Designing Effective Phase 1 Trials for Drug-Device Combination Products

Introduction

The intersection of drugs and medical devices in a single product—known as a drug-device combination (DDC)—is transforming how therapies are delivered across areas like diabetes, asthma, oncology, and pain management. In early development, these products require integrated evaluation of device usability, drug delivery, and clinical performance. Planning a Phase 1 trial for a combination product involves navigating dual regulatory frameworks, conducting device-specific usability testing, and ensuring that drug pharmacokinetics are not compromised by delivery mechanics. This article offers a detailed guide to designing successful early-phase studies for combination products.

What Is a Drug-Device Combination Product?

A DDC product integrates a therapeutic drug and a delivery device into a unified product. Common examples include:

• Prefilled syringes and auto-injectors (e.g., biologics like adalimumab)
• Metered-dose inhalers (e.g., salbutamol)
• Transdermal patches with delivery controllers
• Implantable drug-eluting stents

In a Phase 1 context, these products must demonstrate both clinical safety and functional device performance.

Key Objectives of Phase 1 DDC Studies

• Evaluate pharmacokinetics (PK) of the drug via the intended device
• Assess local tolerability and usability of the device
• Identify any device-related risks or failures during administration
• Support dose selection and delivery feasibility for later phases

Early Planning Considerations

1. Determine Primary Mode of Action (PMOA)

• Is the product primarily pharmacologic or mechanical?
• PMOA determines the regulatory lead center (e.g., FDA CDER vs CDRH)

2. Device Maturity

• Prototype device vs commercial design?
• Will the device undergo changes post-Phase 1?

3. Human Factors Integration

• Usability testing may be required even in healthy volunteers
• Capture errors in handling, actuation, priming, etc.

Study Design Components

1. Subject Population

• Healthy volunteers: Used for systemically safe drugs and devices
• Target patients: Needed when safety risks, disease-specific devices, or non-healthy interaction expected

2. Administration and Training

• Provide standardized training on device usage
• May require site personnel to observe and document administration

3. Dose and Device Configuration

• Fixed-dose vs variable dosing devices
• Evaluate dose delivery accuracy, reproducibility, and device retention

4. Pharmacokinetic Assessments

• Determine if device alters absorption rate or bioavailability
• Compare with IV or non-device comparator arm if applicable

Device Usability and Performance Data

• Actuation force, injection depth, dose emission, aerosol characteristics
• Record device failures, misfires, or user errors
• Use questionnaires or observer checklists for qualitative insights

Regulatory Expectations

FDA

• Drug-device studies must meet requirements of both CDER (drug) and CDRH (device)
• Expectations vary based on Combination Product Review Process (per 21 CFR Part 3)
• Human factor studies are strongly recommended

EMA

• Requires device information in Quality Module 3.2.R of IMPD
• Drug delivery mechanism must support clinical dose accuracy

CDSCO (India)

• Published draft guidance on combination products in 2019
• Requires device performance data and safety testing aligned with ISO standards

Case Examples

Example 1: Subcutaneous Biologic via Auto-Injector

• Phase 1 study compared prefilled syringe vs auto-injector in 36 volunteers
• PK equivalence and usability endpoints both met

Example 2: Inhaled Antibiotic in COPD

• Device fine-particle fraction and aerosol consistency validated pre-study
• Local tolerability included cough frequency and throat irritation scoring

Example 3: Intranasal Rescue Therapy

• Real-time administration usability tested under simulated seizure stress
• Time to dose delivery and caregiver handling documented

Human Factors and Risk Management

• Conduct formative usability assessments in early development
• Design error analysis and use-scenarios for at-risk steps
• Generate risk management file per ISO 14971

Best Practices for Early Phase DDC Trials

• Collaborate early with device engineers, regulatory experts, and clinical ops
• Integrate device validation with clinical timelines
• Predefine usability, PK, and device performance success criteria
• Ensure data from device metrics are captured, analyzed, and reported
• Align documentation for combination product regulatory classification