082: Swallowability of Solid Oral Drug Products in Regulatory Submissions: Patient-Specific Features, Product Physical Attributes & Clinical Swallowability Study Designs

Statement of Purpose, Innovation or Hypothesis: Swallowability is a critical property of solid oral dosage forms (SODFs), the most common dosage forms on the market. While the swallowability of SODFs is influenced by patient-specific factors and formulation-specific physical attributes, no guidelines are currently available on how to evaluate the swallowability of an SODF. To determine features of SODFs that may predict swallowability issues during the regulatory process, we examined the patient-specific factors and physical attributes of SODFs with swallowability issues in submissions to the US Food & Drug Administration (FDA). We also analyzed approaches taken to evaluate swallowability in these submissions to determine common practices.
Description of Methods and Materials: SODF drug products where swallowability was discussed in regulatory documents were identified by searching an FDA internal database for “swallowability,” which yielded 373 documents (e.g., internal meeting minutes, communications between the Agency and industry, study plans and study reports) corresponding to 142 pre-investigational new drug applications (pre-INDs), INDs and new drug applications for 67 SODF new drug products. The documents were reviewed to determine the reasons for swallowability issues. The size (length of the maximum dimension) and shape of the highest strength and details of evaluating swallowability were collected from the documents and/or the regulatory submission packages as available.
Data and

Results: Regarding patient-specific factors for the 67 drug products with swallowability issues, 22.4% (n=15) were blood glucose regulators and none were indicated for patients experiencing diseases complicated by dysphagia. Interestingly, swallowability in pediatric patients was an issue for 80.5% (n=54) of the products. For physical attributes, the products were large (62% ≥17 mm, n=55) and oval or capsule shaped (69.8%, n=53). Most large products (≥17 mm) were oval or capsule shaped (84.8%, n=33), and no large products were round. For products with data on evaluating swallowability (n=19), clinical swallowability assessments were preferred (94.7%) over in vitro approaches (5.3%). These assessments involved pediatric patients (83.3%, n=18) and were often a supplementary endpoint (77.8%, n=14) for which a study was not sufficiently powered. The assessment methodologies differed in product administration frequency, swallowability measurement frequency and use of a placebo. Swallowability was always evaluated with a questionnaire, but the questions and reporters varied. Subjects frequently responded using a Likert scale (71.4%, n=14). Most studies (61.1%, n=18) used dichotomization to report questionnaire responses as positive/negative with limited analysis.
Interpretation, Conclustion or Significance: Primary reasons for swallowability issues for SODF products in regulatory submissions were pediatric suitability, large size and oval or capsule formulations. When swallowability for products was evaluated, a clinical approach was preferred. Clinical swallowability assessments exhibited trends in design (e.g., pediatric patients, endpoint, questionnaires, Likert scales, dichotomization); however, they also exhibited inconsistencies (e.g., administration frequency, placebo, reporter). These significant and substantial variations in study design may affect the swallowability measurement obtained because of sample size, questionnaire design, learning effect in swallowing, quality of a placebo, reliability of a reporter, properties of a response scale and the data analysis approach. Altogether, there remains a need for developing standardized designs, validated assessment tools and quality assurance for clinical swallowability assessments.
Disclosures: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies. This project was supported in part by an appointment to the Research Participation Program at the US Food & Drug Administration administered by the Oak Ridge Inst for Science & Education through an interagency agreement between the US Department of Energy and the US Food & Drug Administration (MRM).