{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:13:27Z","timestamp":1788412407064,"version":"build-2803163510"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["825575"],"award-info":[{"award-number":["825575"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["964908"],"award-info":[{"award-number":["964908"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["825575"],"award-info":[{"award-number":["825575"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["825575"],"award-info":[{"award-number":["825575"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>In clinical research, the most appropriate way to assess the effect of an intervention is to conduct a randomized controlled trial (RCT). In the field of rare diseases, conducting an RCT is challenging, resulting in a low rate of clinical trials, with a high frequency of early termination and unpublished trials. The aim of the EPISTOP trial was to compare outcomes in infants with tuberous sclerosis (TSC) who received vigabatrin preventively before the seizures onset with those who received it conventionally after. The study was designed as a prospective, multicentre, randomized clinical trial. However, ethics committees at four centres did not approve this RCT design, resulting in an open-label trial (OLT) in these four centres and an RCT in the other six centres. In this paper, we re-analyse the data from the EPISTOP trial using methods to investigate the influence of allocation bias on the results of the EPISTOP trial.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Method<\/jats:title>\n<jats:p>A bias-corrected analysis is used to support and strengthen the published results. We included a term representing the effect of selection bias as an influencing factor on the corresponding endpoint in the statistical model. Thus, the treatment effect estimates for the primary endpoint of time to first seizure and additional secondary endpoints are adjusted for the bias effect.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Result<\/jats:title>\n<jats:p>The bias-corrected analyses for the primary endpoint show that the estimated hazard ratio and associated confidence intervals are in a very similar range (original analysis: HR 2.91, 95%-CI [1.11 to 7.67], p-value 0.0306; bias-corrected analysis: HR 2.89, 95%-CI [1.10 to 7.58], p-value 0.0316). This was also the case for the secondary endpoints.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The statistical re-analysis of the raw trial data therefore supports the published results and confirms that there is no additional bias introduced by randomization, thereby increasing the value of the results. However, this highlights that this aspect needs to be considered in future trials, especially in rare diseases, to avoid additional biases in an already small sample size where it may be difficult to reach significance.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0312936","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T18:24:38Z","timestamp":1733250278000},"page":"e0312936","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Methodological insights from the EPISTOP trial to designing clinical trials in rare diseases\u2014A secondary analysis of a randomized clinical trial"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-6610","authenticated-orcid":true,"given":"Stephanie","family":"Wied","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-1119","authenticated-orcid":true,"given":"Ralf-Dieter","family":"Hilgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Heussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kotulska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Dirani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5944-2204","authenticated-orcid":true,"given":"Mathieu","family":"Kuchenbuch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiusz","family":"Jozwiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Nabbout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"pone.0312936.ref001","first-page":"1","article-title":"Orphan medicinal products","author":"European Parliament and Council of the European Union","year":"2016","journal-title":"Regul No 141\/2000"},{"key":"pone.0312936.ref002","first-page":"1","article-title":"Part 316\u2014Orphan Drugs","volume":"316","author":"Food and Drug Administration","year":"1992","journal-title":"Code Fed Regul"},{"key":"pone.0312936.ref003","article-title":"List of rare diseases and synonyms in alphabetical order Methodology","author":"Orphanet","year":"2021","journal-title":"Orphanet report series"},{"issue":"5","key":"pone.0312936.ref004","doi-asserted-by":"crossref","first-page":"e0127242","DOI":"10.1371\/journal.pone.0127242","article-title":"Terminated trials in the clinicaltrials.gov results database: Evaluation of availability of primary outcome data and reasons for termination","volume":"10","author":"RJ Williams","year":"2015","journal-title":"PLOS