Literature Review Report (LRR) under IVDR

The In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) requires the literature review report as a mandatory element of the clinical evidence which is included into the Performance Evaluation Report (PER). Its purpose is to provide a systematic understanding of existing data from published sources related to the IVD device. The literature review should show the connection between the scientific evidence from the peer reviewed literature and scientific validity, analytical performance, and clinical performance of the device.

Mapping Of Evidence To Validity Of The Instruments

IVDR (2017/746): Manufacturers of in vitro diagnostic medical devices have to perform a performance evaluation that is based on three pillars within their clinical evaluation:

1. Scientific Validity

2. Analytical Performance

3. Clinical Performance

Validity (scientific) - “‘scientific validity of an analyte’ means the relationship between an analyte and a clinical condition or a physiological state.” (Article 2 (38), IVDR)

Performance (analytical) - “‘analytical performance’ means the ability of a device to properly detect or measure a specific analyte.” (Article 2 (40), IVDR)

Performance (clinical) - “‘clinical performance’ means the ability of a device to produce results that correlate with a specific clinical condition or a physiological or pathological process or state.” (Article 2 (41), IVDR)

Performance evaluation - “‘performance evaluation’ means an assessment and analysis of data for establishing or confirming scientific validity, the analytical and, where appropriate, the clinical performance of a device.” (Article 2 (44), IVDR)

Links to Annex XIII and Article 56:

• Part A of Annex XIII states that your PER must show scientific validity, analytical performance, and clinical performance and must include the methodology, protocol, and search report of the literature search.

• Article 56(3) states that there must be a well defined and scientifically sound method for demonstrating (a) scientific validity, (b) analytical performance, and (c) clinical performance, which become the clinical data of the device.

Regulatory Framework : Literature Review Report

• In Vitro Diagnostic Regulation (IVDR) 2017/746, manufacturers have to generate and keep a record of evidence of their device by conducting Performance Evaluation in an organized manner. This performance evaluation is necessary for ensuring that the device works effectively in its intended performance and is also safe. According to the IVDR, performance evaluation must have three interdependent pillars: Scientific Validity.

• Proving that there is the existence of a relationship between the analyte or biomarker and the clinical or physiological condition. This will prove that the scientific basis of the device is sound and justified.

• Annex XIII, Part A, Section 1.2.1: Manufacturers have to gather and analyze all the available scientific data (peer reviewed literature included) to prove the analyte/marker condition relationship.

Performance of the Analytical Measurement

• Evidence of the ability of the measuring system to determine the concentration of the target analyte that it purports to be able to determine (e.g. precision, accuracy, limit of detection). This pillar is all about laboratory based evidence, not clinical evidence.

• While the evidence for this pillar comes mainly from internal testing, the literature review may provide additional information.

• Annex XIII, Part A, Section 1.2.2

Clinical Performance

• The capability of the device to produce results that are correlated to a particular clinical condition or physiological state and hence prove the clinical usefulness.

• Annex XIII, Part A, Section 1.2.3: Directly says that the data on the clinical performance may be obtained through clinical performance study, literature review, or a combination of both.

• In this case, the literature review itself might suffice in place of conducting new studies, particularly for low risk devices or already proven tests.

Incorporation in the Performance Evaluation Report (PER)

• As per the IVDR guidelines, it is required to incorporate the information obtained during the literature review for the scientific, analytical, and clinical performance into the Performance Evaluation Report (PER):

• Annex XIII, Part A, Section 2.3.2: The PER must contain a critical review of the evidence gathered, including literature. This document shows the conformity of the device to the GSPRs of Annex I.

• The PER serves as the evidence summary, which includes literature information, and forms part of the technical documentation reviewed by the Notified Body.

The Importance of This 

Traceability: Literature findings must be properly traceable to specific performance claims.

Systematic Approach: The systematic approach utilized in identifying literature, the selection criteria, and critical appraisal must all be fully documented for evaluation by the Notified Body.

Continual Updates: Moreover, continual updates to literature review must be made via Post Market Performance Follow Up (PMPF).

The LRR is a mandatory element of the PEP and PER under IVDR. This document supports the three pillars required by IVDR and serves as the necessary documentation for demonstrating conformity to EU standards.

Where The Literature Review Plays A Role In The Performance Evaluation

A literature review plays a key role in the performance evaluation procedure as required under IVDR Article 56 and Annex XIII since it helps to provide the three main evidence pillars that have to be covered in the Performance Evaluation Report (PER).

