Dry Powder Mannitol Passes FDA Committee

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Committee: Pulmonary-Allergy Drugs Advisory Committee (PADAC)

Indications: Dry Powder Mannitol (DPM) in management of cystic fibrosis to improve pulmonary function in patients 18 years of age and older in conjunction with standard therapies

Drug/Device: Drug

Sponsor: Chiesi USA

Question 1: Do the data provide substantial evidence of efficacy for DPM for the proposed indication of the management of cystic fibrosis to improve pulmonary function in patients 18 years of age and older in conjunction with standard therapies?

Vote Results: Yes 10 No 6 abstain 0

Question 2: Are the safety data adequate to support approval of DPM for the proposed indication of the management of cystic fibrosis to improve pulmonary function in patients 18 years of age and older in conjunction with standard therapies?

Vote Results: Yes 10 No 6 abstain 0

Question 3: Is the benefit-risk profile adequate to support approval of DPM for the proposed indication of the management of cystic fibrosis to improve pulmonary function in patients 18 years of age and older in conjunction with standard therapies?

Vote Results:  Yes  9   No  7  abstain  0

FDA Documents:

Background:  

The New Drug Application (NDA) for DPM was originally submitted by the applicant in 2012. Based on the results of two clinical studies conducted among patients 6 years and older, the PADAC panel recommended against approval of the original application because of lack of substantial evidence of efficacy (i.e. lack of strong statistical evidence, frequent and differential dropouts by trial arms, and small effect size) and concerns regarding increased risk of hemoptysis especially among pediatric patients. In response to the Complete Response (CR) action taken by the agency, the applicant submitted results of a new clinical trial study that included patients at least 18 years of age, and modified the indication to restricting its use in adult patients.

Unique Challenges:

Statistical methods

In the original NDA application, the applicant applied a Mixed Model for Repeat Measures (MMRM) in analysis of efficacy endpoints. However, the agency questioned the appropriateness of the chosen method as MMRM operates on a strong assumption that data is missing at random. Trial data submitted by the applicant showed substantial differences in dropout rates between trial arms, suggesting potential violation of such assumption of MMRM and may have inflated the magnitude of the effect size. The FDA therefore chose a Pattern Mixture Model (PMM) with multiple imputation (MI) to estimate the effect from the two clinical studies submitted in the original application. As there was no differential dropout rates between the trial arms, efficacy outcome of the third study was assessed using a MMRM model, using baseline observation carried forward (BOCF) method to address missing data.

Efficacy

The primary efficacy endpoint was changed from baseline forced expiratory volume in one second (FEV1) at 26 weeks.  All three submitted studies demonstrated moderate effect of DPM on FEV1, but only the study submitted for the CR showed statistical significance in achieving a moderate effect size. Post-hoc analysis of the original submission data lacked statistical significance in observed positive treatment effects, most likely due to loss of power as a result of subgroup analysis.

None of the secondary efficacy endpoints were met with statistical significance. Secondary efficacy measures were assessed in terms of Protocol Defined Pulmonary Exacerbation (PDPE) and patient reported quality of life. The definition of PDPE was based upon specific signs and symptoms of an exacerbation and was considered acceptable by the agency. Patient-reported quality of life was measured and assessed using a standardized questionnaire designed specifically for patients with cystic fibrosis. Although not statistically significant, the rate of PDPE was actually slightly higher in the PDM arm in 2 out of the 3 studies; and there was no difference in change in quality of life between treatment arms.

Safety

The safety outcome focused on hemoptysis as well as CF exacerbations in terms of condition aggravated SAEs. Although in the original application, DPM was associated with an increased risk of hemoptysis, there was no significant imbalance in number of patients experiencing hemoptysis when analyses were restricted to pooled data on adult patients. Therefore, the agency ruled out safety concerns regarding hemoptysis of DPM treatment in the adults. The DPM treated arm, however, sustained a slight increased number of condition-aggravated SAEs compared with the control arm. Furthermore, the difference was more prominent when the analysis was restricted to the U.S. patients.

Risk/Benefit Analysis

Lack of statistical significance, clinically meaningful effect size, and safety concerns were the primary reasons that lead to unsuccessful application in the original submission by the applicant.  With the resubmission, the applicant conducted a third study that only included relevant patients, was larger, and was designed to minimize missing data by following up patients after discontinuation of study medications.  This study successfully demonstrated a statistically significant difference from control for the primary endpoint of change in FEV1 at 26 weeks, and risk of hemoptysis was nil.  This has led to the AC to vote in favor for the risk/benefit profile of the indication.

Next Steps: