Material Risk/benefit analysis and management Contents

Introduction 1.0 Scope 2.0 General requirements for risk/benefit management 2.1 Risk/benefit management process 2.3 Risk/benefit management plan 2.6 Risk/benefit management file 3 0 Risk/benefit analysis 3.1 Risk/benefit analysis process 3.2 Intended use/intended purpose and identification of characteristics related to the safety of the medical device 3.3 Identification of benefits, or hazardous situations. 3.4 Estimation of the risk/benefit(s) for each hazardous situation 4.0 Risk/benefit evaluation 5.0 Risk/benefit control 5.1 Risk reduction 5.2 Risk/benefit control option analysis 5.3 Implementation of risk/benefit control measure(s) 5.4 Residual risk/benefit evaluation 5.5 Risk/benefit analysis 5.6 Completeness of risk/benefit evaluation 6 Evaluation of overall risk/benefit acceptability 7 Risk/benefit management report 8 Production and post-production information

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Introduction Manufacturers of materials should regard this document as a framework for effective management of the risk/benefit associated with the use of materials for the manufacture of medial devices. The recommendations contained in this document provide a framework within which experience, insight, and judgment are applied systematically to manage this risk/benefit. This document was developed specifically for material manufacturers, notified bodies, and Competent Authorities using established principles of risk/benefit management. This document deals with processes for evaluating risk/benefit ratio, primarily to the patient, but also to the operator, other persons, other equipment and the environment. As a general concept, activities in which an individual, organization, or government is involved can expose those or other stakeholders to hazards which can cause loss or damage of something they value. Risk/benefit management is a complex subject because each stakeholder places a different value on the probability of harm or benefit occurring and their level of magnitude. All stakeholders need to understand that the use of a medical device entails some degree of risk. Factors affecting each stockholders perception of the risk/benefit include the socio-economic and educational background of the society concerned and the actual and perceived state of health of the patient. The way a risk/benefit is perceived also takes into account, for example, whether exposure to the risk seems to be involuntary, avoidable, from a man-made source, due to negligence, arising from a poorly understood cause, or directed at a vulnerable group within society. The decision to embark upon a clinical procedure utilizing a medical device requires the residual risks to be balanced against the anticipated benefits of the procedure. Such judgments should take into account the intended use/intended purpose, performance and risks associated with the medical device, as well as the risks and benefits associated to the exposed patient group, the clinical procedure or the circumstances of use. Some of these judgments may be made only by a qualified medical practitioner with knowledge of the state of health of an individual patient or the patient's own opinion.

1- Scope: This document specifies a procedure for manufacturers to identify the hazards associated with the material used in medical devices and to balance these versus the benefit for the patient resulting from the use of such devices containing such materials.

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2- General requirements for risk/benefit management Because of the wide variety of potential materials used in medical device manufacturing process, the following clauses apply as appropriate.

2.1 Risk/benefit management process The manufacturer shall establish, document and maintain a process for identifying (ISO 14971:2002) hazardous or improved situations associated with a material used in the manufacture of medical device, estimating and evaluating the associated risks and/or benefits, controlling these and monitoring the effectiveness of the controls throughout the life-cycle. This process shall include the following elements keeping in mind the intended use on patient and its safety: Risk Analysis Evaluation Control Type of Medical procedure Exposed Patient group Exposure level Impact of Production process Post production information 2.2 Risk/benefit management plan For the particular material being considered, the manufacturer shall establish and document a risk/benefit management plan in accordance with the risk/benefit management process. The risk/benefit management plan shall be part of the risk/benefit management file. This plan shall include at least the following: a) The scope of the plan, identifying and describing the material, the device and the life-cycle phases for which each element of the plan is applicable; b) Assignment of responsibilities and authority; c) Requirements for review of risk/benefit management activities; d) Criteria for risk/benefit acceptability including criteria for accepting risk/benefits outcome when the probability of occurrence of harm cannot be estimated; e) Verification activities; and f) Method or methods for obtaining relevant production and post-production information.
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Benefits Analysis Evaluation Control Type of Medical procedure Which Patient group benefit Exposure level Production Post production information

2.3 Risk/benefit management file For the particular material being considered, the results of all risk/benefit management activities shall be recorded and maintained in the risk/benefit management file.

