A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population

A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older... Pharm Res (2018) 35: 136 https://doi.org/10.1007/s11095-018-2424-3 RESEARCH PAPER A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population 1 2 3 4 4 5 Thibault Vallet & Emilie Belissa & Sandra Laribe-Caget & Alain Chevallier & François-Xavier Chedhomme & Patrick Leglise & 4 6 7,8 3 3 5 Matthieu Piccoli & Hugues Michelon & Vanessa Bloch & Sylvie Meaume & Anne-Sophie Grancher & Nathalie Bachalat & 5 5 5 5 5 5 Imad Boulaich & Fattima Abdallah & Maite Rabus & Jean-Paul Rwabihama & Annie-Claude Ribemont & Celia Lachuer & 4 6 6 9 9 7 Ines Perquy & Laurent Lechowski & Anne Delahaye & Mathieu Depoisson & Yann Orven & Caroline Guinot & 10 11 11 11 2,8 Stephane Gibaud & Corinne Michel & Abdel Mahiou & Sid-Ahmed Belbachir & Jean-Hugues Trouvin & 2 2,8 1 Amelie Dufaÿ-Wojcicki & Vincent Boudy & Fabrice Ruiz Received: 30 January 2018 /Accepted: 2 May 2018 /Published online: 7 May 2018 The Author(s) 2018 ABSTRACT the 1079 evaluations. Factors of interest (medicines, user fea- Purpose Medicine acceptability, which is of the utmost im- tures…) were positioned on the map at the barycentre of their portance for vulnerable patients’ adherence, is driven by both evaluations and assigned to an acceptability profile. Focusing user and product characteristics. Herein, a novel multivariate on patients’ ability to swallow, we have highlighted the tool’s approach integrating the many aspects of acceptability is used efficacy in demonstrating the impact of user features on med- to discriminate positively and negatively accepted medicines icine acceptability. in the older population. Conclusions This multivariate approach provides a rele- Methods An observational study was carried out in eight vant judgement criterion for this multi-dimensional con- hospitals and eight nursing homes to collect a large set of cept. Facilitating the choice of the most appropriate real-life data on medicines uses in older patients (≥65 years). dosage form to achieve optimal acceptability in a Mapping and clustering explored these multiple observational targeted population, this tool is of real potential to improve measures and summarised the main information into an intel- clinical decisions. ligible reference framework. Resampling statistics were used to validate the model’s reliability. . . Results A three-dimensional map and two clusters defining KEY WORDS drug formulation elderly medicine . . acceptability profiles, as positive or negative, emerged from acceptability multivariate analysis swallowability * Fabrice Ruiz Hôpital Sainte Périne, Groupe Hospitalier Universitaire Paris fabrice.ruiz@clinsearch.net Ile-de-France Ouest, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France 1 7 ClinSearch, 110 Avenue Pierre Brossolette, 92240 Malakoff, France Hôpital Fernand Widal, Groupe Hospitalier Universitaire Saint-Louis – Lariboisière – Fernand-Widal, Assistance Publique-Hôpitaux de Paris Département Recherche et Développement Pharmaceutique, Agence (AP-HP), Paris, France Générale des Equipements et Produits de Santé (AGEPS), Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Université Paris Descartes, Paris, France 3 9 Hôpital Rothschild, Groupe Hospitalier Universitaire Est Hôpital Vaugirard, Groupe Hospitalier Universitaire Paris Parisien, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Ouest, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France 4 10 Hôpital Broca, Groupe Hospitalier Universitaire Paris Centre, Assistance Centre Hospitalier de l’Ouest Vosgien, Neufchâteau, France Publique-Hôpitaux de Paris (APHP), Paris, France Hôpital René Muret, Groupe Hospitalier Universitaire Paris Hôpital Joffre Dupuytren, Groupe Hospitalier Universitaire Henri Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Draveil, France (AP-HP), Sevran, France 136 Page 2 of 12 Pharm Res (2018) 35: 136 ABBREVIATIONS methodology. The study aimed to confirm the validity of this API Active Pharmaceutical Ingredient multivariate approach and to develop a decision support tool ATC Anatomical Therapeutic Chemical classification providing a judgment criterion for a multi-dimensional system concept. EMA European Medicine Agency FDA Food and Drug Administration IADL Lawton’s Instrumental Activities of Daily Living MATERIALS AND METHODS ICH International Council for Harmonization of Technical Requirements for Pharmaceuticals for Study Design Human Use MCA Multiple Correspondence Analysis A multicentre, prospective, cross-sectional, and strictly obser- MD Missing Data vational study was conducted in France between October MMSE Mini Mental State Examination 2016 and November 2017. This study was carried out in SmPC Summary of Product Characteristics collaboration with a network of physicians and pharmacists SODF Solid Oral Dosage Form in eight hospitals and eight nursing homes. The study focused on any medicine use in older patients (65 years and over), with the exception of the infusions with a catheter already present, INTRODUCTION considering that the insertion of the catheter belongs to the administration sequence of the medicine. Patients were re- Physical and cognitive deterioration due to aging may nega- cruited at random on a voluntary basis in the recruiting cen- tively impact the safety and efficacy of some medications. tres. Approvals were obtained from the French advisory com- Swallowing disorders are one such age-related alteration af- mittee for data processing in health research and the data fecting solid oral dosage form (SODF) administration (1–3). protection authority. Crushing tablets and opening capsules are commonly used to The multivariate approach aimed to design a model that achieve administration, despite pharmacokinetic/ fits with real-life data reflecting different users’ behaviours for pharmacodynamic issues that may induce dosage errors various medicines. A massive data set would be needed to (4–12). thoroughly encompass this multi-dimensional concept due to Recently, regulatory authorities such as the European the large variety of users and the wide range of products on the Medicine Agency (EMA) (13,14), the Food and Drug market. However paediatric results have demonstrated the Administration (FDA) (15) and the International Council for reference framework reliability with 680 evaluations (20). Harmonization (ICH) (16) raised the importance to develop medicinal products well suited to the characteristics of the Data Collection targeted patients, especially in frail populations. In this context medicines acceptability has been identified as a key factor of The healthcare professional observing the first medicine use the patient adherence. Acceptability could be defined as Ban following study inclusion (oral participation agreement) filled overall ability of the patient and caregiver (defined as ‘user’)to in a standardised web-questionnaire, which consists of mea- use a medicinal product as intended (or authorised)^ (17). The sures describing acceptability and information explaining EMA defined acceptability as a multi-dimensional concept acceptability. driven by characteristics of both medicines and users, be they paediatric and older populations (13,14). Measures Describing Acceptability Various methods have been used to assess medicine accept- ability in clinical studies (18), however none of the referenced Some patients from paediatric and older populations are un- studies simultaneously considered the many different dimen- able to provide reliable and valid self-evaluations due to de- sions of acceptability (swallowability, palatability, complexity velopment or deterioration of physical and cognitive abilities. of use,…). To bridge this gap a multivariate approach has To standardise data collection in these populations we used been developed and tested in the paediatric population observer reports that include only those events or behaviors (19,20). Based on a large set of medicine use evaluations com- that can be observed as encouraged (21,22). Observers had to bining multiple observational measures, an acceptability ref- report the result of the intake (fully, partly or not taken); the erence framework allows discrimination between positively patient’s reaction (positive, neutral or negative reaction); the and negatively accepted medicines in distinct subpopulations time needed to prepare - starting from the opening of the of patients. cardboard box - and to administrate - starting from the mo- This paper presents the development of an acceptability ment it is ready to use - the prescribed dose of medication. This discrete variable (10-s accuracy) was transformed into a reference framework in the older population using this Pharm Res (2018) 35: 136 Page 3 of 12 136 categorical one (Short, Medium or Long time), based on data own medications, and ability to handle finances) was used to distribution and clinical practice expertise of the authors. evaluate the patient’s autonomy. For a specific research issue, Furthermore, the use of any of the following methods to the Fried frailty phenotype (24) and the Mini-Mental State achieve administration was recorded resulting in four dichot- Examination (MMSE) (25) were collected in a specific omous variables (use or non-use): alteration of the intended recruiting centre. use (manipulate dosage form such as tablet crushed or capsule Regarding the informant, we collected the occupation of opened; use a device not provided; use another route/mode of the healthcare professional (doctor, intern, non-resident, phar- administration); divide the intake of the required dose; use macist, nurse, research associate or other). drink, texture-modified water or food to mask the taste or ease To illustrate explorations of factors affecting acceptability, swallowing; use of restraint. Each evaluation of one medicine we focused on the influence of swallowing disorders on accept- taken by one patient corresponded to a particular combina- ability of a particular medicine anonymously labelled BY^. tion of observed measures (categories) for the seven observa- tional variables. These variables