Streamlining the Path to Market for Generic Drug-Device Combinations

Generic drugs play an important role in healthcare, ensuring broader, more affordable access to essential treatments. They often cost much less than brand-name products, encouraging competition in the market and helping patients remain compliant with their treatment plans. Despite the increased need for generics, bringing them to market can be complex, cost-prohibitive, and time-consuming.

What is a Generic Drug-Device Combination Product (g-DDCP)?

A g-DDCP is a medical product that combines a generic drug with a drug-device combination product to deliver the drug to a patient. This could include prefilled syringes, injector pens, inhalers, and infusion pumps.

A g-DDCP is expected to:

• Be therapeutically equivalent to a reference listed drug (RLD) product.
• Produce the same clinical effect.
• Have a similar safety profile.
• Be safe and effective.
• Be a substitution for an RLD without any additional training or healthcare provider intervention.

The Search for a Better Solution: Substitution, Not Replication

The FDA does not require a g-DDCP to replicate the RLD directly. However, it must be a suitable substitute. This means the g-DDCP must have the same clinical effect as the RLD and a similar safety profile. 

When the focus shifts from replication, manufacturers have the freedom to improve existing designs, including increasing safety or reducing known use issues.

g-DDCPs are typically approved via the Abbreviated New Drug Applications (ANDA) process. Unlike new drug applications, the ANDA process does not require clinical trials. Instead, manufacturers must demonstrate that their products perform similarly to the RLD and have a comparable safety profile.

Any differences in the device's form, function, user interface, and labeling must be documented and assessed to ensure that the differences do not affect users' safety, effectiveness, and/or substitutability.

The drug submission process is well known, but there remains a lack of clarity and guidance for the g-DDCP device component. The FDA's draft guidance suggests using a comparative use human factors (cuHF) study to determine the device is as safe and therapeutically equivalent as the RLD.

cuHF studies can be time-intensive and expensive and do not always provide the necessary data to support the g-DDCP's claim of safety, effectiveness, and substitutability. However, many manufacturers view a full cuHF study as the only viable option due to the lack of specific alternatives mentioned.

An Alternative Process for Generic Drug-Device Combination Products (g-DDCPs)

Battelle set out to develop an alternative clear and actionable process, using a risk-based approach to identify, categorize, and characterize design differences to better assess their potential impact. This six-phase process quickly identifies design differences that could impact user safety. It enables faster and more affordable data collection through studies that assess safety, effectiveness, and substitutability.

Phase 1: Risk Definition and Management

The development process involves aligning stakeholders in the early process. This includes creating a comparative use specification and a comparative risk management plan. These documents form the foundation of the development and assessment process.

Key Activities:

• Create a comparative use specification.
• Identify the intended use and use environment(s).
• Include the unique context of use where a generic product may be substituted for an RLD with or without the user’s knowledge.
• Identify any intended design differences and known use issues from the RLD.
• Create a comparative risk management plan.

Phase 2: Threshold Analysis

Phase two involves a systematic threshold evaluation. This is an assessment of all design differences in the task analysis, physical device, and labeling (including package labeling, on-device labeling, Instructions for Use (IFU), and any other package inserts). This phase evaluates design differences and their impact on the user, user interface, subsequent clinical effects, and safety profile.

Key Assessments:

• Comparative Task Assessment: Integrates task analyses of the g-DDCP and the RLD to identify differences in use, sequence, and critical tasks.
• Comparative Physical Device Assessment: A straightforward evaluation of the physical aspects of the delivery device, assessing differences and their potential impact.
• Comparative Labeling Assessment: Analyzes all labeling characteristics, assessing for user perception and potential misinterpretation that could affect the safety profile.

Phase 3: Comparative Risk Assessment

This phase aims to integrate the findings from the threshold analysis with potential use errors, known use issues, hazards, and validation methods. The comparative risk assessment provides a clear picture of the overall risk profile. This assessment is essential for regulatory submissions. It ensures that all design differences are assessed for impact on the clinical effect and safety profile.

Focus Areas:

• Evaluation of potential use errors and hazardous situations.
• Assessing design differences using a structured risk analysis approach.
• Finalization of the risk profile before proceeding to validation.

Phase 4: Validation of Generic System

Phase four is dedicated to validating that the g-DDCP is safe, effective, and substitutable when used by the intended user in the intended environment. This phase proposes using Bridging Studies and traditional Human Factors summative studies, following industry best practices and the FDA precedent.

Validation Methods:

• Bridging Study: Compares critical product attributes to leverage existing data and support the safety and effectiveness of the generic product.
• Traditional Simulated Use Human Factor Study: Validates critical tasks and design differences, ensuring safe and effective use by all intended users.

Phase 5: Comparative Residual Risk Assessment

The fifth phase thoroughly reviews all usability risks identified throughout the product development process, particularly those found during validation or summative testing. This phase ensures that any necessary design changes are made before finalizing the product, effectively mitigating risks.

Key Tasks:

• Analyze validation use issues for root causes and impact on the risk profile.
• Update and final review of the Comparative Use-Related Risk Assessment (cURRA) to ensure it reflects all current and accurate information.

Phase 6: Comparative Human Factors Engineering (HFE)/Usability Engineering (UE) Report

The final step involves compiling all information, evaluations, and validation findings into a final report. This report demonstrates that the generic product is safe, effective, and substitutable when used by the intended users in the intended use environment. This documentation is crucial for regulatory approval and must be detailed yet concise to facilitate a smooth review process.

Documentation Includes:

• Summary of all data gathered and analyzed.
• Reports on safety-related considerations and resolutions.
• Comparative residual risk assessment.

The six-phase approach to creating g-DDCPs aims to simplify the process. It helps lessen the load on manufacturers and regulatory bodies and ensures that generics are safe and therapeutically equivalent and can be substituted for RLDs. 

Battelle's team of experts has helped hundreds of clients prepare for the regulatory submission process.