The US Food and Drug Administration (FDA), the authority responsible for medical device regulation, issued guidance intended to assist the manufacturers of In Vitro Diagnostic Devices (IVD) in filing applications for the CLIA Waiver.
CLIA Waiver: The Scope of Application
The Clinical Laboratory Improvement Amendments (CLIA) Waiver allows the manufacturer of a simple medical device to waive required tests if they could be determined as “simple” or if the possible incorrectness of their results is associated with insignificant risk. In accordance with the general procedure, all laboratories are subject to oversight by the Centers for Medicare & Medical Services (CMS). This authority can also issue waiver certificates. All clinical laboratories are required to obtain the appropriate certificates to be allowed to perform testing of materials derived from the human body. At the same time, under certain conditions, the laboratories could apply for the Certificate of Waiver. For this purpose, they would need to confirm that all the tests they perform could be determined as “simple” and any risk associated with the potentially erroneous results are insignificant.
The guidance describes in detail the particular scope of tests the laboratories holding the Certificate of Waiver are allowed to perform, namely:
- Tests explicitly approved by the Food and Drug Administration for home use,
- Simple tests with insignificant risk of incorrect results, when the methodology applied reduces the probability of incorrectness in the results to the lowest extent possible, or when the Secretary of Health and Human Services defines that they bear no unreasonable risk when conducted properly.
In particular, the guidance is intended to assist medical device manufacturers in providing the information confirming that the device is admissible for the CLIA waiver. Under the general procedure, the manufacturers apply for the FDA 510(k) approval first and only then file the CLIA waiver submission. At the same time, since the Dual 510(k) and CLIA Waiver application (Dual Submission) framework has been implemented, the manufacturer is allowed to file one single submission covering both applications. It is also important to mention that the scope of the guidance does not cover devices intended for over-the-counter or prescription home use – such devices are determined as CLIA-waived ab initio.
“Simple” Test for CLIA Waiver
The CLIA Waiver framework includes two important concepts regarding the eligibility of the tests performed: they should be “simple”, and the risk of an erroneous result should be insignificant. First of all, the device subject to the CLIA waiver should be simple. In order to meet the simplicity criteria, the device should:
- Be a fully automated or self-contained,
- Be based on the utilization of initial unprocessed specimens,
- Be used only for general manipulations,
- Not require any additional intervention during operations,
- Not require any additional training for the person using it, especially related to the interpretation of error codes,
- Not require special electronic or mechanical service or maintenance,
- Provide the outgoing data in the format that does not require any additional interpretation,
- Provide the results in a clear and understandable format,
- Be accompanied by the quick reference instructions.
At the same time, the guidance also provides the list of criteria used to define that the particular device could not be determined as a “simple” one, namely:
- It is necessary to perform certain manipulations with the samples before it would be possible to use the device,
- Certain conditions could impact the measurement of the analyte.
If the manufacturer determines the device as “simple” due to the criteria provided hereabove, it would be also useful to discuss the matter with the authority before commencing studies designed to collect the data necessary to confirm compliance with the appropriate criteria. The manufacturer should describe the features of the device confirming that it meets the “simplicity” concept and also provide samples of the device (if possible) to assist the authority that is accessing it.
The Concept of Insignificant Risk
The second important concept used to determine the eligibility of the device to the CLIA waiver is related to the risk associated with potential errors related to the results of the test performed using the device. Under the general rule, the aforementioned risk should be significantly lower than for other types of devices. In particular, the manufacturer must provide information confirming that the test system is unresponsive to the impact caused by external conditions due to its design, and all potential sources of error already known by the manufacturer are effectively controlled. Actually, the flex studies are usually performed to confirm the durability of the design, and the risk management approach is utilized to confirm that all potential error sources had been duly identified and controlled. Thus, both these two elements are needed to be included in the CLIA waiver submission.
As usual, the risk control measures are represented by the fail-safe measures or failure alert mechanisms intended to reduce substantially the risk of obtaining incorrect results. For instance, such a mechanism could be represented by the special feature preventing the device from providing results in case if the conditions could impact their accuracy. The manufacturer may also provide guides or other additional measures implemented in order to prevent the operator from using the device in an inappropriate way. It is advised to include fail-safe mechanisms in the design of the devices in each case when it is reasonably possible due to the design of the device and its technical features.
At the same time, if for certain reasons the appropriate fail-safe mechanisms could not cover some of the risks, the manufacturer shall implement additional failure alert mechanisms intended to notify the person using the device in case something goes wrong. When such mechanisms are implemented, the person using the device would either be able to correct the error or at least be acknowledged that certain errors may take place.
To confirm the compliance with the aforementioned criteria, the authority recommends medical device manufacturers to use the following two-tier approach:
- Tier 1. Risk Analysis and Flex Studies. Risk analysis performed by the manufacturer should be rigorous enough to cover all potential sources of error, providing that all potential sources related to both malfunction of the device and errors related to the person using the device are duly covered by the studies. Flex studies are used to assess the operational limits of the device and the way it performs under the stress conditions, as well as to evaluate the performance of control measures.
- Tier 2. Fail-Safe and Failure Alert Mechanisms. The manufacturer should implement the appropriate control measures intended to mitigate the risks associated with the incorrect results. In particular, the manufacturer of the device shall check the way the control measures had been actually implemented, and also assess the actual effectiveness of such control measures (each separately).
The guidance published by the FDA covers the most important aspects related to the devices eligible for the CLIA waiver, providing the description of the core elements and concepts, including the criteria used to determine the eligibility of the device and the particular criteria such device should meet.
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