Literature Reviews Under The In Vitro Diagnostic Regulation (IVDR)
Ethan Drower
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Literature reviews are an essential part of the clinical evaluation process for medical devices. The clinical evaluation report assesses a medical device's benefit-risk profile to ensure its continued safety, efficiency, and compliance.
Most regulatory staff and medical writers are typically quite familiar with the clinical evaluation process, clinical evaluation report (CER), and demonstrating compliance with the European Medical Device Regulation (MDR; 2017/745) for medical devices.
Fewer of us might be familiar with the processes required for compliance with the In Vitro Diagnostic Regulation (IVDR; 2017/746).
Today we are looking at the systematic literature review under the IVDR and how it fits into the more extensive performance evaluation process.
Performance evaluation
Performance evaluation for in vitro diagnostic devices (IVDs) is the equivalent of clinical evaluation for medical devices.
Performance evaluation is defined in the IVDR as:
"Performance evaluation of a device is a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of that device for its intended purpose as stated by the manufacturer. To plan, continuously conduct and document a performance evaluation, the manufacturer shall establish and update a performance evaluation plan. The performance evaluation plan shall specify the characteristics and the performance of the device and the process and criteria applied to generate the necessary clinical evidence."
Similar to the clinical evaluation for medical devices, performance evaluation for IVDs is an assessment and analysis of clinical data to establish and verify the device's scientific validity and analytical and clinical performance.
MDCG guidance
Previously, the information available on performance evaluation for IVDs was scarce. However, in January 2022, the Medical Device Coordination Group (MDCG) issued their guidance document for clinical evidence under the IVDR, Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs).
The guidance document outlines the general principles of clinical evidence and guides the performance evaluation process for in vitro diagnostic medical devices.
It is an invaluable resource for anyone looking to do performance evaluations.
Literature review for IVDR
The literature review for IVDR aims to demonstrate and document the in vitro diagnostic device's scientific validity. The scientific validity should be demonstrated for each device that provides information on and with respect to a clinical condition or physiological state.
As listed in the MDCG guidance,
"... scientific validity may be demonstrated through the use of existing data, where available, while taking into account the generally acknowledged state-of-the-art... (it) may be appropriately demonstrated based on available information such as peer-reviewed literature, textbooks, historical data, and experience."
As you can see, while the definitions and terms are different, gathering and analyzing clinical evidence for IVDs is quite similar to the process for medical devices.
Literature reviews in the context of performance evaluation seek to establish your device within the current state-of-the-art and demonstrate that your device lives up to the same standards as similar devices in the field. It must also seek to verify your device's continued safety and efficiency.
Literature review process
Systematic literature reviews consider the whole catalog of scientific data available on a specific topic. Besides scientific publications, gray literature, such as white papers, unpublished manuscripts, conference proceedings, and clinical trials, should also be evaluated.he literature review process typically consists of seven steps:
Defining your research question
Defining your research question is perhaps the most crucial step in a systematic literature search but also the most underappreciated.
How can you ensure you find the most relevant and high-quality information if you are not 100% sure what you are looking for?
You can't.
Your research question is the first step in a long process, and as in other situations in life, the first step defines the rest of the journey.
As defined in the IVDR, the clinical evidence for an IVD is established by demonstrating and substantiating scientific validity, analytical performance, and clinical performance.
The clinical evidence should also be based on a sufficient amount and quality of clinical data.
If you are not getting the search results you expected or need - review your research question. It is the most likely culprit.
Searching relevant databases
Not all databases are made equal.
To find the information you need, you need to consider where you are most likely to find the information you need.
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PubMed
is generally an excellent place to start. It contains an extensive catalog of peer-reviewed literature and links to other relevant literature based on your search. It is not, however, a complete search tool. It might not fully cover European and Asian literature, and many articles are not open access.
EMBASE
contains good coverage of medical devices and therapies used in Europe. The search is not as user-friendly as PubMed and can require a little getting used to.
Besides PubMed and EMBASE, it is highly recommended that you choose at least a third scientific database and at least one clinical trial database.
LIVIVO
is a German database focusing on life science in general and also includes publications on environmental and agricultural sciences. By de-selecting the option to include the Medline database (PubMed), you will find many European and Asian publications not available in PubMed, and most of the articles here are open access.
For clinical trials, clinicaltrials.gov is the most commonly used database. The European clinical trial registry and the International Clinical Trials Registry Platform (ICTRP) are also valuable databases.
Your literature search should be efficient, transparent, and easy to replicate. Do not forget to properly document every search made and make it as easy as possible for outsiders to understand your search strategy and to replicate it, if necessary.
Data screening
Literature searches usually return hundreds and hundreds of search results. Don't read all of them!
It is enough to quickly sort publications that are obviously irrelevant for your first pass on the search results. From the abstract, you should be able to distinguish any publications that don't have anything to do with the device under evaluation and publications that are not relevant to the clinical assessment (for example, letters to the editor or non-clinical studies).
Some publications can be excluded based on the title alone, while others require a review of the abstract. At this point, there is no need to read the first article.
Full-text retrieval
Once you've separated out all the irrelevant articles, it is time to review the full text of any publications and literature that might be relevant to your performance evaluation.
This is where you read the full article to understand if it fits into your performance evaluation. It is important to remember that literature searches should be objective and complete, meaning you cannot exclude results if they put the subject device in an unfavorable light.
Your previously established exclusion and inclusion criteria should be followed to a tee.
Data extraction and appraisal
Once you have sorted out all the irrelevant data, you must appraise the extracted data set. This can be done by following established appraisal methodologies from international organizations, such as the Oxford Center for Evidence-Based Medicine or the International Medical Device Regulators Forum (IMDRF).
This is where you extract PICO data for your Scientific Validity Report (SVR) and identifies relevant clinical safety and performance outcome data for the Clinical Performance Report.
In this step, using clinical data-extraction forms that have already been established and proven is recommended, as it helps limit human error and bias in the extraction process.
Documenting data
You've done all your searches and extracted and appraised clinical data - now you must document and report the results of your screening process.
Documentation requirements vary depending on your device and its intended use. A detailed methodology overview must be provided, demonstrating that your search is transparent and reproducible. You should also include the search strategy, which includes sources, search terms, inclusion and exclusion criteria, search output, and included/excluded references.
Evidence-based systematic flow diagrams, such as PRISMA, are also highly recommended.
A less appreciated step in the documentation process is to make your report as easily understandable and straightforward as possible. Do not use too many technical or complicated words if not necessary. Limit your "science-speak" and make it as accessible as possible. Even clinical evidence should be as enjoyable to read as possible.
Monitoring for new data and adjusting research questions and/or search methodology
The last step in your literature review is to keep it going. Literature searches are not static processes performed once and then left in the drawer.
The clinical evidence for your device should be updated throughout its lifetime. This includes your literature search.
You must monitor new data and adjust the research question or search methodology when necessary.
A methodologically sound literature search and Scientific Validity Report can help you leverage published data for the critical reports required under the In Vitro Diagnostic Regulation.
The literature search is not just an internet search for relevant literature. It is a clear and well-planned process for the identification, retrieval, selection, appraisal, and weighting of published data.
A systematic literature search is a requirement under the In Vitro Diagnostic Regulation. Even more so, it is a process of evidence-based research to gather and document clinical data for your in vitro diagnostic device that is critical to its safety, performance, and compliance.