were included in the analysis Data Analysis without weighting in order to describe the overall ability and willingness of patients and caregivers to use (prepare and ad- Acceptability Reference Framework minister) any medicine as intended. To develop the acceptability reference framework we followed Factors Affecting Acceptability the multivariate data analysis procedure previously published (19,20) as described briefly hereafter. Each evaluation was related to many explanatory variables in A Multiple Correspondence Analysis (MCA) was used for order to investigate their impact on acceptability and conse- the mapping process. This factorial method was performed on quently, to highlight factors affecting acceptability. a data table where each row corresponded to one medicine Observers reported the following information on medicine taken by one patient (e.g. patient n°10 taking the medicine use circumstances: the person(s) in charge of preparing and BY^), each column represented one of the seven observational administrating the medicine (patient, healthcare professionals, variables (e.g. result of the intake), with an observed measure and/or other caregiver), the location, and time of day. They (e.g. fully taken) being entered into each corresponding cell. were also required to report the exact name of the medicine The key relationships between the observed measures were under investigation (Brand name + Strength + summarised and visualised by the MCA that provided Pharmaceutical form), selected from a list specifying all an acceptability map in an intelligible, low-dimensional medicinal products available on the French market, and space. The dimensions of the map revealed those asso- some informationonthe treatmentsuchasthe required ciations and dissociations of observed measures that dose, the required dosing frequency, the treatment du- most contributed to explaining variability observed in ration, the disease/symptom treated, and the number of the data. Thus, the map highlighted the major informa- concomitant medications. Thereafter, additional data on tion in terms of medicine acceptability variation. the medicine under investigation were extracted from Subsequently, hierarchical clustering on principal compo- the summary of product characteristics (SmPC) such as nents and k-means consolidation gathered the evaluations into theactivepharmaceuticalingredient(API),the classifi- clusters defining distinct acceptability profiles. The clusters cation of API using the Anatomical Therapeutic were described by the categories significantly over- Chemical classification system (ATC), the excipients represented into their subset of evaluations in comparison to (e.g. flavour and sweetener), the physical characteristics a random distribution: v-test value greater than 1.96 (p-val- (e.g. size and colour), the method of administration, the ue<0.05). The higher the v-test value, the more strongly the nature of device (if any) or the nature and contents of category was over-represented in the cluster. container. The R packages BFactoMineR^ (26)and BMissMDA^ (27) Information on the patient were also collected: socio- were used to perform multivariate analysis and to handle miss- demographic characteristics (gender, age and weight), living ing data, respectively. situation, treatment history (first, occasional, or ongoing treat- ment with the medicine), comorbidities (coded using Model Reliability MedDRA, a standardised international medical terminology, as well as diseases), and disabilities (swallowing disorders, mus- To validate the statistical reliability of the acceptability refer- cular or rheumatologic disorders of the upper limbs, or mem- ence framework we used resampling statistics (20). ory disorders). Furthermore, the Lawton’s Instrumental To demonstrate the significance of the percentage of data Activities of Daily Living (IADL) scale (23) with 4 items (ability set variance summarised by the map (inertia) we used a non- to use telephone, mode of transportation, responsibility for parametric statistical significance test: permutation testing 136 Page 4 of 12 Pharm Res (2018) 35: 136 (28). Inertia distribution under the null hypothesis - rearrange- a Jaccard coefficient value superior or equal to 0.75 denotes a ment of labels among the observed data has no effect on the ‘good recovery’ of the cluster. We averaged the values over all test statistic - was estimated using 10,000 rearrangements of the resampling rounds and computed the 95% confidence in- data. For each round, rearrangement of the categories was terval around the mean to quantify the dispersion. performed at random for the seven constituting variables in- dependently, then mapping was performed and the inertia Acceptability Scoring explained by the newly created map was recorded. The null hypothesis could be disproved, if the proportion of rearrange- To assess medicine acceptability using the reference frame- ment with an inertia value at least as extreme as the observed work we followed the procedure previously published (19,20) statistic was less than the 5% significance level. as described hereafter. To explore the impact on the model of variations in the data The barycentre of the evaluations related to a particular we used bootstrapping (29). Tenthousandroundsofresam- medicine defined its position on the map. The medicine was pling were performed. For each simulated data set a new ref- assigned to the cluster with the nearest barycentre, which de- erence framework was created, then statistical indicators mea- fined its acceptability profile. The profiles zones were plotted sured change compared with the original one based on ob- on the acceptability map using simulations of all the possible served data. The RV coefficient (30) measured the closeness barycentre positions. Confidence ellipses surrounding the between the categories’ coordinates on the maps, and the barycentre for all dimension pairs defined an area containing Jaccard coefficient (31) measured the similarity between the its true position with 90% probability if the experiment were subsets of evaluations gathered into the clusters. For each orig- to be repeated. Each ellipse was made of 1000 points. Each inal cluster, the maximum Jaccard coefficients indicated the point was assigned to one of the clusters. The proportion of most similar cluster found among the new ones. The values points belonging to the different clusters were then recorded. ranged from 0 to 1 for both indicators. We used FactoMineR The acceptability score was structured by the acceptability to demonstrate the significance of the RV coefficient (32), while profile of the barycentre and the proportion of confidence Table I Demographic Characteristics of patients (n = 1079) n (%) Characteristics of the Patients Gender Women 758 (71) Men 307 (29) md :14 Age (years) Mean: 86.4 sd(7.2) [65, 75) 67 (6) [75, 85) 324 (30) [85, 95) 556 (52) [95, 104] 126 (12) md: 6 Place Hospital 848 (79) Nursing home 231 (21) Disabilities Swallowing disorder 187 (18) Muscular or rheumatologic disorders of the upper limbs 261 (25) Memory disorder 614 (58) IADL Scale 4 126 (12) 3 119 (11) 2 153 (14) 1 323 (31) 0 320 (32) md: 38 Number of prescribed medicines [0, 5) 81 (8) [5, 10) 428 (41) [10, +∞) 537 (51) md: 33 md: missing data Overall score calculated as a sum of the four items. For each item, a score of 1 defined an autonomous patient while a score of 0 a dependent one Pharm Res (2018) 35: 136 Page 5 of 12 136 ellipses belonging to it. We consider that a minimum of 30 and reflected existing users’ behaviours. The following ideal evaluations are required to obtain a reliable score. combination reflecting a medicine use without any problem Acceptability scores were significantly different if confidence was the most used (32% of the evaluations): BFully taken^, ellipses did not overlap on the map. BNeutral reaction^, BShort time^, BNo divided dose^, BNo Similarly, acceptability scoring may be performed for any alteration^, BNo food drink^ and BNo restraint^. The same product and user characteristic in order to explore factors combination with the category BMedium time^ and BLong affecting acceptability. time^ to replace BShort time^ were the second (14%) and the third (8%) most observed, respectively. The median prep- aration and administration time was 30 s. There were 6 miss- RESULTS ing data (md). The preparation and administration time was transformed into a categorical variable with three categories Study Participation corresponding to BShort time^ (20 s and less - 44% of the evaluations), BMedium time^ (from 30 s to 1 min - 34%) There were 1079 patients included in the study. Table I pre- and BLong time^ (more than 1 min - 22%). sents the demographic characteristics of these patients from The following combination of the worst categories was 65 years of age to centenarians. used only once: BNot taken^, BNegative reaction^, BLong Table II presents the characteristics of the 280 distinct me- time^, BUse divided dose^, BUse alteration^, BUse food dicinal products assessed: 59% were assessed only once, while drink^ and BUse restraint^. These negatively connotated cat- 3% were assessed 30 times or more. Considering, the fifth egories were used less frequently than the others. Indeed, none level of the ATC code, there were 125 distinct API in the of the prescribed dose was taken in only 0.4% of evaluations sample of medicines. and a partial dose was taken for 3.5%, while the required dose was fully taken in 96.1% of cases (md: 27). Regarding the Measures Describing Acceptability patient’s reaction, 76% of the evaluations were neutral while 11% positive and 13% negative (md: 6). The 1079 evaluations were comprised of 106 distinct combi- The results from the methods used to achieve administra- nations of categories, of the 432 mathematically possibilities, tion revealed that the required dose was divided for 13% of Table II Characteristics of the Medicines Characteristics of medicines (n =280) n(%) Formulations Divisible tablet 39 (14) Coated tablet 38 (14) Divisible coated tablet 36 (13) Capsule 35 (13) Tablet 20 (7) Orally disintegrating tablet 