biologics, injectables, inhalers, wearable delivery systems, and on-body injectors, drug-device combination products are reshaping how therapies are administered. In early-phase trials, particularly Phase 1, these combinations pose unique challenges. Both the drug and the device must be evaluated for safety, usability, and compatibility—often under compressed timelines. This tutorial explores how to plan, design, and execute early-phase studies involving drug-device combinations with a focus on human factors, regulatory compliance, and integrated clinical endpoints.

What Are Drug-Device Combination Products?

According to regulatory authorities, a drug-device combination is a therapeutic product that includes both a drug and a medical device component that are physically or functionally combined.

• Examples: Autoinjectors (e.g., insulin pens), inhalers (MDIs, DPIs), prefilled syringes, on-body pumps, transdermal systems

Why They Need Special Planning in Phase 1

• Device performance may affect dose delivery and PK
• Usability failures may lead to protocol deviations
• Human factors validation may need to be incorporated early
• Dual regulatory oversight may apply (e.g., CDRH + CDER at FDA)

Core Objectives in Phase 1 Combination Studies

• Evaluate drug safety and tolerability
• Assess PK and PD profile using the intended device
• Determine device usability, reliability, and acceptability
• Capture user errors and administration time

Study Design Considerations

1. Device Readiness

• Is the device commercially available, investigational, or in development?
• Is the device included in the IND or part of a separate IDE?

2. Population Selection

• Start with healthy volunteers unless the product has high immunogenic or toxicity risk
• Patients may be needed if the device requires disease-specific handling (e.g., arthritis)

3. Device Training and Instructions for Use (IFU)

• Subjects should receive standardized training materials
• Use written IFUs, videos, or simulation tools

4. User Feedback Collection

• Include questionnaires on ease-of-use, comfort, and perceived safety
• Capture qualitative comments on usability and acceptability

Data Collection Specific to Device Performance

• Time to dose administration
• Device malfunctions (e.g., leakage, jamming)
• Incomplete dosing or incorrect use
• Site reactions, pain scores, and mechanical failure rates

PK/PD Integration with Device Metrics

• Correlate failed or partial delivery with altered plasma concentration
• Determine if dosing deviations affect PD endpoints (e.g., insulin-glucose response)

Human Factors Studies and Usability Testing

• Phase 1 studies may include formative usability testing
• Human factors validation typically occurs later but may be informed by Phase 1 data
• Simulated-use studies can be conducted in parallel

Regulatory Requirements

FDA

• Drug-device products fall under the Office of Combination Products (OCP)
• Requires combination IND submissions or cross-referenced IDEs
• Human factors guidance applies even in early-phase clinical settings

EMA

• Device information must be part of the Investigational Medicinal Product Dossier (IMPD)
• Must include CE mark status or evidence of device risk classification

CDSCO

• Classifies products under Medical Devices Rules, 2017 (if relevant)
• May require parallel review by drug and device divisions

Common Challenges

• Lack of synchronization between device and drug development timelines
• Device not performing as intended under trial conditions
• Inadequate user training or unclear Instructions for Use (IFU)

Best Practices

• Engage device engineering teams early in clinical planning
• Include device-related endpoints in protocol and CRF
• Pilot the IFU and training tools before FIH use
• Use real-time feedback and observational assessments
• Align on global regulatory pathways for integrated review