ONE"},{"issue":"9","key":"pone.0312936.ref005","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1177\/0883073813495959","article-title":"Clinical trials in rare disease: Challenges and opportunities","volume":"28","author":"EF Augustine","year":"2013","journal-title":"Journal of Child Neurology"},{"key":"pone.0312936.ref006","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1186\/s13063-017-2287-7","article-title":"A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?","volume":"18","author":"A Rath","year":"2017","journal-title":"Trials"},{"key":"pone.0312936.ref007","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.conctc.2018.08.001","article-title":"Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review","volume":"11","author":"DB Fogel","year":"2018","journal-title":"Contemp Clin Trials Commun"},{"key":"pone.0312936.ref008","article-title":"A comparison of interventional clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrials.gov","volume":"170","author":"SA Bell","year":"2014","journal-title":"Orphanet J Rare Dis"},{"issue":"11","key":"pone.0312936.ref009","doi-asserted-by":"crossref","first-page":"e1002966","DOI":"10.1371\/journal.pmed.1002966","article-title":"Noncompletion and nonpublication of trials studying rare diseases: A cross-sectional analysis","volume":"16","author":"CA Rees","year":"2019","journal-title":"PLOS Medicine"},{"issue":"1","key":"pone.0312936.ref010","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/cts.12500","article-title":"Future of Rare Diseases Research 2017\u20132027: An IRDiRC Perspective","volume":"11","author":"CP Austin","year":"2018","journal-title":"Clin Transl Sci"},{"issue":"4","key":"pone.0312936.ref011","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1001\/jamainternmed.2016.0137","article-title":"Characteristics and Public Availability of Results of Clinical Trials on Rare Diseases Registered at Clinicaltrials.gov","volume":"176","author":"A Dechartres","year":"2016","journal-title":"JAMA Intern Med"},{"key":"pone.0312936.ref012","article-title":"Directions for new developments on statistical design and analysis of small population group trials","volume":"78","author":"RD Hilgers","year":"2016","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0312936.ref013","article-title":"Recommendations for the design of small population clinical trials","volume":"195","author":"S Day","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0312936.ref014","article-title":"Lessons learned from IDeAl \u2014 33 recommendations from the IDeAl-net about design and analysis of small population clinical trials","volume":"77","author":"RD Hilgers","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0312936.ref015","article-title":"Applicability and added value of novel methods to improve drug development in rare diseases","volume":"200","author":"M Mitroiu","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0312936.ref016","article-title":"Recent advances in methodology for clinical trials in small populations: The InSPiRe project","volume":"186","author":"T Friede","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0312936.ref017","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.pediatrneurol.2015.09.013","article-title":"Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants","volume":"54","author":"JY Wu","year":"2016","journal-title":"Pediatr Neurol"},{"key":"pone.0312936.ref018","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1111\/epi.16892","article-title":"Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes","volume":"62","author":"J De Ridder","year":"2021","journal-title":"Epilepsia"},{"issue":"3","key":"pone.0312936.ref019","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1528-1167.2007.01458.x","article-title":"Early treatment suppresses the development of spike-wave epilepsy in a rat model","volume":"49","author":"H Blumenfeld","year":"2008","journal-title":"Epilepsia"},{"issue":"3","key":"pone.0312936.ref020","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1177\/1073858409354385","article-title":"Is epilepsy a preventable disorder? New evidence from animal models","volume":"16","author":"KA Giblin","year":"2010","journal-title":"Neuroscientist"},{"key":"pone.0312936.ref021","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/ana.25956","article-title":"Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial","volume":"89","author":"K. Kotulska","year":"2021","journal-title":"Ann Neurol"},{"key":"pone.0312936.ref022","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1002\/sim.7299","article-title":"Assessing the impact of selection bias on test decisions in trials with time-to-event outcome","volume":"36","author":"MV R\u00fcckbeil","year":"2017","journal-title":"Statistics in Medicine"},{"issue":"1","key":"pone.0312936.ref023","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12874-017-0428-z","article-title":"ERDO\u2014a framework to select an appropriate randomization procedure for clinical trials","volume":"17","author":"RD Hilgers","year":"2017","journal-title":"BMC Med Res Methodol"},{"key":"pone.0312936.ref024","unstructured":"European Platform on Rare Disease Registration. https:\/\/eu-rd-platform.jrc.ec.europa.eu\/eurocat\/eurocat-members\/registries\/antwerp."