Inability to Distinguish Drug Effect from Confounding Factors in Efficacy Study
Severity: majorThe estimate of efficacy derived from study CH-ACM-01 does not distinguish the effect of Mycapssa from other effects such as inactive disease at the endpoint visit due to cumulative effect of past therapies (e.g., pituitary surgery, drugs, radiation) or residual effects of pre-trial therapy. Responders could be due to inactive disease or carryover effects. Important biases prevent determination of Mycapssa's clinically important effect or its magnitude.
Recommended response: Redesign or conduct new clinical trials with appropriate controls and endpoints to clearly demonstrate Mycapssa's efficacy, accounting for confounding factors and prior treatments. Ensure robust statistical analysis plans are in place.
Evidence of Worsening Control and Rising IGF-1 Levels in Efficacy Study
Severity: majorReview of study CH-ACM-01 data showed an overall worsening of control in the majority of patients, evidenced by rising IGF-1 levels between baseline and last on-treatment assessment. This finding is inconsistent with 'maintenance of response' or 'maintenance of control' for patients with active disease and suggests potential treatment failure.
Recommended response: Provide further analysis or new data to explain the rising IGF-1 levels and demonstrate sustained control. Re-evaluate responder criteria and long-term efficacy endpoints to accurately reflect disease control.
Absence of Pre-specified Responder Criterion in Protocol
Severity: majorThe application did not pre-specify or select which responder criterion would be used to define response for the purpose of presenting the primary efficacy results in the protocol submitted to the Agency at the End-of-Phase-2 (EOP2) meeting.
Recommended response: Clearly define and justify the primary efficacy endpoint and responder criteria, and ensure consistency with the protocol and statistical analysis plan. Submit an amended protocol with these details.
Update to Prescribing Information Required
Severity: minorUpdated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format is required. Comment on proposed labeling is reserved until the application is otherwise adequate. The sponsor is encouraged to review PLR requirements and SRPI checklist.
Recommended response: Revise prescribing information according to 21 CFR 314.50(l)(1)(i) and submit in SPL format. Utilize FDA labeling resources and the Selected Requirements for Prescribing Information (SRPI) checklist.
Cited: 21 CFR 314.50(l)(1)(i)
Revision of Carton and Container Labeling
Severity: minorDraft carton and container labeling must be revised to add 'delayed-release' to the product name on all labels.
Recommended response: Update all carton and container labels to include 'delayed-release' in the product name as specified by the agency.
Resubmit Proposed Proprietary Name
Severity: infoThe proposed proprietary name, Mycapssa, was found acceptable pending approval of the application. The sponsor is requested to resubmit the proposed proprietary name when responding to the application deficiencies.
Recommended response: Include the proprietary name resubmission with the overall response to deficiencies, confirming its acceptability.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required when responding to deficiencies. This update must include details on significant changes, new safety data from all studies, retabulations, case report forms for deaths/SAEs, updated exposure information, and a summary of worldwide safety experience.
Recommended response: Prepare a comprehensive safety update per 21 CFR 314.50(d)(5)(vi)(b), including all requested data and analyses from nonclinical and clinical studies, ensuring all new safety information is thoroughly presented.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