14 (5) Other (2% < n < 5%): oral solution, powder for oral solution, capsule sustained release, oral solution in drops, solution for injection. Other (n ≤ 2%): coated tablet sustained release, tablet sustained release, effervescent tablet, dispersible tablet, oral suspension, powder for oral suspension, patch, enrobed tablet, collyre, syrup, capsule gastro-resistant, tablet gastro-resistant, suspension for inhalation, granule sustained release, oral gel, divisible coated tablet sustained release, gastro-resistant enrobed tablet, lozenge. Anatomic Analgesics (N02) 41 (15) therapeutic Psycholeptics (N05) 39 (14) subgroups Psychoanaleptics (N06) 32 (12) (ATC2) Antiepileptics (N03) 23 (8) Drugs used in diabetes (A10) 21 (8) Antithrombotic agents (B01) 10 (5) Other (2% < n < 5%): Agents acting on the renin-angiotensin system (C09), Beta blocking agents (C07), Anti-parkinson drugs (N04), Drugs for constipation (A06), Mineral supplements (A12), Calcium channel blockers (C08), Drugs for acid related disorders (A02), Thyroid therapy (H03). Other (n ≤ 2%): Antianemic preparations (B03), Ophthalmologicals (S01), Antibacterials for systemic use (J01), Lipid modifying agents (C10), Antihypertensives (C02), Urologicals (G04), Cardiac therapy (C01), Diuretics (C03), Other nervous system drugs (N07), Antivirals for systemic use (J05), Vasoprotectives (C05), Endocrine therapy (L02), Muscle relaxants (M03), Drugs for functional gastrointestinal disorders (A03), Drugs for obstructive airway diseases (R03), Corticosteroids for systemic use (H02), Antimycobacterials (J04), Anti-inflammatory and antirheumatic products (M01), Antihemorrhagics (B02). 136 Page 6 of 12 Pharm Res (2018) 35: 136 the patients as it could not be taken whole (md: 1), in 19% of Acceptability Reference Framework the evaluations food or drink were used, either mixed with drug or taken just before or after administration, to mask the The MCA explained the total variance of the data set with 10 taste or ease swallowing (md: 1), and 5% of the patients forced dimensions. The first dimensions extracted the observed mea- themselves to take the medicine (md: 1). For 10% of the sures associations that contribute the most in explaining the evaluations a form modification, predominantly crushing variations in the data set while the last ones are restricted to tablets or opening capsules, was performed before ad- noise. The acceptability map is comprised of the first three- ministration. For 3% a device not provided with the dimensions, as they accounted for 47.2% of the data set var- medication was used to perform administration (those iance in a stable and intelligible form. Figure 1 presents the using a similar device in institution for hygienic reasons first two dimensions of the acceptability map, although it re- were not counted). For 3% an unintended route/mode mains a three-dimensional space for the following clustering of administration was used, mainly oral administration and scoring processes. of an injectable solution, swallowable tablet chewed, and The zero of the map is the barycentre of all categories and orally disintegrating tablet swallowed. These alterations evaluations. The less often the category appeared as a re- of the use were merged in a binary variable employed sponse, the furthest it was placed from the zero of the map. in 14% of the evaluations (md: 1). There were only Thus, the category BNot taken^ selected for only 0.4% of the 0.6% of missing data. evaluations is the furthest point from zero. Proximity between Fig. 1 Acceptability map Pharm Res (2018) 35: 136 Page 7 of 12 136 Table III Clusters Description Defining BPositively Accepted^ and categories revealed that they were often selected together in BNegatively Accepted^ Profiles the evaluations. For example, the categories BFully taken^ and BNo restraint^ were often selected together, but rarely with Cluster 1 - BPositively accepted^ BLong time^ and BNegative reaction^. Similarly, evaluations a b Category significantly over-represented Clust/Cat Cat/Clust v.test completed in a comparable manner, converged on the map. No alteration 91 97 19.0 Figure 1 illustrates how the ideal and the worst combinations No food/drink 92 93 18.2 were positioned onto the map. Between these extreme com- No divided dose 88 95 13.8 binations the remaining 104 combinations were positioned No restraint 85 100 13.1 according to their similarity. Short time 94 51 10.4 The dimensions structure the acceptability map. The first Neutral reaction 87 83 9.7 dimension that juxtaposes the positively connoted categories Fully taken 82 98 5.9 on the left side of the map (dimension 1 negative coordinates) Positive reaction 90 12 2.8 to the categories that are negatively connoted on the right side Cluster 2 - BNegatively accepted^ (dimension 1 positive coordinates). On the right side of the map (Fig. 1) the second dimension opposes those evaluations Category significantly over-represented Clust/Cat Cat/Clust v.test related to BUse alteration^, BUse food/drink^ and BMedium Use alteration 84 59 19.0 time^ placed at negative coordinates at the bottom of the map Use food/drink 69 68 18.2 to those related to the negatively connoted categories BUse Use divided dose 67 46 13.8 restraint^, BNot taken^, BLong time^ and BPartly taken^ on Negative reaction 67 45 13.6 the top (dimension 2 positive coordinates). The third dimen- Use restraint 100 24 13.1 sion illustrates the contrast (on the left side of the map, Fig. 1) Long time 40 45 8.4 between those evaluations related to BPositive reaction^ and Partly taken 57 10 5.1 BMedium time^ (dimension 3 negative coordinates) to those Not taken 100 2 3.2 related to BShort time^ and BNeutral reaction^ (dimension 3 Medium time 24 41 2.5 positive coordinates). Percentage of all evaluations with the category belonging to the cluster The set of evaluations was partitioned into two meaningful Percentage of all evaluations belonging to the cluster with the category clusters characterised by the categories significantly over- represented into each of them (Table III). All the categories 0.951 [0.948; 0.955]. For other rounds, the RV coefficient positively connoted were over-represented in the first cluster mean value was 0.948 [0.947; 0.949]. The averaged maxi- defining the BPositively accepted^ profile, while all the cate- mum Jaccard coefficient were 0.966 [0.965;0.967] for the first gories negatively connoted were over-represented in the sec- cluster defining the ‘Positively accepted’ profile and 0.873 ond cluster defining the BNegatively accepted^ profile. The [0.870;0.876] for the second cluster defining the ‘Negatively first cluster gathered 81% of the evaluations. accepted’ profile. Model Reliability Acceptability Scoring The sampling distribution of the inertia explained by the three-dimensional map under the null hypothesis was based We focused on a medicinal product anonymously labelled on 10,000 permutation rounds. The inertia value ranged from medicine BY^ to illustrate acceptability scoring. Figure 2 pre- 31.9 to 34.8, with a mean of 33.3 (SD 0.4). There was no sents the acceptability score of this psycholeptic drug as it was rearrangement where the statistic was superior or equal to assessed in 36 patients. The green and the red zones on the the observed inertia value (47.2%). The null hypothesis could acceptability map defined the BPositively accepted^ and the be clearly disproved and consequently the combinations of BNegatively accepted^ profiles, respectively. Even if the categories obtained from each completed evaluation question- barycentre of these evaluations was assigned to the naire were not due to chance. Higher inertia value represents BPositively accepted^ profile, this tablet cannot be assigned greater data set structure, therefore the reliability of the to this profile as a significant part of the confidence ellipses model. belong to the second cluster. The RV coefficient was significantly higher than 0 (no cor- Although the ideal combination was the most frequently relation) in all the 10,000 resampling rounds. The under-used observed, accounting for 31% of the evaluations, almost two- category BNot taken^ was not represented through 1.8% of thirds of the 19 combinations used gathered into the second the simulated data sets. In such exceptional cases the mean cluster as BNegatively accepted^, accounting for 39% of the value of the RV coefficient evaluating the likeness between the evaluations. This heterogeneity of evaluations brought us to coordinates on the maps of the remaining categories, was explore acceptability differences in subpopulations of patients. 136 Page 8 of 12 Pharm Res (2018) 35: 136 Fig. 2 Medicine BY^ acceptability score (zoom on the acceptability map) Factors Affecting Acceptability Differences in the acceptability scores reflect the significant differences observed for all the constituting variables using As age-related swallowing alteration is a major issue Fisher’s exact test for count data, with the exception of ma- affecting SODF administration, we studied the influence nipulation and administration time and divided dose of swallowing disorders on the medicine BY^ acceptabil- (Table IV). Negatively connotated categories were found to ity to illustrate explorations of factors affecting accept- be used in patients with swallowing disorders more often ability. Due to the insufficient number of patients in than their counterparts with no such disorder. As an each sub-population (n < 30) we cannot draw any con- example, there were alterations of the dosage form for clusions, nonetheless, Fig. 3 illustrates that the accept- 19% of the patients without swallowing disorders (60% ability tended to be negatively affected by swallowing tablet crushed, 20% tablet halved, and 20% tablet alteration. Indeed, the medicine BY^ tended to be ac- chewed), against 80% for the patients with swallowing cepted in those older patients without a swallowing dis- disorders (100% tablet crushed). order, while not in those with a swallowing disorder. Other than swallowing alteration, there were no sig- The larger confidence ellipses observed here reflect the nificant differences