The new article addresses the aspects related to the design considerations for diagnostic clinical performance studies. 

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 considerations for pivotal clinical investigations. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers, study sponsors, and other parties involved in order to ensure compliance thereto. It is also important to mention that provisions of the guidance are non-binding in their 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 existing regulatory requirements and has been agreed with the authority in advance. 


Regulatory Background 

The scope of the guidance covers, inter alia, the aspects related to diagnostic clinical performance studies. According to the guidance, diagnostic clinical performance studies are often conducted as pivotal clinical studies for diagnostic devices. As further explained by the FDA, in such a study, diagnostic clinical performance of the diagnostic device is characterized by measure(s) that quantify how closely the diagnostic device output is associated with a clinical reference standard that is used to assess subjects for the target condition. When choosing clinical performance measures to be applied, a party responsible for a clinical study should take into consideration the intended use of the device in question, the output it provides, and also the applicable clinical reference standard. The authority also mentions that the goal of a diagnostic clinical performance study is to establish device diagnostic clinical performance and to support a favorable risk/benefit analysis related to the clinical performance of the device in the target population. 

As further explained by the FDA, the matters related to the safety and effectiveness of the device should be assessed together. In case the output provided by a diagnostic medical device is incorrect, harm can be caused to a patient due to the wrong actions taken based on such an incorrect result. In certain cases, the device should provide an accurate and reliable response on whether a specific condition is present or not. Apart from this, certain risks could be associated with the way the device operates when used for its intended purpose. To illustrate this statement, the authority provides an example of a medical device that is using radiation – in such a case, harm to a patient could be caused due to malfunction of the device even without the incorrect result provided by the device. These risks should also be taken into consideration when deciding on a study design and assessing the risks study participants will be exposed to in the course of a study. 

According to the guidance, the most important factors to be considered when developing a study design include, inter alia, the following ones:

  • The intended use of the device, 
  • Study population;
  • Measures to be taken in order to mitigate potential bias. 

The document further describes each of the above mentioned factors in detail and provides additional recommendations associated thereto. 

Considerations of Intended Use 

As it was mentioned before, it is vitally important to take into consideration the intended use of the device when deciding on the design of a diagnostic performance study. Diagnostic medical devices subject to review could have various intended uses and, consequently, provide various results. Hence, the approaches applied with respect to study design should vary as well. 

According to the guidance, the pivotal diagnostic clinical performance study should support the intended use of the diagnostic device. In general, the latter could be intended to be used:

  • As a stand-alone diagnostic;
  • To replace an existing diagnostic medical device or procedure; 
  • Together with other sources of information; or
  • To provide additional information. 

Thus, the intended use of the device should be taken into consideration when making decisions on the diagnostic performance study design. In particular, the following aspects are to be taken into consideration: 

  • The measurements the device is intended to make or conditions it should identify;
  • The reports the device provides;
  • Specific organs or systems examined by the device;
  • Specifics of the specimens to be used;
  • The way the device should be used (in accordance with the instructions for use provided by the manufacturer);
  • Conditions for which the device should be used;
  • Target population, and others. 

The authority also mentions that sometimes in case of changes to the way the device is to be used require the approach to evaluation to be reconsidered. 


Clinical Reference Standard for the Target Condition

Another important aspect covered by the guidance relates to the clinical reference standard. It is stated that in order to assess the performance of a diagnostic medical device, it is important to have information about the actual status of a study participant. As further explained by the authority, in a diagnostic clinical performance study, each subject is assessed for the target condition, using a clinical reference standard. A clinical reference standard, for regulatory purposes, is the best available method for establishing a subject’s true status with respect to a target condition. According to the guidance, this could include a single method or a combination thereof. The authority mentions that in each case, the “best available method” should be applied. In order to determine it, recent developments should be considered. Furthermore, it is also stated that clinical reference standards could be subject to changes due to the new technologies being used and additional information collected. 

In summary, the present FDA guidance highlights the most important aspects related to diagnostic clinical performance studies. The document explains the approach to be applied when determining the proper scope of assessment, as well as the key factors to be considered in this respect.  



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