},{"key":"pone.0312936.ref025","unstructured":"EUROCAT Central Registry. Registry Prenatal Screening Policies in Europe. https:\/\/eu-rd-platform.jrc.ec.europa.eu\/eurocat\/eurocat-data\/prenatal-screening-and-diagnosis\/guide."},{"issue":"6","key":"pone.0312936.ref026","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.ejpn.2018.08.005","article-title":"Diagnosis of tuberous sclerosis complex in the fetus","volume":"22","author":"P Dragoumi","year":"2018","journal-title":"Eur J Paediatr Neurol"},{"issue":"5","key":"pone.0312936.ref027","doi-asserted-by":"crossref","first-page":"e002287","DOI":"10.1136\/bmjgh-2020-002287","article-title":"Regulating international clinical research: an ethical framework for policy-makers","volume":"5","author":"B Aguilera","year":"2020","journal-title":"BMJ Glob Health"},{"key":"pone.0312936.ref028","unstructured":"European Clinical Research Infrastructure Network (ECRIN). https:\/\/ecrin.org\/regulatory-and-ethical-tools."},{"issue":"4","key":"pone.0312936.ref029","first-page":"225","article-title":"Detection of Congenital Anomalies by Fetal Ultrasonographic Examination across Europe","volume":"4","author":"C Stoll","year":"2001","journal-title":"Community Genet"},{"issue":"2","key":"pone.0312936.ref030","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1258\/jms.2010.010050","article-title":"EUROCAT website data on prenatal detection rates of congenital anomalies","volume":"17","author":"E Garne","year":"2010","journal-title":"J Med Screen"},{"issue":"9","key":"pone.0312936.ref031","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1002\/pd.427","article-title":"Ethical decision-making in prenatal diagnosis and termination of pregnancy: a qualitative survey among physicians and midwives","volume":"22","author":"M Garel","year":"2002","journal-title":"Prenat Diagn"},{"key":"pone.0312936.ref032","unstructured":"Center for Reproductive Rights. The World\u2019s Abortion Laws. 2021. https:\/\/maps.reproductiverights.org\/worldabortionlaws."},{"issue":"13","key":"pone.0312936.ref033","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1002\/pd.5594","article-title":"Feticide in second- and third-trimester termination of pregnancy for fetal anomalies: Results of a national survey","volume":"39","author":"P Maurice","year":"2019","journal-title":"Prenat Diagn"},{"key":"pone.0312936.ref034","author":"D Welter","journal-title":"FAIR in action\u2014a flexible framework to guide FAIRification"},{"issue":"4","key":"pone.0312936.ref035","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0197-2456(99)00014-8","article-title":"Detecting Selection Bias in Randomized Clinical Trials","volume":"20","author":"VW Berger","year":"1999","journal-title":"Controlled Clinical Trials"},{"issue":"2","key":"pone.0312936.ref036","first-page":"1","article-title":"Exact and Asymptotic Weighted Logrank Tests for Interval Censored Data: The interval R Package","volume":"36","author":"MP Fay","journal-title":"Journal of Statistical Software"},{"key":"pone.0312936.ref037","unstructured":"EUROSTAT. 2022. https:\/\/ec.europa.eu\/eurostat."},{"key":"pone.0312936.ref038","unstructured":"Food and Drug Administration. Accelerated Approvals. https:\/\/www.fda.gov\/drugs\/nda-and-bla-approvals\/accelerated-approvals."},{"key":"pone.0312936.ref039","unstructured":"Food and Drug Administration. CDER Continues to Advance Rare Disease Drug Development with New Efforts, Including the Accelerating Rare Disease Cures (ARC) Program. https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/cder-continues-advance-rare-disease-drug-development-new-efforts-including-accelerating-rare-disease."},{"key":"pone.0312936.ref040","unstructured":"European Medicines Agency. Orphan medicines in the EU. https:\/\/www.ema.europa.eu\/en\/documents\/leaflet\/leaflet-orphan-medicines-eu_en.pdf."},{"key":"pone.0312936.ref041","unstructured":"European Medicines Agency. Repurposing of authorised medicines: pilot to support not-for-profit organisations and academia. https:\/\/www.ema.europa.eu\/en\/news\/repurposing-authorised-medicines-pilot-support-not-profit-organisations-academia."},{"key":"pone.0312936.ref042","unstructured":"IRDiRC. Orphan Drug Development Guidebook. https:\/\/irdirc.org\/activities\/task-forces\/orphan-drug-development-guidebook-task-force\/."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312936","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T18:24:50Z","timestamp":1733250290000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312936"}},"subtitle":[],"editor":[{"given":"Dragan","family":"Hrncic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,3]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0312936","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,3]]}}}