The new article describes in detail the approach to be applied with respect to an investigation plan and also provides definitions of the most important terms and concepts used in the context of the guidance.

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 for medical devices. The document provides an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be considered by medical device manufacturers and other parties involved 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, an alternative approach could be applied, provided such an approach is in line with the underlying legislation and has been agreed with the authority in advance. 

In particular, the document highlights the key aspects to be taken into consideration in the context of study design in order to ensure the accuracy and reliability of the results. The scope of the guidance covers, inter alia, the aspects related to the investigational plan or protocol – the document which outlines the main points of the study. 


The Investigation Plan or Protocol 

In accordance with the applicable legislation, the investigational plan or study stands for a written document that provides the detailed plan for the design, conduct, and analysis of the clinical study (the authority further refers to 21 CFR 812.25 and 21 CFR 860.7(f)(1)). As further explained by the FDA, the study protocol should include the following key elements:

  • Scientific rationale for the study;
  • Definition of the subject populations to be evaluated (including the inclusion/exclusion criteria); 
  • Identification of the proposed intended use for the device;
  • Listing of the study endpoints;
  • Statement of the procedures (treatment and tests) that will be applied to study subjects; and
  • A summary of the methods of analysis and an evaluation of the data derived from the study, including any appropriate statistical method utilized. 

The authority also mentions that apart from the elements outlined hereabove, the protocol should also include the details about the statistical analysis of the primary endpoint(s) in order to justify the approach applied for sample size calculation. In particular, it will be necessary to include a Statistical Analysis Plan describing in detail the approach to be applied when analyzing the data. As explained by the FDA, the said plan could either be included in the study protocol or provided separately. At the same time, the authority additionally emphasizes the importance of finalizing the Statistical Analysis Plan before actually processing data in order to ensure scientific integrity. 

Furthermore, the authority also requests the study sponsors to duly document all the decisions made with respect to the study protocol, the overall design of the study, and the main endpoints. Such documentation will facilitate the review to be conducted by the authority. According to the guidance, the authority expects to see the rationale behind selecting specific study designs in comparison to the ones with less potential bias. 

Apart from that, the authority also encourages study sponsors to contact FDA at the initial study design stage to discuss all the aspects associated thereto in order to ensure the study design selected is the most appropriate one based on the scope of the study and specific aspects associated thereto. The authority can provide informal feedback and recommendations based on previous experience, and this could be helpful for study sponsors.

Terms and Definitions 

The guidance also contains a glossary that provides definitions of the most important terms and concepts used in the context of design considerations for pivotal investigational studies. The glossary describes, inter alia, the following terms:

  • Active Control Investigation (Active Treatment Control Investigation) – a study that uses an intervention whose effectiveness has been previously established. As explained by the FDA, in case of a study related to a new medical device, the one already approved for the same intended use could be the active control. 
  • Aesthetic Device stands for a device intended to provide a desired change in visual appearance in the subject through physical modification of the structure of the body. 
  • Agreement Study – a diagnostic clinical performance study in which the diagnostic device result is compared with a result that is not from a clinical reference standard. 
  • Benefit-Risk Assessment is one of the most important concepts, and refers to the valuation of the potential benefit resulting from the use of the device in question weighted against potential risks associated thereto. 
  • Bias refers to a situation when a systematic error appears, and such an error could result in incorrect conclusions made. 
  • Blinding (masking) refers to the approach applied in order to mitigate the bias based on the availability of information about the study and its specific aspects. According to the guidance, blind (mask) stands for a condition placed on an individual or group of individuals to keep them from knowing the intervention (or test) assignment of the subjects or subject specimens. 
  • Clinical Outcome Study – a study in which subjects are assigned to an intervention and then studied at planned intervals using validated assessment tools to assess clinical outcome parameters or their validated surrogates to determine the safety and effectiveness of the intervention. 


In summary, the present FDA guidance provides additional clarifications regarding the key points to be taken into consideration with respect to the design of pivotal clinical investigations. The document outlines the approach to be applied in order to ensure the accuracy and reliability of the study results, as well as their scientific integrity. 




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