{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T08:57:01Z","timestamp":1787907421712,"version":"build-2784847793"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum D\u00fcsseldorf. Anstalt \u00f6ffentlichen Rechts"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ther Innov Regul Sci"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>A medicine\u2019s acceptability is likely to have significant impact on pediatric adherence. The importance is underlined in EMA and FDA guidance on this topic where investigation of acceptability is stated as a regulatory expectation. Demonstrating acceptability can be challenging given there is no globally recognized definition and no standardized testing methodology or assessment criteria. Palatability and swallowability are generally recognized as important elements of acceptability, and this work proposes a definition of acceptability using these elements to give a composite endpoint for acceptability for pediatric subjects across all age ranges.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This composite acceptability endpoint is based on validated assessment methods for swallowability and palatability in children of different age groups using different galenic placebo formulations, in line with criteria proposed by EMA for assessing acceptability in children from newborn to 18\u00a0years of age. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films, and syrup were analyzed to establish the validity, expediency, and applicability of the suggested composite acceptability assessment tool.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The new composite endpoint is an efficient and suitable way to distinguish preferences of oral formulations: Mini-tablets and oblong tablets had significantly better acceptability than syrups and orodispersible films.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Since the suggested acceptability criteria takes both swallowability and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined valid approach, which meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as a pragmatic, standardized method to assess and compare acceptability of pediatric formulations with active substances.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s43441-022-00406-z","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T09:12:38Z","timestamp":1650964358000},"page":"903-909","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A Composite Endpoint for Acceptability Evaluation of Oral Drug Formulations in the Pediatric Population"],"prefix":"10.1007","volume":"56","author":[{"given":"Manfred","family":"Wargenau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Reidemeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Klingmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0533-2082","authenticated-orcid":false,"given":"Viviane","family":"Klingmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"key":"406_CR1","volume-title":"Guidance for industry: general clinical pharmacology considerations for pediatric studies for drugs and biological products","author":"Food and Drug Administration (US)","year":"2014","unstructured":"Food and Drug Administration (US). Guidance for industry: general clinical pharmacology considerations for pediatric studies for drugs and biological products. Silver Spring: FDA; 2014."},{"key":"406_CR2","unstructured":"European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use. European Medicines Agency (EMA) CfMPfHU, 2013."},{"key":"406_CR3","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.ijpharm.2017.08.088","volume":"536","author":"R Ternik","year":"2018","unstructured":"Ternik R, Liu F, Bartlett JA, et al. Assessment of swallowability and palatability of oral dosage forms in children: report from an M-CERSI pediatric formulation workshop. Int J Pharm. 2018;536:570\u201381.","journal-title":"Int J Pharm"},{"key":"406_CR4","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.drudis.2018.01.038","volume":"23","author":"SR Ranmal","year":"2018","unstructured":"Ranmal SR, O\u2019Brien F, Lopez F, et al. Methodologies for assessing the acceptability of oral formulations among children and older adults: a systematic review. Drug Discov Today. 2018;23:830\u201347.","journal-title":"Drug Discov Today"},{"key":"406_CR5","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1016\/j.jpeds.2013.07.014","volume":"163","author":"V Klingmann","year":"2013","unstructured":"Klingmann V, Spomer N, Lerch C, et al. Favourable acceptance of mini-tablets compared to syrup: a randomised controlled trial in small children. J Pediatr. 2013;163:1728\u201332.","journal-title":"J Pediatr"},{"key":"406_CR6","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1136\/archdischild-2011-300958","volume":"97","author":"N Spomer","year":"2012","unstructured":"Spomer N, Klingmann V, Stoltenberg I, et al. