Dose-finding studies in drug development for rare genetic diseases
Abstract Background The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization fo...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-022-02298-6 |
| _version_ | 1819061365015314432 |
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| author | Lingshan Wang Jie Wang Ji Feng Mary Doi Salvatore Pepe Michael Pacanowski Robert N. Schuck |
| author_facet | Lingshan Wang Jie Wang Ji Feng Mary Doi Salvatore Pepe Michael Pacanowski Robert N. Schuck |
| author_sort | Lingshan Wang |
| collection | DOAJ |
| description | Abstract Background The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Results Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Conclusions Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases. |
| first_indexed | 2024-12-21T14:41:43Z |
| format | Article |
| id | doaj.art-b4c43e84434c4e4da686f28dd247da2c |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-21T14:41:43Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-b4c43e84434c4e4da686f28dd247da2c2022-12-21T19:00:10ZengBMCOrphanet Journal of Rare Diseases1750-11722022-04-011711810.1186/s13023-022-02298-6Dose-finding studies in drug development for rare genetic diseasesLingshan Wang0Jie Wang1Ji Feng2Mary Doi3Salvatore Pepe4Michael Pacanowski5Robert N. Schuck6Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Translational Sciences Immediate Office, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Translational Sciences Immediate Office, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Translational Sciences Immediate Office, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug AdministrationOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug AdministrationAbstract Background The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Results Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Conclusions Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.https://doi.org/10.1186/s13023-022-02298-6Clinical pharmacologyDose-findingBiomarkerDrug developmentOrphan drugRare disease |
| spellingShingle | Lingshan Wang Jie Wang Ji Feng Mary Doi Salvatore Pepe Michael Pacanowski Robert N. Schuck Dose-finding studies in drug development for rare genetic diseases Orphanet Journal of Rare Diseases Clinical pharmacology Dose-finding Biomarker Drug development Orphan drug Rare disease |
| title | Dose-finding studies in drug development for rare genetic diseases |
| title_full | Dose-finding studies in drug development for rare genetic diseases |
| title_fullStr | Dose-finding studies in drug development for rare genetic diseases |
| title_full_unstemmed | Dose-finding studies in drug development for rare genetic diseases |
| title_short | Dose-finding studies in drug development for rare genetic diseases |
| title_sort | dose finding studies in drug development for rare genetic diseases |
| topic | Clinical pharmacology Dose-finding Biomarker Drug development Orphan drug Rare disease |
| url | https://doi.org/10.1186/s13023-022-02298-6 |
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