between these two subpopulations heterogeneity of the small group of evaluations placed reinforcing the impact of the studied patient character- on the acceptability map. istic on acceptability. Pharm Res (2018) 35: 136 Page 9 of 12 136 Fig. 3 Influence of swallowing disorder on acceptability score of medicine BY^ (zoom on the acceptability map) DISCUSSION user and medicine characteristics on acceptability has been highlighted. The reference framework appears to be a valid and relevant The acceptability reference frameworks in paediatric and tool to score the multi-dimensional concept of acceptability in older populations shared a great deal of similarities. The cat- the elderly in institutional care. The acceptability reference egories positively connoted and the related evaluations were framework is composed of an acceptability map providing a found adjacent to one another on both three-dimensional unique Euclidian space where elements are positioned, and maps, clearly separated from the categories negatively connot- two acceptability profiles (BPositively accepted^ and ed and the related evaluations. Two coherent clusters defining BNegatively accepted^) giving meaning to every position with- meaningful acceptability profiles, as positive or negative, in the coordinate system. Acceptability could be scored using emerged in both populations. A partition with two clusters at least 30 evaluations from the standardised questionnaire. provides an effective cut-off and consequently a relevant These results obtained using the method developed in the judgement criterion. In both populations the first cluster gath- paediatric population (19,20) validate the appropriateness of ered more than two-thirds of the evaluations. this multivariate approach to address evaluation of acceptabil- Permutation testing validated robustness and significance ity defined as a multi-faceted concept. Furthermore, the ref- of the relationships among categories highlighted by the ac- erence framework efficacy to demonstrate the impact of both ceptability map, and bootstrapping demonstrated a high 136 Page 10 of 12 Pharm Res (2018) 35: 136 Table IV Measures Related to Medicine BY^ in Patients with and without patients compared with the paediatric group (96 vs 82%). Swallowing Disorder Likewise, the reaction was neutral (76 vs 36%), the prepara- tion and administration time lower or equal to one minute (78 No swallowing Swallowing Fisher’sExact disorder disorder Test vs 52%) and the absence of restraint (95 vs 78%) were all more (n =26) (n = 10) favourably scored in the older population. These differences may have highlighted the healthcare professionals’ operation- Result of the intake al capabilities in the preparation and administration of med- Fully taken 26 (100) 7(70) 0.02 icines. Nurses reported that they returned at a later time, Partly taken 0 (0) 3 (30) sometimes without the observer, when faced with difficult pa- Nottaken 0(0) 0(0) tients refusing their treatments during the medicines delivery Patient’s reaction round: caregivers in the hospital setting may have thus Positive reaction 4 (15) 0 (0) 0.04 Neutral reaction 20 (77) 6 (60) lowered use of the category BNot taken^.Asaconsequence, the positively connoted categories were closer to the zero of Negative reaction 2 (8) 4 (40) this map, while the category BNot taken^ is farther from zero Manip. and admin. Time than it had been placed onto the paediatric acceptability map. Short time 13 (50) 2 (20) 0.18 Medium time 10 (38) 5 (50) In the paediatric population the required dose was divided Long time 3 (12) 3 (30) more often than in this study (43 vs 14%). This emphasised the Divided dose need for flexible dosage formats, and suitable measuring de- Use 4 (15) 5 (50) 0.08 vices for children, all the more so as the required dose is age- No 22 (85) 5 (50) related. There was a very low frequency of medicine alteration Alteration observed in the paediatric study, therefore the variable has not Use 5 (19) 8 (80) 0.001 yet been included in the multivariate analysis. This could be No 21 (81) 2 (20) due to a lower proportion of SODF evaluations when com- Food/drink pared to the older population (7% against 63%), as tablets and Use 3 (12) 6 (60) 0.01 capsules were more frequently altered for the elderly (74% of No 23 (88) 4 (40) BUse alteration^). Similarly, the larger proportion of SODF in Restraint the older population could explain a shorter manipulation Use 0 (0) 3 (30) 0.02 and administration time observed (78% inferior or equal to No 26 (100) 7 (70) 1 min) compared with the paediatric population (52%). number and percentage: n(%) Indeed, in the older people the SODF manipulation and ad- ministration time was inferior or equal to 1 min for 89% of stability of the map and a good recovery of the two clusters evaluations. regardless of variations in the set of evaluations. These results Age-related swallowing alteration is a major issue affecting establish the reliability of the acceptability reference frame- the overall ability and willingness of the patient to use some work in the older population, as in the paediatric population medicines as intended. Crushing tablets and opening capsules (20). are commonly used to achieve administration in patients with Although a larger set of evaluations was collected in the a swallowing disorder (4,6). That was verified by the negative older than in the paediatric populations, fewer combinations impact of swallowing disorders on the acceptability score of of categories were used (106 vs 138). In this study we did not medicine BY^. Indeed, this tablet was crushed for 80% of the include medicine uses at home. Thus, some user behaviours patients with a swallowing disorder. Alteration was related to specifically related to this setting could be missing from our a substantial increase of a required dose not fully taken, a current data. As such, most of the patients had no need to longer preparation and administration time, a negative reac- handle the primary and secondary medicine containers as tion of the patient and the use of methods to achieve admin- the required doses were dispensed by healthcare professionals. istration. Even if additional data are still needed, another In the paediatric population, the following categories were psycholeptic tablet mostly taken by patients without observed more often in hospital (n =214) than at home (n = swallowing disorders (9/10) tended to be BPositively 466): BFully taken^ (93 vs 77%), BNeutral reaction^ (42 vs accepted^ corroborating these results. Furthermore, 33%), BShort time^ (75 vs 41%), BNo food/drink^ (91 vs psycholeptic oral solutions, when used in patients without 72%), BNo reward^ (98 vs 84%), and BNo restraint^ (84 vs swallowing disorders (12/14), tended to be BNegatively 76%). The differences in the observational measures between accepted^. This suggests that, even if swallowability remains these two subpopulations reflect these differences between crucial in oral medicine acceptability, especially in older pa- medicine uses at home and in hospital. Indeed, the required tients with swallowing alteration, other aspects of oral medi- dose was fully taken significantly more often in the older cine such as palatability drive this multi-dimensional concept. Pharm Res (2018) 35: 136 Page 11 of 12 136 Further investigations have been carried out to identify the 75,013 Paris; Résidence John Lennon - 95,370 Montigny- formulations best accepted by patients with swallowing disor- lès-Cormeilles; Korian Les Arcades - 75,012 Paris; Korian ders and to highlight the critical aspect of palatability in the Nymphéas Bleus - 27,200 Vernon; Korian Samarobriva - acceptability of oral liquid preparations. 80,000 Amiens) for their help in the data collection. Finally, This study underlines the need to consider the specific fea- many thanks to all of the students who have actively recruited tures of each targeted users to prescribe or develop a medicine patients in this study: Sacha Barsan, Jonathan Mimoun, with the best adapted characteristics to reach an optimal ac- Laetitia Valery, Ingrid Vallée (Hôpital Rothschild), Hugues ceptability. The acceptability reference framework could pro- Feltize-Nanguem, Isaure Magnus (Hôpital Sainte-Périne) vide us with relevant knowledge on such factors positively and Inès Dufier (Hôpital René Muret). affecting this multi-dimensionnal concept, and so appears to be a relevant decision support tool for medicinal product de- FUNDING signers and healthcare profesionnals. No funding was received for this study. ClinSearch and the Paris Public Hospital (AP HP) financed this study. The publi- cation of study results was not contingent on the sponsor’s CONCLUSION approval or censorship of the manuscript. This article presents a novel tool assessing the multi- Open Access This article is distributed under the terms of the dimensional concept of medicines acceptability in the elderly Creative Commons Attribution 4.0 International License in institutional care. Based on a large set of medicine use (http://creativecommons.org/licenses/by/4.0/), which per- evaluations combining several objective measures, an accept- mits unrestricted use, distribution, and reproduction in any ability reference framework has been developed. Medicines, medium, provided you give appropriate credit to the original as well as user or product characteristics, may be positioned on author(s) and the source, provide a link to the Creative a three-dimensional acceptability map and assigned to an ac- Commons license, and indicate if changes were made. ceptability profile: BPositively accepted^ or BNegatively accepted^. The reliability and relevancy of this acceptability reference framework validate the multivariate approach trans- REFERENCES posed from the paediatric population. Due to the wide range of medicines available on the global market, and the large 1. Stegemann S, Gosch M, Breitkreutz J. Swallowing dysfunction and variety of users, additional data are being collected to contin- dysphagia is an unrecognized challenge for oral drug therapy. Int J uously improve our knowledge on this complex phenomenon Pharm. 2012;430(1):197–206. through the investigation of further settings, pathologies and 2. Lindgren S, Janzon L. Prevalence of swallowing complaints and clinical findings among 50-79-year-old men and women in an ur- formulations. This decision support tool facilitates the identi- ban population. Dysphagia. 1991;6(4):187–92. fication of those medicine features that best fit user character- 3. Nilsson H, Ekberg O, Olsson R, Hindfelt B. 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Abstract

