According to ISO 14971, medical device manufacturers must perform a benefit-risk analysis of their products as part of the certification procedure. For this reason, this article provides readers with information on what BRA is, how to evaluate the benefits and risks of a medical device and what guidance documentation to use.
I. What is benefit-risk analysis?
The benefit-risk analysis is not a choice. It is a requirement of ISO 14971. It helps a manufacturer establish if the benefits of a medical device outweigh its risks. However, before performing benefit-risk analysis, they must be able to answer the following questions:
- What are the potential benefits?
- What are the potential risks?
It’s important to know that the benefits and risks are usually not of the same units. Thus, it’s often not easy or even possible to objectively balance the benefits against the risks. It’s like comparing apples with mandarins. However, the manufacturer must make a subjective decision to answer the following:
- Is the user/patient willing to accept the medical device’s potential risks for the potential benefits that it offers?
When answering the above question, something to keep in mind is that the risks and benefits aren’t the same for everyone. This means that the same medical device could pose different levels of risks to different patients and provide varying degrees of benefit.
II. What factors to consider when evaluating the benefits of a medical device?
The benefits of a medical device are presumed under the condition that the medical device works reliably and as intended. To determine the benefits of a device, a manufacturer typically needs to perform a clinical evaluation. However, sometimes, a non-clinical assessment can also be used to establish the benefits of a medical device: E.g. usability testing, computer modelling and simulations, and cell-based testing.
To evaluate the benefits of a medical device, a medical device manufacturer must consider several factors. Namely:
- Type of the benefit (e.g. improving quality of life, providing relief from symptoms, and aiding the improvement of patient function)
- Magnitude of the benefit: This is usually measured against a scale according to specific criteria.
- Probability of the benefit: This represents the likelihood that a patient will receive the intended benefit because not all patients receive it.
- Duration of the benefit: How long does the intended benefit persist?
III. What factors to consider when evaluating the risks of a medical device?
To estimate the residual risks of a medical device, a manufacturer must perform risk management. The risk estimation can be either quantitative or qualitative. Also, both clinical and non-clinical methods can confirm the estimated risks and the effectiveness of the implemented risk controls.
The factors manufacturers should consider when estimating risks subjectively and qualitatively are as follows:
- Severity, type, likelihood and duration of the harms: These harms result from the use of the medical device. They can be short-lasting (e.g., skin cut) and long-lasting (e.g., organ damage).
- Procedure-related harms: These harms are incidental and not a result of the use of the product. For instance, implanting the medical device requires surgery.
IV. What factors to use when judging the risks vs the benefits of a device?
Besides all the above factors, there are some additional factors a manufacturer must consider when judging the risks versus the benefits of a medical device. Namely:
- Quality of the clinical data: Poorly designed and executed clinical evaluations could render the clinical results unreliable and weaken the claim of the dominance of benefit over risks.
- The disease characteristics: Is the disease degenerative or stable? Does the disease worsen over time if untreated?
- The patient’s risk tolerance: The patient risk tolerance depends a lot on the severity of the disease. E.g., patients with severe illnesses that will lead to death may tolerate higher risks.
- Availability of alternative therapies: Are there available alternative therapies for treating the disease?
In regard to the last point, generally, if a device provides a benefit, though very small, for a disease for which no alternative therapy exists, the device may still get approved. However, a higher-risk device may also be approved for commercial use if it has greater efficiency for a subpart of the patients or under specific conditions (e.g. tropical environments).
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To visually demonstrate the benefit-to-risk ratio’s acceptability, a manufacturer may use the following figure. The State-of-the-Art (SOTA) represents a medical device that has received market approval and is in use already. SOTA could represent an own device or a competitor’s device. The figure has four quadrants, which can be explained as follows:
- Upper-left quadrant: If the analysed device delivers more benefit for the same or lower risk, the benefit to risk ratio is improved, and the benefit outweighs the risks.
- Lower-right quadrant: If the analysed device delivers less benefit for the same or more risk, the benefit doesn’t outweigh the risk.
- Upper-right and lower-left quadrants: Deeper analysis is needed to determine if the benefit outweighs the risks.
Lastly, the benefit-risk analysis should be done on the overall target population. That’s because the benefit to risk ratio may be acceptable for a part of the target population.
V. CE and FDA guidance documents for benefit-risk analysis
Medical device manufacturers who plan to sell their products in the United States must obtain FDA certification. To do so, they need to use the following guidance documents to perform the benefit-risk analysis:
- Factors to Take Into Account When Making Benefit-Risk Determinations in MD Premarket Approval & De Novo Classifications – FDA guidance document
- Benefit-Risk Factors to Consider When Establishing Substantial Equivalence in Premarket Notifications with Different Technological Characteristics – Download FDA guidance document
- Factors to Take Into Account When Making Benefit-Risk Determinations for Medical Device IDEs – FDA guidance document
- Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, & Enforcement Decisions – FDA guidance document
- Uncertainty in Making Benefit-Risk Determinations in MD Premarket Approvals, De Novo Classifications, & Humanitarian Device Exemptions – FDA guidance document
- Providing Periodic Benefit-Risk Evaluation Report – FDA guidance document
- E2C(R2) Periodic Benefit-Risk Evaluation Report. Questions & Answers – FDA guidance document
- E2C(R2) Periodic Benefit-Risk Evaluation Report – FDA guidance document.
However, to access the EU market, the above documents are of no use. To pass the CE marking process, manufacturers must comply with Annex XIV of the EU MDR 2017/745 or Annexes XIII and XIV of the EU IVDR 2017/746. Additionally, the following guidance documents can be used for performing benefit-risk analysis:
- Clinical Evaluation – Equivalence. A guide for manufacturers & notified bodies. EU MDR 2017/745 – MDCG 2020-5
- Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under MDD 93/42/EEC or AIMDD 90/385/EEC – MDCG 2020-6
- PMCF Plan Template – MDCG 2020-7
- PMCF Evaluation Report Template – MDCG 2020-8
- Summary of safety & clinical performance – MDCG 2019-9
- Safety reporting in clinical investigations of medical devices under the EU MDR 2017/745 – MDCG 2020-10/1
- Safety reporting in clinical investigations – MDCG 2020-10/2
- Clinical evaluation assessment report template – MDCG 2020-13.
VI. Benefit-risk analysis for clinical evaluations
In a clinical evaluation, the medical device may not be approved for commercial use. That’s because it may not bring any patient benefits and still present safety risks to the participants in the clinical study. Still, the device’s benefit-risk profile needs to be assessed and shown to be acceptable for the intended study group before the clinical evaluation begins.
The benefit-risk analysis for clinical evaluations must contain the following items:
- Clinical background, including information on the clinical condition to be treated, managed or diagnosed, the prevalence of the condition, and the natural course of the condition.
- Alternative medical devices that are already available to the target population. The following should be provided: historical treatments, available medical options (conservative, surgical, medicinal) and existing devices.
Additionally, when deciding on the acceptability of the risks, manufacturers should identify the deficiencies in current therapies to ascertain whether their device addresses a significant gap in the currently available healthcare. If the gap is not significant, then the device’s benefit-risk profile should be better than that of existing products and therapies.
