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Pulmonary-Allergy Drugs Advisory Committee. NDA 21-395 Spiriva ® (tiotropium bromide) Inhalation Powder Eugene J. Sullivan, MD FCCP Medical Officer Division of Pulmonary and Allergy Drug Products. Outline. Background PK/PD characteristics Overview of P3 clinical program

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Pulmonary allergy drugs advisory committee l.jpg

Pulmonary-Allergy Drugs Advisory Committee

NDA 21-395

Spiriva® (tiotropium bromide)

Inhalation Powder

Eugene J. Sullivan, MD FCCP

Medical Officer

Division of Pulmonary and Allergy Drug Products


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Background: COPD Indication

  • Proposed Indication for tiotropium:

    “treatment of bronchospasm

    and dyspnea associated with COPD”

  • No drugs approved in the US carry an Indication for the treatment of specific symptoms of COPD, or for the “treatment of COPD”


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Background: COPD Indication

  • Currently approved drugs:

    • “treatment of bronchospasm associated with COPD”

  • Distinction: treatment of bronchospasm vs. treatment of the disease

  • FEV1

    • direct measure of bronchospasm

    • “surrogate” measure of the disease itself (a constellation of physical signs and symptoms, physiologic processes, and histopathologic features)


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Background: COPD Indication

  • Presumed clinical benefit of bronchodilators

    • approved based on spirometry, but clinically detectable benefit is presumed

    • “as-needed” use of the bronchodilator albuterol reflects bronchodilator-mediated symptom benefit


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Background: COPD Efficacy Variables

  • Primary: Measure of bronchodilation

    • Usually FEV1

      • After chronic use (for maintenance drugs)

      • Peak FEV1, FEV1-Time Curve AUC

  • Secondary (supportive)

    • Other spirometry variables

    • “Rescue” albuterol use

    • Peak flow

    • Six-minute walk test

    • Exacerbations, Patient-Reported Outcomes, etc.


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Background: Tiotropium P3 Primary Efficacy Variables

  • All studies:

    • Change from baseline in “trough” (pre-dose) FEV1

  • Two studies:

    • Change from baseline in “trough” (pre-dose) FEV1

      and

    • Transitional Dyspnea Index (TDI)


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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PK/PD Characteristics

  • Bioavailability of tiotropium

    • Oral ingestion 2-3%

    • Oral inhalation 19.5%

  • Single dose PK (oral inhalation):

    • Cmax= 5 minutes

    • Detectable in blood for 2-4 hours

    • Prolonged urinary excretion

      • detectable in urine for 25 days after a dose of 108mcg

  • Volume of distribution: 32 liters/kg


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PK/PD Characteristics

  • Elimination:

    • 74% eliminated in urine as parent compound

      • 44% by 4 hours, 54% by 24 hours, 61% by 96 hours

      • active renal secretion (renal clearance > creatinine clearance)

    • Fate of remaining 26% not well established

      • non-enzymatic hydrolysis

      • hepatic metabolism (CYP2D6 and CYP 3A4)


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PK/PD Characteristics

  • Terminal elimination half-life = 5-6 days

  • Multiple-dose accumulation: 2-3 fold

    • suggests effective T1/2= 24-36 hours

  • PK characteristics are indicative of extensive tissue binding, with slow release back into circulation

    • large volume of distribution and long terminal elimination half-life


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PK/PD Characteristics

  • Pharmacodynamic effect increases with multiple daily dosing

    • Spirometry data from Phase 3 studies

    • Separate “sub-study” of one of the Phase 3 studies (122A, ipratropium-controlled)

      • N= 28

      • six-hour, serial spirometry on Days 1, 2, 3, 8, and 50

    • Maximum (“steady state”) effect is achieved by Day 8


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PD Effect Increases with Multiple Dosing

Phase 3, one-year, placebo-controlled studies:


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PD Effect Increases with Multiple DosingOnset of Steady State “Sub-study”

  • Daily AM PEFR reached maximum effect at Day 6


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Phase 3 Clinical Program


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Phase 3: Patients Studied

  • Inclusion Criteria:

    • age  40 years

    • smoking history > 10 pack-years

    • FEV1  60% or 65% predicted

    • FEV1  70% of FVC

  • Exclusion Criteria:

    • h/o asthma, allergic rhinitis, or atopy

    • elevated blood eosinophil count

    • significant disease other than COPD

    • symptomatic prostatic hypertrophy or bladder outlet obstruction

    • narrow angle glaucoma

    • MI (1 year), cardiac arrhythmia requiring drug treatment, or hospitalization for heart failure (3 years)


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Phase 3: Demographic and Baseline Features


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Safety Database

  • 1308 patients exposed in P3

  • Phase 3 Safety Evaluations:

    • adverse events

    • vital signs

    • physical examination

    • clinical labs

    • ECGs (timing not specified)


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Safety Database

  • Additional Safety Data (Phase 2)

    • timed ECGs (multiple dose study, up to 44mcg QD)

    • Holter monitors (n=72 patients, pre- and on-treatment)


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Safety Database

  • Focus on one-year, placebo-controlled studies

  • Median exposure 10 days longer for tiotropium patients (338 days) than for placebo patients (328 days).


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Adverse Events with Tiotropium(One-year, placebo-controlled studies)

  • Gastrointestinal:

    • dry mouth (16% vs. 2.7%)

    • dyspepsia (5.8% vs. 4.6%)

    • abdominal pain (4.7% vs. 3.0%)

    • constipation (3.5% vs. 1.6%)

    • vomiting (3.5% vs. 2.4%)


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Adverse Events with Tiotropium(One-year, placebo-controlled studies)

  • Respiratory System:

    • upper respiratory tract infection (41.1% vs. 37.2%)

    • epistaxis (3.6% vs. 1.9%)

    • pharyngitis (8.9% vs. 7.3%)

    • sinusitis (11.3% vs. 9.4%)

  • Chest pain (6.9% vs. 4.6%)

  • Rash (4.2% vs. 2.2%)

  • Urinary Tract Infection (7.3% vs. 5.1%)


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Adverse Events with Tiotropium(Six-month studies)

  • Fewer differences between tiotropium and placebo.

  • AEs more common in tiotropium:

    • Dry mouth (8.2% vs. 2.3%)

    • Upper Respiratory Tract Infection (19.4%vs. 16%)

    • Pharyngitis (4.5% vs. 3.0%)

    • Sinusitis (3.2% vs. 2.5%)

    • Influenza-like symptoms (6.7% vs. 4%)


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Safety Interactions with Tiotropium(One-year, placebo-controlled studies)

  • Age (60, 61-70, 71):

    • Dry Mouth: 11%, 16%, 21% (Pbo values: 3%, 1.9%, 3.5%)

    • Constipation: 2%, 2.8%, 6% (Pbo values: 3%, 0.6%, 1.7%)

    • Urinary Tract Infection: 3.3%, 5.2%, 12% (Pbo values: 2%, 3.9%, 6.1%)

  • Gender:

    • Dry Mouth: women 23%, men 13% (Pbo values: 2.9% and 2.6%)


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Other Safety Observations(One-year, placebo-controlled studies)

  • Urinary Retention:

    • 4 patients, all treated with tiotropium

    • all required Foley catheter; three were started on medication for BPH following the event

  • “Micturation disorder” or “micturation frequency”

    • 6 (1.1%) tiotropium patients vs. 0 placebo patients


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Other Safety Observations(One-year, placebo-controlled studies)

  • Constipation:

    • one patient treated with tiotropium was hospitalized with fecal impaction

  • “Diabetes mellitus”, “diabetes mellitus aggravated,” or “hyperglycemia”

    • 14 (2.5%) tiotropium patients vs. 1 (0.3%) placebo patients


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Other Safety Observations(One-year, placebo-controlled studies)

  • Cardiovascular Effects

    • “Heart Rate and Rhythm Disorders”:

      • AEs: 24 (4.4%) tiotropium patients vs. 8 (2.2%) placebo patients

      • SAEs: 1.3% tiotropium patients vs. 0.5%placebo patients

      • (signal not seen in ipratropium-controlled studies)

    • No safety signal on ECGs


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Other Safety Observations(One-year studies)

  • Deaths

  • One-year studies:

    • incidence of death similar in all groups

    • placebo-controlled: 5/7 tiotropium deaths were attributable to cardiac ischemia or arrhythmia (compared with 1/7 placebo deaths)

    • ipratropium-controlled: deaths due to MI = 3/9 tiotropium deaths, 0/3 ipratropium deaths


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Other Safety Observations

Phase 2 Study:

  • No safety signal on Holter monitors

    • N=72 patients, pre- and on-treatment

      • compared with n = 284 patients during five, 24-hour periods described in Serevent MDI label

    • One subject developed a four-fold increase in ventricular ectopy on-treatment (tiotropium).


