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Step by Step

Clinical evaluation reports (CERs) are an obligatory component of technical files for medical devices, but their increasing importance is a new development. This is partly due to public scandals related to faulty medical devices that caused global health scares: French company Poly Implant Prosthèse was found to be using cheaper, industrial-grade silicone in breast implants; while recent investigations revealed that metal-on-metal hip implants could be releasing toxic debris into the blood. Similarly, transvaginal mesh implants used to treat pelvic organ prolapse may also expose patients to serious complications, such as tissue erosion. The need to prevent these prominent issues from reoccurring has led to revision of medical device regulations, bringing CERs to the fore.

Every medical device sold in Europe must have an updated CER as part of its technical file, regardless of classification. Yet guidelines for manufacturers are not always clear or comprehensive, especially on the topic of clinical data. The 2007 amendment to the Medical Device Directive attempted to address the inadequate use of clinical data by manufacturers during the evaluation process. However, recent scandals showed that it had failed to fully address the problem, and further developments were needed.

New Thinking

The new Medical Device Regulation (MDR) will come into force by 2018, and manufacturers are now faced with the laborious task of figuring out the modified procedures if they wish to introduce or maintain their devices on the European market. With this in mind, the following 10 steps aim to help manufacturers draft compliant CERs.

Avoid Complacency
CERs should not be put to one side once manufacturers have received a Conformité Européenne (CE) mark. A product technical file must be regularly reviewed, maintained and updated. The problem is that even manufacturers who do maintain their files to some extent are not doing enough to keep them up to date. They are then left confused when notified bodies (NBs) consider their CERs out of date or inadequate, especially since they passed the test the first time round. NBs are now under more pressure than ever to thoroughly scrutinise CERs, so laidback maintenance will not cut it.

Put Together a CEP

Before starting the evaluation, it is useful to plan how it will be carried out. A clinical evaluation plan (CEP) can provide an appendix to the CER and should include a detailed description of the aims of the CER; methodologies for identifying, screening, appraising and analysing data; and the methods used to reduce bias. An effective CEP demonstrates to NBs that a considered, robust methodology has been employed, utilising both favourable and unfavourable data for utmost transparency.

Assess Clinical Data in Existing CERs
For new products, manufacturers base their CERs on literature reviews of equivalent products and product components. Equivalent devices (EDs) must have similar clinical, technical and biological characteristics to the new product, as well as the same intended use. Any differences between the ED and the new product should not lead to clinically significant differences in terms of performance and safety. The CER may include one, several, or all identified EDs. In the absence of concrete data, a sound and informed hypothesis using suitable EDs is acceptable. However, once the product is on the market, the data in this initial CER is no longer satisfactory as actual data starts to become available. Manufacturers should check whether their existing CERs are being updated regularly enough.

Collect New Evidence

When a product has been on the market for a few years, a large body of clinical data will become available and this should be included in the CER to provide a better picture of the device’s performance. The results of clinical investigations and post-market surveillance activities should all be added to the CER. NBs are less likely to find fault with a technical file if they are provided with complete data allowing them to properly assess device safety. The CER should therefore show how the product has withstood real world use and responded to unforeseen complications and risks.

Feed in Risk Management Data
Clinical evaluation is interconnected with risk management. Risk management activities should identify risks that must be mentioned in the CER and post-market surveillance (PMS), which in turn highlight previously identified risks. As well as addressing essential requirements, manufacturers should pinpoint potential risks related to device design and its intended population, along with residual risks that may arise from risk management activities.

The CER should also demonstrate how risks have been dealt with as they arose, thus confirming the safety and efficacy of the product. This is especially important for new products, and manufacturers can understandably expect NBs to pay close attention to the consistency and relevance of their risk management activities. NBs expect that foreseeable risks – as well as any adverse events – are minimised and acceptable when weighed against the benefits of the intended use of the product.

Integrate All Existing Clinical Information
The results of all investigations carried out for a product should be integrated to present a coherent review of a product. Individual tests should not be analysed separately; rather, the results collected should be joined together to form an ecosystem. Data produced by one test may complement and enrich other findings. The CER must therefore collate data from clinical evaluation, risk management and PMS activities.

Refresh Data Regularly
New data should regularly be added to the CER. Updating the CER ensures that the risk:benefit assessment remains valid, and that the safety and performance claims of the device are supported at all times. Furthermore, technology evolves swiftly, and this may necessitate product development or change the way data is collected. Medical research and innovation continually transform product markets and provide new insights into product performance. CERs must also evolve accordingly. It is advisable to devise a system that schedules updates to ensure CERs stay on the agenda.

Be Ready for Stringent Evaluation
Even products that are not affected by medical advances and data development are not exempt from stricter regulations. Highly publicised scandals have increased pressure on NBs to improve conformity assessment to safeguard public safety. Manufacturers should therefore make CERs a high priority in their technical files and ensure CER content withstands scrutiny, especially when clinical data is not available.

Prepare in Advance
The new MDR will soon be effective; therefore, manufacturers are recommended to plan a full review of their product CERs before this happens. This way, they can ensure compliance with existing regulations and address any difficulties immediately. The MDR is expected to provide clear definitions and requirements on the topic of clinical data. NBs will be able to turn to these new guidelines where ambiguity currently exists, and manufacturers can prepare by implementing good practices, such as modifying their approach to CERs. This will place them in a better position in advance of the MDR, but also in anticipation of other new or unexpected developments.

Develop an SOP
One way to implement good practice is to draft a detailed standard operating procedure (SOP) taking into account all the steps above. The SOP should include detailed instructions to ensure that the correct processes are applied consistently to every new product, while ensuring that employees are familiar with regulations. Even if the CER is outsourced, it is essential to train staff on evaluation processes to reduce dependence on guidance. In turn, this will eliminate the need for revisions during the production phase or after NB review, and render the CER writing process more efficient.

Recognise the Importance of CERs

Manufacturers can expect CERs to remain crucial in producing technical files. The combined effects of faulty medical devices and new regulations mean that NBs are under ever-greater pressure to rigorously evaluate CERs. Investing time and resources to follow these recommendations will help medical device manufacturers to save time and money in the long term. Failure to do so could incur avoidable costs and irreparably damage reputation. In our experience, most medical device manufacturers urgently need to revise their approach to CERs in order to bring them up to date. It is a mistake to neglect CERs after obtaining a CE mark or passing an initial inspection; manufacturers should establish a system to ensure that their CERs are always updated and ready to pass an inspection.

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Chris Rule is an experienced regulatory and quality professional with an engineering background, who has gained a wealth of experience in the development of medical devices and the management of quality systems. In addition to CE marking, Chris has first-hand knowledge and experience of the stringent requirements demanded by the European and FDA regulatory requirements, including clinical evaluations and biological compatibility rationales.
Chris Rule
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