Scientific Validity Report (SVR): Demonstrates that there is a scientifically established relationship between the marker or analyte measured by the device and the clinical condition or physiologic condition under evaluation.

Analytical Performance Report (APR): Shows the studies and literature that prove that the device is able to accurately measure the analyte.

Clinical Performance Report (CPR): Contains the data that show the clinical performance of the device via clinical studies, real world data, or peer reviewed literature.

As per Annex XIII, the literature review should be pre defined in the Performance Evaluation Plan (PEP), in which the objective of the review, search strategy, inclusion and exclusion criteria, as well as the assessment of literature, should be included. Moreover, if the manufacturer does not carry out a clinical performance study, then the literature review becomes even more crucial.

PER should include:

Methodology for searching literature: information on the databases that were searched, search terms, and filters applied.

• Search protocol: defining the search parameters such as timelines, language limitations, and peer reviewed articles only limitation.

• Search report: with summary tables of relevant literature that has been reviewed, critical evaluation, and performance claims.

• References: Regulation (EU) 2017/746, Annex XIII Part A, Sections 1.2 and 1.3

Designing The Literature Review In A Way That Meets Requirements

Search Strategy

• Databases: Make sure you employ reputable scientific databases including PubMed, Embase, Scopus, and Cochrane Library, NIH Clinical Trials, NICE, and Zmed (Livivo),  MAUDE (FDA's adverse event reporting system), MHRA (UK), HPRA (Ireland), and TGA (Australia).

• Filters: Indicate the appropriate language and date of publication based on the research and device design purpose.

• Boolean operators: Utilize keywords combined with Boolean operators (AND, OR, NOT) to increase the sensitivity and specificity of search.

• Inclusion/Exclusion criteria: Indicate the criteria for study design (clinical trials, review studies, et al.), population relevance, technology and device application.

Linkages Between Updates, PMS/PSUR, And PMPF

The literature reviews carried out in accordance with the requirements of IVDR form a part of the continuous dynamic performance evaluation process and should be regularly updated based on new data generated following the placing of the medical device on the market. This is especially important in case of Class C and D devices, as Article 56(6) and Annex XIII Part A Section 1.3.2 stipulate the need for annual PER updates.

Integration of Post Market Surveillance (PMS)

Your PMS Plan, in compliance with Articles 78 to 80, shall provide an outline for your continuous collection and assessment of appropriate clinical and performance information that is inclusive of:

• Feedback from users and customer complaints

• Market experience and technical malfunctions

• Newly available scientific literature pertaining to the device and devices of a similar nature

This data has to be analyzed in respect to its effect on your current performance claims.

Periodic Safety Update Report (PSUR)

For Class C and Class D medical devices, the PSUR (Article 81) should be compiled no less than once a year, as follows:

• Summary of PMS results

• Important findings of the Post Market Performance Follow up (PMPF) activity

• Concluding assessment of the benefit risk

The PSUR must consider the most recent data that come from PER and literature review. Any new risks or ineffectiveness that become apparent through the literature review must be incorporated into the PSUR.

Relationship Between PMPF and Literature Review

Exercises on PMPF, which are explained in Annex XIII B, gather real data regarding clinical performance after the introduction of a product into the market. These could be obtained from studies, registries, and surveys. Information gained through PMPF Exercises:

• Help in reinforcing the scientific basis and clinical significance

• Help identify gaps that require further study

• Help in revisiting the literature review and PER

Feedback Loop

1. Notified Bodies require a well documented feedback loop:

2. PMS generates new data

3. Data is filtered based on its relevance to performance claims

4. Literature review is updated as per that

5. Updated information is fed into the PER, SSP, and PSUR

References: Regulation (EU) 2017/746 — Articles 56(6), 78 to 81; Annex XIII Part A Section 1.3.2; Annex XIII Part B

Conclusion

The Literature Review Report (LRR) is a pivotal document for proving adherence to the IVDR. It is a scientific, effective way of collecting data on the performance of medical devices, particularly where clinical studies are not necessary or impossible to conduct. To stay compliant, the manufacturer should treat the Literature Review Report as a dynamic document, regularly updating it during post market surveillance activities.

How Morulaa Will Support

The Morulaa helps IVD Manufacturers with their compliance to the IVDR requirements through literature review and preparation of Performance Evaluation Report (SVR, APR, CPR). We help in implementing PMS Plans and PSURs of class C and D devices. We will ensure traceability of your claims and make you ready for the review by the notified bodies.