The new article highlights the aspects related to various types of modifications to be introduced to a medical device based on the information included in the initial submission and also provides an overview of the regulatory matters associated with the Modification Protocol.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a draft guidance document dedicated to a Predetermined Change Control Plan (PCCP) to be included in applications for marketing approval for medical devices utilizing Artificial Intelligence/Machine Learning (AI/ML) technologies. The approach described in the guidance is intended to reduce the regulatory burden for medical device manufacturers (software developers), and also to streamline the regulatory procedures while ensuring the safety and proper performance of the products allowed for marketing and use in the US. It is important to mention that provisions of the guidance 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 existing regulatory requirements, as well as recommendations to be considered by medical device manufacturers in order to ensure compliance thereto. 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. 

Under the general rule, the changes covered by the scope of a PCCP included in the initial application for marketing approval could be implemented without the need for a new submission, provided the said PCCP has been reviewed and authorized by the FDA. Such an approach allows us to accommodate specific regulatory needs associated with ML-enabled device software functions (ML-DSFs) based on the nature of these products and their unique characteristics, limiting the applicability of general rules applied to software-based products.

scription of Modifications: Types

The document describes, in detail, the existing types of modifications. According to the guidance, the aforementioned plan could cover modifications including the ones that are expected to ensure or improve the safety or performance of the product in question. Furthermore, the authority additionally emphasizes the importance of ensuring such modifications are duly verified and validated in line with the quality system developed and implemented by the manufacturer. At the same time, it is important to mention that not all modifications are eligible to be included in such a plan. According to the document, eligible modification types include:

  • Modifications related to quantitative measures of ML-DSF performance specifications;
  • Modifications related to device inputs to the ML-DSF; and
  • Limited modifications related to the device’s use and performance (e.g., for use within a specific subpopulation). 

For instance, a medical manufacturer may submit a PCCP covering the modifications intended to improve the analytical and clinical performance of the device in question by training the ML model with the new data related to the intended use population. 

As further explained by the FDA, modifications related to device inputs to the ML-DSF may involve expanding the algorithm to include new sources of the same signal type (e.g., different makes, models, or versions of a data acquisition system) or limited modifications related to new types of inputs, while modifications related to the device’s use and performance could include authorization of a device for a specific subset of a population within the originally indicated population based on re-training on a larger data set for that subpopulation that was not previously available.  

At the same time, the authority additionally emphasizes the importance of ensuring any and all modifications described in a plan submitted by the manufacturer are in line with the intended use of a medical device and its indications for use since any changes thereto could affect the safety and proper performance of the product and thus would require special attention and assessment. 

Apart from the aspects highlighted above, the authority also intends to pay attention to the product’s benefit-risk profile in the context of modifications proposed. 

Modification Protocol: Overview

A Modification Protocol is another important component of a PCCP described in the present FDA guidance. According to the guidance, the Modification Protocol includes the documentation describing the methods that will be followed when developing, validating, and implementing modifications delineated in the Description of Modifications section of the PCCP; it actually includes the verification and validation activities (including pre-defined acceptance criteria) for those modifications and is intended to provide a step-by-step delineation of how the modifications proposed in the PCCP will be implemented while assuring the device remains safe and effective. 

The authority additionally emphasizes the importance of ensuring that the documentation provided complies with the quality system regulation, which requires medical device manufacturers to conduct a review of any modifications to the design of the device or manufacturing process, indicating that all the changes and approvals associated thereto should be duly documented. 

Modification Protocol: Goals

As explained by the authority, the Modification Protocol section’s main purpose is to describe how the modifications outlined in the Description of Modifications should actually be implemented while ensuring the continuous safety and effectiveness of the device in question. The FDA also emphasizes the importance of ensuring consistency between these two sections of a PCCP. 

According to the guidance, the goals of the Modification Protocol are to:

  • Identify the methods and data used to develop, validate, and implement all proposed modifications;
  • Identify the test methods, data, statistical analyses, and specified acceptance criteria for all proposed modifications;
  • Ensure that the information that would otherwise be generated and submitted to the FDA will be generated by the manufacturer for each modification and maintained consistent with record-keeping requirements and in accordance with the manufacturer’s QS;
  • Ensure that the risks that have been identified in the Impact Assessment as related to modifications detailed in the description of Modifications will be mitigated; and
  • Be least burdensome for the manufacturer to develop and for FDA to review. 

The goals described herein are the main ones the authority expects to be achieved due to the Modification Protocol being included in a PCCP submitted by the medical device manufacturer when applying for the initial marketing approval. 

In summary, the present FDA guidance provides additional clarification regarding the changes and modifications to an ML-based medical device that could be included in a PCCP. The document also provides an overview of the regulatory requirements for a Modification Protocol being another important component of a PCCP, as well as additional recommendations associated thereto.

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