{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T06:29:21Z","timestamp":1787898561940,"version":"build-2784847793"},"reference-count":79,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":85,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["101034344"],"award-info":[{"award-number":["101034344"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2025,1]]},"abstract":"Abstract<\/jats:title>\n \n INTRODUCTION<\/jats:title>\n Biomarkers (BMs) are valuable tools to facilitate early diagnosis of (subtypes of) diseases, improve patient selection and stratification, and detect therapeutic effects or safety concerns. This study explores the extent to which BMs are utilized in the development of treatments for neurodegenerative diseases (NDDs), as well as topics of discussion regarding BMs in regulatory advice\u2010 and decision\u2010making processes and sharing of BM\u2010related data.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n The European Medicines Agency's marketing authorization application (MAA), qualification (QA\/QO), and scientific advice (SA) procedures regarding NDDs were screened, and those that mention BMs were analyzed. Data were extracted on the intended disease, BM type, and context of use proposed by applicants. BMs were categorized based on both nature and function.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n In total, 105 procedures that discussed BMs were analyzed, 57 SAs (January 2020 to December 2022), 19 QAs\/QOs (January 2008 to December 2023), and 29 MAAs (January 1995 to December 2023). The majority involved Alzheimer's disease (AD;\n n<\/jats:italic>\n \u00a0=\u00a030), Parkinson's disease (PD;\n n<\/jats:italic>\n \u00a0=\u00a09), and multiple sclerosis (MS;\n n<\/jats:italic>\n \u00a0=\u00a033). Imaging BMs were the most common type of BMs discussed, and most BMs were used as pharmacodynamic\/response measures. The acceptance and role of BMs differed between AD, PD, MS, and other NDDs. In regulatory procedures for AD, for example, diagnostic BMs guiding patient selection were commonly discussed, whereas in MAAs for MS, imaging BMs (particularly lesions) were generally accepted as supportive\/secondary endpoints.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n Despite the established role of certain BMs, mainly imaging BMs for MS, there remains a major need for more precise and reliable BMs to improve diagnostic accuracy and treatment monitoring for NDDs. To implement novel BMs and facilitate development of new treatments and to eventually improve clinical practice, robust evidence bases showcasing biological plausibility or clear clinical benefits are essential. Collaboration and data\u2010sharing among stakeholders is vital in generating this evidence and enhancing the understanding and management of NDDs.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n The European Medicines Agency's marketing authorization applications and qualification and scientific advice procedures.<\/jats:p>\n <\/jats:list-item>\n \n One hundred five procedures were analyzed regarding neurodegenerative diseases that discuss biomarkers.<\/jats:p>\n <\/jats:list-item>\n \n We found that acceptance and role of biomarkers differ per disease.<\/jats:p>\n <\/jats:list-item>\n \n Biological plausibility\/clinical benefits are essential for biomarker implementation.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/trc2.70072","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T01:37:58Z","timestamp":1743298678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Biomarkers for neurodegenerative diseases in regulatory decision\u2010making by the European Medicines Agency"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0952-767X","authenticated-orcid":false,"given":"Audrey M. M.","family":"Hermans","sequence":"first","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen University of Groningen Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen University of Groningen Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoriia","family":"Starokozhko","sequence":"additional","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen University of Groningen Groningen The Netherlands"},{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loes","family":"den Otter","sequence":"additional","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"Mental Health and Neuroscience Research Institute Maastricht University Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 