Insufficient evidence from Human Factors validation studies for Mannitol Tolerance Test (MTT)
Severity: criticalSubmitted data from human factors (HF) validation studies do not provide sufficient evidence to demonstrate that healthcare providers can reliably and accurately perform the Mannitol Tolerance Test (MTT) to correctly identify the intended target patient population. HF study results demonstrated several use errors and use difficulties with critical tasks in administering the MTT, which could result in healthcare providers prescribing the medication to patients who cannot tolerate mannitol inhalation powder, leading to severe bronchospasm and patient harm.
Recommended response: Revise the product user interface to address the errors and use difficulties seen in HF validation studies, and then conduct a supplemental HF validation study to demonstrate the effectiveness of additional risk mitigations and ensure no new risks are introduced.
Proprietary name resubmission required
Severity: minorThe proposed proprietary name, Bronchitol, was found acceptable pending approval of the application in the current review cycle. Resubmission of the proposed proprietary name is required when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name when responding to the application deficiencies.
Comprehensive safety update required
Severity: majorA comprehensive safety update is required, including data from all nonclinical and clinical studies/trials of the product, detailed description of significant changes or findings in the safety profile, retabulation of adverse events and discontinuations, provision of case report forms and narrative summaries for deaths and serious adverse events, and an updated summary of worldwide experience.
Recommended response: Provide a comprehensive safety update as described at 21 CFR 314.50(d)(5)(vi)(b), incorporating new safety data, retabulations, case report forms, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Unfavorable benefit-risk balance and insufficient efficacy data for cystic fibrosis
Severity: criticalThe submitted data do not provide a favorable benefit-risk balance to support the use of inhaled mannitol in patients with cystic fibrosis 6 years of age and older. Efficacy determination is inadequate due to treatment-related frequent early dropouts in trial 301 and lack of statistical significance in trial 302. Safety findings show a high occurrence of hemoptysis, particularly in pediatric patients, which does not balance favorably with the submitted efficacy data.
Recommended response: Conduct a clinical program including at least one adequate clinical trial to show substantial evidence of efficacy in patients with cystic fibrosis and balancing safety findings.
