Devices for oral and respiratory paediatric medicines: What do healthcare professionals think?

G Model IJP 14911 No. of Pages 12

International Journal of Pharmaceutics xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Devices for oral and respiratory paediatric medicines: What do healthcare professionals think? Jennifer Walsh a, * , Marie-Christine Math b , Jörg Breitkreutz c, Thomas Zerback d , Herbert Wachtel e On behalf of the European Paediatric Formulation Initiative (EuPFI) a

Jenny Walsh Consulting Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, UK Sanofi R&D, Pharmaceutical Sciences Department, 371 Rue du Professeur Blayac, 34184 Montpellier Cedex 04, France Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1,40225 Duesseldorf, Germany d Department of Communication Studies and Media Research, LMU Munich, Oettingenstraße 67, 80538 Munich, Germany e Boehringer Ingelheim Pharma GmbH & Co. KG, Analytical Development, Packaging Development Center, Binger Straße 173, 55216 Ingelheim am Rhein, Germany b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 March 2015 Received in revised form 7 May 2015 Accepted 14 May 2015 Available online xxx

Medical devices are crucial for the proper administration of paediatric medicines to children, but handling and dosing errors commonly appear in daily practice. As both the understanding and the usage of medical devices for oral and respiratory drug administration are heterogeneous among patients and caregivers, the European Paediatric Formulation Initiative (EuPFI) consortium performed a European survey among healthcare professional stakeholders in France, Germany, Hungary, Italy, Spain and UK. The results show country- and age-dependent usage of devices for oral administration of liquid formulations, with a clear preference for oral droppers and syringes in the neonatal phase and in early infancy. In older children, spoons and cups are more frequently used although it is recognized that they may fail in delivering correct doses. The percentage of medicinal products definitely requiring an oral administration device was estimated as 68.8% by the participants. The survey elaborated a similar usage pattern for medical devices for respiratory drug delivery: in young children drug solutions are nebulized, using face-masks and subsequently valved holding chambers or spacers, with increasing age metered-dose inhalers and later dry powder inhalers are preferably used. 56% of the responding healthcare professionals believed that providing an administration device helps to ensure that the patient receives the correct dose of medicine, and 41% agreed that patients must be given an administration device with each supply of medicine. Interestingly, 6.7% thought that patients tend not to use the device provided and remarkably 25.4% stated that patients already have a device. Although there is the highest count of treated children with device supply in Germany and Hungary, there are no observed significant differences in the six investigated European countries (p = 0.057). Patient difficulties in correct oral and respiratory device use were identified by respondents and potential solutions discussed. ã2015 Elsevier B.V. All rights reserved.

Keywords: Paediatric Respiratory device Oral administration Dosing device Survey

1. Introduction Medical devices are crucial and often essential for the proper administration of paediatric medicines to children. However, current practice shows some major pitfalls and challenges (Walsh et al., 2011). Drug administration procedure is among the most

* Corresponding author. Tel.: +44 7757948052. E-mail addresses: [email protected] (J. Walsh), marie-christine.math@sanofi.com (M.-C. Math), [email protected] (J. Breitkreutz), [email protected] (T. Zerback), [email protected] (H. Wachtel).

pronounced risk factors in preventable adverse drug events in children (Zandieh et al., 2008). The consequences are often serious, ranging from insufficient efficacy to severe clinical courses of intoxications, e.g. from oral drug administration (HermannClausen et al., 2009). The reasons for inappropriate drug administration are manifold and dosing errors occur in practice frequently. Parents may fail in the proper selection, handling and usage of an administration device (Yin et al., 2010a). Dosing directions may be insufficient or inconsistent (Yin et al., 2010b) or parents’ understanding of the dosing instructions may be limited (Tanner et al., 2014; Budnitz et al., 2014). Furthermore, the medical devices delivered with the

http://dx.doi.org/10.1016/j.ijpharm.2015.05.041 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: J. Walsh, et al., Devices for oral and respiratory paediatric medicines: What do healthcare professionals think?, Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.041

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medicinal product may be inappropriate for precise dosing. There are many reports showing superiority of oral dosing syringes over dosing cups, dosing spoons and household spoons (Grießmann et al., 2007; Sobhani et al., 2008), but syringes are rarely provided with commercialized products (Yin et al., 2010b). Inhalation devices have often been developed for older children and adults and hence, they generally fail to adequately deliver the needed dose to the lung in younger children, who show lower inspiration flow and higher breathing frequency (Everard, 2004; Below et al., 2014). The administration device subgroup of the European Paediatric Formulation Initiative (EuPFI) consortium has previously recognised the gaps and the need for improvement, and has continuously investigated all issues associated with medical devices for use in paediatric patients (Walsh et al., 2011; Wachtel, 2012). These investigations have indicated that the devices for oral and respiratory drug administration are of major importance and that they often lack age-appropriateness, efficacy and safety. The availability of administration devices delivered with or without the medicinal product may vary throughout the world and even from country to country. Within the European Union, medicinal products are not consistently authorized in all member countries (Breitkreutz, 2008) and the national competent authorities may judge differently on the need, the type or the functionality of an administration device accompanying a licensed medicinal product or being separately marketed as a medical device. Little is known about the sociocultural differences on the experiences and preferences of paediatric patients, parents, caregivers and healthcare professionals (HCPs) regarding the use of administration devices. Therefore, the aim of the present exploratory study, which was conducted on behalf of EuPFI, was to gain information from all HCP stakeholders first in a pilot-study in UK and subsequently in a follow-up study in six European countries (France, Germany, Hungary, Italy, Spain and UK), on how administration devices are prescribed and dispensed. The objectives of the study were to collect the opinions on usage, benefits and challenges of administration devices and to request HCP stakeholders' suggestions for future improvements. 2. Method This exploratory survey was conducted using an electronic selfadministered questionnaire, which was developed using a basic process of survey research as described by Burgess (Burgess, 2001): 1. 2. 3. 4. 5. 6. 7.

