addressed under the Medical Device Regulation (MDR) (EU 2017/745) and the In Vitro Diagnostic Medical Devices Regulation (IVDR) (EU 2017/746). The regulations establish criteria for the classification of combination products based on their primary mode of action.

• MDR Article 117: Outlines the requirements for combining medical devices with medicinal products.
• IVDR Article 24: Discusses the requirements for in vitro diagnostic medical devices when combined with medicinal products.

United Kingdom

The UK Medicines and Healthcare products Regulatory Agency (MHRA) enforces regulations similar to those of the EU post-Brexit. The classification and regulatory oversight mirror that of the EU, adapting the requirements of the MDR and IVDR where necessary.

• UK Medical Devices Regulations 2002: Regulates the approval of drug–device combinations, including requirements for CE marking.
• UK Medicines Regulations 2012: Covers medicinal products within the context of combination products.

Documentation Standards

Proper documentation is essential for regulatory compliance regarding drug–device combination products. Documentation must demonstrate that the product meets regulatory standards and is safe and effective for its intended use.

Device Master File (DMF)

The Device Master File (DMF) is a crucial component in the regulatory documentation for combination products. It provides confidential information about the device component of a combination product, ensuring that sponsors can efficiently manage their submissions and maintain compliance.

• Contents of a DMF: The DMF must include information related to device specifications, manufacturing, and controls, and quality assurance practices.
• Filing Requirements: FDA allows sponsors to submit a DMF to the FDA to provide essential details referenced by other regulatory submissions.

Technical Documentation

In the context of the EU, technical documentation for drug–device combinations must comply with the requirements set forth in the MDR and IVDR.

• General Requirements: Technical documentation must include a description of the product, intended purpose, safety and performance data, and risk management analysis.
• Sufficient Data: It should also include clinical evaluation data that justifies the safety and effectiveness of the product in its intended use.

Review/Approval Flow

The review and approval process for drug–device combination products involves multiple regulatory pathways depending on the classification and intended use of the product. This flow often intersects various regulatory agencies and departments within an organization.

FDA Approval Pathway

The FDA offers several pathways for the approval of combination products, typically categorized as New Drug Applications (NDAs), Premarket Approval Applications (PMAs), or 510(k) submissions.

1. Determine Classification: Accurately classify the product as drug, device, or combination to identify the appropriate approval pathway.
2. Compile DMF: Prepare and submit a DMF if the device component is significant.
3. Submit Application: Complete the appropriate application (NDA, PMA, or 510(k)) including reference to the DMF as needed.
4. Respond to Agency Queries: Prepare for potential additional information requests from the FDA, addressing their findings promptly.

EU Approval Pathway

The EU pathway involves Notified Bodies (NBs) for medical device assessment and may require coordination with different authorities based on product classification.

1. Initial Assessment: Determine whether the combination product should be classified as a device or a medicinal product or both.
2. Engage a Notified Body: Select an appropriate Notified Body if the product is classified as a medical device.
3. Compile Technical Documentation: Assemble and prepare technical documentation compliant with MDR or IVDR requirements.
4. Clinical Evaluation: Conduct clinical evaluations and justify the placement of the combination product in these trials.

Common Deficiencies

Common deficiencies in regulatory submissions for drug–device combinations often arise from inadequate documentation or failure to align with regulatory expectations.

Documentation Gaps

One prevalent issue is incomplete or unclear technical documentation, which can lead to delays or refusal of applications.

• Insufficient Device Information: Failure to provide comprehensive device specifications or details in the DMF can raise red flags.
• Inadequate Risk Analysis: Not conducting or poorly conducting risk assessments can result in the non-compliance of regulatory safety expectations.

Regulatory Misalignment

Another frequent deficiency is the lack of alignment with the intended regulatory pathway, leading to incorrect submissions.

• Poor Classification Decisions: Misclassifying the combination product could necessitate re-filing under a different regulatory route.
• Inconsistent Data Presentation: Not aligning clinical evidence with regulatory expectations can lead to audits and questioning.

Regulatory Affairs-Specific Decision Points

Regulatory affairs professionals are faced with key decision points that can significantly influence the regulatory pathway for drug–device combinations.

When to File as Variation vs. New Application

Determining whether to file an application as a new application or a variation can be critical. Factors influencing this decision include:

• Extent of Changes: Evaluate how significant the changes to the formulation, device, or manufacturing process are.
• Regulatory Guidance: Consult the relevant regulatory guidelines which often provide clear thresholds for determining whether a change constitutes a new application or a variation.

Justifying Bridging Data

In submitting documentation, justifying bridging data becomes necessary when transferring data from a non-combination product to a new combination product. This requires careful consideration:

• Relevance of Data: Confirm that the bridging data is relevant and applicable to the new combination product’s intended use.
• Data Integrity: Ensure that the source data supports the claims being made concerning safety and efficacy of the new product.

In conclusion, regulatory affairs compliance for drug–device combination products involves navigating a complex regulatory landscape with thorough documentation, strategic decision-making, and an understanding of agency requirements. By structuring submissions diligently and anticipating typical deficiencies, regulatory professionals can facilitate successful product approvals in the global market.