Pharm Res (2018) 35: 136 https://doi.org/10.1007/s11095-018-2424-3 RESEARCH PAPER A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population 1 2 3 4 4 5 Thibault Vallet & Emilie Belissa & Sandra Laribe-Caget & Alain Chevallier & François-Xavier Chedhomme & Patrick Leglise & 4 6 7,8 3 3 5 Matthieu Piccoli & Hugues Michelon & Vanessa Bloch & Sylvie Meaume & Anne-Sophie Grancher & Nathalie Bachalat & 5 5 5 5 5 5 Imad Boulaich & Fattima Abdallah & Maite Rabus & Jean-Paul Rwabihama & Annie-Claude Ribemont & Celia Lachuer & 4 6 6 9 9 7 Ines Perquy & Laurent Lechowski & Anne Delahaye & Mathieu Depoisson & Yann Orven & Caroline Guinot & 10 11 11 11 2,8 Stephane Gibaud & Corinne Michel & Abdel Mahiou & Sid-Ahmed Belbachir & Jean-Hugues Trouvin & 2 2,8 1 Amelie Dufaÿ-Wojcicki & Vincent Boudy & Fabrice Ruiz Received: 30 January 2018 /Accepted: 2 May 2018 /Published online: 7 May 2018 The Author(s) 2018 ABSTRACT the 1079 evaluations. Factors of interest (medicines, user fea- Purpose Medicine acceptability, which is of the utmost im- tures…) were positioned on the map at the barycentre of their portance for vulnerable patients’ adherence, is driven by both evaluations and assigned to an acceptability profile. Focusing user and product characteristics. Herein, a novel multivariate on patients’ ability to swallow, we have highlighted the tool’s approach integrating the many aspects of acceptability is used efficacy in demonstrating the impact of user features on med- to discriminate positively and negatively accepted medicines icine acceptability. in the older population. Conclusions This multivariate approach provides a rele- Methods An observational study was carried out in eight vant judgement criterion for this multi-dimensional con- hospitals and eight nursing homes to collect a large set of cept. Facilitating the choice of the most appropriate real-life data on medicines uses in older patients (≥65 years). dosage form to achieve optimal acceptability in a Mapping and clustering explored these multiple observational targeted population, this tool is of real potential to improve measures and summarised the main information into an intel- clinical decisions. ligible reference framework. Resampling statistics were used to validate the model’s reliability. . . Results A three-dimensional map and two clusters defining KEY WORDS drug formulation elderly medicine . . acceptability profiles, as positive or negative, emerged from acceptability multivariate analysis swallowability * Fabrice Ruiz Hôpital Sainte Périne, Groupe Hospitalier Universitaire Paris fabrice.ruiz@clinsearch.net Ile-de-France Ouest, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France 1 7 ClinSearch, 110 Avenue Pierre Brossolette, 92240 Malakoff, France Hôpital Fernand Widal, Groupe Hospitalier Universitaire Saint-Louis – Lariboisière – Fernand-Widal, Assistance Publique-Hôpitaux de Paris Département Recherche et Développement Pharmaceutique, Agence (AP-HP), Paris, France Générale des Equipements et Produits de Santé (AGEPS), Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Université Paris Descartes, Paris, France 3 9 Hôpital Rothschild, Groupe Hospitalier Universitaire Est Hôpital Vaugirard, Groupe Hospitalier Universitaire Paris Parisien, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Ouest, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France 4 10 Hôpital Broca, Groupe Hospitalier Universitaire Paris Centre, Assistance Centre Hospitalier de l’Ouest Vosgien, Neufchâteau, France Publique-Hôpitaux de Paris (APHP), Paris, France Hôpital René Muret, Groupe Hospitalier Universitaire Paris Hôpital Joffre Dupuytren, Groupe Hospitalier Universitaire Henri Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Draveil, France (AP-HP), Sevran, France 136 Page 2 of 12 Pharm Res (2018) 35: 136 ABBREVIATIONS methodology. The study aimed to confirm the validity of this API Active Pharmaceutical Ingredient multivariate approach and to develop a decision support tool ATC Anatomical Therapeutic Chemical classification providing a judgment criterion for a multi-dimensional system concept. EMA European Medicine Agency FDA Food and Drug Administration IADL Lawton’s Instrumental Activities of Daily Living MATERIALS AND METHODS ICH International Council for Harmonization of Technical Requirements for Pharmaceuticals for Study Design Human Use MCA Multiple Correspondence Analysis A multicentre, prospective, cross-sectional, and strictly obser- MD Missing Data vational study was conducted in France between October MMSE Mini Mental State Examination 2016 and November 2017. This study was carried out in SmPC Summary of Product Characteristics collaboration with a network of physicians and pharmacists SODF Solid Oral Dosage Form in eight hospitals and eight nursing homes. The study focused on any medicine use in older patients (65 years and over), with the exception of the infusions with a catheter already present, INTRODUCTION considering that the insertion of the catheter belongs to the administration sequence of the medicine. Patients were re- Physical and cognitive deterioration due to aging may nega- cruited at random on a voluntary basis in the recruiting cen- tively impact the safety and efficacy of some medications. tres. Approvals were obtained from the French advisory com- Swallowing disorders are one such age-related alteration af- mittee for data processing in health research and the data fecting solid oral dosage form (SODF) administration (1–3). protection authority. Crushing tablets and opening capsules are commonly used to The multivariate approach aimed to design a model that achieve administration, despite pharmacokinetic/ fits with real-life data reflecting different users’ behaviours for pharmacodynamic issues that may induce dosage errors various medicines. A massive data set would be needed to (4–12). thoroughly encompass this multi-dimensional concept due to Recently, regulatory authorities such as the European the large variety of users and the wide range of products on the Medicine Agency (EMA) (13,14), the Food and Drug market. However paediatric results have demonstrated the Administration (FDA) (15) and the International Council for reference framework reliability with 680 evaluations (20). Harmonization (ICH) (16) raised the importance to develop medicinal products well suited to the characteristics of the Data Collection targeted patients, especially in frail populations. In this context medicines acceptability has been identified as a key factor of The healthcare professional observing the first medicine use the patient adherence. Acceptability could be defined as Ban following study inclusion (oral participation agreement) filled overall ability of the patient and caregiver (defined as ‘user’)to in a standardised web-questionnaire, which consists of mea- use a medicinal product as intended (or authorised)^ (17). The sures describing acceptability and information explaining EMA defined acceptability as a multi-dimensional concept acceptability. driven by characteristics of both medicines and users, be they paediatric and older populations (13,14). Measures Describing Acceptability Various methods have been used to assess medicine accept- ability in clinical studies (18), however none of the referenced Some patients from paediatric and older populations are un- studies simultaneously considered the many different dimen- able to provide reliable and valid self-evaluations due to de- sions of acceptability (swallowability, palatability, complexity velopment or deterioration of physical and cognitive abilities. of use,…). To bridge this gap a multivariate approach has To standardise data collection in these populations we used been developed and tested in the paediatric population observer reports that include only those events or behaviors (19,20). Based on a large set of medicine use evaluations com- that can be observed as encouraged (21,22). Observers had to bining multiple observational measures, an acceptability ref- report the result of the intake (fully, partly or not taken); the erence framework allows discrimination between positively patient’s reaction (positive, neutral or negative reaction); the and negatively accepted medicines in distinct subpopulations time needed to prepare - starting from the opening of the of patients. cardboard box - and to administrate - starting from the mo- This paper presents the development of an acceptability ment it is ready to use - the prescribed dose of medication. This discrete variable (10-s accuracy) was transformed into a reference framework in the older population using this Pharm Res (2018) 35: 136 Page 3 of 12 136 categorical one (Short, Medium or Long time), based on data own medications, and ability to handle finances) was used to distribution and clinical practice expertise of the authors. evaluate the patient’s autonomy. For a specific research issue, Furthermore, the use of any of the following methods to the Fried frailty phenotype (24) and the Mini-Mental State achieve administration was recorded resulting in four dichot- Examination (MMSE) (25) were collected in a specific omous variables (use or non-use): alteration of the intended recruiting centre. use (manipulate dosage form such as tablet crushed or capsule Regarding the informant, we collected the occupation of opened; use a device not provided; use another route/mode of the healthcare professional (doctor, intern, non-resident, phar- administration); divide the intake of the required dose; use macist, nurse, research associate or other). drink, texture-modified water or food to mask the taste or ease To illustrate explorations of factors affecting