Definition of research aims Identification of the population and sample Decision on how to collect replies Questionnaire design Pilot survey Main survey Analysis of the data

2.1. Definition of research aims The aim of the survey was to gain information on the experiences and opinions of European hospital HCPs regarding paediatric medicine administration devices. Initially, data were to be collated on paediatric devices for all routes of administration. However, during the design of the questionnaire (see Section 2.4) this was restricted to oral and respiratory devices. The planned outcomes of the survey included extent of prescribing and supply of different administration devices by HCPs, patient age groups for which the devices are prescribed and supplied, extent to which training or demonstration of appropriate device use is given to patients/caregivers, awareness of patients having difficulty in

using administration devices and opinions on how devices and their instructions for use may be improved. In addition, it was hoped to be able to compare responses between different HCP roles (doctors, pharmacists and nurses) and between different European countries. 2.2. Identification of the population and sample Patient facing hospital-based doctors, nurses and pharmacists were identified as the target population for the survey. As the research was to be conducted within the framework of the EuPFI, a multi-national distribution was considered mandatory. Ideally a representative sample of hospital HCPs from all European countries would have been included, but this was unrealistic from a logistical perspective. Therefore six countries were selected in order to represent the geographical and cultural diversity of Europe; UK, Italy, Spain, France, Hungary and Germany. 2.3. Decision how to collect replies Taking into consideration the target population and limited resources of the EuPFI research group, a self-administered electronic questionnaire was selected as the means by which the questions were to be distributed and the responses collected. Electronic circulation had the advantage of enabling the questions to be distributed quickly to a large yet targeted geographically disperse population. Data management for subsequent analysis was expected to be simpler than by conventional paper-based methods. Potential ways in which to identify and contact survey participants were evaluated and included the use of professional organizations, via paediatric hospitals or through the European Medicines Evaluation Agency (EMA). Contact via paediatric hospitals was selected because this appeared to be the most feasible approach for reaching the target audience in all the countries selected since for example there appeared to be a high degree of diversity in professional organizations between the individual countries. Key hospitals in each country were identified and contacted by email. 2.4. Design of questionnaire During the design phase, questions were developed in order to address the aims of the study and a preliminary electronic questionnaire was set up to create a first impression of the appearance of the questions with their expected answers. A variety of question types were included; list where the respondent is offered a list of items and can select more than one item, category where only one response can be selected, scale where a scaling device is used to record a response and quantity where a number is the response. In addition, some open questions were included to allow respondents to add their comments. The initial draft was reviewed by fellow EuPFI members and then updated to reduce the number and ambiguity of questions, with the focus being on oral and respiratory devices to avoid confusion regarding device type. Oral and respiratory devices are commonly used in a hospital outpatient setting. 2.5. Pilot survey A pilot survey was conducted with HCPs from Nottingham Children’s Hospital Queen’s Medical Centre and Birmingham’s Children Hospital in the UK. Participants were identified and recruited by personal contact. The results were analysed in collaboration with an experienced survey unit and response rate was on average between 35% (Nottingham) and 46% (Birmingham), which was considered to be high for this type of survey. Overall, the

Please cite this article in press as: J. Walsh, et al., Devices for oral and respiratory paediatric medicines: What do healthcare professionals think?, Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.041

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questionnaire was considered to be acceptable, with the time to answer all the questions being below 15 min. Minor modifications were made following feedback from the pilot survey participants. 2.6. Main survey The updated survey which was developed in English, was translated into the native languages of the other five European countries. As the roll-out of the survey to the different countries represented a considerable technical challenge, the use of an experienced survey provider was required. Participants were contacted and questioned using the non-commercial online survey platform “SoSci Survey” (www.soscisurvey.de), and the technical part of the survey was managed by a research consultant from the Ludwig-Maximilians-University of Munich (TZ). A total of 2064 emails were sent out to hospitals across the six countries as follows; France 532, Germany 425, Hungary 144, Italy 361, Spain 487, UK 185. Email contacts were requested to circulate the survey which was provided via a link, to their paediatric teams. Reminder emails were sent after 14 days. During the monitoring of the survey responses, it became clear that response rates were very low for some markets, e.g. the UK. In order to increase the number of responses, a second approach was used to recruit participants whereby named individuals (paediatric HCPS) were contacted and requested to participate and circulate the survey within their hospital. The number of individuals contacted during this second phase of the main survey were 9 in France, 3 in Germany, 1 in Hungary and 6 in the UK. The Authors did not have any personal contacts in Italy or Spain. 2.7. Analysis of the data In addition to the distribution of the survey, the soscisurvey.de software enabled the web-based automated collection of survey responses. All answers were compiled in an Excel sheet for further analysis. Statistical tests were performed using the SPSS software package version 20 (IBM). Because most of the variables examined in the survey violated the normality assumption, only nonparametric tests were employed. The respective test procedure selected depended on three aspects: (1) the level of measurement of the independent and dependent variable, (2) whether comparisons were based on independent or paired samples, and (3) the number of comparisons made (two or more). For nominal dependent variables and paired samples (explanation of devices to patients, difficulties in using devices) McNemar tests were used, whilst for ordinal dependent variables and paired samples (adequate supply of usage instructions, assistance with device usage, frequency of device supply), Wilcoxon tests were performed. Where more than two variables were compared (differences in frequencies of device supply) Friedman-tests were conducted. Comparisons of means between several independent groups were tested by the Kruskal–Wallistest (differences in frequency of device supply according to countries or professions). If both independent and dependent variables were nominal (children treated per week according to countries or professions) an exact Fisher test was computed. 3. Results The results from both phases of the main survey were pooled and are discussed in the following sections. 3.1. Participants 180 participants from the six European countries that were involved in the survey started the questionnaire. As shown in Fig. 1,

Fig. 1. Profession of the survey participants (152 answers out of 180).

among those who answered the question regarding their profession (n = 152), 39% were nurses, 34% were doctors and 16% were pharmacists. The average working experience of the respondents was about 17 years and the majority of respondents were from UKbased HCPs. 74% of the participants (134/180) who indicated they have direct contact with patients were able to continue the survey, whilst the others were directly forwarded to the end of the questionnaire. Hence data on device use were collected from patient-facing HCPs only. Among them, 71.6% (96/134) were involved in respiratory devices administration. As presented in Table 1, 107 fully completed questionnaires were finally received, corresponding to an overall response rate of 59.4% varying according to country, from 37.5% for Spain (6 questionnaires completed/16 started) to 71.4% for UK (50/70) and 75.0% for Italy (3/4). The answers received demonstrate that most respondents were from the UK, Hungary and Germany with a higher drop out rate of those based in Spain, France and Italy. 3.2. Current practice regarding supply of devices Table 2a and b characterize the HCPs in terms of number of patients treated or supplied with medication per week, according to country and profession. On average and also in the UK, approximately half of the HCPs treat or supply up to ten children per week and the other half treat 11–100 patients. In Germany and in Hungary there is a trend towards a larger number of patients, while in Italy and Spain a small number of patients is treated. However, according to Fisher’s exact test the effect of the country is not significant (p = 0.057). As far as the profession of the respondents is concerned, approximately 58% of the doctors and 78% of the pharmacists treat 11–100 patients while 65% of the nurses care for up to ten patients. Fisher’s exact test indicates a significant effect of the profession on the number of patients treated/supplied with medication per week (p < 0.001). In general, the percentage of paediatric medication requiring an oral administration device was estimated by n = 90 participants to be 68.8  25.2%. Responses to the question on how often oral administration devices were prescribed or supplied to patients are provided in Table 3a and b. The Friedman test indicates that significant general differences existed with respect to their supply frequency (p = 0.001). Oral syringes were on average the most frequently prescribed/supplied devices by HCPs for the majority of the countries, with an overall mean of 27 per week. While the supply of spoons was also commonplace, the frequency of supply of droppers was rather low, except for Hungary and France. HCPs

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Table 1 Overview of survey response rates. Country

Survey started (n)

Survey started (%)

Language used (n)

Drop out (n)

Drop out (%)

Completed (n)

Completed (%)

UK France Germany Hungary Italy Spain

70 13 34 43 4 16

38.9 7.2 18.9 23.9 2.2 8.9

70 13 34 43 4 16

20 8 14 20 1 10

28.6 61.5 41.2 46.5 25.0 62.5

50 5 20 23 3 6

71.4 38.5 58.8 53.5 75.0 37.5

Overall

180

100

180

73

40.6

107

59.4

Survey started: individuals who started the survey. Drop out: individuals who started the survey, but did not complete it. Completed: individuals who finished the survey.

Table 2 Number of children treated/supplied with medication per week. a) Percent of HCPs (number n) in the indicated countries treating up to 10, between 11 and 100 and over 100 patients per week Country

Number of patients per week

Percent of HCPs

UK France Germany Hungary Italy Spain Mean (all) Min (all) Max (all)

n

63 9 28 18 3 7 128

No answer

0–10

11– 100

>100

47.6 22.2 35.7 11.1 66.7 71.4 42.2 11.1 71.4

46.0 33.3 57.1 50.0 33.3 14.3 46.1 14.3 57.1

4.8 11.1 3.6 11.1 0.0 0.0 5.5 0.0 11.1

1.6 33.3 3.6 11.1 0.0 14.3 6.3 0.0 33.3

b) Percent of indicated HCPs (number n) treating up to 10, between 11 and 100 and over 100 patients per week Profession

n

Number of patients per week

Percent of HCPs

50 49 18 6 123

Doctor Nurse Pharmacist Other Mean (all) Min (all) Max (all)

No answer

0–10

11–100

>100

32.0 65.3 11.1 50.0 43.1 11.1 65.3

58.0 26.5 77.8 50.0 48.0 26.5 77.8

8.0 2.0 11.1 0.0 5.7 0.0 11.1

2.0 6.1 0.0 0.0 3.3 0.0 6.1

(All): mean and min, max considering the total data set.

Table 3 Frequency of device supply: oral. a) Frequency of prescription/supply of oral devices depending on country Country

Oral syringe n = 89

Spoon n = 64

Cup n = 60 Mean (min

Frequency/week

UK France Germany Hungary Italy Spain Mean (all)

33 (0 40 (10 19 (0 18 (0 22 (1 16 (5 27 (0

210) 100) 150) 100) 60) 30) 210)

12 (0 22 (5 16 (0 10 (0 0 15 (15 14 (0

100) 50) 200) 50) 15) 200)

Dropper n = 62

Other n = 15

2 (0 30) 20 (0 50) 5 (0 20) 18 (0 100) 0 0 6 (0 100)

5 5 1 1 0 6 3

max)

4 (0 50) 0 6 (0 60) 13 (0 50) 0 0 6 (0 60)

(0 (5 (0 (0

20) 5) 5) 1)

(6 (0

6) 20)

b) Frequency of prescription/supply of oral devices depending on profession Profession

Oral syringe n = 89

Spoon n = 64

16 (0 27 (0 55 (0 15 (2 27 (0

14 (0 200) 9 (0 100) 21 (0 50) 6 (0 12) 14 (0 200)

Cup n = 60 Mean (min

Frequency/week

Doctor Nurse Pharmacist Other Mean (all)

100) 210) 200) 25) 210)

4 9 4 4 6

(0 (0 (0 (2 (0

Dropper n = 62

Other n = 15

9 4 5 2 6

1 (0 5) 6 (0 20) 2 (1 2) 10 (10 10) 3 (0 20)

max)

50) 60) 20) 5) 60)

(0 (0 (0 (0 (0

100) 50) 30) 4) 100)

n is the number of responses. The average frequency per week is given as mean. Since the distributions are not normally-distributed, minimum and maximum are stated.