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Adverse Events with Tiotropium(One-year, ipratropium-controlled studies)

EventTiotropiumIpratropium

Chest Pain 5.3%2.2%

Dry Mouth 12.1%6.1%

Dyspepsia 1.4%0.6%

Moniliasis 2.8%1.7%

Pharyngitis 6.5%2.8%

Sinusitis 3.4%2.2%

URTI 43%34.6%

UTI 3.9%2.2%


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Bronchodilator Efficacy:Studies 114 and 115

  • Trough FEV1 statistically superior on all other clinic visits (1, 7, 25, 37, and 49 weeks), with mean effect sizes of 0.11 - 0.16 liters.

  • Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 3-hour serial spirometry performed on all clinic visits.


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Bronchodilator Efficacy:Studies 114 and 115

  • Peak FEV1 Data

    • Mean Peak FEV1 response was 0.24 liters on Day 1 and 0.25 - 0.31 liters on subsequent clinic visits.

    • On Day 1, the mean peak FEV1 at each time point (0.5, 1, 2, and 3 hours) was <0.20 liters

    • This is because patients reached their personal peak FEV1 at differing time points:


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Bronchodilator Efficacy:Studies 114 and 115

  • Tiotropium was statistically superior to placebo:

    • FVC response (trough, average, and peak)

    • AM and PM PEFR, for most weeks, with mean effect sizes of 8 - 31 liters/minute (morning) and 13 to 40 liters/minute (evening)


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Bronchodilator Efficacy:Studies 122A and 122B

  • Primary Efficacy Endpoint: Trough FEV1 at 13 weeks

    • Note: Ipratropium not expected to show significant efficacy at this time point

    • Tiotropium was superior to ipratropium on this variable at all clinic visits, with mean effect sizes of 0.11 to 0.18 liters (over ipratropium)


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Bronchodilator Efficacy:Studies 130 and 137

  • Trough FEV1 was statistically superior on all other clinic visits (Day 1, and Weeks 2, 8, and 16), with mean effect sizes of 0.11 - 0.15 liters.

  • Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 12- or 3-hour serial spirometry performed on all clinic visits.


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Bronchodilator Efficacy:Studies 130 and 137

  • Tiotropium was statistically superior to placebo:

    • FVC response (trough, average, and peak)

    • AM and PM PEFR, with mean effect sizes of 14.9 - 27 liters/minute (morning) and 21 - 33 liters/minute (evening)


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Dyspnea Efficacy:Studies 130 and 137

TDI “responders” at 6 months

(Co-primary Endpoint)

StudyTiotropiumPlaceboSalmeterol

130 42%** 26% 35%

137 45%* 33% 48%**

*p<0.05 (placebo comparison)

**p<0.01 (placebo comparison)

[Responders defined as patients with TDI score  1]


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Exclusions from TDI Data Set


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Dyspnea Efficacy:Studies 130 and 137

Number Needed to Treat (NNT) Analyses*

StudyNNT

1306.45

1378.6

Combined7.5

*To achieve one “responder,” defined as TDI  1


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Dyspnea Efficacy:Studies 130 and 137

TDI “responders” at 8 and 16 weeks

(Secondary Endpoints)

8 Weeks

StudyTiotropiumPlaceboSalmeterol

130 40%* 24% 34%

137 44%* 31% 47%**

16 Weeks

StudyTiotropiumPlaceboSalmeterol

130 43%* 27% 34%

137 42%* 30% 47%**

* p<0.05 (placebo comparison) **p<0.01 (placebo comparison)


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Dyspnea Efficacy:TDI - Analyses of Mean Values

Statistically Difference

Superior  1

(Weeks) (Weeks)

  • Study 130 8, 16, 24 (all) 8, 24

  • Study 1378, 16, 24 (all)8, 16, 24 (all)

  • Study 1147, 13, 25, 37, 49 (all) 49

  • Study 1157, 13, 25, 37, 49 (all) 37, 49

  • Study 122A*1, 26, 39, 52 (not 7, 13) -

  • Study 122B*1,7,13,26,39,52 (all)1, 26, 29, 52

    *comparison: ipratropium


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Dyspnea Efficacy:Shuttle Walk Test/ Borg Dyspnea Scale

  • Studies 130 and 137 included a post-dose Shuttle Walk Test on Day 1, and Weeks 8, 16, and 25.

