Lesson 10 – Systematic Literature Review Course: Comprehensive Guide to IVDR Literature

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Introduction to IVDR and Its Importance

If you’ve been working on literature reviews for medical devices, you may already know how important it is to understand the regulatory frameworks behind them. But what about in vitro diagnostic devices (IVDs)? How do literature reviews for IVDs differ under the EU In Vitro Diagnostic Regulation (IVDR)?

The IVDR (Regulation (EU) 2017/746) sets more stringent requirements for IVDs in the European Union, focusing on performance evaluation, clinical evidence, and post-market surveillance. This regulation brings specific challenges and opportunities for manufacturers who want to place their IVDs on the EU market.

In this post, we’ll explore the key differences between IVDR and MDR (Medical Device Regulation) literature reviews, and provide you with a comprehensive guide to conducting IVD-specific reviews for analytical performance, scientific validity, and clinical performance.

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Key Differences Between IVDR and MDR Literature Reviews

While both IVDR and MDR focus on ensuring the safety and efficacy of medical devices, the regulations are quite different when it comes to literature reviews. Here are some of the main distinctions:

• Scope: IVDR specifically targets in vitro diagnostic medical devices (IVDs), whereas MDR applies to general medical devices.
• Classification: IVDR introduces a risk-based classification system for IVDs, unlike MDR’s broader classification.
• Performance Evaluation: IVDR mandates a comprehensive evaluation of analytical performance, clinical performance, and scientific validity.
• Regulatory Scrutiny: Under IVDR, more IVDs require the involvement of a notified body compared to the MDR.

Understanding these differences is crucial for manufacturers aiming to submit their IVDs for EU approval. Now, let’s dive into the structure of an IVDR literature review.

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The IVDR Literature Review Process

A literature review for IVDs must focus on three distinct performance categories: Analytical Performance, Clinical Performance, and Scientific Validity. This is different from the more general approach used in MDR reviews, which tend to focus more on clinical outcomes and safety.

Analytical Performance (AP) Literature Review

The Analytical Performance (AP) review assesses the test’s ability to measure the analyte accurately under different conditions. It looks at key elements like:

• Sample stability
• Method comparisons
• Reference intervals and cut-off values
• Sensitivity, specificity, and accuracy
• Detection limits
• Precision and trueness

The AP review ensures that the device can reliably detect or measure the target analyte in a sample, which is crucial for the device’s credibility and accuracy.

Clinical Performance (CP) Literature Review

The Clinical Performance (CP) review examines the effectiveness of the IVD in real-world clinical settings. It covers topics such as:

• Diagnostic sensitivity and specificity
• Positive and negative predictive values
• Clinical cut-off points
• Clinical utility and impact on patient management

This review helps to validate that the device performs as expected in the clinical context, providing accurate and actionable results that can influence patient treatment decisions.

Scientific Validity (SV) Literature Review

The Scientific Validity (SV) review looks at the relationship between the analyte or biomarker and the clinical condition it is meant to detect. Key focus areas include:

• The pathophysiological relevance of the biomarker
• Association with disease state
• Evidence of clinical decision-making value

Scientific validity confirms that the biomarker or analyte you’re measuring is truly relevant to assessing the patient’s clinical condition, making it a critical part of the review process.

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Determining State of the Art (SoTA) for IVDs

In addition to the three main reviews, State of the Art (SoTA) analysis is often included to support the literature review. The SoTA review helps to:

• Establish current medical practices
• Demonstrate compliance with safety and performance standards
• Compare the device to existing alternatives

This review may involve looking at recent technological advancements, current best practices, and unmet clinical needs.

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Selecting Search Terms for IVDR Literature Reviews

When conducting a literature review under IVDR, the search terms are similar to those used in MDR reviews. However, for IVDs, you need to focus on the specific aspects of performance:

For Analytical Performance:

Search terms might include “analytical sensitivity,” “precision,” “specificity,” “accuracy,” and “detection limits.”

For Clinical Performance:

Look for terms like “diagnostic accuracy,” “predictive values,” “clinical sensitivity,” and “clinical outcome studies.”

For Scientific Validity:

Search for “biomarker validation,” “clinical evidence,” “clinical decision-making,” and terms related to the analyte and disease association.

Using controlled vocabularies (e.g., MeSH terms) and Boolean operators (AND, OR) will help narrow down relevant studies.

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Screening Abstracts for IVDR Literature Reviews

Once you’ve gathered your search results, the next step is screening abstracts. During this process, make sure to:

• Focus on studies that are relevant to the specific IVD or similar devices
• Prioritize studies with appropriate study design and patient population
• Exclude studies that are outdated or use non-human subjects unless they relate to analytical performance

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Data Extraction for IVD Literature Reviews

Data extraction for IVDs involves pulling out key details from selected studies to support the three main performance categories: analytical performance, scientific validity, and clinical performance.

For example, when reviewing data for an HIV diagnostic test, you might extract:

• For Analytical Performance: Limit of detection, cross-reactivity, and precision data.
• For Scientific Validity: Correlation between viral markers and disease progression.
• For Clinical Performance: Diagnostic sensitivity, specificity, and clinical utility.

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Conclusion: Mastering IVDR Literature Reviews

Conducting literature reviews for IVDs under IVDR requires a structured approach focused on analytical performance, scientific validity, and clinical performance. While the process may seem complex, it becomes more manageable once you understand the core differences between IVDR and MDR reviews.

By following the steps outlined in this guide—choosing the right search terms, evaluating state-of-the-art information, and carefully screening studies—you can build a robust and evidence-backed literature review that supports your IVD’s compliance with the IVDR.

If you need more resources on the IVDR review process or have any questions, feel free to reach out. Happy reviewing!