The second article describes in detail the categories used for the determination of non-substantial equivalence, as well as the flowchart to be used for the decision-making process. 




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 substantial equivalence under the 510(k) framework and the way it should be determined when applying for marketing approval under the respective pathway. In particular, the document addresses the matters related to the way substantial equivalence should be determined concerning similar medical devices already placed on the market. Such an approach is intended to reduce the regulatory burden and accelerate the process of placing new medical devices on the market while ensuring their safety and effectiveness when used for the intended purpose. 

It is important to mention that due to their legal nature, guidance documents issued by the FDA are not intended to introduce new rules or requirements to be followed. Moreover, an alternative approach could be applied, provided such an approach has been agreed with the authority in advance and is in line with existing legislation. The guidance is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be followed by medical device manufacturers and other parties involved to ensure compliance thereto. 


Categories of NSE Determinations 

Among other aspects, the scope of the guidance covers the matters related to the determination of non-substantial equivalence (NSE) to be applied in case the new device subject to review could not be considered as substantially equivalent to the one already placed on the market (predicate). The respective guidance states that if it is clear from an initial review that a new device has an [n] intended use or technological feature that makes it NSE, the Center will not review or require performance information in the 510(k). Instead, the applicant will be notified that the device is NSE, and any performance data will be reviewed in a PMA or reclassification petition. However, this should not be applied in case of such determination made due to the lack of data regarding the performance of the product – in this case, a new application containing sufficient details should be submitted. 

Hence, NSE determination should be applied in the following cases:

  1. The product subject to review is a Class III medical device and, consequently, is not eligible for placing on the market under the 510(k) framework, so the PMA pathway should be applied instead. 
  2. The inadequacies in the evidence provided by the applicant prevent from determining a substantial equivalence. 

These are the categories the Agency may refer to when making NSE determinations. The first one applies in cases when there is no predicate device similar to the one that is subject to review, or if the differences between devices give rise to concerns regarding the safety and effectiveness of a medical device in question. However, the Agency mentions that in case of concerns, an applicant will have a right to provide its response regarding such concerns, and/or additional information to be considered by the FDA when reviewing the application. Thus, in case the FDA makes the NSE determination as per the first category, the device should be either assigned to Class III and thus be subject to the PMA pathway or the De Novo framework. In particular, should the Agency determine that the medical device in question is eligible for placing on the market under the De Novo pathway, which is a special regulatory regime for novel medical devices, the appropriate recommendation will be included in the NSE letter issued by the authority.

The second category applies in cases when the information provided by the applicant is not sufficient to demonstrate substantial equivalence. At the same time, it should not be applied in cases when the device is not considered to be substantially equivalent due to different technological characteristics resulting in additional concerns regarding safety- and performance-related matters. According to the guidance, in this situation, FDA generally first identifies the specific additional information – typically related to performance testing – that needs to be provided so that the FDA may complete its evaluation of substantial equivalence. Once the appropriate request has been received by the applicant, the latter may provide additional information requested by the Agency. Should the applicant fail to provide such information or the appropriate justification (in case the information cannot be provided), the application will be considered incomplete and placed on hold. Moreover, should the delay in providing such information exceed the timeline specified in respective legislation, the application will be considered withdrawn. Additional information regarding this matter is provided in the guidance document dedicated to the FDA Review Clock and Goals. It is important to mention that in case the application will be considered withdrawn due to the lack of response, the applicant will be allowed to submit a new application containing the details that initially were missing. In such a case, an application should be resubmitted completely, so the review process will be commenced from the very beginning. The authority also states that additional information regarding the acceptance and refusal of 510(k) submissions is provided in the respective guidance document Refuse to Accept Policy for 510(k)s published earlier by the FDA. The Agency explicitly emphasizes the importance of making references to the previous submission in terms of specific matters that were not addressed properly in the initial application – failure to do this may result in a Refuse to Accept decision taken by the FDA. 

Decision-Making Process Flowchart 

To assist medical device manufacturers in interpreting the regulatory concepts described herein, the guidance also contains the 510(k) Substantial Equivalence Decision-Making Process Flowchart which was initially introduced in previous versions of the guide dedicated to the matter. At the same time, the authority also mentions that the current version of the flowchart hasn’t been amended for a long period, hence, certain important matters are not addressed therein. Thus, to ensure correct interpretation, the aforementioned Flowchart should be construed only in connection with the present guidance documents and interpreted in line with the provisions thereof.

In summary, the present FDA guidance highlights the key aspects to be considered by a medical device manufacturer submitting a 510(k) application under the respective framework about the cases when the authority is entitled to determine the NSE. The document describes in detail the appropriate NSE categories and specifies the way these categories could be applied, including the criteria to be considered by the Agency when making such a determination. 



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