  • Shuttle Walk Test (SWT): a standardized test in which patients walk at a steady pace on a 10-meter course until they are unable to maintain the required speed without becoming unduly breathless.

  • The Modified Borg Dyspnea Scale was administered before and after each SWT.

    • Scale: ranges from 0 (“nothing at all”) to 10 (“maximal”)


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Dyspnea Efficacy:Shuttle Walk Test/ Borg Dyspnea Scale

  • SWT (Walking Distance)

    • No difference between groups in either study

    • Placebo numerically superior in 1 study

    • Walking distance did not increase during the study in any of the groups

  • Modified Borg Dyspnea Scale

    • Study 130: No differences between tiotropium and placebo, except Week 8 (Difference: 0.24 pre-exercise, 0.32 post-exercise)

    • Study 137: No differences between tiotropium and placebo


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Dyspnea Efficacy:“COPD Symptom Score”

  • Studies 130/137 and 114/115

  • Investigator’s assessment of the prior week

  • Wheezing, Shortness of Breath, Coughing, and Tightness of Chest

  • Each scored from 0-3

  • Results: Tiotropium statistically superior to placebo for “Shortness of Breath” at most visits

  • Effect Size: 0.13 to 0.36

  • Interpretation: Uncertain significance (validation, effect size)


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Other Efficacy Findings

  • Studies 114 and 115

    • Tiotropium was statistically superior to placebo:

      • Physician’s Global Evaluation (effect size of 0.25 to 0.59 on a scale of 1-8)

      • As-needed albuterol (5-6 fewer doses per week)

    • No consistent meaningful difference shown:

      • COPD exacerbations or hospitalizations

      • St. George’s Hospital Respiratory Questionnaire

      • Medical Outcomes Study SF-36


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Other Efficacy Findings

  • Studies 122A and 122B (ipratropium-controlled)

    • No consistent effect:

      • as-needed albuterol use

      • COPD exacerbations or hospitalizations


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Other Efficacy Findings

  • Studies 130 and 137

    • Tiotropium was statistically superior to placebo:

      • Physician’s Global Evaluation (all test days except one; effect size of 0.11 to 0.59 on a scale of 1-8)

    • No consistent, meaningful difference shown:

      • As-needed albuterol

      • COPD exacerbations or hospitalizations

      • St. George’s Hospital Respiratory Questionnaire

      • Patient Satisfaction Questionnaire


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Outline

  • Background

  • PK/PD characteristics

  • Overview of P3 clinical program

  • Safety findings

  • Efficacy findings

    • Bronchodilator efficacy

    • Dyspnea efficacy

    • Other efficacy findings

  • Summary


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Summary

  • PK features of tiotropium are somewhat unique among inhaled bronchodilators

    • Very large volume of distribution

    • Very long terminal elimination half-life

    • Apparent tight tissue binding with slow release back into the circulation


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Summary

  • Safety:

    • Dry mouth is common, shows an age and gender interaction, and is more frequent than with ipratropium

    • Several AEs occurred more frequently with tiotropium than placebo. Based on the mechanism of action and the observed age interaction, constipation and urinary tract infection may be important.

    • Possible effect on heart rate/rhythm may merit further evaluation


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Summary

  • Efficacy:

    • Appears to provide clinically meaningful bronchodilation

    • Duration of action supports once-daily dosing

    • Maximum bronchodilator effect reached after multiple daily doses

    • Demonstrable effect on TDI. However, the clinical significance of this effect is not known.

      • Issues with the instrument and its implementation in the studies

      • Effect size (NNT)


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Summary

  • Other:

    • Safety/efficacy of concurrent “as-needed” ipratropium not addressed


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Questions for the Committee

1. Is the safety database for tiotropium bromide inhalation powder for the treatment of COPD patients adequate?

A) If not, what further safety data should be obtained?

B) Which of the safety data should be obtained prior to approval?

2. Are there specific safety concerns regarding the use of tiotropium bromide inhalation powder in the COPD patient population that merit specific attention in the product label?


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Questions for the Committee

3. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful bronchodilator effect when used in the chronic treatment of patients with COPD?


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Questions for the Committee

4. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful effect for the symptom of dyspnea in patients with COPD?

5. In general, what quality and quantity of data would constitute substantial and convincing evidence of a clinically meaningful benefit for the symptom of dyspnea in patients with COPD?


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