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End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

ABSTRACT: To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.

SUBMITTER: Farrell AT

PROVIDER: S-EPMC6963248 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

Farrell Ann T AT Panepinto Julie J Desai Ankit A AA Kassim Adetola A AA Lebensburger Jeffrey J Walters Mark C MC Bauer Daniel E DE Blaylark Rae M RM DiMichele Donna M DM Gladwin Mark T MT Green Nancy S NS Hassell Kathryn K Kato Gregory J GJ Klings Elizabeth S ES Kohn Donald B DB Krishnamurti Lakshmanan L Little Jane J Makani Julie J Malik Punam P McGann Patrick T PT Minniti Caterina C Morris Claudia R CR Odame Isaac I Oneal Patricia Ann PA Setse Rosanna R Sharma Poornima P Shenoy Shalini S

Blood advances 20191201 23

To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-pa ...[more]

PMID: 31809537

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Project description:BACKGROUND:Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly popular in health-related research in both high- and low-resource settings. There may be specific ethical issues that researchers face when designing and conducting SW-CRTs in low-resource settings. Knowledge of these issues can help to improve the ethical conduct of SW-CRTs in a global health context. METHODS:We performed an ethical analysis of two studies using SW-CRT designs in low-resource settings: the Que Vivan Las Madres study conducted from 2014 to 2017 in Guatemala and the Atmiyata study conducted from 2017 to 2018 in rural parts of India. For both case studies, we identified and evaluated the classification of the study as research or nonresearch and the ethical issues regarding the justification of the design, including the delayed rollout of an intervention that had a promising effect. RESULTS:In our case studies, some minor ethical issues surfaced about the registration and stakeholder pressure on the order of randomization, but both included good justification for the design and delayed rollout. Our analysis did, however, demonstrate that careful consideration of the role of randomization and registration of the trials is important. DISCUSSION:SW-CRTs can provide an opportunity for rigorous evaluation of interventions destined to be rolled out on the basis of limited evidence. Furthermore, in SW-CRTs, the underlying objective is often to provide a robust evaluation of the effectiveness for generalized dissemination, and this makes the SW-CRT no less a research study than any other form of cluster randomized trial. CONCLUSION:The design and conduct of stepped-wedge cluster randomized trials raises at least two ethical issues that need special consideration in both high- and low-resource settings: the justification for using the design, specifically the delayed rollout of the intervention to the control group, and the classification of the study as research or nonresearch. In our case studies, these issues did not seem to raise special ethical scrutiny in low-resource settings. Further ethical evaluation will hopefully result in specific ethical guidelines for the use of SW-CRTs in both high- and low-resource settings to contribute to responsible functioning of these trials and adequate protection of participants.

Project description:ImportancePredictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first.ObjectiveTo determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis.Design, setting, and participantsThis study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017.Main outcomes and measuresThe primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test.ResultsOf Track's 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS.Conclusions and relevanceReasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach.

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End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

Publications

End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

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