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Inappropriate oral formulations and information in paediatric trials
  1. Sreenivas Pandit2,
  2. Utpal Shah3,
  3. Daniel Jon Kirby4,
  4. Tony Nunn5,
  5. Catherine Tuleu1
  1. 1Department of Pharmaceutics and Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, UK
  2. 2Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, London, UK
  3. 3Alder Hey Children's NHS Foundation Trust and School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
  4. 4Medicines Research Unit, School of Life and Health Sciences, Aston University, Birmingham, UK
  5. 5Alder Hey Children's NHS Foundation Trust and NIHR Medicines for Children Research Network, Liverpool, UK
  1. Correspondence to Dr Catherine Tuleu, Department of Pharmaceutics and Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX UK; catherine.tuleu{at}pharmacy.ac.uk

Abstract

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children <12 years reported in the same journals. Studies published between 2004 and 2008 were hand-searched and classified as containing adequate, some or no formulation information. Those involving solid dosage forms were further analysed. Only 31% (44/140) of publications provided adequate information, 5% less compared to 2002–2004 (28/76). There was a significant 12% rise (p<0.05) of no formulation information at all (37/140) and in tablets/capsules use (53/140), of which 3/4 gave no administration details, even for those under 6 years old, but a 12% decline in suitable paediatric formulations use (52/140 compared to 37/76). Contrary to expectations, overall quality of formulation information reported markedly deteriorated, jeopardising validity of clinical outcomes. The situation may reflect continued lack of awareness among investigators and other stakeholders of the importance of using suitable age-appropriate formulations.

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Important parameters for acceptability and suitability of a paediatric medicine include route of administration, type of dosage form, taste, appropriate strength and safety of excipients. If any of these parameters are inappropriate, it often results in administration difficulty, modification of the dosage form to allow accurate/acceptable administration, increased risk of dose error, lack of efficacy or even toxicity. Thus, authors reporting clinical trials need to give complete pharmaceutical details to allow post trial application in clinical settings. Standing et al explored the quality of formulation information in paediatric clinical trials in 10 highly cited journals from July 2002 to June 2004 and found this to be lacking.1 In light of the standards expected under developing paediatric regulations to provide better formulations for children worldwide, the aim of this work was to assess if papers published between 2004 and 2008 provided adequate or better formulation information when oral dosage forms were used in paediatric clinical trials prior to regulatory implementation in Europe (January 2007).2

Methods

Standing et al methodology was scrupulously followed. The same journals were included and hand searched to identify clinical trials with oral medications used in children <12 years published in the same 10 journals between July 2004 and June 2008, wherein drug, formulation, manufacturer and administration details were extracted and classified as follows:

  • ▶. Adequate: formulation and manufacturer stated; when formulation was tablets/capsules, whether children were able to swallow or how the dose was administered.

  • ▶. Some information: formulation or manufacturer stated; when formulation was a tablet/capsule, no details of how the dose was administered.

  • ▶. No information: no mention of the formulation or the manufacturer.

The manufacturer was considered to be “unclear” when the study was sponsored by a company, but it was not clear that they supplied the medication.

A detailed analysis of papers reporting the use of solid dosage forms was undertaken in order to scope types, administration details and age ranges of enrolled patients.

Results

One hundred and forty articles met the inclusion criteria. Results were compared to those of Standing et al (table 1) and the χ2 statistic applied with a significance level of p<0.05 throughout. There was a significant increase in articles that did not provide any formulations information counterbalanced by a non-significant decrease in the percentage of studies that provided adequate information and those that provided only some information.

Table 1

Percentage of articles publishing details on the formulation used (formulation information, formulation type, administration details and manufacturer) during 2002–2004 (adapted from 1) and 2004–2008

Fifty-three of the 140 studies used tablets/capsules, corresponding to a significant increase, of which a quarter (13/53) only reported administration details (figure 1), similarly to the 2002–2004 period (5/19). There was a noticeable decline in use of appropriate paediatric formulations such as liquids, chewable tablets and granules (table 1).

Figure 1

Type of solid dosage form administered as the function of the age of the patients (<6 years or >6 years) and whether administration details were provided in paediatric clinical studies (n=53) published in 10 highly cited journals during 2004–2008 (MR=Modified Release, ∼=no details/considered immediate release).