3 Risk/benefit analysis 3.1 Risk/benefit analysis process Risk/benefit analysis shall be performed for the particular material as described in 3.2 to 3.4. The conduct and results of the risk/benefit analysis shall be recorded in the risk/benefit management file. NOTE 1 If a risk/benefit analysis or other relevant information is available for a similar material, it can be used as a starting point provided that changes that have been made are considered to discover if they could introduce significant differences in results. This consideration should be based on a systematic evaluation of the changes and the ways they can influence the various hazardous situations. 3.2 Intended use and identification of characteristics related to the safety of the material For the particular material being considered, the manufacturer shall document the medical procedure utilizing this material/device, the intended use, any reasonably foreseeable misuse, the exposed patients groups. The manufacturer shall identify and document those qualitative and quantitative characteristics that could affect the safety of the material and, where appropriate, their defined limits. These documents shall be maintained in the risk/benefit management file. Note: see Eucomed draft kick-off document for more information. 3.3 Identification of benefits, or hazardous situations The manufacturer shall compile documentation on anticipated benefits, hazards and hazardous situations associated with the material in both normal and fault conditions. This documentation shall be maintained in the risk/benefit management file. 3.4 Estimation of the risk/benefit(s) for each hazardous situation For each identified benefit hazardous situation, the risk/benefit(s) in both normal and fault conditions shall be estimated using available information or data. For hazardous situations for which the probability of the occurrence of harm cannot be estimated, the possible consequences shall be listed for use in risk/benefit evaluation
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and risk/benefit control. The results of these activities shall be recorded in the risk/benefit management file. Any system used for qualitative or quantitative categorization of probability of occurrence estimates or severity shall be recorded in the risk/benefit management file. 3.4.1 Risk of substances leaching from the device Two factors determine the degree of risk posed by exposure to a substance leaching from a device: 1. the patients sensitivity to the substance 2. the dose of the substance received by the patient. Clinical evaluation and/or literature review can be used for determining which patient groups will be considered most sensitive to the substance. The dose of substance received by the patient will depend on the type of procedure, exposure time, type of contact with the patient. EN ISO 10993-17:2002, Biological evaluation of medical devices Part 17: Establishment of allowable limits for leachable substances gives a method for determining the Tolerable Daily Intake for a substance, in case such value is not specified by authorities. The TDI is calculated as the NOAEL (no-observed-adverse-effect-level) divided by the MF (Modifying Factor). Instead of a MF, a MOS (Margin Of Safety) can be used. The MOS can be different for different patient groups. The actual dose of substance received by the patient should be lower than the TDI, unless the benefit outweighs the risk associated with the patient exposure to the substance. In the latter case, appropriate risk/benefit control measures must be taken. 4 Risk/benefit evaluation For each identified hazardous situation, the manufacturer shall decide, using the criteria defined in the risk/benefit management plan, whether risk control measures need to be applied or whether the estimated risk(s) is so low that risk reduction need not be pursued. If risk reduction is not required, the requirements given in 5.2 to 5.6 do not apply for this hazardous situation (i.e., proceed to 5.7). The results of this risk/benefit evaluation shall be recorded in the risk/benefit management file. 5 Risk/benefit control 5.1 Risk reduction When risk reduction is required, risk/benefit control, as described in 5.2 to 5.7, shall be performed.
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5.2 Risk/benefit control option analysis The manufacturer shall identify control measure(s) that are appropriate for identifying possible improvement for the risk/benefit balance.

5.3 Implementation of risk/benefit control measure(s) The manufacturer shall implement the risk/benefit control measure(s) selected in 5.2. Implementation of each risk/benefit control measure shall be verified. This verification shall also be recorded in the risk/benefit management file. The effectiveness of the risk/benefit control measure(s) shall be verified or validated as appropriate and the results shall be recorded in the risk/benefit management file. 5.4 Residual risk/benefit evaluation The risk/benefit after control measure(s) are applied shall be evaluated using the criteria defined in the risk/benefit management plan. The results of this evaluation shall be recorded in the risk/benefit management file. If the residual risk/benefit does not meet these criteria, further risk/benefit control measures shall be applied (see 5.2). For risk/benefits that are judged acceptable, the manufacturer shall decide which information to put into the accompanying documents. 5.5 Risk/benefit analysis If the risk/benefit is not judged acceptable using the criteria established in the risk/benefit management plan and further risk/benefit control is not practicable, the manufacturer may gather and review data and literature on the medical benefits of the intended use to determine the risk/benefit acceptability. If this evidence does not support the conclusion that the medical benefits outweigh the residual risk, then the risk/benefit remains unacceptable. Relevant information necessary to explain the residual risk/benefit shall be placed in the appropriate accompanying documents supplied by the manufacturer. The results of this evaluation shall be recorded in the risk/benefit management file. 5.6 Completeness of risk/benefit control The manufacturer shall ensure that the risk/benefit(s) from all identified benefits, hazards and hazardous situations have been considered. The results of this activity shall be recorded in the risk/benefit management file. 6 Evaluation of overall residual risk/benefit acceptability After all risk/benefit control measures have been implemented and verified, the manufacturer shall decide if the overall residual risk/benefit posed by the material is acceptable using the criteria defined in the risk/benefit management plan.
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If the overall residual risk/benefit is not judged acceptable using the criteria established in the risk/benefit management plan, but if the review of available data and literature on the medial benefits of the intended use outweigh the overall risk, this evidence supports the conclusion that the medical benefits outweigh the overall residual risk then the overall residual risk/benefit can be judged acceptable. Otherwise, the overall residual risk/benefit remains unacceptable. If the overall residual risk/benefit is judged acceptable, the manufacturer shall decide which information to put into the accompanying documents in order to disclose the overall residual risk/benefit. The overall residual risk/benefit evaluation shall be recorded in the risk/benefit management file. Compliance is checked by inspection of the risk/benefit management file and the accompanying documents. 7 Risk/benefit management report Prior to marketing a material with a new or modified design, the manufacturer shall carry out a review of the risk/benefit management process. This review shall at least ensure that: the risk/benefit management plan has been appropriately implemented; the overall residual risk/benefit is acceptable; and appropriate methods are in place to obtain relevant production and post-production information. The results of this review shall be recorded as the risk/benefit management report and included in the risk/benefit management file. 8 Production and post-production information The manufacturer shall establish, document and maintain a feedback system to collect and review information about the material in the production and the post-production phases. The feedback system shall also collect and review information about similar materials on the market. This information shall be evaluated for possible relevance to safety, especially the following: a) if previously unrecognized hazards or hazardous situations are present; or b) if the estimated risk/benefit(s) arising from a hazardous situation is no longer acceptable. If any of the above conditions occur: the impact on previously implemented risk/benefit management activities shall be evaluated and shall be fed back as an input to the risk/benefit management process, and a review of the appropriate risk/benefit management file for the material shall be considered. If there is a potential that the residual risk/benefit(s) or its acceptability has changed, the impact on previously implemented risk/benefit control measures shall be evaluated. The results of this evaluation shall be recorded in the risk/benefit management file.
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