J. A.","family":"Elferink","sequence":"additional","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Bradshaw","sequence":"additional","affiliation":[{"name":"Alzheimer Europe Luxembourg Ville Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Guizzaro","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G. M.","family":"Mol","sequence":"additional","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen University of Groningen Groningen The Netherlands"},{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M. G.","family":"Pasmooij","sequence":"additional","affiliation":[{"name":"Dutch Medicines Evaluation Board (MEB) Utrecht The Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences (UIPS) Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00276-9"},{"key":"e_1_2_10_3_1","unstructured":"Nature portfolio.Neurodegenerative diseases.2022.https:\/\/www.nature.com\/subjects\/neurodegenerative-diseases"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000512543"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205013666151116141603"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01382-x"},{"key":"e_1_2_10_7_1","unstructured":"European Medicines Agency.Biomarker.https:\/\/www.ema.europa.eu\/en\/glossary\/biomarker#:~:text=A%20biological%20molecule%20found%20in novel%20methodologies%20for%20medicine%20development%27"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/jlb\/lsx030"},{"key":"e_1_2_10_9_1","unstructured":"U.S. Food and Drug Administration.Accelerated approval program.U.S. Food and Drug Administration;2024.https:\/\/www.fda.gov\/drugs\/nda\u2010and\u2010bla\u2010approvals\/accelerated\u2010approval\u2010program"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2021.6854"},{"key":"e_1_2_10_11_1","unstructured":"European Medicines Agency.Refusal of the marketing authorisation for Aduhelm (aducanumab).European Medicines Agency;2021."},{"key":"e_1_2_10_12_1","unstructured":"U.S. Food and Drug Administration.FDA converts novel alzheimer's disease treatment to traditional approval: action follows confirmatory trial to verify clinical benefit.U.S. Food and Drug Administration;2023.https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010converts\u2010novel\u2010alzheimers\u2010disease\u2010treatment\u2010traditional\u2010approval"},{"key":"e_1_2_10_13_1","unstructured":"European Medicines Agency.Refusal of the marketing authorisation for Leqembi (lecanemab).2024."},{"key":"e_1_2_10_14_1","unstructured":"European Medicines Agency.Lecanemab.European Medicines Agency;2024.https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/leqembi"},{"key":"e_1_2_10_15_1","unstructured":"Alzheimer Europe.FDA grants traditional approval to donanemab for the treatment of early Alzheimer's disease.Alzheimer Europe;2023.https:\/\/www.alzheimer\u2010europe.org\/news\/fda\u2010grants\u2010traditional\u2010approval\u2010donanemab\u2010treatment\u2010early\u2010alzheimers\u2010disease?language_content_entity=en"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1565"},{"key":"e_1_2_10_17_1","unstructured":"U.S. Food and Drug Administration.CDER drug and biologic accelerated approvals based on a surrogate endpoint.U.S. Food and Drug Administration;2024."},{"key":"e_1_2_10_18_1","unstructured":"U.S. Food and Drug Administration.Early Alzheimer's disease: developing drugs for treatment\u2014guidance for industry.U.S. Food and Drug Administration;2024."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2554"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/1177271920974652"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13641"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.753187"},{"key":"e_1_2_10_23_1","unstructured":"European Medicines Agency.2023 annual report of the European Medicines Agency.European Medicines Agency;2024."},{"key":"e_1_2_10_24_1","unstructured":"WHO.International classification of diseases eleventh revision (ICD\u201011) neurology speciality linearization.WHO;2019\/2021. Accessed September 13 2024.https:\/\/icd.who.int\/dev11\/l\u2010neuro\/en#\/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1954798891"},{"key":"e_1_2_10_25_1","unstructured":"European Medicines Agency.Download medicine data.European Medicines Agency;2024.https:\/\/www.ema.europa.eu\/en\/medicines\/download\u2010medicine\u2010data"},{"key":"e_1_2_10_26_1","unstructured":"Opinions and letters of support on the qualification of novel methodologies for medicine development.European Medicines Agency;2024. Accessed August 21 2024.https:\/\/www.ema.europa.eu\/en\/human\u2010regulatory\u2010overview\/research\u2010development\/scientific\u2010advice\u2010protocol\u2010assistance\/opinions\u2010letters\u2010support\u2010qualification\u2010novel\u2010methodologies\u2010medicine\u2010development"},{"key":"e_1_2_10_27_1","unstructured":"European Commission.Union Register of medicinal products for human use.European Commission;2024."