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Importance of the Patient Voice in Drug Development: Eosinophilic Esophagitis as a Case Example
Erica Lyons
Sarrit Kovacs
Matthew Kowalik
Jessica Lee
Division of Gastroenterology, Office of New Drugs, CDER
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.

Here, we present an example of how evaluating the patient experience is essential to assessing the benefit for drugs under investigation for the treatment of eosinophilic esophagitis (EoE). We also present a recommended approach to implementing and analyzing clinical outcome assessment (COA) data to determine clinical benefit to patients in these development programs.

EoE is a Clinicopathologic Disorder

EoE is a chronic immune-mediated disease triggered by allergen exposure and characterized by eosinophil-predominant inflammation and clinical symptoms of esophageal dysfunction. It is part of a larger group of disorders known as eosinophilic gastrointestinal disorders (EGIDs). Untreated, EoE leads to esophageal stricture, dysphagia, and risk of food impaction. Clinical signs and symptoms vary with the patient’s age: Infants and toddlers present with feeding difficulties; school-aged children are likely to have vomiting or pain; and adolescents and adults report dysphagia and food impaction.

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

To address the need to provide evidence of improvement on clinical symptoms, FDA’s Guidance for Industry: Eosinophilic Esophagitis: Developing Drugs for Treatment has recommended that (1) significant improvement from baseline in signs and symptoms (using a well-defined and reliable COA instrument) and (2) histologic response be evaluated as co-primary endpoints in drug development programs for EoE. As a co-primary endpoint, inclusion of a patient-focused COA in these clinical trials is necessary to demonstrate clinical benefit and support both potential drug approvals and labeling claims. Although EoE can present with heterogeneous symptoms, adolescents and adults predominantly present with dysphagia; therefore, this symptom has been the most widely-characterized and identified for inclusion in a COA co-primary endpoint for EoE.

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

Several COA instruments are available for clinical use to evaluate the signs and symptoms of EoE, but no such instrument is yet publicly available and accepted for regulatory use. Developers are therefore encouraged to modify or develop an instrument based on patient or observer input regarding the relevant and meaningful signs and symptoms of EoE that are expected to improve with treatment.

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

Although commonly used in previous studies in patients with EoE, use of percent change from baseline or responder analysis is not recommended, unless the targeted response is complete resolution of signs and symptoms.

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

Assessment of the patient voice and experience is essential to determining the benefit of drugs under investigation for the treatment of EoE. The field of EGIDs, including EoE, is rapidly advancing. In addition to assessing and refining the current approach to evaluating benefit for EoE, the FDA is actively engaging the academic community, patient advocates, and industry on whether the EoE approach of utilizing co-primary endpoints of significant improvement from baseline in signs and symptoms and histologic response could be adapted to support clinical trial development for other EGIDs, as well as other relevant indications.
This article reflects the views of the authors and does not represent FDA’s views or policies.

References available upon request.