The requirements of the Medical Device Regulation (MDR) and especially of the Clinical Part for CE certification have become more complex. Besides new tasks and decisions to be made, i.e. Post Marked Clinical Follow-up (PMCF) and proof of Medical Claims and Clinical Benefits, also the interfaces between the components have become more challenging. Risk Management, Clinical Evaluation and Post Market surveillance (PMS) are closely intertwined now and as continuous, systematic, planned processes also part of the quality management system. They cannot be looked at separately anymore.
We oftentimes experience that our customers do not really know where to begin. This overview points out one possible approach to revision or even regeneration of the Clinical Part. This is only one possible approach out of many possibilities, but it may be of good assistance.
Components of Clinical Part
The components of the Clinical Part are to be found within different documents for CE certification. Those comprise the risk management system – therein especially the processes regarding clinical risk – and, naturally, also the clinical evaluation and PMCF. Furthermore, parts of the technical documentation must be mentioned here, especially the Instructions for Use (IFU) and Usability Engineering are valuable input and output documents regarding the Clinical Part. As mentioned before, the most important processes are part of the quality management system. Responses from the market, derived from post marked surveillance and vigilance system are valuable input for the Clinical Part as well. Output documents of the Clinical Part are required reports like Summary of Safety and Clinical Performance (SSCP). An overview of the corresponding articles within the MDR is presented in the following figure:
The 6 steps
We would like to put forward a 6-step-approach to realize the fulfilment of the requirements for the Clinical Part without losing track:
1. Identification of basic regulatory information per product
2. Revision of Risk Management File
3. Revision of Usability 4. Engineering File
4. (Re-)assessment of market responses (PMS, Vigilance)
5. Revision of Clinical Evaluation incl. PMCF
6. Establishing process flow
Step 1 – Identification of regulatory basic information
The MDR requires an explicit statement on the regulatory basic information of any given product. For your product you must determine:
1. Intention for use
3. Patient population
4. Medical Claims
The regulatory basic information is used as the foundation during the process. These four items are input for the Clinical Part. After you have gone through all 6 steps, they are still input for the open aspects, thus for what to do during PMCF.
From now on, we refer to these four items combined as “regulatory basic information”. On a higher level, the intention for use also defines the specifications for the following three items. Many customers have trouble to distinctly determine number 2 to 4, because the intention for use has earlier been defined as broadly as possible and was designed to encompass as many indications as possible and the biggest possible patient population. Especially the medical claims being made can sometimes be hard to prove. You may start out with your given intention for use but should keep in mind, that these four items must be supported (and proven) with data regarding safety and performance within your risk evaluation and your clinical evaluation. Aspects which could not be supported satisfactorily are to be addressed in PMCF.
During Step 1 and the allocation of regulatory basic information to the product you may be forced to change or divide product families.
A tip for your approach: Do not get discouraged! Start out with your desired or already given regulatory basic information as input parameter. Proceed with the next steps. In case you detect that a Medical Claim can nor be proven in the clinical evaluation neither with PMCF, you can take out the claim or rephrase the claim. It is much easier to take a claim out than to put one in afterwards.
Step 2 – Revision of Risk Management File
Because of the risk-based approach of the MDR, risk management plays a central role during CE certification. Most of our customers do have a risk management report which they have not changed or updated since the product was marketed. Also, an isolated Failure Mode and Effects Analysis (FMEA) is not sufficient anymore. If you operate somewhere in the above-mentioned range, your current practice is very likely to get rejected by the notified body. Start out to plan a systematic process. Appoint a responsible person and issue a risk management plan, which has earned its name.
During analysis, evaluation, and mitigation of risks you concentrate on the clinical risks as well. Those are totally forgotten or sadly underrepresented from our experience. Your starting point for possible risks is once again the above mentioned and determined regulatory basic information.
Discuss truthfully which questions are still open and which aspects should be addressed within the clinical evaluation. It is very helpful to consult with one or several application experts (physician, nurse, therapist) to evaluate all possible clinical risks.
Step 3 – Revision of Usability Engineering File
This part of the technical documentation takes kind of a back seat sometimes as well. It should, however, feature a certain level of quality. Essentially, the usability related risks should be addressed and mitigated at this point and the use case should be accurately described to have all information available for the user. Some customers combine UEF and risk management. Solutions and possible implementation scenarios can be found in the annexes of ISO 62366.
Step 4 – (Re-)assessment of market responses (PMS, Vigilance)
Responses from the market are a very important and valuable source of evidence regarding the Medical Claims. Those responses are therefor also input for the clinical evaluation and ultimately for PMCF.
Step 5 – Revision of Clinical Evaluation incl. PMCF
No matter if you author your own clinical evaluation or outsource it, make sure that the regulatory basic information, the risks, and the responses from market are thoroughly being used and integrated.
Gaining enough clinical data for every single medical claim made will be the most difficult thing. Depending on how good or bad data availability is, there is still the possibility to clarify open questions or non-proven medical claims by collection of specific PMCF data. Some results from the clinical evaluation will be transferred to the technical documentation, for example the instructions for use. This is mostly the case for single risks and instructions. It might be the case, however, that risks are identified which need to be addressed within the risk management. In that case you start over with Step 2.
Step 6 – Establishing process flow
At this point you should implement a flow for the required processes, because there might be changes (updates) of the clinical evaluation, new responses from the market, or results through PMCF, or even design changes, which can have an influence on your regulatory basic information and thus on the Clinical Part. Each of the above-mentioned aspects should trigger someone’s (at best a responsible person’s) thinking about which one, some, or even all of the 6 steps should be repeated again. These process loops need to be established and implemented into your QMS.
Foremost and centre of the Clinical Part are the regulatory basic information of your Product, namely:
1. Intention for use
3. Patient population
4. Medical Claims
Those are defined within the steps and their Safety and Performance is demonstrated. Risk Management is one of the central aspects of MDR requirements and should be started and implemented as early as possible.
Do not shy away from those tasks but take one step at a time and get started. Decisions you made in the beginning might even be changed in the process. And we would like to stress, that it is important to look for competent and reliable partners, who are familiar with the complexity of your tasks.
About the author
Dr. Nadine Leistner
Chief Scientific Officer of MEC-ABC GmbH
Dr. Nadine Leistner is the Chief Scientific Officer of the MEC-ABC GmbH, where she supports medical device manufacturer with the clinical part of the CE certification. The MEC-ABC consults and writes clinical evaluations, PMCF-activities and clinical investigations. Core competency is to find out which data the Manufacturer’s devices will need and how to get them. She is QM-Auditor, Clinical Trials Manager and Regulatory Affairs Manager and so efficiently combines these fields for her clients.
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