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Fig. 2. Frequency of oral administration device recommendation/supply per week. Significant differences are marked with * and **.

from Hungary also appeared to favour the supply of dosing cups compared to HCPs in the other countries. The Kruskal–Wallis-test indicated that dosing cups were statistically significantly distributed with respect to countries (p = 0.037), while for the other oral devices there were only trends (p > 0.05). A high degree of variability in responses between different HCPs was noted. Pharmacists supplied oral syringes at the highest frequency of 55 per week. In addition, spoons appeared to be frequently administered. The existence of general differences between professions was documented using the Kruskal–Wallistest which showed statistical significance for oral syringes (p=0.004), measuring spoons (p < 0.001), and oral droppers (p = 0.018). The pattern of overall frequency of supply of different oral administration devices is illustrated in Fig. 2. The variability obtained has not been included, although the minimum supply was 0 per week and the maximum value reached from 20 (other oral) to 210 (oral syringe). The use of oral administration devices was compared with the use of respiratory devices and the results of the mean frequency of prescription/supply of respiratory administration devices are provided in Table 4 a and b. Solutions for inhalation have been included as they are nebulized and therefore indicate the use of re-

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usable nebulizers. Among the countries, HCPs in France indicated the greatest use of metered dose inhalers (MDIs), probably in combination with valved holding chambers (VHCH) and face masks. Hungarian HCPs and Italian HCPs indicated solutions for nebulization and nebulizers were used quite frequently (20 and 15 per week respectively). HCPs in Hungary used significantly more nebulized solutions than those in the UK (Mann–Whitney-Utest, p = 0.04). However, these trends were not statistically significant on a general level (Kruskal–Wallis-test, p > 0.05). This was also the case for general differences between the respiratory devices with respect to professions. As a trend, MDIs and VHCH were widely used and nurses tended to supply nebulized solutions. The question ‘Which age groups of children do you think each of the following administration devices are appropriate for?’ was presented to the respondents in multiple tick-box format. Applying multiple ticks along the time axis indicated the age range within which the device was assessed as being appropriate. Fig. 3a indicates the high supply rate of oral syringes and the onset of its use in the first year. The older the child, the less frequently oral syringes appear to be used. Measuring spoons reached 50% appropriateness ratings within the age range from 12 to 23 months. The 50% appropriateness of measuring cups was reached at 2–5 years. Oral droppers were seen as appropriate at birth and levelled off slowly with increasing age. Other oral devices were only mentioned by 19/134 HCPs and their rate of application was low and showed a continuous increase from 12 months to 12 years. Explicitly mentioned were alternative dosage forms, soothers containing drug and tablet cutters. A corresponding question was asked in the context of respiratory administration devices and the responses are summarized in Fig. 3b. Solutions for nebulization and the corresponding application of nebulizers was deemed appropriate from birth to the oldest age group in the survey. Conventional MDIs, and to a similar extent VHCH or spacers were judged to be appropriate from below 1 month of age (VHCH) or 1–11 months (MDI) respectively, the onset being defined by the level of 50% appropriateness. Also face masks were seen as being appropriate at a very young age, however above 6–8 years the appropriateness decreased. Dry powder inhalers (DPIs) had the lowest frequency of prescription/ supply; their 50% value of appropriateness was reached at

Table 4 Frequency of device supply: respiratory. a) Frequency of prescription/supply of respiratory devices depending on country Country

Solution n = 52

pMDI n = 47

DPI n = 40

UK France Germany Hungary Italy Spain Mean (all)

6 (0 30) 10 (10 10) 5 (0 30) 20 (1 50) 15 (15 15) 5 (2 7) 8 (0 50)

12 (0 40) 70 (70 70) 6 (0 25) 14 (1 50) 0 0 12 (0 70)

2 2 5 3 0 0 3

VHCH n = 49 Mean (min

Frequency/week

(0 (2 (0 (0

10) 2) 10) 10)

(0

10)

Mask n = 48

Other n=4

8 (0 40) 10 (10 10) 3 (0 10) 12 (0 50) 1 (1 1) 5 (2 7) 7 (0 50)

1 (1 0 1 (0 0 0 0 1 (0

Mask n = 48

Other n=4

4 (0 20) 9 (0 50) 10 (0 40) 0 7 (0 50)

1 (0 1 (1 0 0 1 (0

max) 9 (0 30) 70 (70 70) 6 (0 20) 15 (1 50) 0 5 (2 7) 10 (0 70)

1) 1)

1)

b) Frequency of prescription/supply of respiratory devices depending on profession Profession

Solution n = 52

pMDI n = 47

DPI n = 40

6 (0 30) 11 (0 50) 7 (0 30) 0 8 (0 50)

11 (0 70) 8 (0 50) 16 (0 40) 0 12 (0 70)

4 2 2 0 3

VHCH n = 49 Mean (min

Frequency/week

Doctor Nurse Pharmacist Other Mean (all)

(0 (0 (0

10) 7) 10)

(0

10)

max) 11 10 11 0 10

(0 (0 (0

70) 50) 30)

(0

70)

1) 1)

1)

n is the number of responses. The average frequency per week is given as mean (all). Since the distributions are not normally-distributed, minimum and maximum are stated.

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Fig. 3. (a) Age-appropriateness of different devices: Oral. The differences between average supplies of oral syringe, spoon and (cup, and dropper) are statistically significant (p  0.028). The normalized use in the age groups is graphically displayed. (b) Age-appropriateness of different devices: Respiratory. The differences between average supplies of (MDI, or VHCH), (solution, or facemask), and DPI are statistically significant (p  0.039). The normalized use in the age groups is graphically displayed.

approximately 5 years of age and above, the age at which DPIs are widely used. HCP opinions on the general characteristics of administration devices and patient use were investigated by asking the HCPs (n = 134) to tick pre-formulated sentences if they agreed to the statement. Multiple ticks were allowed. 56% of the HCPs agreed with the statement ‘Providing an administration device helps ensure the patient receives the correct dose of medicine’, 41% ticked the statement ‘Patients must be given an administration device with each supply of medicine’ and only 25.4% agreed that ‘Some patients already have an administration device.’ Remarkably, a small proportion of respondents (6.7%) thought that ’Patients/carers tend not to use an administration device provided to them.’ 3.3. Challenges associated with device use Since patients and caregivers may find their administration device difficult to use, participants were asked if they explain or demonstrate how to use the supplied device. The results for both oral and respiratory devices are provided in Fig. 4. Approximately

