Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials
Experimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials ide...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmed.2019.00122/full |
| _version_ | 1818765594562920448 |
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| author | Channing J. Paller Erich P. Huang Thomas Luechtefeld Holly A. Massett Christopher C. Williams Jinxiu Zhao Amy E. Gravell Tami Tamashiro Steven A. Reeves Gary L. Rosner Michael A. Carducci Lawrence Rubinstein S. Percy Ivy |
| author_facet | Channing J. Paller Erich P. Huang Thomas Luechtefeld Holly A. Massett Christopher C. Williams Jinxiu Zhao Amy E. Gravell Tami Tamashiro Steven A. Reeves Gary L. Rosner Michael A. Carducci Lawrence Rubinstein S. Percy Ivy |
| author_sort | Channing J. Paller |
| collection | DOAJ |
| description | Experimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials identified from ClinicalTrials.gov between January 1, 2003 and November 30, 2017 to assess trial design and the progress of combinations toward regulatory approval. Online surveys (N = 289, 23 questions total) were emailed to Principal Investigators (PIs) of early-phase National Cancer Institute and/or industry trials; 263 emails (91%) were received and 113 surveys completed (43%). Among phase 1 combination trials, 24.9% (95%CI: 15.3%, 34.4%) progressed to phase 2 or further; 18.7% (95%CI: 5.90%, 31.4%) progressed to phase 3 or regulatory approval; and 12.4% (95%CI: 0.00%, 25.5%) achieved regulatory approval. Observations of “clinical promise” in phase 1 combination studies were associated with higher rates of advancement past each milestone toward regulatory approval (cumulative OR = 11.9; p = 0.0002). Phase 1 combination study designs were concordant with Clinical Trial Design Task Force (CTD-TF) Recommendations 79.6% of the time (95%CI: 72.2%, 87.1%). Most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Investigator-defined “clinical promise” of a combination is associated with progress toward regulatory approval. Although concordance between study designs of phase 1 combination trials and CTD-TF Recommendations was relatively high, it may be beneficial to raise awareness about the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected. |
| first_indexed | 2024-12-18T08:20:35Z |
| format | Article |
| id | doaj.art-cd7815f522cd4ad1b572ff59f04dc918 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-12-18T08:20:35Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-cd7815f522cd4ad1b572ff59f04dc9182022-12-21T21:14:45ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2019-06-01610.3389/fmed.2019.00122447872Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination TrialsChanning J. Paller0Erich P. Huang1Thomas Luechtefeld2Holly A. Massett3Christopher C. Williams4Jinxiu Zhao5Amy E. Gravell6Tami Tamashiro7Steven A. Reeves8Gary L. Rosner9Michael A. Carducci10Lawrence Rubinstein11S. Percy Ivy12Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United StatesBiometrics Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, United StatesEnvironmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesCancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, United StatesClinical Trials Information Management Services, Emmes Corporation, Rockville, MD, United StatesClinical Trials Information Management Services, Emmes Corporation, Rockville, MD, United StatesClinical Trials Information Management Services, Emmes Corporation, Rockville, MD, United StatesClinical Trials Information Management Services, Emmes Corporation, Rockville, MD, United StatesCoordinating Center for Clinical Trials, National Cancer Institute, Rockville, MD, United StatesDivision of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United StatesDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United StatesBiometrics Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, United StatesCancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, United StatesExperimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials identified from ClinicalTrials.gov between January 1, 2003 and November 30, 2017 to assess trial design and the progress of combinations toward regulatory approval. Online surveys (N = 289, 23 questions total) were emailed to Principal Investigators (PIs) of early-phase National Cancer Institute and/or industry trials; 263 emails (91%) were received and 113 surveys completed (43%). Among phase 1 combination trials, 24.9% (95%CI: 15.3%, 34.4%) progressed to phase 2 or further; 18.7% (95%CI: 5.90%, 31.4%) progressed to phase 3 or regulatory approval; and 12.4% (95%CI: 0.00%, 25.5%) achieved regulatory approval. Observations of “clinical promise” in phase 1 combination studies were associated with higher rates of advancement past each milestone toward regulatory approval (cumulative OR = 11.9; p = 0.0002). Phase 1 combination study designs were concordant with Clinical Trial Design Task Force (CTD-TF) Recommendations 79.6% of the time (95%CI: 72.2%, 87.1%). Most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Investigator-defined “clinical promise” of a combination is associated with progress toward regulatory approval. Although concordance between study designs of phase 1 combination trials and CTD-TF Recommendations was relatively high, it may be beneficial to raise awareness about the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected.https://www.frontiersin.org/article/10.3389/fmed.2019.00122/fullclinical trialscombination therapyregulatory approvalearly phasetrial designdrug combinations |
| spellingShingle | Channing J. Paller Erich P. Huang Thomas Luechtefeld Holly A. Massett Christopher C. Williams Jinxiu Zhao Amy E. Gravell Tami Tamashiro Steven A. Reeves Gary L. Rosner Michael A. Carducci Lawrence Rubinstein S. Percy Ivy Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials Frontiers in Medicine clinical trials combination therapy regulatory approval early phase trial design drug combinations |
| title | Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials |
| title_full | Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials |
| title_fullStr | Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials |
| title_full_unstemmed | Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials |
| title_short | Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials |
| title_sort | factors affecting combination trial success facts investigator survey results on early phase combination trials |
| topic | clinical trials combination therapy regulatory approval early phase trial design drug combinations |
| url | https://www.frontiersin.org/article/10.3389/fmed.2019.00122/full |
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