The new article provides additional details regarding some of the matters related to evidence, including the benefit-risk assessment. 

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 scope of the guidance covers, inter alia, the aspects related to evidence to be provided by medical device manufacturers when applying for marketing approval to demonstrate compliance with the applicable requirements in terms of safety, quality, and effectiveness. 

It is also important to mention that FDA guidance documents are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered to ensure compliance thereto. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with existing regulatory requirements and has been agreed with the authority in advance. 


Benefit-Risk Assessment: Key Points 

According to the guidance, the factors to be taken into consideration when making a benefit-risk determination in the course of a review should include, inter alia, the ones related to the intended use of the product in question, such as the target population. As set forth by the applicable regulation, the authority should determine whether the application submitted by an interested party provides “reasonable assurance of safety and effectiveness” by “weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use”. The regulation also prescribes the authority to weigh “the probable benefit to health from the use of the device against any probable injury or illness from such use” when assessing the safety and effectiveness of the product subject to review. 

The aforementioned determination should be based on valid scientific evidence the authority expects the applicant to provide. In particular, the evidence provided should demonstrate that the benefits of using the device outweigh any risks associated thereto. Furthermore, it should be demonstrated that the device provides clinically significant results when used for its intended purpose. In this respect, the authority refers to a separate guidance document dedicated to the factors to be considered when making benefit-risk determinations in medical device Premarket Approval (PMA) and De Novo Classification. 

Thus, the authority will assess all the information and data provided concerning the device, and consider the factors related to the risks and benefits associated thereto. According to the document, the factors to be considered include, inter alia, the following ones:

  • The type of benefit(s),
  • The magnitude of the benefit(s),
  • The probability of the patient experiencing one or more benefits, and
  • The duration of effect(s). 

At the same time, concerning risks, the authority will take into consideration the following factors:

  • The severity, type, number, and rates of harmful events associated with the use of the device,
  • The probability of a harmful event, 
  • The duration of harmful events, and 
  • The risk of false-positive or false-negative results for diagnostic devices. 

According to the guidance, the factors listed hereabove should be taken into account by a responsible party when developing a study design to make sure they are duly addressed in the course of an investigation conducted, and all the necessary data is collected. Thus, the aspects related to benefit-risk factors should be included in the clinical study protocols. 

Clinical Study Level of Evidence and Regulation 

By the applicable legislation, in certain cases, an Investigational Device Exemption (IDE) application should be approved before the clinical trial will be commenced. The authority mentions that a party responsible for a study should determine whether it falls within the category of significant risk or non-significant risk. However, it is important to mention that the authority will have the final say, and its determination on the above matter will be final and non-negotiable. Should it be determined that the study in question is of significant risk, an IDE application is required, while for non-significant risk studies an IDE is not required unless explicitly requested by the FDA. 

The authority further explains that the scientific rigor necessary for a clinical study and the robustness of evidence that need to be collected is not dependent on whether an IDE is required to initiate the study; the rigor and robustness should not be influenced by the categorization of the clinical study as a study of a significant risk device, non-significant risk device, or device exempt from the IDE regulation. In this respect, the authority encourages the parties responsible for medical devices to get in touch in advance to discuss the study design to make sure the study will cover all the important matters. In particular, the Pre-Submission pathway could be applied in such cases. The authority additionally emphasizes that such an approach is advisable even in situations when IDE approval is not required under the applicable regulations. 


The Least Burdensome Concept and Principles of Study Design 

Another important aspect addressed in the guidance in terms of evidence is related to the least burdensome approach introduced by the FDA to reduce the unneeded regulatory burden. In such a way, the authority intends to reduce the time required for the regulatory procedures to be completed, and also to make the related procedures more efficient – it is expected that this will contribute to expanding the availability of novel medical devices based on innovative technologies while ensuring their safety and proper quality.  

The least burdensome principles could also be applied concerning clinical study design. According to the said principles, the scope of assessment should be limited to factors that are important in terms of the safety, quality, and effectiveness of a medical device. 

In summary, the present FDA guidance describes the approach to be applied concerning clinical evidence to be submitted to substantiate the claims made by the manufacturer when applying for marketing approval for the new medical device. The authority highlights the key points to be taken into consideration, and also describes the main concepts to be applied, such as the least burdensome approach. 



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