30% participants indicated they always explain (oral 41/134, 30.6%; respiratory 30/96, 31.3%), with 30.2% (29/96) indicating they always check patient inhaler use. Fewer participants explain how to use the supplied device to new patients only (oral (22/134), 16.4%; respiratory (13/96), 13.5%), whilst 11.2% (15/134) (oral device) and 5.2% (5/96) (respiratory device) only explain or demonstrate correct device use if asked. None of these differences in responses between oral and respiratory devices were considered to be significant (McNemar test). Almost a tenth of participants believed that oral devices are easy to use and hence it is not necessary to explain how to use them. Indeed, over half the participants indicated that graduations on oral devices are either always or usually suitable for measuring the required doses. In contrast, only one participant indicated that respiratory devices are easy to use. Key reasons for not providing an explanation included lack of time, especially for oral devices where there was a statistically significant difference compared to respiratory devices (McNemar test, p = 0.031) and another member of staff would do this (pharmacists and nurses were mentioned). Some respondents indicated that ideally all patients should be trained in and checked for correct device use, but time constraints prevented this.

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Fig. 4. Responses to “Do you explain how to use the supplied device?” *Question for respiratory devices only. **p = 0.031, McNemar test. Sum of percentages do not add up to 100% since multiple answers were possible. Participants n = 134 oral; n = 96 respiratory.

When questioned about the quality of administration device instructions, as seen in Fig. 5, almost half of those who responded believed usage instructions provided with oral devices are usually adequate (48.3%, 43/89). Conversely, 15.7% (14/89) indicated oral device use instructions to be never adequate, which may be due to instructions not being provided for certain oral devices, e.g. measuring spoons. Indeed, one respondent commented that their hospital buys oral syringes in bulk, without the provision of a leaflet for each device. Suggestions to improve instructions for oral devices included the use of diagrams or pictures. It was also recommended to standardise oral devices in terms of units of measure, e.g. mL. As with oral devices, the majority of respondents believed that instructions for respiratory devices were usually adequate (38.6%, 22/57) or sometimes adequate (43.9%, 25/57). Fewer respondents indicated respiratory device instructions as never adequate compared to those for oral devices (7.0%, 4/57), whilst a greater number indicated respiratory device instructions to be always adequate (10.5%, 6/57). There were no statistically significant differences between responses for oral and respiratory devices (Wilcoxon signed-rank test). The use of “visuals” such as diagrams, animation and video clips were suggested as improvements for respiratory device usage instructions. Fig. 6 shows responses to how often survey participants have been asked for assistance with using an administration device. Almost two thirds of those who responded indicated that they are

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Fig. 6. Responses to “How often have you been asked for assistance with how to use a device?” Respondents n = 89 oral; n = 57 respiratory.

rarely asked for assistance with how to use an oral device (64.0%, 57/89), whilst almost a quarter of respondents (24.7%, 22/89) indicated they are often asked. Examples of where help has been sought included caregivers with little or no experience of using the device, requests for clarity on the required dose (especially for the measurement of very small doses) and explanation of how to measure a dose from a bottle with a stopper. A different pattern of responses was observed for requests for help with respiratory devices, where similar numbers of respondents indicated they have been either rarely or often asked for help (47.4%, 27/57 and 42.1%, 24/57 respectively). In addition, a higher proportion of respondents have often been asked for assistance with respiratory devices compared to oral devices. Several respondents commented that parents often assume they know how to use a respiratory device, but upon checking by a HCP, the technique can be improved. A statistically significant higher proportion of respondents were aware of their paediatric patients/caregivers having difficulty in using respiratory devices compared to oral administration devices, as shown in Table 5 (p = 0.002, McNemar test). The oral syringe was the most frequently cited problematic oral device, whilst MDIs either alone or in combination with a face mask was often mentioned as being the most difficult respiratory device to use correctly. Perceived reasons for difficulties in using oral and respiratory devices are shown in Fig. 7. Identifying the correct dose and having difficulty in measuring the required dose were most frequently reported for oral devices (12.7% (17/134) and 16.4% (22/134) respectively). Other reasons included poor patient acceptance, stiff syringe plunger and spillage of medicine (especially if the patient is refusing the medication). In addition, it was noted that writing on oral devices can be too small and therefore difficult to see. For respiratory devices, difficulty with co-ordination (inhalation at time of dose release) was the most frequently reported difficultly (25.0% (24/96). In addition, lack of patient acceptance and tolerance, in particular for spacers and/or facemasks, leading to Table 5 Awareness of patients/caregivers having difficulty in using an administration device. % Respondents

Fig. 5. Responses to “Are devices supplied with adequate usage instructions?” Respondents n = 89 oral; n = 57 respiratory.

Yes No a b

Oral devicesa

Respiratory devicesb

42.0 58.0

70.2 29.8

Of those who gave a response, n = 88. Of those who gave a response, n = 57.

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Fig. 7. Reasons for difficulty in using devices. *Reason for oral devices only. **Reason for respiratory devices only. ***p = 0.031, McNemar test. Note: sum of percentages does not equal 100% as multiple responses were possible. Participants n = 134 oral; n = 96 respiratory.

poor compliance was frequently reported. Poor technique for inhaler use was also cited. A larger proportion of respondents considered instructions difficult to follow, the device being too complicated to use and the device having an unpleasant taste to be issues for respiratory devices compared to oral devices, (10/96, 10.4% versus 7/134, 5.2%; 11/96, 11.5% versus 5/134, 3.7%; 9/96, 9.4% versus 4/134, 3.0% for respiratory and oral devices respectively). Of these, device too complicated to use reached a difference that was statistically significant (p = 0.031 McNemar test). 3.4. Suggestions for improvement According to the results obtained, on average almost 70% of paediatric medications prescribed by HCPs would require an oral administration device. Respondents did not indicate which oral medications do not require an administration device, but it is recognised that delivery devices for solid oral dosage forms such as tablets and capsules are generally not required (Walsh et al., 2011). Although 78% of those who responded (71/91) believed that graduations on oral devices (mainly syringes as most the frequently

