Importance of Clinical Data in EU MDR Compliance & Device Safety

Introduction

This newfound flexibility will be appreciated by device manufacturers who may have faced potential refusal or limitation of indications. It’s made clear that they can utilize all types of clinical data defined in Article 2(48) to prove their devices’ safety and performance, including demonstrating equivalence with devices from other manufacturers. This also has the potential to aid future product development by broadening the range of clinical evidence accessible to manufacturers. However, two points regarding PMCF should be noted:

• The guidance specifies that exemption cases from completing PMCF studies cannot be used to justify failure to fulfill prior certification requirements.
• Typically, when clinical evaluation relies on equivalence, there’s an expectation for PMCF studies to be conducted to ensure that appropriate quality clinical data is gathered on the device in question.

A fresh MDCG guidance document has been released today, offering much-needed clarity on how EU MDR Articles 61(4)–(6) are practically applied. This new guidance, titled “MDCG 2023-7: Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4)-(6) MDR and on’sufficient levels of access’ to data needed to justify claims of equivalence,” reveals pathways and approaches that were previously thought to be inaccessible under EU MDR. It brings attention to the following:

• Conditions determining the necessity of contracts to assert equivalence, thereby utilizing clinical data from another manufacturer’s device.
• Circumstances under which implantable and class III devices can be exempt from the mandatory clinical investigation requirements (as outlined in Article 61(4)).
• The definition of “sufficient levels of access” to the data necessary for validating claims of equivalence (as detailed in Annex XIV Section 3).

Understanding Contract Requirements and Equivalence Claims

The clarification regarding contract requirements and equivalence claims may come as a surprise to some. It confirms that contracts are not obligatory for claiming equivalence with another manufacturer’s device. However, certain conditions apply: for implantable and class III devices, a manufacturer might still need to conduct clinical investigations, regardless of the robustness of their clinical evidence, unless one of the four exemption cases outlined in Articles 61(4) – (6) applies.

In essence, the guidance underscores that Articles 61(4)-(6) do not dictate when equivalence can or cannot be utilized, but rather when implantable and class III devices may be exempted from the necessity for premarket clinical investigations. While this may seem like a matter of semantics, it carries significant implications that could notably lower market entry barriers for many implantable and class III devices.

Practical Implications for Implantable and Class III Devices

What this means practically for implantable and class III devices is:

• Regarding the legacy MDD and AIMDD devices as outlined in Article 61(6)(a), along with the listed WET devices in Article 61(6)(b), the clinical evaluation can incorporate data from a demonstrated equivalent device by another manufacturer, even without a contract, in assessing their own device. If all the conditions specified in these Articles are met, manufacturers can introduce these devices to the EU market without needing pre-market clinical investigations.
• The guidance also clarifies a common point of confusion: Both Articles 61(6)(a) and 61(6)(b) stipulate that the clinical evaluation must be “based on sufficient clinical data.” Some have interpreted this to mean “clinical data specific to the device in question, not from equivalent devices”; however, the guidance explicitly states that any clinical data falling within the definition in Article 2(48), including equivalence data, is acceptable. Thus, equivalence data could constitute part or all of the clinical evidence package submitted to demonstrate compliance with the relevant safety and performance requirements as per Article 61(1).
• Likewise, for devices that are alterations of existing device(s) already sold by the same maker, and meet the other criteria outlined in Article 61(4) bullets one to three, clinical data from a device made by another maker can be included in the clinical evidence package. Even though Article 61(4) bullet two requires that “the clinical assessment of the marketed device is adequate to demonstrate conformity of the modified device with the relevant safety and performance requirements,” the guidance specifies that “The MDR does not forbid the utilization of data from another maker’s [equivalent device] in the clinical assessment of the maker’s already sold device.”
• Data from another manufacturer’s equivalent device can even be utilized without a contract in what is termed as exemption CASE 4, provided the manufacturer has a contract with at least one manufacturer. However, the applicability of this is somewhat restricted, as data from additional manufacturers’ devices can only be used to support the same indications covered by the contract.
• Lastly, in cases where the device falls under class III or is implantable and none of the exemption cases are applicable, necessitating premarket clinical investigations, the guidance indicates that clinical data from another manufacturer’s equivalent device can still be employed, without a contract, alongside clinical data obtained from the clinical investigation(s).

