pharmacy Research, 29-39 Brunswick Square, London, WC1N 1AX, UK. E-mail:
Mr Standing is funded by Rosemont Pharmaceuticals as a doctoral student to investigate clinical pharmacology and pharmacokinetics of pediatric analgesics. Dr Wong’s post is funded by a UK Department of Health Public Health Career Scientist Award. Dr Wong has received funding from both public bodies and pharmaceutical companies in formulation research, but none was related to the present study.
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- Copyright © 2005 by the American Academy of Pediatrics