acceptability, swallowing; use of restraint. Each evaluation of one medicine we focused on the influence of swallowing disorders on accept- taken by one patient corresponded to a particular combina- ability of a particular medicine anonymously labelled BY^. tion of observed measures (categories) for the seven observa- tional variables. These variables were included in the analysis Data Analysis without weighting in order to describe the overall ability and willingness of patients and caregivers to use (prepare and ad- Acceptability Reference Framework minister) any medicine as intended. To develop the acceptability reference framework we followed Factors Affecting Acceptability the multivariate data analysis procedure previously published (19,20) as described briefly hereafter. Each evaluation was related to many explanatory variables in A Multiple Correspondence Analysis (MCA) was used for order to investigate their impact on acceptability and conse- the mapping process. This factorial method was performed on quently, to highlight factors affecting acceptability. a data table where each row corresponded to one medicine Observers reported the following information on medicine taken by one patient (e.g. patient n°10 taking the medicine use circumstances: the person(s) in charge of preparing and BY^), each column represented one of the seven observational administrating the medicine (patient, healthcare professionals, variables (e.g. result of the intake), with an observed measure and/or other caregiver), the location, and time of day. They (e.g. fully taken) being entered into each corresponding cell. were also required to report the exact name of the medicine The key relationships between the observed measures were under investigation (Brand name + Strength + summarised and visualised by the MCA that provided Pharmaceutical form), selected from a list specifying all an acceptability map in an intelligible, low-dimensional medicinal products available on the French market, and space. The dimensions of the map revealed those asso- some informationonthe treatmentsuchasthe required ciations and dissociations of observed measures that dose, the required dosing frequency, the treatment du- most contributed to explaining variability observed in ration, the disease/symptom treated, and the number of the data. Thus, the map highlighted the major informa- concomitant medications. Thereafter, additional data on tion in terms of medicine acceptability variation. the medicine under investigation were extracted from Subsequently, hierarchical clustering on principal compo- the summary of product characteristics (SmPC) such as nents and k-means consolidation gathered the evaluations into theactivepharmaceuticalingredient(API),the classifi- clusters defining distinct acceptability profiles. The clusters cation of API using the Anatomical Therapeutic were described by the categories significantly over- Chemical classification system (ATC), the excipients represented into their subset of evaluations in comparison to (e.g. flavour and sweetener), the physical characteristics a random distribution: v-test value greater than 1.96 (p-val- (e.g. size and colour), the method of administration, the ue<0.05). The higher the v-test value, the more strongly the nature of device (if any) or the nature and contents of category was over-represented in the cluster. container. The R packages BFactoMineR^ (26)and BMissMDA^ (27) Information on the patient were also collected: socio- were used to perform multivariate analysis and to handle miss- demographic characteristics (gender, age and weight), living ing data, respectively. situation, treatment history (first, occasional, or ongoing treat- ment with the medicine), comorbidities (coded using Model Reliability MedDRA, a standardised international medical terminology, as well as diseases), and disabilities (swallowing disorders, mus- To validate the statistical reliability of the acceptability refer- cular or rheumatologic disorders of the upper limbs, or mem- ence framework we used resampling statistics (20). ory disorders). Furthermore, the Lawton’s Instrumental To demonstrate the significance of the percentage of data Activities of Daily Living (IADL) scale (23) with 4 items (ability set variance summarised by the map (inertia) we used a non- to use telephone, mode of transportation, responsibility for parametric statistical significance test: permutation testing 136 Page 4 of 12 Pharm Res (2018) 35: 136 (28). Inertia distribution under the null hypothesis - rearrange- a Jaccard coefficient value superior or equal to 0.75 denotes a ment of labels among the observed data has no effect on the ‘good recovery’ of the cluster. We averaged the values over all test statistic - was estimated using 10,000 rearrangements of the resampling rounds and computed the 95% confidence in- data. For each round, rearrangement of the categories was terval around the mean to quantify the dispersion. performed at random for the seven constituting variables in- dependently, then mapping was performed and the inertia Acceptability Scoring explained by the newly created map was recorded. The null hypothesis could be disproved, if the proportion of rearrange- To assess medicine acceptability using the reference frame- ment with an inertia value at least as extreme as the observed work we followed the procedure previously published (19,20) statistic was less than the 5% significance level. as described hereafter. To explore the impact on the model of variations in the data The barycentre of the evaluations related to a particular we used bootstrapping (29). Tenthousandroundsofresam- medicine defined its position on the map. The medicine was pling were performed. For each simulated data set a new ref- assigned to the cluster with the nearest barycentre, which de- erence framework was created, then statistical indicators mea- fined its acceptability profile. The profiles zones were plotted sured change compared with the original one based on ob- on the acceptability map using simulations of all the possible served data. The RV coefficient (30) measured the closeness barycentre positions. Confidence ellipses surrounding the between the categories’ coordinates on the maps, and the barycentre for all dimension pairs defined an area containing Jaccard coefficient (31) measured the similarity between the its true position with 90% probability if the experiment were subsets of evaluations gathered into the clusters. For each orig- to be repeated. Each ellipse was made of 1000 points. Each inal cluster, the maximum Jaccard coefficients indicated the point was assigned to one of the clusters. The proportion of most similar cluster found among the new ones. The values points belonging to the different clusters were then recorded. ranged from 0 to 1 for both indicators. We used FactoMineR The acceptability score was structured by the acceptability to demonstrate the significance of the RV coefficient (32), while profile of the barycentre and the proportion of confidence Table I Demographic Characteristics of patients (n = 1079) n (%) Characteristics of the Patients Gender Women 758 (71) Men 307 (29) md :14 Age (years) Mean: 86.4 sd(7.2) [65, 75) 67 (6) [75, 85) 324 (30) [85, 95) 556 (52) [95, 104] 126 (12) md: 6 Place Hospital 848 (79) Nursing home 231 (21) Disabilities Swallowing disorder 187 (18) Muscular or rheumatologic disorders of the upper limbs 261 (25) Memory disorder 614 (58) IADL Scale 4 126 (12) 3 119 (11) 2 153 (14) 1 323 (31) 0 320 (32) md: 38 Number of prescribed medicines [0, 5) 81 (8) [5, 10) 428 (41) [10, +∞) 537 (51) md: 33 md: missing data Overall score calculated as a sum of the four items. For each item, a score of 1 defined an autonomous patient while a score of 0 a dependent one Pharm Res (2018) 35: 136 Page 5 of 12 136 ellipses belonging to it. We consider that a minimum of 30 and reflected existing users’ behaviours. The following ideal evaluations are required to obtain a reliable score. combination reflecting a medicine use without any problem Acceptability scores were significantly different if confidence was the most used (32% of the evaluations): BFully taken^, ellipses did not overlap on the map. BNeutral reaction^, BShort time^, BNo divided dose^, BNo Similarly, acceptability scoring may be performed for any alteration^, BNo food drink^ and BNo restraint^. The same product and user characteristic in order to explore factors combination with the category BMedium time^ and BLong affecting acceptability. time^ to replace BShort time^ were the second (14%) and the third (8%) most observed, respectively. The median prep- aration and administration time was 30 s. There were 6 miss- RESULTS ing data (md). The preparation and administration time was transformed into a categorical variable with three categories Study Participation corresponding to BShort time^ (20 s and less - 44% of the evaluations), BMedium time^ (from 30 s to 1 min - 34%) There were 1079 patients included in the study. Table I pre- and BLong time^ (more than 1 min - 22%). sents the demographic characteristics of these patients from The following combination of the worst categories was 65 years of age to centenarians. used only once: BNot taken^, BNegative reaction^, BLong Table II presents the characteristics of the 280 distinct me- time^, BUse divided dose^, BUse alteration^, BUse food dicinal products assessed: 59% were assessed only once, while drink^ and BUse restraint^. These negatively connotated cat- 3% were assessed 30 times or more. Considering, the fifth egories were used less frequently than the others. Indeed, none level of the ATC code, there were 125 distinct API in the of the prescribed dose was taken in only 0.4% of evaluations sample of medicines. and a partial dose was taken for 3.5%, while the required dose was fully taken in 96.1% of cases (md: 27). Regarding the Measures Describing Acceptability patient’s reaction, 76% of the evaluations were neutral while 11% positive and 13% negative (md: 6). The 1079 evaluations were comprised of 106 distinct combi- The results from the methods used to achieve administra- nations of