What is the Benefit-Risk Determination?
According to the EU MDR 2017/745, the ‘benefit-risk determination’ is “the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer”[1].
Why is it Crucial?
The benefit-risk analysis is required to be performed for all medical devices to be placed on the market–manufacturers must demonstrate that the benefits of their device outweigh the risks. The benefit-risk analysis should be documented in the Technical Documentation (EU MDR Annex II, section 5), including in the Risk Management File (EU MDR Annex I, Chapter I, section 3, (e)), Clinical Evaluation (EU MDR Chapter VI, Article 61, section 1; EU MDR Annex XIV, Part A), and Post-Market Surveillance documentation (EU MDR Articles 83 and 86). Trend reporting should also assess whether any safety event significantly impacts the benefit-risk analysis (EU MDR Article 88).
Although the MDR does not define what an acceptable benefit-risk ratio is, it is important to note that both a qualitative and quantitative analyses of the benefit-risk ratio should be performed. This post provides NAMSA expert’s recommendations on how to discuss the benefit-risk determination from the Clinical Evaluation Report (CER) standpoint, with an insight on the common mistakes and how to avoid them. These recommendations are given according to the interpretation of the EU MDR 2017/745 (including Chapter VI, Article 61, section 1; Annex XIV, Part A; Annex I, Chapter I, sections 1 and 8) as well as guidance documents (MDCG 2020-6[2]; MDCG 2020-13[3]; MEDDEV 2.7/1 rev. 4).
Common Mistake #1: Neglecting to Thoroughly Consider the State-of-the-Art Can Lead to Skewed Benefit-Risk Assessments
According to the General Safety and Performance Requirement (GSPR) #1, any risks which may be associated with the use of the device “constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state-of-the-art”[4]. Therefore, the first important aspect of the benefit-risk determination is the consideration of the state-of-the-art. The CER’s state-of-the-art section should include a robust discussion about the most effective treatment options[5] relevant to the device’s intended purpose. This ensures alignment with the prevailing medical landscape. Several factors impact the appropriateness and relevance of an alternative treatment option, and it is important to note that although some devices may not be best-in-class, they may show an acceptable benefit-risk ratio for specific conditions or specific sub-groups of patients.
Common Mistake #2: Not Positioning the Device of Interest Within the Medical Landscape
The state-of-the-art section of the CER must be written in a way that it provides a discussion on the generally accepted most effective treatment options for the indications relevant to the device under evaluation. Once the state-of-the-art is established and the generic device group associated with the device under evaluation is positioned within this medical landscape, it is possible to conclude on the benefit-risk ratio of a given treatment option.
Common Mistake #3: A Lack of Quantitative Parameters to Determine the Benefit-Risk Ratio
Although the discussion mentioned under Common Mistake #2 can mostly be qualitative, the state-of-the-art should also establish an indicative list and specification of parameters used to “determine […] the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device”[6]. These parameters are usually defined using data on benchmark products and other alternative treatment options. The end-goal of setting up these parameters is to demonstrate that the device under evaluation shows an improved or at least equivalent benefit-risk profile compared to existing benchmark products or other treatment options. Quantitative analysis of the benefit-risk ratio must be performed by comparing the subject device’s data with the parameters defined from the state-of-the-art to confirm the acceptability of the benefit-risk ratio.
Common Mistake #4: Failing to Summarize the Clinical Benefits Associated with the Device Under Evaluation
This discussion should also provide a summary of the clinical benefits associated with the device under evaluation, as supported by the clinical evidence, and their positive impact on patient management or public health. They should be described in relation to the meaningful and measurable patient-relevant clinical outcomes, including those related to diagnosis. The clinical benefits, as supported by the subject device’s data, may be compared with the clinical benefits of the generic device group as discussed in the state-of-the-art. Are they aligned?
Common Mistake #5: Failing to Appropriately Discuss and Assess the Risks Associated with the Device Under Evaluation
The benefit-risk assessment discussion should not only list the risks identified with the device under evaluation, but also discuss their clinical relevance (e.g., uncertainties or limitations of clinical data, undesirable side effects, potential for misuse, etc.), their severity, frequency, specific risk factors, and solutions to mitigate or reduce these risks. The undesirable side effects identified from the subject device’s data may be compared with the side effects of the generic device group as discussed in the state-of-the-art. Are they aligned?
Common Mistake #6: Skipping the Main Point: The Final Conclusion
Finally, the discussion of the impact of the risks in relation to the clinical benefits should allow for a conclusion on the overall benefit-risk ratio. This final conclusion should compare the benefits and the risks in terms of magnitude (How significant are the benefits? How severe are the risks?), frequency and probability (How many people experience the benefits and the risks [i.e., large or small populations]? How often?), and duration of the effects (How long the benefits can be expected to last, if applicable?). According to MEDDEV 2.7/1 Rev. 4, “a large benefit, even if experienced by a small population, may be significant enough to outweigh risks, whereas a small benefit may not, unless experienced by a large population of subjects”[7].
How Can NAMSA Help?
At NAMSA, our team understands the complexities and requirements related to the Clinical Evaluation process. Our team of medical writers is comprised of seasoned MDR professionals with extensive experience in guiding medical device manufacturers through the preparation and remediation of technical documentation, including the CEP and CER. Our medical writers partner with our EU Regulatory consultants, many of whom are former Notified Body employees, on CEP and CER development.
In addition to CER medical writing services, at NAMSA, we can provide a wide range of laboratory, quality, regulatory and clinical services to support you in obtaining and maintaining the CE mark for your medical devices.
Contact NAMSA today and let us be your trusted partner on the road to MDR compliance.
[1] MDR, Article 2, definition (24).
[2] MDCG 2020-6: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC, A guide for manufacturers and notified bodies (April 2020)
[3] MDCG 2020-13: Clinical evaluation assessment report template (July 2020)
[4] MDR, Annex I, Chapter I, section 1.
[5] This post will refer to “alternative treatment options” for the purpose of simplified wording, however, depending on the medical device under evaluation, alternative options may be alternative diagnostic options, or more generally, alternative medical options if the device is not intended to treat or diagnose any medical condition.
[6] MDR, Annex XIV, Part A, section 1(a).
[7] MEDDEV 2.7/1, Rev. 4, A7.2.
Caroline Guidicelli, MSc
Caroline began her career in the medical device field as a Manufacturing Engineer for a multinational company selling implantable orthopedic devices. Following, she worked as a self-employed Medical Writer authoring Clinical Evaluation Reports (CERs). She joined NAMSA in 2019, where the focus of her role is to write and review CERs for compliance with the European Medical Device Directive 93/42/EEC (MDD) and/or with the European Medical Device Regulation 2017/745 (MDR). She has also been involved in developing Clinical Study Reports (CSRs) following ISO 14155 and Annual Progress Reports (APRs) for the FDA. She has worked with numerous manufacturers on all classes of medical devices and a variety of therapeutic areas, including surgical instruments, wound care, orthopedics, dental bone substitutes and neurovascular aneurysm repair. She also participates in the development of templates, work instructions and Standard Operating Procedures (SOPs) for clinical evaluation. Caroline holds a Master of Engineering in mechanical engineering and polymer processing, as well as a Master of Science in innovative materials.