The new article highlights certain specific aspects related to clinical outcome 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 consideration for pivotal clinical studies. The document is intended to provide additional clarifications regarding the existing regulatory framework, 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. 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, the authority explicitly states that 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. 

The scope of the guidance covers, inter alia, various aspects related to clinical outcome studies, including the way they should be developed and conducted. 


Diagnostic Clinical Outcome Studies  

Under the general rule, diagnostic medical devices should undergo diagnostic clinical performance studies. At the same time, in certain cases, clinical outcome studies could be required. As further explained by the FDA, in a diagnostic clinical outcome study, the diagnostic device result is used during a treatment or management intervention; device performance is assessed in part by the intervention’s effect on a subject’s outcome. In the course of such a study, diagnostic clinical performance could also be subject to evaluation. According to the guidance, this type of studies could be applied in cases when diagnosis and treatment are conducted simultaneously if the clinical benefit from a diagnosis provided by the device in question is not clear. The authority additionally emphasizes that in the case when intervention is conducted merely to collect a specimen, and the diagnostic result is not used for the clinical decision-making process, such a study will not be considered a diagnostic clinical outcome study. 

According to the guidance, in the case of diagnostic clinical outcome studies, the assessment of the safety and effectiveness of a medical device subject to review could be based on either respective clinical endpoints, diagnostic performance, or both. In certain cases, it is reasonable to engage a control group – the one for which the diagnostic results provided by the device will not be used. Comparison of the results for both these groups will provide additional information regarding the safety and effectiveness of the product in question when used for its intended purpose. 

The authority also mentions that in certain cases blinding, which is usually recommended in order to avoid bias and other issues that could potentially impact the safety and reliability of the results, cannot be applied since healthcare professionals participating in a study are aware of whether the device was used for a specific patient or group. 

Clinical Outcome Studies: Advantages and Disadvantages 

The document also outlines the main advantages and disadvantages of clinical outcome studies. As explained by the FDA, determination of an appropriate study design for a given device and desired intended use is dependent on many factors, including characteristics of the device, conditions of use, existence of alternative interventions (or diagnostic tests) for the same intended use, existence of adequate warning regarding use of the device, and extent of experience with the device. The authority also emphasizes the importance of taking into consideration the aspects related to labeling to be used for the device and claims to be included therein, as one of the main purposes of the study is to collect sufficient evidence supporting the claims made by the medical device manufacturer with respect to functionality, safety, and effectiveness of the product. In accordance with the recommendations provided in the guidance, when deciding on a specific type of studies to be conducted, study sponsors should take into consideration the matters related to clinical evidence required to support the claims in the context of the intended use of the device, its functions, and features. It is further stated that the level of evidence could vary depending on the specific study design. Should a party responsible for a clinical investigation decide to conduct a study with a lower level of evidence, such an approach should be duly justified. In particular, in such cases, it will be necessary to demonstrate that the study design applied is appropriate in terms of clinical evidence to be collected and covers all the key points related to the safety and effectiveness of a medical device in question. The same approach should be applied in case a study sponsor considers certain elements (e.g., blinding) as not mandatory for a specific study – measures intended to minimize potential bias are vitally important since they improve the accuracy and reliability of study results ensuring the stronger level of evidence. 

The document further describes in detail several types of clinical outcome studies and highlights the main advantages and disadvantages of each of them. The studies described in this section include:

  • Randomized, double-blinded, controlled, parallel-group clinical studies;
  • Randomized, subject as own control, paired clinical studies;
  • Randomized, non-blinded studies with concurrent control;
  • Non-randomized studies with concurrent control;
  • Single-group studies compared to baseline;
  • Single-group studies with historical control of information. 


IDE Application Considerations

The scope of the guidance also covers the matters to be considered with respect to medical devices subject to an Investigational Device Exemption (IDE), a special framework for investigational products. According to the guidance, for clinical outcome studies, a sponsor’s IDE application must, under 21 CFR 812.20, include the details of the proposed study design and a rationale for the study design chosen. In particular, a study sponsor will have to justify the approach applied when choosing the study design. The authority also mentions that it could be useful to provide additional information about alternative study designs considered during the initial discussion.

In summary, the present FDA guidance covers certain specific aspects related to clinical outcome studies. By virtue of the guidance, the authority provides additional clarifications regarding the matters to be considered in the case of diagnostic medical devices and also outlines the factors to be taken into account when deciding on a study design. 



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