categories, of the 432 mathematically possibilities, tion revealed that the required dose was divided for 13% of Table II Characteristics of the Medicines Characteristics of medicines (n =280) n(%) Formulations Divisible tablet 39 (14) Coated tablet 38 (14) Divisible coated tablet 36 (13) Capsule 35 (13) Tablet 20 (7) Orally disintegrating tablet 14 (5) Other (2% < n < 5%): oral solution, powder for oral solution, capsule sustained release, oral solution in drops, solution for injection. Other (n ≤ 2%): coated tablet sustained release, tablet sustained release, effervescent tablet, dispersible tablet, oral suspension, powder for oral suspension, patch, enrobed tablet, collyre, syrup, capsule gastro-resistant, tablet gastro-resistant, suspension for inhalation, granule sustained release, oral gel, divisible coated tablet sustained release, gastro-resistant enrobed tablet, lozenge. Anatomic Analgesics (N02) 41 (15) therapeutic Psycholeptics (N05) 39 (14) subgroups Psychoanaleptics (N06) 32 (12) (ATC2) Antiepileptics (N03) 23 (8) Drugs used in diabetes (A10) 21 (8) Antithrombotic agents (B01) 10 (5) Other (2% < n < 5%): Agents acting on the renin-angiotensin system (C09), Beta blocking agents (C07), Anti-parkinson drugs (N04), Drugs for constipation (A06), Mineral supplements (A12), Calcium channel blockers (C08), Drugs for acid related disorders (A02), Thyroid therapy (H03). Other (n ≤ 2%): Antianemic preparations (B03), Ophthalmologicals (S01), Antibacterials for systemic use (J01), Lipid modifying agents (C10), Antihypertensives (C02), Urologicals (G04), Cardiac therapy (C01), Diuretics (C03), Other nervous system drugs (N07), Antivirals for systemic use (J05), Vasoprotectives (C05), Endocrine therapy (L02), Muscle relaxants (M03), Drugs for functional gastrointestinal disorders (A03), Drugs for obstructive airway diseases (R03), Corticosteroids for systemic use (H02), Antimycobacterials (J04), Anti-inflammatory and antirheumatic products (M01), Antihemorrhagics (B02). 136 Page 6 of 12 Pharm Res (2018) 35: 136 the patients as it could not be taken whole (md: 1), in 19% of Acceptability Reference Framework the evaluations food or drink were used, either mixed with drug or taken just before or after administration, to mask the The MCA explained the total variance of the data set with 10 taste or ease swallowing (md: 1), and 5% of the patients forced dimensions. The first dimensions extracted the observed mea- themselves to take the medicine (md: 1). For 10% of the sures associations that contribute the most in explaining the evaluations a form modification, predominantly crushing variations in the data set while the last ones are restricted to tablets or opening capsules, was performed before ad- noise. The acceptability map is comprised of the first three- ministration. For 3% a device not provided with the dimensions, as they accounted for 47.2% of the data set var- medication was used to perform administration (those iance in a stable and intelligible form. Figure 1 presents the using a similar device in institution for hygienic reasons first two dimensions of the acceptability map, although it re- were not counted). For 3% an unintended route/mode mains a three-dimensional space for the following clustering of administration was used, mainly oral administration and scoring processes. of an injectable solution, swallowable tablet chewed, and The zero of the map is the barycentre of all categories and orally disintegrating tablet swallowed. These alterations evaluations. The less often the category appeared as a re- of the use were merged in a binary variable employed sponse, the furthest it was placed from the zero of the map. in 14% of the evaluations (md: 1). There were only Thus, the category BNot taken^ selected for only 0.4% of the 0.6% of missing data. evaluations is the furthest point from zero. Proximity between Fig. 1 Acceptability map Pharm Res (2018) 35: 136 Page 7 of 12 136 Table III Clusters Description Defining BPositively Accepted^ and categories revealed that they were often selected together in BNegatively Accepted^ Profiles the evaluations. For example, the categories BFully taken^ and BNo restraint^ were often selected together, but rarely with Cluster 1 - BPositively accepted^ BLong time^ and BNegative reaction^. Similarly, evaluations a b Category significantly over-represented Clust/Cat Cat/Clust v.test completed in a comparable manner, converged on the map. No alteration 91 97 19.0 Figure 1 illustrates how the ideal and the worst combinations No food/drink 92 93 18.2 were positioned onto the map. Between these extreme com- No divided dose 88 95 13.8 binations the remaining 104 combinations were positioned No restraint 85 100 13.1 according to their similarity. Short time 94 51 10.4 The dimensions structure the acceptability map. The first Neutral reaction 87 83 9.7 dimension that juxtaposes the positively connoted categories Fully taken 82 98 5.9 on the left side of the map (dimension 1 negative coordinates) Positive reaction 90 12 2.8 to the categories that are negatively connoted on the right side Cluster 2 - BNegatively accepted^ (dimension 1 positive coordinates). On the right side of the map (Fig. 1) the second dimension opposes those evaluations Category significantly over-represented Clust/Cat Cat/Clust v.test related to BUse alteration^, BUse food/drink^ and BMedium Use alteration 84 59 19.0 time^ placed at negative coordinates at the bottom of the map Use food/drink 69 68 18.2 to those related to the negatively connoted categories BUse Use divided dose 67 46 13.8 restraint^, BNot taken^, BLong time^ and BPartly taken^ on Negative reaction 67 45 13.6 the top (dimension 2 positive coordinates). The third dimen- Use restraint 100 24 13.1 sion illustrates the contrast (on the left side of the map, Fig. 1) Long time 40 45 8.4 between those evaluations related to BPositive reaction^ and Partly taken 57 10 5.1 BMedium time^ (dimension 3 negative coordinates) to those Not taken 100 2 3.2 related to BShort time^ and BNeutral reaction^ (dimension 3 Medium time 24 41 2.5 positive coordinates). Percentage of all evaluations with the category belonging to the cluster The set of evaluations was partitioned into two meaningful Percentage of all evaluations belonging to the cluster with the category clusters characterised by the categories significantly over- represented into each of them (Table III). All the categories 0.951 [0.948; 0.955]. For other rounds, the RV coefficient positively connoted were over-represented in the first cluster mean value was 0.948 [0.947; 0.949]. The averaged maxi- defining the BPositively accepted^ profile, while all the cate- mum Jaccard coefficient were 0.966 [0.965;0.967] for the first gories negatively connoted were over-represented in the sec- cluster defining the ‘Positively accepted’ profile and 0.873 ond cluster defining the BNegatively accepted^ profile. The [0.870;0.876] for the second cluster defining the ‘Negatively first cluster gathered 81% of the evaluations. accepted’ profile. Model Reliability Acceptability Scoring The sampling distribution of the inertia explained by the three-dimensional map under the null hypothesis was based We focused on a medicinal product anonymously labelled on 10,000 permutation rounds. The inertia value ranged from medicine BY^ to illustrate acceptability scoring. Figure 2 pre- 31.9 to 34.8, with a mean of 33.3 (SD 0.4). There was no sents the acceptability score of this psycholeptic drug as it was rearrangement where the statistic was superior or equal to assessed in 36 patients. The green and the red zones on the the observed inertia value (47.2%). The null hypothesis could acceptability map defined the BPositively accepted^ and the be clearly disproved and consequently the combinations of BNegatively accepted^ profiles, respectively. Even if the categories obtained from each completed evaluation question- barycentre of these evaluations was assigned to the naire were not due to chance. Higher inertia value represents BPositively accepted^ profile, this tablet cannot be assigned greater data set structure, therefore the reliability of the to this profile as a significant part of the confidence ellipses model. belong to the second cluster. The RV coefficient was significantly higher than 0 (no cor- Although the ideal combination was the most frequently relation) in all the 10,000 resampling rounds. The under-used observed, accounting for 31% of the evaluations, almost two- category BNot taken^ was not represented through 1.8% of thirds of the 19 combinations used gathered into the second the simulated data sets. In such exceptional cases the mean cluster as BNegatively accepted^, accounting for 39% of the value of the RV coefficient evaluating the likeness between the evaluations. This heterogeneity of evaluations brought us to coordinates on the maps of the remaining categories, was explore acceptability differences in subpopulations of patients. 