Dataset Information

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

ABSTRACT:

Background and objectives

As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor).

Methods

Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy.

Results

The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy.

Conclusion

The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.

SUBMITTER: Huh Y

PROVIDER: S-EPMC10954884 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

Huh Yeamin Y Wojciechowski Jessica J Purohit Vivek S VS

Clinical pharmacokinetics 20240215 3

<h4>Background and objectives</h4>As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor).<h4>Methods</h4>Long ...[more]

PMID: 38358645

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Project description:BackgroundDecision making for adult tracheostomy and prolonged mechanical ventilation is emotionally complex. Expectations of surrogate decision makers and physicians rarely align. Little is known about what surrogates need to make goal-concordant decisions. Currently, little is known about the decisional needs of surrogates and providers, impeding efforts to improve the decision-making process.MethodsUsing a thematic analysis approach, we performed a qualitative study with semistructured interviews with surrogates of adult patients receiving mechanical ventilation (MV) being considered for tracheostomy and physicians routinely caring for patients receiving MV. Recruitment was stopped when thematic saturation was reached. We describe the decision-making process, identify core decisional needs, and map the process and needs for possible elements of a future shared decision-making tool.ResultsForty-three participants (23 surrogates and 20 physicians) completed interviews. Hope, Lack of Knowledge Data, and Uncertainty emerged as the 3 main themes that described the decision-making process and were interconnected with one another and, at times, opposed each other. Core decisional needs included information about patient wishes, past activity/medical history, short- and long-term outcomes, and meaningful recovery. The themes were the lens through which the decisional needs were weighed. Decision making existed as a balance between surrogate emotions and understanding and physician recommendations.ConclusionsTracheostomy and prolonged MV decision making is complex. Hope and Uncertainty were conceptual themes that often battled with one another. Lack of Knowledge & Data plagued both surrogates and physicians. Multiple tangible factors were identified that affected surrogate decision making and physician recommendations.ImplicationsUnderstanding this complex decision-making process has the potential to improve the information provided to surrogates and, potentially, increase the goal-concordant care and alignment of surrogate and physician expectations.HighlightsDecision making for tracheostomy and prolonged mechanical ventilation is a complex interactive process between surrogate decision makers and providers.Qualitative themes of Hope, Uncertainty, and Lack of Knowledge & Data shared by both providers and surrogates were identified and described the decision-making process.Concrete decisional needs of patient wishes, past activity/medical history, short- and long-term outcomes, and meaningful recovery affected each of the larger themes and represented key information from which surrogates and providers based decisions and recommendations.The qualitative themes and decisional needs identified provide a roadmap to design a shared decision-making intervention to improve adult tracheostomy and prolonged mechanical ventilation decision making.

Dataset Information

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

Background and objectives

Methods

Results

Conclusion

Publications

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

Similar Datasets

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