The new article highlights the aspects related to validation and verification activities to be conducted by medical device manufacturers to ensure the safety and proper performance of a new combination of an instrument and assay.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to replacement reagent and instrument family policy for in vitro diagnostic (IVD) medical devices intended to be marketed and used in the US. The document provides additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the underlying legislation and has been agreed with the authority in advance.
The approach described in the guidance is intended to expand the availability of in vitro diagnostic medical devices while ensuring their safety and proper performance.
The scope of the guidance covers, inter alia, the aspects related to design verification and/or validation activities. Under the general rule, the assay manufacturer is responsible for verifying and/or validating the modified test system as part of design controls; verification and validation activities should be based upon the manufacturer’s quality processes, including its risk-based assessment for the specific device and changes involved.
Protocols and Acceptance Criteria
First of all, the document describes considerations of protocols and acceptance criteria to be applied with respect to the changes introduced to a medical device in question. In particular, the document provides additional clarifications regarding the methods and criteria to be applied in order to verify and validate the modification subject to review. As explained by the authority, assay manufacturers are responsible for developing a testing protocol together with the relevant pre-specified acceptance criteria to be applied to each assay before the testing begins. According to the guidance, protocols should be sufficiently robust and challenging to ensure that any significant changes to the performance of the new combination of instrument and assay (relative to the performance of the cleared instrument-assay system) will be identified. The authority also mentions that the respective acceptance criteria should be justified in the context of any and all claims the device manufacturer makes with respect to its performance. The FDA emphasizes that in case additional verification or validation test methods or acceptance criteria are required, the changes in question most probably would significantly impact the safety and/or performance of the medical device subject to review and, consequently, require a new submission.
The document further provides a list of protocols which, if included in the initial submission, could also be needed for a new combination of assay and instrument being reviewed. These protocols include inter alia, the following ones:
- Testing in accordance with CLSI (Clinical and Laboratory Standards Institute) guidelines EP-17 to support a specified Limit of Blank, Limit of Detection, and Limit of Quantitation;
- Testing in accordance with CLSI guidelines EP-05 to support precision at limits of the claimed measuring range, and at medical decision points;
- Linearity across the assay measuring interval in accordance with CLSI guidelines EP-06, or, if appropriate, recovery to standard materials or methods;
- Method comparison studies in accordance with CLSI guidelines EP-09.
Apart from the abovementioned protocols, the document also provides a list of studies to be considered by the party responsible for a medical device in the context of verification and validation activities, namely:
- Interference studies in accordance with CLSI guidelines EP-07, as needed for the particular reagents, or detection methods;
- Carry-over or cross-contamination studies;
- Matrix equivalence studies in accordance with CLSI guidelines EP-35;
- On-board stability for reagent, calibrator, and sample;
- Hook-effect studies.
It is important to mention that the above list of studies is not exhaustive and should be considered as a set of examples, while the actual tests to be conducted should be determined by a party responsible for a medical device on a case-by-case basis.
Another important note is related to standards and guidelines used: as explained by the authority, medical device manufacturers may apply either initial guidelines used in the context of the initial application for marketing approval or modified guidelines dedicated to the same matter – when applicable.
In certain cases, medical device manufacturers may come to the conclusion that some of the tests initially conducted for marketing approval are no longer relevant. Such a decision is acceptable. However, it should be duly justified with reference to risks associated with the product in question.
In summary, the present FDA guidance describes in detail the approach to be applied with respect to validation and verification activities to be conducted by medical device manufacturers with respect to a new combination of an assay and instrument in order to ensure their proper performance. The document highlights the key points to be taken into consideration in terms of applicable standards and protocols to be included in a new submission when necessary.
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