},{"key":"e_1_2_10_28_1","unstructured":"European Medicines Agency.Assessment report: Axura.European Medicines Agency;2002."},{"key":"e_1_2_10_29_1","unstructured":"European Medicines Agency.Qualification opinion of Alzheimer's disease novel methodologies\/biomarkers for the use of CSF AB 1\u201042 and t\u2010tau and\/or PET\u2010amyloid imaging (positive\/negative) as biomarkers for enrichment for use in regulatory clinical trials in mild and moderate Alzheimer's disease.European Medicines Agency;2012."},{"key":"e_1_2_10_30_1","unstructured":"European Medicines Agency.Qualification opinion of low hippocampal volume (atrophy) by MRI for use in clinical trials for regulatory purpose\u2014in pre\u2010dementia stage of Alzheimer's disease.European Medicines Agency;2011."},{"key":"e_1_2_10_31_1","unstructured":"European Medicines Agency.Qualification opinion of novel methodologies in the predementia stage of Alzheimer's disease: cerebro\u2014spinal fluid related biomarkers for drugs affecting amyloid burden.European Medicines Agency;2011."},{"key":"e_1_2_10_32_1","unstructured":"European Medicines Agency.Qualification opinion of Alzheimer's disease novel methodologies\/biomarkers for BMS\u2010708163.European Medicines Agency;2011."},{"key":"e_1_2_10_33_1","unstructured":"European Medicines Agency.Assessment report: Amyvid.European Medicines Agency;2013."},{"key":"e_1_2_10_34_1","unstructured":"European Medicines Agency.Assessment report: Neuraceq.European Medicines Agency;2013."},{"key":"e_1_2_10_35_1","unstructured":"European Medicines Agency.Assessment report: Vizamyl.European Medicines Agency;2014."},{"key":"e_1_2_10_36_1","unstructured":"European Medicines Agency.Letter of support for molecular imaging of the dopamine transporter biomarker as an enrichment biomarker for clinical trials for early Parkinson's disease.European Medicines Agency;2016."},{"key":"e_1_2_10_37_1","unstructured":"European Medicines Agency.Qualification opinion on dopamine transporter imaging as an enrichment biomarker for Parkinson's disease clinical trials in patients with early Parkinsonian symptoms.European Medicines Agency;2018."},{"key":"e_1_2_10_38_1","unstructured":"European Medicines Agency.Assessment report: Betaferon vials.European Medicines Agency;1995."},{"key":"e_1_2_10_39_1","unstructured":"European Medicines Agency.Assessment report: AUBAGIO.European Medicines Agency;2013."},{"key":"e_1_2_10_40_1","unstructured":"European Medicines Agency.Assessment report: Lemtrada.European Medicines Agency;2013."},{"key":"e_1_2_10_41_1","unstructured":"European Medicines Agency.Assessment report: Nerventra\u2014refusal report.European Medicines Agency;2014."},{"key":"e_1_2_10_42_1","unstructured":"European Medicines Agency.Assessment report: Ponvory.European Medicines Agency;2021."},{"key":"e_1_2_10_43_1","unstructured":"European Medicines Agency.Assessment report: Tecfidera.European Medicines Agency;2013."},{"key":"e_1_2_10_44_1","unstructured":"European Medicines Agency.Assessment report: Vumerity.European Medicines Agency;2021."},{"key":"e_1_2_10_45_1","unstructured":"European Medicines Agency.Assessment report: Zinbryta.European Medicines Agency;2016."},{"key":"e_1_2_10_46_1","unstructured":"European Medicines Agency.Assessment report: Tysabri.European Medicines Agency;2006."},{"key":"e_1_2_10_47_1","unstructured":"European Medicines Agency.Assessment report: Rebif.European Medicines Agency;1997."},{"key":"e_1_2_10_48_1","unstructured":"European Medicines Agency.Assessment report: Plegridy.European Medicines Agency;2014."},{"key":"e_1_2_10_49_1","unstructured":"European Medicines Agency.Assessment report: Ocrevus.European Medicines Agency;2017."},{"key":"e_1_2_10_50_1","unstructured":"European Medicines Agency.Assessment report: Kesimpta.European Medicines Agency;2021."},{"key":"e_1_2_10_51_1","unstructured":"European Medicines Agency.Assessment report: Mayzent.European Medicines Agency;2019."},{"key":"e_1_2_10_52_1","unstructured":"European Medicines Agency.Assessment report: Briumvi.European Medicines Agency;2023."},{"key":"e_1_2_10_53_1","unstructured":"European Medicines Agency.Assessment report: Mavenclad.European Medicines Agency;2017."