Oral formulations for paediatrics: palatability studies

The palatability of paediatric medicines is one of the most important formulation factors with potential to influence adherence to therapeutic regimens and outcomes.¹ Palatability has been defined as, “the overall appreciation of a (often oral) medicine by organoleptic properties such as vision (appearance), smell, taste, aftertaste and mouth feel (for example, texture, cooling, heating, trigeminal response) and possibly also sound (auditory clues)”.² Although this paper focuses on palatability of oral formulations, it may also be an important aspect to consider for products designed for inhaled or nasal administration. The importance and incentive to study the palatability of paediatric formulations was discussed in the reflection paper³ and endorsed in the latest European paediatric guideline on pharmaceutical development of formulations for paediatric use.⁴

Taste was reported to be the most common reported barrier to oral medicines administration in a recent study on children with chronic diseases affecting 35% of all prescribed oral formulations.⁵ Studies show that making medications more pleasing to the child can have a positive effect on compliance.⁶ Market research has previously shown that fruity, sweet oral medicines are preferred by children; citrus and red berry flavours are preferred across Europe, liquorice in Scandinavia, while bubblegum and grape flavours were reported to be preferred in the US.⁷

Existing products where taste has been identified as an issue in children with chronic illnesses include ranitidine liquid, prednisolone soluble tablets and trimethoprim liquid.⁵

As the physiological development of children changes markedly with age, they should not be regarded as miniature adults, therefore involving children in studies investigating problems with paediatric medicines is essential.

Methods used most commonly to assess palatability have included scale methods such as visual analogue (VAS) and hedonic. Other methods have focused on a forced choice or preference between multiple products (ranking products in order of preferred taste), or a simple question as to whether the child would be prepared to take the medicine again. The prevalence of complaints or refusal to take the medicine was used to assess taste in one study.⁸ Another evaluated the time taken for a nurse to administer the medicine as a measure of acceptability, where it was stated that the average administration time was 60 seconds.⁹ For infants and very young children, an assessment of palatability can be performed by a nurse or parent noting the willingness to swallow. Further reviews on methods used to test acceptability are available.^10,11

The methodology needs to be appropriate for the age and cognitive function of the child involved in the study; hedonic scales can be used in children as young as three years of age, whereas VAS are more widely used for children of six years and older.¹⁰ Open answer questionnaires are typically only suitable for older children who are judged able to articulate more detailed responses themselves. Age ranges for the use of hedonic scale and/or VAS are consistent with those used in pain management, an application that is widely used and validated, with children as young as three years of age using them effectively. However, there is no standard, globally acceptable approach for confirmation of formulation acceptability in children.

Children are considered to be the most appropriate sample population to test the acceptability of a new paediatric medicine, however ethical issues arise here including whether to use healthy volunteers, or current patients. This is supported by the Royal College of Paediatrics and Child Health (RCPCH), who suggest that the views of children with regard to taste of medicines need to be investigated owing to differing perspectives between adults and children.¹² A high quality palatability study relies upon the experience and training of the assessors and how the samples are presented. Although expert adults trained in sensory analysis may be considered the best to evaluate taste, children are the end users and it is known that taste preferences differ between adults and children.⁷ Therefore it is important that the study is designed to account for the fact that children are not ideal assessors.

Illness can affect taste and sensory perception, therefore in an ideal situation the palatability testing should be conducted in children with the condition to be treated. However, there is also a need to minimise the burden of clinical testing in children who are already dealing with illness. EU guidance states that although healthy children should not be involved in clinical trials, exceptions can be made for palatability studies for new flavoured medicines, particularly when a swirl and spit method is employed.¹³ In a review (unpublished review by authors) of palatability studies conducted in children, 16 out of 41 studies were undertaken using healthy children. Medicines testing in healthy children were antibiotics (seven studies); activated charcoal;³ oral rehydration solutions² plus other commonly used OTC medicines.

A swish and spit (also known as swirl and spit) test is one where the product is taken into the mouth and then spat out rather than swallowed. This type of study can be beneficial in minimising the risk of adverse effects due to absorption of swallowed agents. However, it is important in such tests that the assessor is able to follow the instructions given, which may be difficult for very young children. Alternatively the taste is evaluated during routine clinical practice where the medicine is swallowed as required.

Typical sample sizes in taste testing of medicines in children ranged from 20 to 965.¹⁰ Draft regulatory guidance on assessment of the palatability of veterinary medicinal products proposed that the overall voluntary acceptance rates should at least reach the threshold of 80% in dogs, and 70% for all other species. The threshold should be reached in a group of at least 50 animals in case the product is administered only once, and in a group of at least 25 animals in case of multiple administrations.¹⁴ Interestingly, there is no such threshold defined for human medicines but the current thinking is that it has to be acceptable to 80% of patients for the medicine to be deemed acceptable.

The EMA recommend a maximum of four samples to taste (the younger the child, the fewer samples).³ Single- or double-blinded, randomised studies are the preferred methodology, however this is not always possible due to the nature of the product itself, for example, comparisons of various flavour is easily unblinded. Taste studies that are nested within other clinical studies should be encouraged as a pragmatic approach to evaluate new formulations in children.

A review on palatability studies conducted in children reported that the majority were based on a single exposure to the medicine although there were a few studies that reported on palatability following exposure over a longer period (5–10 days).¹⁰ In all cases the palatability study should mimic typical clinical usage and therefore, multidose studies are more representative than single-dose studies for chronic treatments.

Clinical Trials of Investigational Medicinal Products (CTIMPs) must adhere to the European Clinical Trials Directive (2001/20/EC), the Medicines for Human Use (Clinical Trials) Regulations 2004 and the Good Clinical Practice Directive (2005/28/EC). The rules and regulations that cover CTIMPs are extensive and it is critical to define whether a palatability test is a CTIMP study or not. Palatability is not a pharmacological effect, therefore the purpose of a palatability study falls outside this definition and such tests are not classified as CTIMPs.

However, when a palatability study is nested within another clinical study it may be classified as a CTIMP. It is essential to obtain guidance from local governance bodies to determine whether a palatability study will be classified as a CTIMP. Assessment of the palatability of medicines administered for routine clinical use would not be classified as CTIMP studies but would be subject to local research governance policies.

Electronic taste sensing systems have been developed and used for taste evaluation in both the pharmaceutical and food/beverage industry. These ‘electronic tongues’ measure changes in electrical potential while testing liquid samples on sensors. They are non-specific and measure taste of any tastant, for example, drug and excipients. However there is a need to correlate electronic tongue data with human taste data in order to validate the suitability of the sensing system for taste evaluation of tastants (for example, drugs).

The measurement of the amount of drug released/dissolved in simulated oral cavity conditions can provide an indication about the taste of the drug as only dissolved drug molecules are able to interact with taste receptors on the tongue. However, analytical methods typically only measure drug concentrations and not those of other excipients so there may be a need to understand the taste of excipients as well as the drug in formulated medicines. In addition, the correlation to taste thresholds in children is required to adequately interpret this type of in vitro data.

Although there are currently regulations in place to ensure that any new medicines are acceptable and palatable to children it is acknowledged that there are several existing medicines where palatability is an issue. Consultation with healthcare professionals provided some advice in administration of medicines to children where palatability is an issue.¹⁵

It is acknowledged that further work is required to develop evidence-based methodology to assess palatability of medicines designed for children. It is anticipated that there will be regulatory guidance that will specify requirements for the design, conduct, and evaluation of palatability studies for all oral dosage forms developed for use in paediatric populations.