The new article highlights the key points related to study population and planning, selection of study participants (subjects), and specimen collection. 

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 design consideration for pivotal clinical investigations. The scope of the guidance covers, inter alia, the aspects related to diagnostic clinical performance studies. The document is intended to provide additional clarifications regarding the existing regulatory requirements, as well as recommendations to be taken into consideration in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their nature, nor are intended to introduce new rules or impose new obligations. Moreover, an alternative approach could be applied, provided such an approach is in line with the existing legislation and has been agreed with the authority in advance. 


Study Population for Evaluation of Diagnostic Performance 

The scope of the guidance covers, inter alia, the aspects related to the study population. Under the general rule, sites from which subjects or samples are chosen for studies that support the intended use of the device should be representative of the types of sites where the device is intended to be used, while subjects or samples should also represent the proposed target population. Should study participants or sites involved in the investigation be irrelevant, the results could be unreliable and subject to bias. According to the document, the specific method used for subject selection in the context of a study should be clearly outlined in the respective study protocol. 

As further explained by the FDA, the study participants involved should be representative with respect to the target condition, otherwise, the deviations from this approach would impact the results of a performance assessment. This applies, inter alia, to representation in the context of the condition spectrum. In this respect, the authority mentions that in case all the study participants would represent only one extreme end of a condition spectrum, the performance demonstrated by the device would not be representative with respect to the whole condition spectrum, as the device will ensure better results from the lower end of the condition spectrum where target condition is less severe. 

Should the target population require participants with rare conditions to be enrolled, this should be taken into consideration when deciding on a study design, as it could be reasonably difficult to enroll a sufficient number of such participants. In particular, it is important to ensure the results of such an assessment are not affected by bias. 

Study Planning, Subject Selection, and Specimen Collection 

Depending on the principal mode of action, a diagnostic medical device may either test a patient directly or be used to analyze specimens collected. Furthermore, depending on the way the device operates, specimens could either be tested immediately after being collected, or collected and stored for some time. As further explained by the FDA, specimens or subject data are said to be prospectively obtained when a pre-specified protocol is used, and only specimens or subject data from subjects meeting the protocol criteria are obtained. In this respect, the authority mentions that specimens that have been collected for a purpose, different from a specific study, are not considered to be prospectively obtained. However, they could also be used to obtain additional data regarding the performance of the device. At the same time, specimens collected for a specific study could be stored and later used for other purposes – for instance, for another study. 

With respect to specimen collection, a study protocol should describe in detail all the key aspects to be considered in order to ensure the accuracy and reliability of the study results. According to the guidance, these aspects include, inter alia, inclusion/exclusion criteria, method of subject recruitment and selection, testing protocol, and analysis methods to be used. Proper planning is vitally important to ensure that all the study participants enrolled are representative in the context of the target population and condition. 

The authority also mentions that in certain cases it would be reasonable to use specimens initially collected for other purposes (e.g., biobank), especially in cases if the target condition is rare and it is difficult to enroll a sufficient number of study participants in order for the study results to be reliable and accurate enough. According to the guidance, in order to prevent bias, when bank specimens or previously collected data or images are added to a study, the person performing the test or interpreting the test results should not be able to differentiate the added specimens or data from the obtained prospectively. However, the selection and use of the specimens collected before for other purposes could raise additional concerns, as the selection is to be conducted using specimens that already exist while in the case when specimens are initially collected to be used in the context of a specific study, a party responsible for the study has full control over the collection process. The concerns arising could be related, inter alia, to the representativeness of the specimens to the current data population. Due to the importance of the abovementioned factors, the authority encourages study sponsors to get in touch and discuss such matters in advance. 

In summary, the present FDA guidance describes in detail the approach to be applied with respect to subject selection in order to ensure that the participants enrolled duly represent the target population. The document also provides recommendations to be considered in the context of specimens and the way they are collected and selected. 



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