Navigating Clinical Evaluation Process for Combination Products!

Combination products are a niche class of medical devices whereby two or more regulated constituents, such as drugs and devices are combined to achieve a specific therapeutic purpose.

These products necessarily require careful consideration of pharmaceutical and medical device regulations that ensure compliance and demonstrate both safety, performance as well as clinical benefit.

This article details the step-by-step approach and considerations that guide the Clinical Evaluation Process in the context of combination products that fall under the EU’s Medical Device Regulation 2017/745.

What Are Combination Devices?

Combination devices are products that either:

1. Incorporate a medicinal substance as an integral part of the medical device, or

2. Combine a medicinal product with a medical device in a single product.

Article 117 of the EU MDR 2017/745 requires proof of conformity with GSPRs for single integral Drug-Device Combinations under the Marketing Authorization Application.

This provision, which was effective as of 26 May 2021, requires an opinion from a Notified Body to assure compliance with MDR. Despite limited guidance on dossier preparation for such products, the industry effort is aimed at establishing clarity and consistency in aligning with GSPR obligations.

Such efforts focus on addressing overlaps with medicinal product requirements and encouraging collaboration among stakeholders to streamline regulatory processes for Drug-Device Combinations (DDCs).

In the case of combination devices, the clinical evaluation should fulfill the relevant General Safety and Performance Requirements (GSPRs) as specified in Annex I of the EU MDR 2017/745. This includes safety, performance, and biocompatibility, among others, the compatibility and functionality of a drug-device combination.

Evidence to support these needs shall be included in the clinical evaluation section, using clinical data, risk assessments, and post-market surveillance data available for GSPRs.

The integration of medical devices with medicinal products has increased in marketing authorization applications, which reflects of the advancements in drug delivery technologies.

These Drug-Device Combinations can be categorized as integral or non-integral. Integral DDCs, as described in Articles 1(8) and 1(9) of MDR (EU) 2017/745, are products where the device and medicinal product form a single, non-reusable unit. Examples include pre-filled syringes, auto-injectors, drug-releasing implants, and intra-uterine devices, all designed for seamless administration.

Non-integral DDCs have separate components, such as nebulizers, reusable pens, oral dosing devices, or injection needles. Such devices are either co-packaged with the medicinal product or referenced in the product information and are obtained separately, requiring CE marking to meet regulatory standards.

With advanced devices, particularly with automated functions, DDCs improve patient convenience in easy self-administration or caregiver assistance for long-term outpatient care, thereby reducing the burden on healthcare systems.

An Example-Based Explanation: Prefilled Syringe (PFS)

A prefilled syringe (PFS) is a combination product comprising:

• Syringe device: A delivery mechanism ensuring accurate administration of the drug.
• Drug formulation: A therapeutic agent pre-filled into the syringe for intended use.

For the PFS Clinical Evaluation Report (CER), the clinical evaluation must particularly address relevant aspects:

1. Mechanical Safety and Performance: Functional integrity of the syringe, such as needle sharpness, plunger functionality, and accurate dose delivery.

1. Drug Stability and Compatibility: Chemical stability of the drug within the syringe material, supported by stability data and compatibility studies.
2. Combination-Specific Risks: Risks such as leachable from syringe components, potential interaction between the drug and syringe material, and needle stick injuries.

Steps in the Clinical Evaluation Process

Step 1: Understand Regulatory Requirements Combination products must address both:

• Medical Device Regulations: Under MDR 2017/745, the CER is required to assess the safety, performance, and clinical benefits of the device component, according to Article 61, Annex I, and conformity assessment requirements under Annex IX or Annex X.
• Pharmaceutical Regulations: The drug component of the drug-device combination must comply with Directive 2001/83/EC, demonstrating safety, efficacy, pharmacokinetics, pharmacodynamics, and potential interactions with the device.

Step 2: Define Scope and Objectives

The combination product’s intended purpose and each of the individual component parts along with their overall therapeutic benefit should be clearly defined. For instance, a drug-eluting stent combines the stent, which will restore blood flow, and a drug, preventing restenosis.