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch Dis Child. 2012;97:283\u20136.","journal-title":"Arch Dis Child"},{"key":"406_CR7","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.jpeds.2015.07.010","volume":"167","author":"V Klingmann","year":"2015","unstructured":"Klingmann V, Seitz A, Meissner T, et al. Acceptability of uncoated mini-tablets in neonates\u2014a randomized controlled trial. J Pediatr. 2015;167:893\u20136.","journal-title":"J Pediatr"},{"key":"406_CR8","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.jpeds.2018.05.031","volume":"201","author":"V Klingmann","year":"2018","unstructured":"Klingmann V, Linderskamp H, Meissner T, et al. Acceptability of multiple uncoated mini-tablets in infants and toddlers: a randomized controlled trial. J Pediatr. 2018;201:202\u20137.","journal-title":"J Pediatr"},{"key":"406_CR9","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.ejpb.2020.03.018","volume":"151","author":"V Klingmann","year":"2020","unstructured":"Klingmann V, Pohly CH, Meissner T, et al. Acceptability of an orodispersible film compared to syrup in neonates and infants: a randomized controlled trial. Eur J Pharm Biopharm. 2020;151:239\u201345.","journal-title":"Eur J Pharm Biopharm"},{"key":"406_CR10","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.ejpb.2021.06.007","volume":"166","author":"J M\u00fcnch","year":"2021","unstructured":"M\u00fcnch J, Meissner T, Mayatepek E, et al. Acceptability of small-sized oblong tablets in comparison to syrup and mini-tablets in infants and toddlers: a randomized controlled trial. Eur J Pharm Biopharm. 2021;166:126\u201334.","journal-title":"Eur J Pharm Biopharm"},{"key":"406_CR11","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1208\/s12249-016-0639-3","volume":"18","author":"V Klingmann","year":"2016","unstructured":"Klingmann V. Acceptability of mini-tablets in young children: results from three prospective cross-over studies. AAPS PharmSciTech. 2016;18:263\u20136.","journal-title":"AAPS PharmSciTech"},{"key":"406_CR12","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1111\/bcp.14388","volume":"86","author":"C Timpe","year":"2020","unstructured":"Timpe C, Stegemann S, Barrett A, et al. Challenges and opportunities to include patient-centric product design in industrial medicine development to improve therapeutic goals. Br J Clin Pharmacol. 2020;86:2020\u20137.","journal-title":"Br J Clin Pharmacol"},{"key":"406_CR13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.ijpharm.2014.03.057","volume":"469","author":"P Kozarewicz","year":"2014","unstructured":"Kozarewicz P. Regulatory perspectives on acceptability testing of dosage forms in children. Int J Pharm. 2014;469:245\u20138.","journal-title":"Int J Pharm"},{"issue":"2","key":"406_CR14","doi-asserted-by":"publisher","first-page":"e235","DOI":"10.1542\/peds.2008-2059","volume":"123","author":"SA Thomson","year":"2009","unstructured":"Thomson SA, Tuleu C, Wong ICK, et al. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;123(2):e235\u20138.","journal-title":"Pediatrics"},{"issue":"1","key":"406_CR15","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s12887-018-1080-4","volume":"18","author":"J Blume","year":"2018","unstructured":"Blume J, Ruano AL, Wang S, Jackson D, Tyllesk\u00e4r T, Strand LI. Oral medicine acceptance in infants and toddlers: measurement properties of the caregiver-administered children\u2019s acceptance tool. BMC Pediatr. 2018;18(1):117.","journal-title":"BMC Pediatr"},{"key":"406_CR16","doi-asserted-by":"publisher","first-page":"337","DOI":"10.3390\/pharmaceutics14020337","volume":"14","author":"V Klingmann","year":"2022","unstructured":"Klingmann V, Vallet T, M\u00fcnch J, Stegemann R, Wolters L, Bosse HM, Ruiz F. Dosage forms suitability in pediatrics: acceptability of analgesics and antipyretics in a german hospital. Pharmaceutics. 2022;14:337.","journal-title":"Pharmaceutics"}],"container-title":["Therapeutic Innovation &amp; Regulatory Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43441-022-00406-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43441-022-00406-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43441-022-00406-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T16:29:20Z","timestamp":1669998560000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43441-022-00406-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,26]]},"references-count":16,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["406"],"URL":"https:\/\/doi.org\/10.1007\/s43441-022-00406-z","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.20.21262333","asserted-by":"object"}]},"ISSN":["2168-4790","2168-4804"],"issn-type":[{"value":"2168-4790","type":"print"},{"value":"2168-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,26]]},"assertion":[{"value":"22 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}