supplied) are usually or always suitable for measuring the required dose, over a quarter of the respondents (26%, 23/87) indicated they always or usually customize devices for individual patients, for example by marking the dose volume on an oral syringe barrel. The most frequent issue reported was the risk of inaccuracy and nonreproducibility of low or rounded doses. Therefore, practitioners mentioned the need of administration devices capable of measuring small volumes (<0.5 mL) and with more graduations. Almost half of the respondents for oral devices (43/89) and less than a half for respiratory devices (22/57) found instructional leaflets usually adequate for usage (see Fig. 5). Consequently, some improvements were proposed and are presented in Table 6. As described above, identifying and measuring the correct dose were reported as being common issues with oral devices, whilst difficulty with co-ordination when using respiratory devices was frequently reported. Suggestions made by the study participants to enhance the user-friendliness of these devices are also provided in Table 6. 4. Discussion Numerous studies have investigated or reviewed the accuracy, ease and/or correct of use of oral and respiratory paediatric administration devices (Yin et al., 2010a; Tanner et al., 2014; Grießmann et al., 2007; Sobhani et al., 2008; Beckett et al., 2012; Dockhorn et al., 2010; Ryu and Lee, 2012; Malot et al., 2007; Melani et al., 2011; Galffy et al., 2013; Crompton et al., 2006) but there appears to be little information in the literature on HCP opinions and current practice regarding the use and supply of these devices. This exploratory survey has provided some valuable insights into the views and experiences of European hospital doctors, nurses and pharmacists, regarding oral and respiratory administration devices for paediatric patients. Oral and respiratory devices were selected for investigation since these are commonly used in hospitals and also community settings after hospital discharge. It is recognised that if the survey had been conducted in community-based HCPs, it is likely that some of the results and trends would differ to those identified in this study. This may be due to for example, the nature and degree of illness of the paediatric patient, the experience of the parent/caregiver and availabilityof oral administration devices such as spoons in the home. The oral route is the most frequently used route of administration for systemic medicinal products and oral liquids are

Table 6 Improvements proposed for information leaflets and devices. Proposals for information leaflets Use of plain language and pictures for use and after care of device (e.g., cleaning) More detailed instructions Training and use of video clips (e.g., YouTube) to show how to use the device and that patients/caregivers can refer to later Separate leaflet for patients Clear indication of how often/how long to be used for Correspondence between the dose (mg/kg) and the volume Standard and consistent units of measure (e.g., mL) Training and use of video clips (e.g., YouTube) to show how to use the device and that patients/caregivers can refer to later Troubleshooting information Proposals for devices Device to be supplied with the product Clearer marking of dose or colour coding of dose Robust, clear and suitable graduations Smaller volume (<0.5 mL) Use of one syringe for one dose Colourful devices for children Spacer recommended (valved holding chamber) Portable spacer Appropriate size facemask (for the very young)

Oral

Inhalation

X

X X X X X

X X X X X X X Oral X X X X X X

X X Inhalation

X X X X

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considered acceptable for the whole paediatric age range (birth to 18 years) (CHMP, 2012). A key challenge with the administration of oral liquid medicines is to ensure the correct dose is measured. Therapy via inhalation is regarded as the best route of drug administration for the treatment of acute and chronic airway diseases. Efficacy of the product depends on appropriate drug deposition in the lungs, which is affected by the respiratory device and how it is used. A similar proportion of responses were received from doctors and nurses, whilst approximately half this number of responses were reported from pharmacists. This may reflect the numbers of individuals in each of these professions who have direct contact with paediatric patients. The differences in response rates from participants from different countries may be attributed to a number of factors. For example, the general email addresses utilised for the first phase of the main survey may not have been the most appropriate for contacting the target audience in each country. Indeed, a high response rate was observed for Germany during the first phase, whilst a very low response rate was recorded for the UK. In contrast, use of personal contacts at UK hospitals led to a much greater response rate, resulting in the majority of all responses being from UK-based HCPs (70/180, 38.9%). None of the survey authors are affiliated to a hospital, which made access to HCPs challenging. The structure of individual country healthcare systems and cultural differences may also have led to the observed variation in response rates, as well as different working practices, whereby the specific roles and responsibilities of doctors, nurses and pharmacists may differ between each of the countries investigated. It is of interest to note that lower response rates were reported for the southern (Mediterranean) European countries (Spain 16/180, 8.9%; France 13/180, 7.2%; Italy 4/180, 2.2%). Oral syringes were found overall to be the most frequently supplied oral administration devices followed by measuring spoons, with a trend for pharmacists to supply the most per week. It is likely that this is due to the pharmacist supplying the relevant administration device at time of patient discharge. The oral syringe is considered to be the measuring device of choice, with high dosing accuracy and uniformity, especially when small volumes are required (Tanner et al., 2014; Dockhorn et al., 2010). However, the use of calibrated measuring spoons has also been found to produce accurate dosing (Beckett et al., 2012). Hence, the frequent supply of these devices is not unexpected. Droppers and measuring (dosing) cups were the least often supplied except for Hungary (droppers and cups) and France (droppers). Measuring cups are reported to be commonly used at home (Tanner et al., 2014; Sobhani et al., 2008) and are usually provided with over-thecounter (OTC) oral liquid medicines (Yin et al., 2010b; Budnitz et al., 2014). Poor dosing accuracy compared to other oral administration devices has been reported with these devices (Yin et al., 2010a; Tanner et al., 2014; Sobhani et al., 2008; Ryu and Lee, 2012) which may partially account for their limited supply by HCPs in five out of the six countries. The cost of oral devices is also likely to influence supply, although this was not explored in this study. There were no clear trends regarding the supply of respiratory devices between the professions, although French HCPs appeared to show the greatest use of MDIs, probably in combination with VHCH and face masks. Nebulisers and nebuliser solution were also frequently supplied in some markets, these being acceptable for use in the whole paediatric age range. It is likely that device supply is influenced by the availability of a particular drug in that device and local prescribing practices, although these were not explored in this study. HCP opinions on the age-appropriateness of the oral administration devices reflect the capability of each device type to

