Statistical Evaluation of Responder Analysis in Stem Cell Clinical Trials.
Clinical meaningful difference
Power analysis
Relative change
Responder endpoint
Stem cell clinical trials
Journal
Therapeutic innovation & regulatory science
ISSN: 2168-4804
Titre abrégé: Ther Innov Regul Sci
Pays: Switzerland
ID NLM: 101597411
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
received:
10
05
2023
accepted:
19
07
2023
medline:
23
10
2023
pubmed:
9
8
2023
entrez:
9
8
2023
Statut:
ppublish
Résumé
In evaluating treatment efficacy, there is an ongoing discussion about which endpoint is more efficient to represent the treatment effect. Absolute change (AC) is the difference between before and after treatment, while relative change (RC) is the AC relative to the baseline value. Principal investigators sometimes support the credibility of relative change, but the FDA is more likely to support absolute change. Therefore, whether these two endpoints can be translated or combined is worth investigating in order to satisfy both parties. In this article, a motivating example is presented to show that the choice of endpoint will result in different conclusions. The compared relationship of AC and RC is discussed in terms of required sample size, power, and precision. A new type of responder endpoint that combines the concepts of AC and RC is proposed. The comparative relationship regarding sample size, power, and precision of the proposed responder endpoint and the original two endpoints are also investigated. As a result, the performance of AC and RC is highly dependent on the choice of threshold that is often informed based on minimum clinically important difference or other clinical experience. Therefore, an absolute translation between them is hard to achieve. Inspired by the concept of responder analysis, three types of responder endpoints are proposed and discussed. The pattern of the third type of responder endpoint is having higher power, higher precision, and less required sample size in estimating the treatment effect compared to AC and RC within a range of thresholds. This advantage becomes more obvious when applying higher AC and RC thresholds and lower [Formula: see text] threshold. The proposed endpoint incorporates the information from the AC and RC endpoints and could be another wise choice when designing clinical trials especially when there is no absolute preference between AC and RC.
Sections du résumé
BACKGROUND
In evaluating treatment efficacy, there is an ongoing discussion about which endpoint is more efficient to represent the treatment effect. Absolute change (AC) is the difference between before and after treatment, while relative change (RC) is the AC relative to the baseline value. Principal investigators sometimes support the credibility of relative change, but the FDA is more likely to support absolute change. Therefore, whether these two endpoints can be translated or combined is worth investigating in order to satisfy both parties.
METHODS
In this article, a motivating example is presented to show that the choice of endpoint will result in different conclusions. The compared relationship of AC and RC is discussed in terms of required sample size, power, and precision. A new type of responder endpoint that combines the concepts of AC and RC is proposed. The comparative relationship regarding sample size, power, and precision of the proposed responder endpoint and the original two endpoints are also investigated.
RESULTS
As a result, the performance of AC and RC is highly dependent on the choice of threshold that is often informed based on minimum clinically important difference or other clinical experience. Therefore, an absolute translation between them is hard to achieve. Inspired by the concept of responder analysis, three types of responder endpoints are proposed and discussed. The pattern of the third type of responder endpoint is having higher power, higher precision, and less required sample size in estimating the treatment effect compared to AC and RC within a range of thresholds. This advantage becomes more obvious when applying higher AC and RC thresholds and lower [Formula: see text] threshold.
CONCLUSION
The proposed endpoint incorporates the information from the AC and RC endpoints and could be another wise choice when designing clinical trials especially when there is no absolute preference between AC and RC.
Identifiants
pubmed: 37555886
doi: 10.1007/s43441-023-00556-8
pii: 10.1007/s43441-023-00556-8
doi:
Banques de données
ClinicalTrials.gov
['NCT03473301']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1238-1247Informations de copyright
© 2023. The Author(s), under exclusive licence to The Drug Information Association, Inc.
Références
Rosenbaum PL, Walter SD, Hanna SE, et al. Prognosis for gross motor function in cerebral palsy: creation of motor development curves. JAMA. 2002;288(11):1357–63.
doi: 10.1001/jama.288.11.1357
pubmed: 12234229
Hanna SE, Bartlett DJ, Rivard LM, Russell DJ. Reference curves for the gross motor function measure: percentiles for clinical description and tracking over time among children with cerebral palsy. Phys Ther. 2008;88(5):596–607.
doi: 10.2522/ptj.20070314
pubmed: 18339799
pmcid: 2390723
Chow SC, Shao J, Wang H, Lokhnygina Y. Sample size calculations in clinical research. 3rd ed. Boca Raton: Chapman and Hall; 2017.
doi: 10.1201/9781315183084
Sun JM, Song AW, Case LE, et al. Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized placebo-controlled trial. Stem Cells Transl Med. 2017;6(12):2071–8.
doi: 10.1002/sctm.17-0102
pubmed: 29080265
pmcid: 5702515
Sun JM, Case LE, McLaughlin C, et al. Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: an open-label, randomized trial. Dev Med Child Neurol. 2022;64(12):1477–86.
doi: 10.1111/dmcn.15325
pubmed: 35811372
pmcid: 9796267
Oeffinger D, Bagley A, Rogers S, et al. Outcome tools used for ambulatory children with cerebral palsy: responsiveness and minimum clinically important differences. Dev Med Child Neurol. 2008;50(12):918–25.
doi: 10.1111/j.1469-8749.2008.03150.x
pubmed: 19046185
pmcid: 2990955
Henschke N, van Enst A, Froud R, Ostelo RW. Responder analyses in randomised controlled trials for chronic low back pain: an overview of currently used methods. Eur Spine J. 2014;23(4):772–8.
doi: 10.1007/s00586-013-3155-0
pubmed: 24419902
pmcid: 3960418
McLeod C, Norman R, Litton E, Saville BR, Webb S, Snelling TL. Choosing primary endpoints for clinical trials of health care interventions. Contemp Clin Trials Commun. 2019;16: 100486.
doi: 10.1016/j.conctc.2019.100486
pubmed: 31799474
pmcid: 6881606