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US Food and Drug Administration
ssessment of the patient voice has become recognized as a vital component in the evaluation of new candidate therapies. To address this, FDA has partnered with stakeholders on multiple patient-focused drug development (PFDD) initiatives to facilitate incorporation of patient and caregiver input into drug review and evaluation. These include the FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making.
EoE is a Clinicopathologic Disorder
EoE has an estimated incidence of five to ten cases per 100,000 persons per year, and a prevalence of 50 to 100 cases per 100,000 persons in North America and Europe. Clinical features and histologic activity can vary independently in patients with EoE; the resolution of symptoms may accompany ongoing histologic activity, and clinical symptoms can persist during histologic remission (defined by decrease in eosinophil count). Thus, treatment of EoE has two goals: eliminate or decrease symptoms of active disease and normalize esophageal histology.
Assessment of Benefit
Although the importance of evaluating the patient voice in these development programs is widely accepted and FDA guidance exists on a recommended approach to increase the interpretability of these COA endpoints, challenges during their development, implementation, and analysis remain.
Development and Implementation of Fit-for-Purpose COA Endpoints
To meet the challenges of COA instrument and endpoint development in this patient population, developers should seek FDA input as early as possible and at important milestones throughout the drug development process. Discussions should include:
- planned assessments of the COA instrument’s psychometric properties and performance (reliability, validity, and ability to detect change);
- proposals for patient/caregiver global impression of severity and change in anchor scales to be included to help interpret meaningful within-patient change and confirm the proposed COA endpoint definition; and
- appropriateness of the planned recall and assessment periods.
When developing or modifying COA instruments and determining their administration schedule, developers should strive to minimize burden while identifying the information that is most important to patients. They should capture information regarding patient preferences related to treatment and to acceptability of tradeoffs between benefit and risk.
Analyses and Interpretation
Alternatively, signs and symptoms should be assessed on a continuous or ordinal scale. To aid in the interpretation of COA endpoint results, developers should propose an appropriate range of within-patient score change that patients consider to be clinically meaningful using anchor-based methods (using the aforementioned scales), supplemented with empirical cumulative distribution function (eCDF) curves using data pooled across trial arms. Additionally, developers should submit a supportive graph (i.e., eCDF) of within-patient change from baseline by treatment arms for review, to determine whether there appears to be a treatment difference in the range representing a meaningful improvement to patients.
These analyses were recommended to detect and characterize clinically meaningful change and facilitate interpretation of results across development programs.
Discussion and Future Opportunities
References available upon request.