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accurately measure the likely dose volumes required by different ages of children, together with the ability of the child to use the device; oral syringes and droppers were considered particularly appropriate for infants, whilst measuring spoons and dosing cups were considered more appropriate for children aged from 2 to 5 years and 6 to 8 years respectively. Indeed, oral syringes are most often used by caregivers for dosing children up to the age of 3 years and spoons are often used for those between 3 and 6 years of age (Kairuz et al., 2007). The most frequently supplied respiratory devices were MDIs and spacers/VHCH. These may be used in combination for patients from approximately 4 years and in younger patients from birth with a facemask. Effective use of MDIs requires co-ordination of actuation and inhalation, which many paediatric patients find difficult. In contrast, the inhalation technique required with a spacer or VHCH is much simpler and hence may lead to more effective respiratory therapy (Pedersen et al., 2010; Ari and Fink, 2011). DPIs were the least frequently supplied, which may be in part due to their suitability for use in older children only. However, the availability and cost of the various devices may also be an influence on supply, although this aspect was not investigated in the survey. The age-appropriateness of different respiratory devices is in line with current literature recommendations and reflects the ability of different ages of paediatric patients to use the devices correctly (Pedersen et al., 2010; Ari and Fink, 2011). Nebulizers were listed as being appropriate for the whole paediatric population from birth, and do not require any special co-ordination or breathing technique, whilst all devices were considered to be appropriate for adolescent patients (12 years). DPIs were considered appropriate for children aged from 6 to 8 years. Factors that significantly affect aerosol generation from DPIs include peak inspiratory flow, flow acceleration and inhalation volume (Kamin et al., 2002), and paediatric patients must generate sufficient inspiratory flow to in order to generate enough fine drug aerosol particles that can enter the lung. The ability of pre-school age children to generate adequate inspiratory flow increases with age, with most children aged 5 and above being able generate sufficient flow to use a DPI (Adachi et al., 2006). It has been suggested that selection of device should be based on the ability of the patient to co-ordinate actuation and inhalation (Laube et al., 2011), and that where more than one respiratory device is required, those which are used in a similar way should be prescribed and supplied, since it is difficult to successfully train paediatric patients in different inhalation techniques simultaneously (Kamin and Kreplin, 2007). Despite these proposals, only approximately 8% of respondents (5/ 96) indicated they would never combine MDIs with DPIs, and over 50% of respondents indicated they prescribe or supply the most appropriate drug, independent of device (data not provided). It is not known if these practices are due to a lack of HCP understanding regarding differences in device technique. It is crucial that patients and caregivers use all administration devices appropriately to maximise therapeutic benefit. Medication administration errors, many of which are due to dosing errors, are common in paediatric patients, and may lead to adverse events (Ghaleb et al., 2010; Kaushal et al., 2001). Confusion with units of measure and administration of an incorrect amount have been reported with oral liquid medicines (Smith et al., 2014; Yin et al., 2014), and a large proportion of caregivers are unable to measure accurate doses (Yin et al., 2010a; Sobhani et al., 2008). Notwithstanding these observations, almost a tenth of participants believed it is not necessary to explain how to use an oral administration device. It is possible that these HCPs based their views on measuring spoons with which the majority of parents/ caregivers may be familiar. For the respiratory route of administration, poor inhaler technique may lead to insufficient drug

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delivery and hence reduced drug efficacy and disease control. A patient may be compliant in terms of dosing regimen, but a lack of competence in respiratory device use can lead to treatment failure (Lavorini et al., 2008; Everard, 2003). Paediatric patient error in inhaler technique is well documented, especially with MDIs (Malot et al., 2007; Melani et al., 2011; Crompton et al., 2006; Lavorini et al., 2008). Despite these difficulties, only approximately one third of survey participants indicated that they always explain how to use an administration device, with half this number explaining to new patients only. Reasons for not providing training included a lack of time and also the assumption that another member of staff will provide counselling, e.g. pharmacist or nurse. From the data, it was not possible to determine the proportion of pharmacists, nurses and doctors who indicated they provide training. The triggers for explaining correct device use to a patient or caregiver may differ depending on the device type and perceived previous experience of device use. For example, certain oral administration devices such as measuring spoons may be considered to be easy to use by HCPs and therefore not require explanation. Caregiver training and counselling on correct oral administration device use reduces dosing errors and improves dosing accuracy (Yin et al., 2008; Hu et al., 2013), especially when used in combination with patient information leaflets (PILs). Training and regular repeated checks on correct inhaler technique and adherence is vital to reduce errors (Crompton et al., 2006; Lavorini et al., 2008; Pedersen et al., 2010; Laube et al., 2011). It is therefore recommended that explanation of and training in correct device use is an integral part of routine patient care and that clear roles and responsibilities for this are defined within the healthcare team. It is possible that HCPs assume patients and caregivers know how to correctly use a device, and that they will refer to the PIL for help if required. Indeed, the majority of respondents believed that device usage instructions were either usually or sometimes adequate. However, there is clearly room for improvement since few respondents believed the instructions to be always adequate. There may also be an assumption that caregivers and patients will ask for assistance if they are unsure how to correctly use a device. Almost three quarters of respondents indicated that they are either never or rarely asked for assistance with oral devices, suggesting that caregivers may perceive such devices to be reasonably easy to use. Data are not available for different oral device types, although considering comments made, it is likely that when assistance is requested, it is for oral syringes. It is unsurprising that a larger proportion of respondents indicated that they are often or very often asked for help with respiratory devices, compared with oral devices, since the former are more complex to use correctly, and have greater reliance on the ability of the paediatric patient. However, in spite of the complexity of respiratory devices, approximately half the respondents are rarely or never asked for help; this may be due to patient factors such as a reluctance to ask or an assumption of correct use, or differences in HCP roles. The results for HCP awareness of patients and/or caregivers having difficulty with oral and respiratory devices are in line with the above trends for requests for assistance; over 70% were aware of patient difficulties with respiratory devices compared to approximately 40% for difficulties with oral device use. The most frequently cited reasons for difficulty in using oral devices (measuring and/or identifying the correct dose) are in line with observations from previous studies (Yin et al., 2010a; Tanner et al., 2014; Ryu and Lee, 2012; Yin et al., 2014, 2008). Difficulty with coordination (inspiration with device actuation) was the most frequently cited issue with respiratory devices, which has also been previously reported (Melani et al., 2011; Crompton et al., 2006; Lavorini et al., 2008; Pedersen et al., 2010; Laube et al., 2011). Hence the key difficulties in using devices for respiratory

