Applicability and added value of novel methods to improve drug development in rare diseases
Abstract Background The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development program...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13023-018-0925-0 |
| _version_ | 1819098852710416384 |
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| author | Marian Mitroiu Katrien Oude Rengerink Caridad Pontes Aranzazu Sancho Roser Vives Stella Pesiou Juan Manuel Fontanet Ferran Torres Stavros Nikolakopoulos Konstantinos Pateras Gerd Rosenkranz Martin Posch Susanne Urach Robin Ristl Armin Koch Spineli Loukia Johanna H. van der Lee Kit C. B. Roes |
| author_facet | Marian Mitroiu Katrien Oude Rengerink Caridad Pontes Aranzazu Sancho Roser Vives Stella Pesiou Juan Manuel Fontanet Ferran Torres Stavros Nikolakopoulos Konstantinos Pateras Gerd Rosenkranz Martin Posch Susanne Urach Robin Ristl Armin Koch Spineli Loukia Johanna H. van der Lee Kit C. B. Roes |
| author_sort | Marian Mitroiu |
| collection | DOAJ |
| description | Abstract Background The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. Methods The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were ‘innovative trial designs’ (six methods), ‘level of evidence’ (one method), ‘study endpoints and statistical analysis’ (four methods), and ‘meta-analysis’ (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Results and discussion Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Conclusion Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes. |
| first_indexed | 2024-12-22T00:37:34Z |
| format | Article |
| id | doaj.art-62ce11d1d252459895811aa84238b1e0 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-22T00:37:34Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-62ce11d1d252459895811aa84238b1e02022-12-21T18:44:46ZengBMCOrphanet Journal of Rare Diseases1750-11722018-11-0113111610.1186/s13023-018-0925-0Applicability and added value of novel methods to improve drug development in rare diseasesMarian Mitroiu0Katrien Oude Rengerink1Caridad Pontes2Aranzazu Sancho3Roser Vives4Stella Pesiou5Juan Manuel Fontanet6Ferran Torres7Stavros Nikolakopoulos8Konstantinos Pateras9Gerd Rosenkranz10Martin Posch11Susanne Urach12Robin Ristl13Armin Koch14Spineli Loukia15Johanna H. van der Lee16Kit C. B. Roes17Clinical Trial Methodology, Julius Center for Health Sciences and Primary Care, Biostatistics and Research Support, University Medical Center Utrecht, University of UtrechtClinical Trial Methodology, Julius Center for Health Sciences and Primary Care, Biostatistics and Research Support, University Medical Center Utrecht, University of UtrechtDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Unitat Docent Parc TaulíDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Unitat Docent Parc TaulíDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Unitat Docent Parc TaulíDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Unitat Docent Parc TaulíDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Hospital de Sant PauBiostatistics Unit, Faculty of Medicine, Universitat Autònoma de BarcelonaClinical Trial Methodology, Julius Center for Health Sciences and Primary Care, Biostatistics and Research Support, University Medical Center Utrecht, University of UtrechtClinical Trial Methodology, Julius Center for Health Sciences and Primary Care, Biostatistics and Research Support, University Medical Center Utrecht, University of UtrechtSection for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of ViennaSection for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of ViennaSection for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of ViennaSection for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of ViennaHannover Medical SchoolHannover Medical SchoolPaediatric Clinical Research Office, Woman-Child Center, Academic Medical Center, University of AmsterdamClinical Trial Methodology, Julius Center for Health Sciences and Primary Care, Biostatistics and Research Support, University Medical Center Utrecht, University of UtrechtAbstract Background The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. Methods The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were ‘innovative trial designs’ (six methods), ‘level of evidence’ (one method), ‘study endpoints and statistical analysis’ (four methods), and ‘meta-analysis’ (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Results and discussion Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Conclusion Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.http://link.springer.com/article/10.1186/s13023-018-0925-0OrphanRare conditionClinical trialsSmall populationStatistical methods |
| spellingShingle | Marian Mitroiu Katrien Oude Rengerink Caridad Pontes Aranzazu Sancho Roser Vives Stella Pesiou Juan Manuel Fontanet Ferran Torres Stavros Nikolakopoulos Konstantinos Pateras Gerd Rosenkranz Martin Posch Susanne Urach Robin Ristl Armin Koch Spineli Loukia Johanna H. van der Lee Kit C. B. Roes Applicability and added value of novel methods to improve drug development in rare diseases Orphanet Journal of Rare Diseases Orphan Rare condition Clinical trials Small population Statistical methods |
| title | Applicability and added value of novel methods to improve drug development in rare diseases |
| title_full | Applicability and added value of novel methods to improve drug development in rare diseases |
| title_fullStr | Applicability and added value of novel methods to improve drug development in rare diseases |
| title_full_unstemmed | Applicability and added value of novel methods to improve drug development in rare diseases |
| title_short | Applicability and added value of novel methods to improve drug development in rare diseases |
| title_sort | applicability and added value of novel methods to improve drug development in rare diseases |
| topic | Orphan Rare condition Clinical trials Small population Statistical methods |
| url | http://link.springer.com/article/10.1186/s13023-018-0925-0 |
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