The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of medical devices, has published a guidance document dedicated to the total product lifecycle of infusion pumps. The document is intended to provide medical device manufacturers with additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered in order to achieve and sustain compliance with them.
Due to the legal nature of the guidance, the provisions contained therein are non-binding, and an alternative approach could be applied, provided such an approach complies with the provisions of current legislation and has been approved by the authority in advance. Apart from other aspects, the document addresses the matters related to the safety of infusion pumps, including safety assurance cases and general considerations for safety case development.
Safety Assurance Case
First, the FDA states that in most cases, the new infusion pumps are different from those already placed on the market in terms of materials, design, or performance. This aspect should be considered when the compliance of a new medical device with the applicable regulatory requirements is demonstrated by referring to substantial equivalence to a similar medical device already placed on the market (the predicate). According to the applicable legislation, determinations of substantial equivalence will rely on whether the information submitted, including appropriate clinical or scientific data, demonstrate that the new or modified device is as safe and effective as the legally marketed predicate device and does not raise different questions of safety and effectiveness in comparison to the predicate device.
In this regard, extensive information about the new device (safety assurance case) should be submitted in order to determine the substantial equivalence of a new medical device or the one subject to significant changes or modifications. The safety assurance case should contain a statement supplemented by evidence confirming that all the safety-related issues associated with the new device are properly mitigated. The scope of information to be provided will depend on the risks associated with the product, its complexity, and identified risks. The Agency explicitly mentions that safety cases are device specific and depend on manufacturer-specified design requirements, associated hazards, design specifications, and other design control documentation. Hence, each medical device should have its own safety assurance case. In the case of applying for changes to a medical device already placed on the market for which no safety assurance case exists, a new one should be developed and provided to the authority.
FDA recommends performing the development of safety assurance cases together with the development of the product itself. Such an approach is beneficial for numerous reasons, including the cost-effectiveness perspective. In order to reduce the time needed to prepare a safety assurance case, medical device manufacturers are allowed to use existing safety assurance cases as examples. At the same time, the manufacturer shall ensure the applicability of such a safety case in the context of a new medical device. Moreover, the safety assurance case should be subject to review on a regular basis in order to ensure it covers the entire lifecycle of the product.
According to the guidance, there is no pre-defined format of the safety case, so the manufacturer should develop it in accordance with the recommendation provided in the present FDA guidance.
General Considerations for Safety Case Development
The guidance further describes the aspects to be taken into consideration in the course of the safety case development. According to the document, a safety assurance case is comprised of the following key elements:
- Claim, which is a statement about a property of the system or some subsystem;
- Argument that links the evidence to the claim. According to the guidance, the types of arguments include deterministic, probabilistic, or qualitative. The argument provides justifications with references to the evidence in place and also confirms that the scope of evidence provided is sufficient to justify the statements made by the medical device manufacturer.
- Evidence, which states for information that demonstrates the validity of the argument. According to the document, the concept of evidence includes facts, analysis, research conclusions, test data, and experts opinions.
The aforementioned elements are intended to demonstrate that the hazards associated with a medical device in question have been duly identified and the appropriate measures have been taken. For this purpose, a rigorous analysis of such hazards should be performed.
Each safety assurance case could contain numerous claims and arguments. The level of details to be provided depends on the medical device subject to review and its specific features. The FDA states that in the case of infusion pumps, the scope of the safety case shall cover the following aspects:
- The person for whose use the device is represented or intended; and
- The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of use.
The authority additionally emphasizes that the safety case should also contain information about the measures taken by the manufacturer with regard to hazards associated with the medical device, including details about the actual effectiveness of such measures in mitigating these hazards.
The FDA also provides additional recommendations to be considered by the medical device manufacturers with regard to safety assurance cases. The recommendations based on the authority’s experience of reviews include the following:
- The aspects related to hazards should be addressed in a separate argument structure (confidence case) covering such aspects as techniques, procedures and results to assure that hazards present within the safety case are accurate and complete.
- Sometimes separate elements of a medical device, e.g., software, would require specific argument structures as well.
- Arguments should include justification for the selection of acceptability criteria for safety controls. Such elements could also be included in the safety assurance case.
- Another important element to be included is a traceability analysis intended to confirm that any and all known hazardous situations are taken into consideration by the manufacturer and the appropriate controls have been implemented.
- Although there are no pre-defined safety case formats that the manufacturer is obliged to use, there are commonly used formats that can serve as a basis. Should the manufacturer decide to apply its own format, additional details should be provided in order to assist the authority in reviewing the document.
- FDA review of safety cases includes the use of postmarket data to confirm the validity of safety case arguments. Hence, a medical device manufacturer may find it useful to conduct a similar exercise during [its] own internal review.
In summary, the present guidance provides additional information and recommendations regarding the safety assurance cases and how they should be developed by medical device manufacturers. The document highlights the most important aspects to be considered during the development stages, including the ones related to the content and structure of a safety assurance case.
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