Step 3: Collect Relevant Data

1. Clinical Data:

• Device Component: Data generated through clinical studies, preclinical testing, and PMS.
• Drug Component: Pharmacological trials’ data
• Combination Product: Research focused on the overall functioning of the combination product.

1. Preclinical Data: Such testing for biocompatibility, chemical stability, and material performance.
2. Post-Market Data: Adverse event reports, complaints and performance analysis regarding component as well as the combination.

Step 4: Perform a Systematic Literature Review Conduct a systematic review to identify:

• Data demonstrating the safety and performance of the device.
• Clinical data on the combination product or similar devices delivering the same drug.
• Reports of adverse events or off-label use.

Step 5: Address Equivalence (if applicable) If claiming equivalence to an existing combination product, provide substantial evidence on:

• Technical characteristics: Materials, design, and functionality.
• Biological characteristics: Interaction with human tissues.
• Clinical characteristics: Safety and performance outcomes.

Step 6: Conduct a Risk-Benefit Analysis Assess potential risks and side effects from the interaction of components. For instance, determine how the drug-release profile affects healing and whether material-drug interactions pose additional risks.

Step 7: Draft the CER Structure the CER to meet MDR requirements:

1. Executive Summary: Give an overview of the device’s safety, performance, and clinical benefit.

2. Product Description: Detail the combination product’s components, intended use, and therapeutic purpose.

3. Clinical Data Evaluation: Summarize literature, clinical trials, and PMS data.

4. Risk-Benefit Analysis: Describe the identified risks, mitigations, and overall benefits.

5. Conclusions: Confirm compliance with MDR and justify the product’s safety and efficacy.

Step 8: Submission and Review

• Internal Review: Ensure the CER is in alignment with the Quality Management System.
• Notified Body Submission: The CER is submitted as part of the Technical Documentation for MDR compliance.

Challenges and Best Practices

Key Challenges:

1. Data Integration: Combining clinical evidence for individual components and the combined product.
2. Regulatory Overlap: Navigating MDR requirements alongside pharmaceutical regulations.
3. Post-Market Surveillance: Ensuring long-term safety and efficacy monitoring.

Best Practices:

• Adopt a structured CER development process.
• Engage cross-disciplinary expertise, including clinical, regulatory, and technical specialists.
• Maintain clear, comprehensive documentation to support regulatory submissions.

MEDDEV 2.1/3 Rev.3 Guidance

The MEDDEV 2.1/3 Rev.3 document provides specific guidance for borderline products and drug-device combinations. Key points include:

1. Determining the Primary Mode of Action (PMOA): Classify the product as a medical device or medicinal product based on its principal function.
2. Requirements for Devices with Medicinal Substances: Address the interplay between MDR and pharmaceutical regulations.
3. Regulatory Pathway Clarifications: Provide detailed instructions for compliance with EU regulatory frameworks.

Conclusion

Navigating the Clinical evaluation process for combination products requires a clear understanding of dual regulatory frameworks and a structured approach to integrating clinical and preclinical data for both the device and medicinal components.

By identifying the primary mode of action, addressing specific MDR requirements, and ensuring robust risk-benefit analysis, manufacturers can achieve regulatory compliance and deliver safe, effective combination products that manufacturers can ensure that combination products meet regulatory expectations and deliver optimal therapeutic outcomes meet patient needs.

A collaborative, well-documented strategy is key to overcoming challenges and optimizing outcomes in this complex process.

Author Name : Athira Unnikrishnan

Author designation: Junior Consultant (CER)

REFERENCES

1. EU MDR:European Union. (2017). Regulation (EU) 2017/745 on medical devices. Official Journal of the European Union.
2. MEDDEV2.1/3Rev.3:European Commission. (2015). Guidelines on the qualification and classification of borderline products, drug-device combination products.
3. Medical device combination products: what regulations should you apply before marketing them in the EU?
4. Guideline on the quality requirements for drug-device 5 combinations
5. Conformity with the relevant General Safety Performance Requirements listed in the European Medical Device Regulation 2017/745: Case study for a prefilled pen (prefilled syringe assembled with autoinjector parts forming a single integral product regulated as a medicinal product).