},{"key":"e_1_2_10_54_1","unstructured":"European Medicines Agency.Assessment report: Zeposia.European Medicines Agency;2020."},{"key":"e_1_2_10_55_1","unstructured":"European Medicines Agency.Assessment report: Gilenya.European Medicines Agency;2011."},{"key":"e_1_2_10_56_1","unstructured":"European Medicines Agency.Assessment report: Spinraza.European Medicines Agency;2017."},{"key":"e_1_2_10_57_1","unstructured":"European Medicines Agency.Assessment report: Zolgensma.European Medicines Agency;2020."},{"key":"e_1_2_10_58_1","unstructured":"European Medicines Agency.Assessment report: Evrysdi.European Medicines Agency;2021."},{"key":"e_1_2_10_59_1","unstructured":"European Medicines Agency.Withdrawal assessment report: Radicava.European Medicines Agency;2019."},{"key":"e_1_2_10_60_1","unstructured":"European Medicines Agency.Assessment report: Libmeldy.European Medicines Agency;2020."},{"key":"e_1_2_10_61_1","unstructured":"European Medicines Agency.Assessment report: Skysona.European Medicines Agency;2021."},{"key":"e_1_2_10_62_1","unstructured":"European Medicines Agency.Letter of support of Neurofilament light in childhood neurological diseases.European Medicines Agency;2022."},{"key":"e_1_2_10_63_1","unstructured":"European Medicines Agency.Letter of support for Braintale platforms.European Medicines Agency;2023."},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.37349\/ent.2024.00075"},{"key":"e_1_2_10_65_1","unstructured":"European Medicines Agency.Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis.European Medicines Agency;2015."},{"key":"e_1_2_10_66_1","unstructured":"European Medicines Agency.Assessment report: AUBAGIO.European Medicines Agency;2013."},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202250228"},{"key":"e_1_2_10_68_1","unstructured":"European Medicines Agency. Search for clinical trials.https:\/\/euclinicaltrials.eu\/search\u2010for\u2010clinical\u2010trials\/?lang=en"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-023-00083-z"},{"key":"e_1_2_10_70_1","unstructured":"European Medicines Agency.New treatment for rare motor neurone disease recommended for approval.European Medicines Agency;2024https:\/\/www.ema.europa.eu\/en\/news\/new\u2010treatment\u2010rare\u2010motor\u2010neurone\u2010disease\u2010recommended\u2010approval"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00120-X"},{"key":"e_1_2_10_73_1","unstructured":"U.S. Food and Drug Administration.Letter of support critical path institute critical path for Parkinson's consortium.U.S. Food and Drug Administration;2024."},{"key":"e_1_2_10_74_1","unstructured":"European Medicines Agency.Qualification opinion for Centiloid measure of Amyloid PET to quantify brain amyloid deposition.European Medicines Agency;2024."},{"key":"e_1_2_10_75_1","unstructured":"European Medicines Agency.Assessment report: Tauvid.European Medicines Agency;2024."},{"key":"e_1_2_10_76_1","unstructured":"World Health Organisation (WHO).WHO publishes preferred product characteristics for blood tests for Alzheimer disease.WHO;2024https:\/\/www.who.int\/news\/item\/23\u201010\u20102024\u2010who\u2010publishes\u2010preferred\u2010product\u2010characteristics\u2010for\u2010blood\u2010tests\u2010for\u2010alzheimer\u2010disease"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.5319"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-022-01114-1"},{"key":"e_1_2_10_79_1","unstructured":"European Medicines Agency.Withdrawal assessment report Aduhelm.European Medicines Agency;2021."},{"key":"e_1_2_10_80_1","unstructured":"European Medicines Agency.Qualification of novel methodologies for medicine development.European Medicines Agency;2024Accessed May 8 2024.https:\/\/www.ema.europa.eu\/en\/human\u2010regulatory\/research\u2010development\/scientific\u2010advice\u2010protocol\u2010assistance\/qualification\u2010novel\u2010methodologies\u2010medicine\u2010development\u20100"}],"container-title":["Alzheimer's & Dementia: Translational Research & Clinical Interventions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70072","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T15:17:18Z","timestamp":1761491838000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/trc2.70072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":79,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/trc2.70072"],"URL":"https:\/\/doi.org\/10.1002\/trc2.70072","archive":["Portico"],"relation":{},"ISSN":["2352-8737","2352-8737"],"issn-type":[{"value":"2352-8737","type":"print"},{"value":"2352-8737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70072"}}