Designing Early-Phase Clinical Trials for Inhaled Drug Products

Introduction

Inhalation drug delivery offers fast, localized therapeutic action with minimal systemic exposure. Used in respiratory diseases like asthma and COPD, and increasingly in systemic applications such as vaccines or insulin, inhaled therapies pose unique clinical challenges in early development. Phase 1 trials for inhaled products must evaluate not just safety and pharmacokinetics (PK), but also drug-device compatibility, pulmonary deposition, and inhalation technique. This tutorial provides a comprehensive guide to designing Phase 1 studies for inhaled drugs, covering PK/PD strategies, device testing, and regulatory expectations.

Why Inhaled Therapies Require Special Phase 1 Designs

• Pulmonary delivery complexity: Absorption depends on particle size, lung deposition, and airflow dynamics
• Device variability: Different inhalers affect dose delivery consistency
• Dual endpoints: Local (lung) and systemic effects must be captured
• Subject variability: Inhalation technique affects bioavailability

Primary Objectives of Inhalation Phase 1 Trials

• Assess local and systemic safety of inhaled product
• Determine pharmacokinetic profile after pulmonary delivery
• Evaluate pharmacodynamic biomarkers (e.g., FEV1, nitric oxide)
• Validate device usability and inhalation reproducibility

Study Design Elements

1. Population Selection

• Healthy volunteers: Used if minimal local toxicity expected
• Target population: May be required for cytotoxic, irritant, or immune-activating inhaled drugs

2. Dose Rationale

• Initial dose based on NOAEL from inhalation toxicology studies in animals
• Include sentinel subjects and staggered dosing

3. Dosing Regimen

• SAD/MAD design: Common in Phase 1 inhaled trials
• Repeat-dose escalation may be limited due to airway reactivity

4. Device Training and Standardization

• Subjects must be trained in correct inhalation technique
• Use inhalation flow meters to confirm inspiratory volume and pressure

Pharmacokinetic Considerations

1. PK Sampling Strategy

• Frequent plasma samples in early hours post-dose (e.g., 0.05, 0.1, 0.25, 0.5, 1 hr)
• Include urine PK if renal clearance is anticipated

2. Systemic PK Parameters

• Cmax: Often lower than oral/IV due to first-pass lung metabolism
• Tmax: Typically short (minutes to 1 hour)
• AUC: Used to compare dose-exposure relationships

3. Lung Retention and Local Exposure

• Gamma scintigraphy: Radiolabeled drug visualized in lungs
• Exhaled breath condensate: Explored for local biomarker analysis

Pharmacodynamic and Local Effect Assessment

1. Lung Function Tests

• FEV1, FVC, and PEF: Recorded at baseline and post-dose
• Changes may indicate local bronchospasm or efficacy

2. Airway Inflammation Markers

• Fractional exhaled nitric oxide (FeNO): Biomarker of airway inflammation
• Sputum eosinophils and neutrophils for exploratory endpoints

3. Local Safety Monitoring

• Airway irritation: Cough, throat discomfort, bronchoconstriction
• Oropharyngeal examination: Check for redness, ulcers, candidiasis

Device Testing and Human Factor Evaluation

1. Inhaler Type and Compatibility

• Dry Powder Inhalers (DPIs) – flow-rate dependent
• Metered Dose Inhalers (MDIs) – require coordination
• Nebulizers – for higher doses or impaired inspiratory flow

2. Usability Testing

• Subjects complete usability questionnaires
• Inhalation maneuvers may be recorded or analyzed

3. Device Logging and Dose Verification

• Many modern inhalers include electronic dose counters
• Helps track dose compliance and technique consistency

Regulatory Expectations

FDA

• Requires both drug and device characterization
• Supports human factor studies in Phase 1 to reduce use errors
• Inhaled product submission falls under drug-device combination pathway

EMA

• Expects device instructions and dose reproducibility data in early trials
• Clinical endpoints must reflect regional deposition and systemic exposure

CDSCO

• Requires in vitro device performance data before human exposure
• Phase 1 ICF must clearly mention device handling, risks, and training

Examples of Inhaled Phase 1 Trials

Example 1: Inhaled Corticosteroid

• Healthy volunteers showed systemic Cmax at 15 minutes
• Local side effect: transient throat irritation, managed with water rinse

Example 2: Inhaled Insulin

• PK lag behind SC insulin but faster onset
• Required extensive pulmonary safety and post-study FEV1 tracking

Example 3: Inhaled mRNA Vaccine

• Experimental nebulized vaccine in early Phase 1
• Evaluated immune biomarkers in BAL fluid and plasma

Best Practices for Inhaled Phase 1 Study Design

• Standardize inhalation technique training for all participants
• Include device usability and feedback as part of study endpoints
• Ensure device dose emission testing in parallel with human exposure
• Combine lung function, local AEs, and systemic PK for safety evaluation
• Align formulation, device, and regulatory documentation from the start