The new article describes in detail the regulatory requirements to be applied concerning pivotal clinical investigations in terms of clinical evidence for domestic and foreign clinical 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 for medical devices. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered by medical device manufacturers, study sponsors, and other parties involved to ensure compliance thereto. It is important to mention that provisions of the guidance are non-binding, 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 existing legislation and has been agreed with the authority in advance. 

The document provides, inter alia, an overview of the existing regulatory framework for the level of evidence and study design, and also describes the regulatory requirements clinical studies should meet to ensure the accuracy and reliability of the results. In particular, the document describes:

  • Regulatory framework applicable to the design of clinical studies that support premarket submissions for medical devices;
  • Statutory standard for approval of a PMA;
  • Regulatory requirements that apply to clinical and other data used to meet the statutory standard for approval of a PMA;
  • How FDA evaluates the data to assess the risks and benefits of a device;
  • Basic information about Investigational Device Exemption (IDE) applications; and 
  • FDA’s current thinking on good regulatory practice is identified as the least burdensome concept. 

The guidance also contains references to the applicable international documents and standards prescribing the requirements to be considered, as well as the Good Clinical Practice, compliance with which is vitally important to ensure the public health protection and safety of patients and users. 

As further explained by the FDA, any clinical investigation carried out in the US should meet the requirements set forth by 21 CFR Part 56 (IRBs), Part 50 (informed consent), and Part 812 (investigational device exemption (IDE)). Should the study be carried out abroad, provisions of 21 CFR Part 812 and 21 CFR 814.15(a) will apply. In such a case, a party responsible for a medical device will have to submit a Premarket Approval application (PMA) accompanied with the supporting data the authority will reasonably need to assess the matters related to the safety, quality, and effectiveness of a medical device in question. In this respect, the authority additionally emphasizes that a PMA based solely on foreign clinical data may be approved if the foreign data apply to the United States population and medical practice; the studies have been performed by clinical investigators of recognized competence; if an inspection is needed, FDA can validate the data through an on-site inspection or other appropriate means; and the application otherwise meets the criteria for approval. Thus, an applicant would have to provide sufficient evidence demonstrating that the data collected in the course of a foreign clinical study is accurate and reliable enough to be used to substantiate the claims. The authority also encourages applicants to get in touch before applying to discuss the approach to be followed. This could be conducted under the Pre-Submission framework. 


Statutory Standard for Approval of a PMA 

The guidance also describes in detail the approach to be applied when reviewing a PMA in terms of safety- and effectiveness-related matters. According to the underlying legislation, a PMA should contain proper evidence of compliance with the applicable requirements. In particular, it is stated that:

The safety and effectiveness of a device are to be determined—

  1. for the persons for whose use the device is represented or intended,
  2. for the conditions of use prescribed, recommended, or suggested in the labeling of the device, and 
  3. weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use.

The authority further provides its interpretation of the applicable regulatory requirements and highlights the key points to be considered. For instance, according to 21 CFR 860.7(d)(1), the scientific evidence to be provided should demonstrate that the benefits of using the device for its intended purpose outweigh the risks associated thereto. Furthermore, it should be demonstrated that the use of the device does not expose patients or users to unjustified risks. In terms of safety, it is necessary to demonstrate that the device is efficient when used for its intended purposes and conditions for use, and provides clinically significant results. 

Valid Scientific Evidence 

As it was mentioned before, the regulatory decisions concerning the device will be based on the scientific evidence provided by the applicant. According to the applicable regulations, such evidence should derive from investigations carried out following all applicable regulatory requirements to ensure the accuracy and reliability of the results. The actual scope of evidence required would depend on the nature of the medical device in question, its intended use, technologies employed, and risks associated thereto. In this respect, such factors as conditions of use or additional warnings should be considered as well. The regulations also outline the types of evidence admissible in the course of the application process. 

In summary, the present guidance provides an overview of the regulatory requirements related to evidence study sponsors should provide concerning the clinical studies conducted in the US or abroad. The document specifies the approach to be applied when determining the reliability of clinical evidence and highlights the most important points related to the interpretation of the underlying regulations. 



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