FDA Guidance on Design Considerations for Pivotal Clinical Investigations: Endpoints

Table of Contents

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 of medical devices. The document is intended to provide additional clarifications regarding the existing regulatory requirements, as well as recommendations to be followed 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, the aspects related to clinical outcome studies. As explained by the FDA, when designing such a study, various factors should be taken into consideration, including the following ones:

• Specific considerations of subject endpoint(s), intervention assignment (randomization), blinding, placebo effect, controls, and non-comparative studies;
• Sources of bias and general considerations for bias minimization.

Endpoints in Clinical Studies: Key Points 

The guidance further describes the approach to be applied with respect to the endpoints in clinical studies. Under the general rule, a party responsible for the clinical study design should determine the main variables to be used as reference points for the purpose of demonstrating the performance of the device in question, as well as the clinical outcomes. In the case of a clinical outcome study, they are the primary and secondary clinical endpoints. The authority additionally emphasizes the importance of ensuring the abovementioned variables are initially determined at the design stage. 

In order to assist medical device manufacturers and study sponsors in following the approach described hereabove, the FDA outlines the main considerations with respect to the endpoints used to assess and measure the performance of the device and clinical outcomes with the minimal bias possible. In this respect, the authority highlights the following:

• The endpoints, outcomes, or measurements should provide sufficient evidence to characterize the clinical effect of the device (for both safety and effectiveness) for the desired intended use. 
• The protocol should specify what endpoints or outcomes are being measured, how and when they are being measured, and how they will be analyzed statistically. In this respect, the authority also mentions that more information regarding the statistical analysis could be provided separately in a Statistical Analysis Plan. 
• The endpoints, outcomes, or measurements should be clinically meaningful and relevant to the stated study objectives and desired intended use. According to the guidance, the pivotal study should be designed in a way ensuring it demonstrates clinical benefit from the use of the device for the target population instead of demonstrating the way the device operates.   
• Whenever possible, the endpoints should be objective, be internally and externally valid, and determined with minimal bias. As further explained by the FDA, it is important to ensure there is no reliance on subjective clinical assessments when determining the endpoints in case there are objective methods to be used. For example, in the case of a therapeutic endpoints with a diagnostic assessment, it is recommended to consider a clinical reference standard. 
• The protocol should specify who will evaluate the endpoints, outcomes, or measurements in relation to the subject and/or study investigators, e.g., an evaluator blinded (masked) to the intervention assignment versus the investigator.
• In certain cases, it will be reasonable to involve an independent adjudication committee to be responsible for assessing the endpoints. Such an approach could be applicable in situations when there are no objective assessments, and a subjective assessment is needed. In such a case, a clinical study protocol should clearly define the specific rules to be used in the course of an assessment. 
• A subject-reported outcome instrument can be used when the outcome of interest and desired intended use are best measured from the subject’s perspective. If such an approach is applied, it will be necessary to use a scoring assessment that will be suitable for the study participants, and conditions addressed in the course of an investigation and will remain consistent throughout the whole period of a trial. In this respect, the authority encourages study sponsors to get in touch during the initial study design stage in order to discuss the key points. It is also stated that in the case of a study covering multiple locations worldwide, it is important to ensure the rating scale used is acceptable for all cultures and languages. For further details, the authority refers to a separate guidance document dedicated to the use of subject-reported outcomes. 
• A composite endpoint is an endpoint that is a pre-defined combination of more than one endpoint. According to the guidance, the use of such endpoints is quite a complex approach and should be discussed with the authority before being applied.   In such a case, the scope of the analysis to be conducted should cover not only the composite endpoint but also each of the endpoints it includes. 
• For multiple primary effectiveness (of safety) endpoints, providing an explanation for the role and relative importance of each endpoint is encouraged. The authority explicitly states that in case of multiple endpoints, the study protocol should describe in detail the applicable success/failure criteria for each of them, and also outline the approach to be applied to minimize the errors. Apart from this, the protocol should contain details regarding the statistical methods to be used to analyze data collected during the investigation and interpret the results. 
• Use of surrogate endpoints may be appropriate when they are validated and directly correlated to clinical benefit. 

In summary, the present guidance highlights the main considerations with respect to the endpoints for pivotal clinical studies. By the virtue of the document, the FDA provides additional clarifications regarding the way the endpoints should be determined. 

Sources:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-clinical-investigations-medical-devices 

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