Quantitative data analysis of stated administration details for solid dosage forms (figure 1) revealed that tablets were crushed and mixed with administration vehicles ranging from water, breast milk, fruit juice, chocolate syrup to Ora-sweet (a pharmaceutical vehicle) or concomitant syrup medication. Some powders, granules and crushed tablets were filled into capsules.

Five studies used modified (extended) release tablets or capsules, one of which included 3-month-old babies without providing any administration details. In one study, results from patients unable to swallow tablets had to be excluded. Four studies mentioned that the dose was re-administered within 30 min of patients vomiting. A tenth (5/53) of the studies using monolithic dosage forms (tablets, capsules) included narrow therapeutic index drugs, but only two studies provided administration details.

Compared to 2002–2004, there were non-significant differences in papers that stated the manufacturer and that did not state the manufacturer (in a ∼1/1 ratio), but a significant increase (14/140) of the studies in which the manufacturer was unclear (table 1).

Discussion

It was anticipated that, following the Standing et al publication,1 there would be an improvement in the quality of formulation information in published paediatric clinical trials of oral medications. Instead, there is a continuous trend of lack of appropriate reporting of dosage forms used in many peer-reviewed journals.3 This review suggests a deterioration which perpetuates questions already raised about the validity and reliability of the outcomes of these studies.4

A European Medicines Agency's reflection paper gave an indication of the ability or preference of children to take different dosage forms.5 It states that children aged <8 years are less likely to swallow tablets or capsules. Trial designers should consider age-appropriateness of formulations in relation to capability, illness (acute/chronic), parent/care giver convenience, childcare and school attendance.

Oral liquids were not the most commonly used dosage form despite being considered to be more appropriate for children, as they provide dose flexibility and can be swallowed by most age groups. However, they often require substantially larger amounts of excipients to ensure stability and palatability. Neonates and infants may not be able to metabolise/eliminate an excipient due to immature renal and hepatic functions. The lack of safety and stability data and inclusion of excipients with elevated toxicological risks might hinder the advantages of liquid formulations, and their use in different paediatric age groups needs to be assessed first.

Although solid dosage forms are more stable than liquids, the major disadvantage is inflexible dosing in relation to age and body weight. When a solid is the only available dosage form, it would be beneficial to screen at recruitment if eligible children could swallow the dosage form.

Worryingly, tablets and capsules use increased while, although non-significant, the use of more suitable formulations decreased. Almost 70% of the studies using tablets/capsules involved children under 6 years old. It is extremely important, particularly when the dosage form may have to be manipulated, to restrict the influence administration could have on intra- and inter-individual variations. There is a high probability that monolithic dosage forms were manipulated in some way in trials involving younger children (eg, cutting/splitting/crushing). This can affect dose accuracy, dissolution profile and drug integrity, all of which can, in turn, affect bioavailability. Similarly, if a formulation is mixed in beverages/food, the dose accuracy, reproducibility and physicochemical stability issues should be considered in these vehicles, with in-use stability and compatibility investigated prior to commencing the trial. The lack of supporting data in the published trials suggests that investigators were not aware or ignored such bioavailability issues. This is especially important for narrow therapeutic index drugs, as relatively small changes in systemic concentrations lead to marked changes in pharmacodynamic response.

Stating manufacturers is important. Unless proven bioequivalent, similar formulations but with different excipients can result in differing therapeutic effects.

These findings highlight that not much has changed since 2004.1 While new regulations are being implemented to ensure better medicines for children,2 poor design and information regarding formulation aspects of clinical trials are compromising their very purposes and outcomes.

Conclusions

After the Standing et al publication, an improvement in the quality of formulation information for oral medications in paediatric clinical trials published in highly cited journals was expected. This was not the case and, alarmingly, a sharp increase in use of tablets/capsules in children and a decline in suitable paediatric formulations and information about manufacturers were noted. The situation may reflect continued lack of awareness among investigators and other stakeholders (sponsors, ethical/institutional review boards and editorial oversight) of the importance of using suitable age-appropriate formulations.

References

Footnotes

  • Funding NIHR MCRN.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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