Examining the Exemption Scenarios and Their Influence

The adaptability showcased here stems from the reduced risk tied to each of these scenarios, which justifies the exemption from the mandatory clinical investigations typically required for implantable and class III devices. Essentially, concerning the scenarios outlined in the guideline:

• Scenario 2: If your device has previously obtained certification under the Directives, it has accrued years of market experience, likely backed by data from Post-Market Clinical Follow-up (PMCF) studies, during which any safety or performance issues should have surfaced. Additionally, most of these devices (except for certain up-classified ones that were previously on the market solely under quality systems certification) would have undergone design examination or renewal within the past five years. During this timeframe, the criteria for clinical data and post-market surveillance have become notably more stringent, and adherence to guidelines such as MedDev 2.7/1 rev 4 implies that the conformity assessment would have been conducted with a similar level of thoroughness as current requirements under the Regulation.
• Scenario 4: If you’re relying on equivalence but have a contractual agreement with the manufacturer of the referenced device granting complete access to the technical documentation per Article 61(5), it reduces the risk associated with unknowns related to device design, clinical outcomes, adverse events, product modifications, etc.
• Scenario 1: Similarly, if your device is a modified version of one of your own devices, and you can prove equivalence according to points 1-3 of Article 61(4), the risk of such unknowns is largely mitigated.
• Scenario 3: Lastly, if your device falls under the listed categories in Article 61(6)(b), which are designated as Well-Established Technologies (WET), these devices inherently pose comparatively lower risk, being part of standard care and typically possessing a well-documented safety and performance history.

Highlighting the Importance of Clinical Data in Device Safety and Performance

This newfound flexibility will be appreciated by device manufacturers who may have faced potential refusal or limitation of indications. It’s made clear that they can utilize all types of clinical data defined in Article 2(48) to prove their devices’ safety and performance, including demonstrating equivalence with devices from other manufacturers. This also has the potential to aid future product development by broadening the range of clinical evidence accessible to manufacturers. However, two points regarding PMCF should be noted:

• The guidance specifies that exemption cases from completing PMCF studies cannot be used to justify failure to fulfill prior certification requirements.
• Typically, when clinical evaluation relies on equivalence, there’s an expectation for PMCF studies to be conducted to ensure that appropriate quality clinical data is gathered on the device in question.

Navigating Adequate Data Access Levels

Regarding the requirement for “sufficient levels of access” to data necessary for validating equivalence claims according to Annex XIV Section 3, the guidance clarifies that a contract isn’t the sole method for a manufacturer to prove this. Additional means are outlined in Appendix II, which also proposes a hierarchy based on the completeness of access and the resulting strength of justification for sufficient access levels.

Key points to consider:

• The guidance reiterates Annex XIV Section 3’s requirement: access to data necessary for justifying equivalence claims (i.e., clinical, technical, and biological parameters of the claimed equivalent) is essential, rather than access to the entire technical documentation. While Article 61(5) mandates access to full technical documentation, the guidance confirms this requirement doesn’t extend beyond that article.
• Insufficient “level of access” only applies if there are gaps in the completeness or expected accuracy of associated clinical, biological, and technical data that would invalidate equivalence claims.
• The table in Appendix II serves as an illustrative example, not an exhaustive or prescriptive list. This is explicitly stated in Section 5 of the guidance and in the footnotes to the table in Appendix II. This reminder allows notified bodies flexibility to employ a risk-based approach in assessing data adequacy.

Next Strategic Moves for MDR Compliance and Clinical Development

If your technical documentation hasn’t been submitted for MDR conformity assessment yet, or if it’s awaiting notified body feedback, you might want to assess your clinical evidence package to see if it could be enhanced through equivalence. If so, it’s wise to also revisit and update related documents like risk or PMCF plans.

For products still in the development phase, reconsider clinical development plans to see if this new insight could impact the clinical investigation strategy or hasten product launch schedules.

By embracing these actions, your organization will be positioned at the forefront of compliance, prepared to navigate the evolving landscape of medical device regulations confidently and clearly.