The new article highlights the aspects related to the measures intended to improve the accuracy of the study results and address potential bias. 

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 the design considerations for pivotal clinical investigations. 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 legal nature, nor are 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 current regulatory framework and has been agreed with the authority in advance. 

The scope of the guidance covers, inter alia, the aspects related to the regulatory requirements for diagnostic clinical performance studies


Diagnostic Clinical Performance Comparison Studies 

As it was mentioned before, diagnosing clinical performance studies are intended to ensure the proper performance of an investigational medical device subject to review. As further explained by the FDA, comparative studies that compare the diagnostic clinical performance of an investigational device with the diagnostic clinical performance of an established device or methods are only possible when a clinical reference standard is used. In this respect, the authority encourages study sponsors to get in touch in order to discuss related matters in advance.

According to the guidance, should an applicable clinical reference standard be unavailable, the performance of an investigational device could be assessed by the virtue of comparison to another medical device. At the same time, in order for the results of such a comparison to be reliable, sufficient information about the performance of a reference device should be available, and such a device should have an acceptable level of performance.

Blinding (Masking) in Diagnostic Performance Studies 

Under the general rule, multiple evaluators and users could be involved in clinical studies related to diagnostic medical devices. In particular, the document mentions that a clinical study for diagnostic performance could involve the user/reader of the investigational device, a person obtaining the clinical reference standard result, and sometimes a user/reader of an established device used in a comparison study. As further explained by the authority, in order to ensure the reliability of study results, the one using an investigation device in question in the course of a study should not be informed about the results of similar investigations or clinical reference standards. 


Total Test Concept 

The document also pays attention to the aspects related to the skill and behavior of persons interacting with the device in the course of an investigation. Usually, certain actions are to be performed by users having different levels of knowledge and skills. Depending on the way the device is intended to be used, these actions could include the collection of samples, placing the device on a study subject, and also interpreting the results. In case specific skills, training, or knowledge are needed in order to complete certain tasks, the actual performance could be different due to the natural difference in the performance of persons operating the device. Hence, these aspects should be taken into consideration when developing a study protocol. In certain cases, it could be even necessary to conduct additional studies in order to assess the performance of the device in question when used by different persons. Furthermore, in case training is required before using the device, such training should be duly documented, and the training materials used should be shared with the authority for review. 

The authority also mentions that in case the assessment of two diagnostic operations with respect to a single study participant is conducted by the same person, reading/interpretation bias can take place. Since it is not possible to read the results of both assessments simultaneously, they are considered one by one, and this creates grounds for a potential bias impacting the accuracy and reliability of the study results as the knowledge and understanding from the first reading could impact the interpretation of the subsequent one. According to the guidance, one way to mitigate reading order bias is to have a long period of time between assessments (“wash-out” period) to eliminate reader memory of the first assessment. However, other measures could also be implemented in order to mitigate this, so the authority encourages the parties responsible for an investigation to get in touch to discuss them in advance. 

Furthermore, should it appear that the study conducted does not properly reflect the existing medical practice, its results could be also subject to bias. For instance, it could be affected by the prevalence of a target condition – in such a case, readers/interpreters may consider investigational device results to be positive more frequently in settings with higher disease prevalence, thereby also affecting estimates of diagnostic device performance. Thus, the parties responsible for a clinical investigation should consider these aspects carefully and make sure all the measures are taken in order to address the impact caused by such a potential bias. 


Common Types of Bias 

The guidance further outlines the common types of bias in diagnostic clinical performance studies and provides an overview of each of them in order to assist study sponsors in addressing them. According to the guidance, common types of bias in diagnostic clinical performance studies are:

  • Selection bias;
  • Verification bias;
  • Disease progression/regression bias;
  • Lead-time bias;
  • Length-time bias (survivor bias);
  • Extrapolation bias;
  • Reading order bias;
  • Bias due to lack of independent evaluation. 

In summary, the present FDA guidance addresses certain important aspects related to clinical investigations for diagnostic devices. The document highlights the key points to be taken into account in order to ensure the accuracy and reliability of study results and minimize the impact of bias that could appear. 



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