administration appear to be well known by HCPs, but those for oral administration may be less well recognised. Indeed, HCPs should be aware that parents/caregivers may require assistance with identifying and measuring the correct dose even from commonly available oral devices such as measuring spoons and dosing cups. As stated above, it is important that caregivers and patients are provided with sufficient training and counselling to enable the correct use of their administration device, and improvements are required with currently provided PILs. The use of clear diagrams and plain language in PILs were recommended by participants. Indeed, PILs with pictograms are preferred by patients to text only PILs (Montagne, 2013). Interestingly, anecdotal evidence suggests that the use of symbols in PILs is not recommended by some regulatory authorities. Health literacy (the ability to understand and use information to promote health) is an important factor for a patient to be able to understand and interpret information provided in PILs. In Europe, it is estimated that nearly 50% of the population has a risk of limited health literacy (HLS-EU Consortium, 2012) and hence it is vital that PILs are written clearly and simply and that any pictograms or diagrams can be easily correctly interpreted (Montagne, 2013). Using plain language pictogram-based instructions can reduce dosing errors, especially in parents with low health literacy (Yin et al., 2008; Yin et al., 2011). The use of other media for example video clips or interactive touch screens to increase correct device use has also been suggested, and has been found to improve MDI co-ordination in adolescent patients (Savage and Goodyer, 2003). The selected administration device can have an impact on the patient acceptability of a product (CHMP, 2012) and the recommendation to develop and use “child-friendly” devices was a common theme for both oral and respiratory devices. Suggestions included appropriate device dimensions (for example, oral syringes that can measure small volumes, and suitably sized face masks for the very young), and visually appealing devices (for example the use of colours, pictures and whistles). Infants become easily distressed when using a face mask and so the design of face masks for young children is particularly important to ensure optimal respiratory drug delivery (Everard, 2003). Paediatric patient inhaler technique may be improved by the use of VHCHs with whistles and/or spinning discs that are activated during inhalation (Schultz et al., 2012) and inhalers and VHCHs can be decorated with pictures. Numerous recommendations suggested for the improvement of oral devices related to oral syringes. This is not unexpected since although oral syringes may provide superior accuracy in dosing compared to other oral devices (Grießmann et al., 2007; Dockhorn et al., 2010), as seen in this survey, they have been frequently identified as being problematic to use. Caregivers may find it difficult to identify the correct dose, and marking or colour-coding the required dose on the device may alleviate this issue (Frush et al., 2004). Other strategies such as controlling the amount of medication that can be drawn up into an oral syringe have been applied (Spiegel et al., 2013). However, there are disadvantages to such approaches, for example, the dose required might change due to the growth of the child, or the marking may be removed during the cleaning of the device. Clear units of measure are required on all oral devices, and should be aligned with dosing instructions. In the USA, improvements have been made to the provision of acceptable oral devices provided with OTC medicines following the introduction of FDA Guidance in 2011 (Yin et al., 2010b; Budnitz et al., 2014; FDA, 2011) although similar data on the availability and nature of OTC medicine devices in Europe do not appear to be readily available. Standard and consistent units of measure should be used and it has been proposed that mL should be adopted as the preferred unit of

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measure to improve clarity and avoid confusion with teaspoons and tablespoons (Yin et al., 2014). Recommendations for improvement in paediatric respiratory devices in addition to those discussed above were in line with current recommended practice (Laube et al., 2011), including for example the use of VHCHs, which should ideally be portable to allow ease of transport. There are some limitations to this study which are mostly related to the sampling procedure. First of all, although the countries selected are from different parts of Europe, they may not be representative of Europe as a whole. It was not possible to conduct this survey in all European countries due to logistical and resource constraints. Second, because email lists of HCPs in the six countries were not available, the sampling was performed on the hospital level. After sending the questionnaires to the paediatric hospitals it was not possible to track their further distribution within the organisations. Therefore exact response rates could not be calculated. However, due to poor initial participation, it was necessary to use personal contacts in order to gain sufficient responses for analysis, which may have resulted in some bias in the results. For example, over a third of respondents were UK-based, and from a small number of hospitals. In addition, the relatively low number of responses has limited the value of statistical analysis. Although the sample may not be representative of European HCPs, the survey still offers first insights into their experiences and practices on an international level. An area of future investigation is to gain an understanding of paediatric patient and caregiver views and experiences regarding their oral and respiratory devices. For example, ease of use, clarity of information provided and if and when they are trained on correct device use. 5. Conclusions This exploratory survey has provided some valuable insights into the views and experiences of European hospital doctors, nurses and pharmacists, regarding oral and respiratory administration devices for paediatric patients. These HCPs are aware of the difficulties patients and caregivers have in using their devices, especially those used for respiratory therapy. Clarity on roles and responsibilities regarding training in and demonstration of correct administration device use is required. HCPs should be given sufficient time to conduct these activities which should also become part of standard routine practice. Industry should endeavour to improve the ease of use and patient acceptability of devices together with the clarity of user information, and also consider the development and distribution of alternative multimedia to facilitate patient understanding. Thus, by increasing correct patient and caregiver use of oral and respiratory devices, therapeutic benefit will be maximised and medical burden reduced. Acknowledgements The authors would like to thank all HCPs who took part in the survey, especially those who forwarded the questionnaire to their colleagues. We would also like to thank Dr Deborah Bickmann and Dr Simon Mills for their valuable contribution to initial drafts of the questionnaire. EuPFI team members provided support for this work in their own time. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.05.041.

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Please cite this article in press as: J. Walsh, et al., Devices for oral and respiratory paediatric medicines: What do healthcare professionals think?, Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.041