136 Page 8 of 12 Pharm Res (2018) 35: 136 Fig. 2 Medicine BY^ acceptability score (zoom on the acceptability map) Factors Affecting Acceptability Differences in the acceptability scores reflect the significant differences observed for all the constituting variables using As age-related swallowing alteration is a major issue Fisher’s exact test for count data, with the exception of ma- affecting SODF administration, we studied the influence nipulation and administration time and divided dose of swallowing disorders on the medicine BY^ acceptabil- (Table IV). Negatively connotated categories were found to ity to illustrate explorations of factors affecting accept- be used in patients with swallowing disorders more often ability. Due to the insufficient number of patients in than their counterparts with no such disorder. As an each sub-population (n < 30) we cannot draw any con- example, there were alterations of the dosage form for clusions, nonetheless, Fig. 3 illustrates that the accept- 19% of the patients without swallowing disorders (60% ability tended to be negatively affected by swallowing tablet crushed, 20% tablet halved, and 20% tablet alteration. Indeed, the medicine BY^ tended to be ac- chewed), against 80% for the patients with swallowing cepted in those older patients without a swallowing dis- disorders (100% tablet crushed). order, while not in those with a swallowing disorder. Other than swallowing alteration, there were no sig- The larger confidence ellipses observed here reflect the nificant differences between these two subpopulations heterogeneity of the small group of evaluations placed reinforcing the impact of the studied patient character- on the acceptability map. istic on acceptability. Pharm Res (2018) 35: 136 Page 9 of 12 136 Fig. 3 Influence of swallowing disorder on acceptability score of medicine BY^ (zoom on the acceptability map) DISCUSSION user and medicine characteristics on acceptability has been highlighted. The reference framework appears to be a valid and relevant The acceptability reference frameworks in paediatric and tool to score the multi-dimensional concept of acceptability in older populations shared a great deal of similarities. The cat- the elderly in institutional care. The acceptability reference egories positively connoted and the related evaluations were framework is composed of an acceptability map providing a found adjacent to one another on both three-dimensional unique Euclidian space where elements are positioned, and maps, clearly separated from the categories negatively connot- two acceptability profiles (BPositively accepted^ and ed and the related evaluations. Two coherent clusters defining BNegatively accepted^) giving meaning to every position with- meaningful acceptability profiles, as positive or negative, in the coordinate system. Acceptability could be scored using emerged in both populations. A partition with two clusters at least 30 evaluations from the standardised questionnaire. provides an effective cut-off and consequently a relevant These results obtained using the method developed in the judgement criterion. In both populations the first cluster gath- paediatric population (19,20) validate the appropriateness of ered more than two-thirds of the evaluations. this multivariate approach to address evaluation of acceptabil- Permutation testing validated robustness and significance ity defined as a multi-faceted concept. Furthermore, the ref- of the relationships among categories highlighted by the ac- erence framework efficacy to demonstrate the impact of both ceptability map, and bootstrapping demonstrated a high 136 Page 10 of 12 Pharm Res (2018) 35: 136 Table IV Measures Related to Medicine BY^ in Patients with and without patients compared with the paediatric group (96 vs 82%). Swallowing Disorder Likewise, the reaction was neutral (76 vs 36%), the prepara- tion and administration time lower or equal to one minute (78 No swallowing Swallowing Fisher’sExact disorder disorder Test vs 52%) and the absence of restraint (95 vs 78%) were all more (n =26) (n = 10) favourably scored in the older population. These differences may have highlighted the healthcare professionals’ operation- Result of the intake al capabilities in the preparation and administration of med- Fully taken 26 (100) 7(70) 0.02 icines. Nurses reported that they returned at a later time, Partly taken 0 (0) 3 (30) sometimes without the observer, when faced with difficult pa- Nottaken 0(0) 0(0) tients refusing their treatments during the medicines delivery Patient’s reaction round: caregivers in the hospital setting may have thus Positive reaction 4 (15) 0 (0) 0.04 Neutral reaction 20 (77) 6 (60) lowered use of the category BNot taken^.Asaconsequence, the positively connoted categories were closer to the zero of Negative reaction 2 (8) 4 (40) this map, while the category BNot taken^ is farther from zero Manip. and admin. Time than it had been placed onto the paediatric acceptability map. Short time 13 (50) 2 (20) 0.18 Medium time 10 (38) 5 (50) In the paediatric population the required dose was divided Long time 3 (12) 3 (30) more often than in this study (43 vs 14%). This emphasised the Divided dose need for flexible dosage formats, and suitable measuring de- Use 4 (15) 5 (50) 0.08 vices for children, all the more so as the required dose is age- No 22 (85) 5 (50) related. There was a very low frequency of medicine alteration Alteration observed in the paediatric study, therefore the variable has not Use 5 (19) 8 (80) 0.001 yet been included in the multivariate analysis. This could be No 21 (81) 2 (20) due to a lower proportion of SODF evaluations when com- Food/drink pared to the older population (7% against 63%), as tablets and Use 3 (12) 6 (60) 0.01 capsules were more frequently altered for the elderly (74% of No 23 (88) 4 (40) BUse alteration^). Similarly, the larger proportion of SODF in Restraint the older population could explain a shorter manipulation Use 0 (0) 3 (30) 0.02 and administration time observed (78% inferior or equal to No 26 (100) 7 (70) 1 min) compared with the paediatric population (52%). number and percentage: n(%) Indeed, in the older people the SODF manipulation and ad- ministration time was inferior or equal to 1 min for 89% of stability of the map and a good recovery of the two clusters evaluations. regardless of variations in the set of evaluations. These results Age-related swallowing alteration is a major issue affecting establish the reliability of the acceptability reference frame- the overall ability and willingness of the patient to use some work in the older population, as in the paediatric population medicines as intended. Crushing tablets and opening capsules (20). are commonly used to achieve administration in patients with Although a larger set of evaluations was collected in the a swallowing disorder (4,6). That was verified by the negative older than in the paediatric populations, fewer combinations impact of swallowing disorders on the acceptability score of of categories were used (106 vs 138). In this study we did not medicine BY^. Indeed, this tablet was crushed for 80% of the include medicine uses at home. Thus, some user behaviours patients with a swallowing disorder. Alteration was related to specifically related to this setting could be missing from our a substantial increase of a required dose not fully taken, a current data. As such, most of the patients had no need to longer preparation and administration time, a negative reac- handle the primary and secondary medicine containers as tion of the patient and the use of methods to achieve admin- the required doses were dispensed by healthcare professionals. istration. Even if additional data are still needed, another In the paediatric population, the following categories were psycholeptic tablet mostly taken by patients without observed more often in hospital (n =214) than at home (n = swallowing disorders (9/10) tended to be BPositively 466): BFully taken^ (93 vs 77%), BNeutral reaction^ (42 vs accepted^ corroborating these results. Furthermore, 33%), BShort time^ (75 vs 41%), BNo food/drink^ (91 vs psycholeptic oral solutions, when used in patients without 72%), BNo reward^ (98 vs 84%), and BNo restraint^ (84 vs swallowing disorders (12/14), tended to be BNegatively 76%). The differences in the observational measures between accepted^. This suggests that, even if swallowability remains these two subpopulations reflect these differences between crucial in oral medicine acceptability, especially in older pa- medicine uses at home and in hospital. Indeed, the required tients with swallowing alteration, other aspects of oral medi- dose was fully taken significantly more often in the older cine such as palatability drive this multi-dimensional concept. Pharm Res (2018) 35: 136 Page 11 of 12 136 Further investigations have been carried out to identify the 75,013 Paris; Résidence John Lennon - 95,370 Montigny- formulations best accepted by patients with swallowing disor- lès-Cormeilles; Korian Les Arcades - 75,012 Paris; Korian ders and to highlight the critical aspect of palatability in the Nymphéas Bleus - 27,200 Vernon; Korian Samarobriva - acceptability of oral liquid preparations. 80,000 Amiens) for their help in the data collection. Finally, This study underlines the need to consider the specific fea- many thanks to all of the students who have actively recruited tures of each targeted users to prescribe or develop a medicine patients in this study: Sacha Barsan, Jonathan Mimoun, with the best adapted characteristics to reach an optimal ac- Laetitia Valery, Ingrid Vallée (Hôpital Rothschild), Hugues ceptability. The acceptability reference framework could pro- Feltize-Nanguem, Isaure Magnus (Hôpital Sainte-Périne) vide us with relevant knowledge on such factors positively and Inès Dufier (Hôpital René Muret). affecting this multi-dimensionnal concept, and so appears to be a relevant decision support tool for medicinal product de- FUNDING signers and healthcare profesionnals. No funding was received for this study. ClinSearch and the Paris Public Hospital (AP HP) financed this study. The publi- cation of study results was not contingent on the sponsor’s CONCLUSION approval or censorship of the manuscript. This article presents a novel tool assessing the multi- Open Access This article is distributed under the terms of the dimensional concept of medicines acceptability in the elderly Creative Commons Attribution 4.0 International License in institutional care. Based on a large set of medicine use (http://creativecommons.org/licenses/by/4.0/), which per- evaluations combining several objective measures, an accept- mits unrestricted use, distribution, and reproduction in any ability reference framework has been developed. Medicines, medium, provided you give appropriate credit to the original as well as user or product characteristics, may be positioned on author(s) and the source, provide a link to the Creative a three-dimensional acceptability map and assigned to an ac- Commons license, and indicate if changes were made. ceptability profile: BPositively accepted^ or BNegatively accepted^. 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Pharmaceutical ResearchSpringer Journals

Published: May 7, 2018

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