According to Article 61, Chapter VI, and Part A of Annex XIV, Literature searches are performed throughout the entire lifecycle of a medical device, from product development, through clinical evaluation, clinical investigation, during post market surveillance (PMS), and vigilance. Notified bodies can then read through the clinical evidence and to determine whether the device conforms to essential requirements. As such, literature searches are a vital part of the CER, and therefore important to a medical device’s technical documentation. By taking the time to ensure that each stage is completed thoroughly and documented accurately, manufacturers will have a literature search that is compliant with new regulations and easy to replicate.
Reaching the State-of-the-Art
Literature reviews are used to establish and document the State of the Art (SOTA) and available treatment options, establish safety and performance of the device and its claimed equivalents, establish equivalence with similar CE market devices and to gather evidence and clinical data. They must be done objectively, identifying both favourable and unfavourable data, and be free of errors. The outcomes of the literature searches are used for several documents in the technical file, including the clinical evaluation report, post market surveillance report and the device description. In fact, the literature search is crucial to the CER’s success at every stage of the product lifecycle, from development to PMS. It is therefore critical to have a good literature search strategy that can be easily replicated throughout the product’s life.
Literature Search: the stages
Literature searches are a complex task—stages include defining the scope, identification of pertinent data, appraisal of pertinent data, analysis of clinical data and then producing the clinical evaluation report. The literature search protocol, report and copies of relevant articles and documents will be required as part of the technical documentation for the device. The search should be carried out according to the search protocol and documented in detail so that the methods can be appraised, results verified and search repeated if needed.
Literature may include journals found by searching MEDLINE/PubMed, Embase, Google Scholar, Research Gate, or from other internet searches. In addition, the literature search will include the manufacturer’s previous data and relevant data from competitors. The scope must be broad enough so that no important information is missed, but specific enough to include only relevant results. During the process, the literature reviewer should record the search terms and parameters used when searching and information about how each were appraised.
Critical appraisal is used to determine the value of identified data, to assess its contribution to the evaluation of the clinical performance and safety of the device. The CER writer will check the clinical validity of the work, looking at the data and methodology. For example, the number of patients in the sample, whether they used the proper statistical models and the reporting of mortality and serious adverse event data. Other factors, like the impact factor of the journal, might be taken into account to help establish the quality of the data. Appraising data against your technical, clinical and biological requirements will also help to establish relevance. The data is then analyzed to see whether it can demonstrate compliance with the regulatory requirements.
Doing It Justice
To perform a literature search to a high enough standard, it is vital to fully understand the requirements in the MDR and MEDDEV guidelines and interpret the guidance as early as possible. It may also help to communicate with a notified body where possible, for guidance and support. Errors can be introduced in a number of places, for example in the volume of evidence, relevance of data and tone of evidence and value to the research topic. An experienced professional will help you to produce an error-free literature review. The CER must be authored by a qualified expert — if a company does not have an in-house technical expert, it is important to consult an external expert to meet the requirements of the regulation.
Post Market Data
One commonly overlooked factor during the literature search is the important clinical data gathered during PMS. If a manufacturer already has a CE mark under the previous Medical Device Directive (MDD) where there was no requirement for PMS, they will have to proactively collect this data under the MDR. Different classes of medical devices are required to collect post market data at different frequencies, for example every six months for a Class III device, or every two years for Class IIa. Under the MDR, the CER is not a static document, and this post market data from both their own and from competitor’s devices can be incorporated. This means for example, a pregnancy test manufacturer would have to gather data on false positive or negative results, and a bandage manufacturer would have to monitor whether the product was meeting its intended use. Manufacturers can then use this data to identify trends and improve their own processes.
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