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What AI-enabled SaMD developers should know before an FDA Pre-Sub

For developers of AI-enabled software as a medical device (SaMD), the FDA Pre-Submission (Pre-Sub) program can be an important component of the development strategy. A focused Pre-Sub can reduce regulatory uncertainty, test key regulatory and technical assumptions, and help align expectations for the evidence needed to support a future 510(k), De Novo or PMA submission. In this article we outline how to prepare and submit a request for a Pre-Sub meeting and identify common pitfalls to avoid.

The Pre-Submission package

In AI-enabled SaMDs the Pre-Sub package should include a detailed description of any artificial intelligence (AI) and/or machine learning (ML) algorithms. A clear, early explanation of the following elements ensures that the FDA can provide actionable feedback that prevents significant delays in subsequent regulatory submissions. The package should cover:

  • Algorithm architecture and operation during inference or runtime
  • Training, tuning or validation, and test dataset descriptions
  • Data representativeness, diversity, provenance, and separation
  • Model risk controls, human factors considerations and failure mode evaluation
  • Performance metrics and acceptance criteria
  • Planned verification and validation (V&V) for both traditional software and AI/ML
  • Change-management strategy, including a predetermined change control plan, when applicable 

Requesting a Pre-Sub

For CDRH-led submissions, FDA permits electronic submission through the CDRH Portal. FDA’s Early Submission Requests eSTAR (PreSTAR), is an interactive PDF template currently available for voluntary use for Pre-Submissions and other early submission requests. PreSTAR provides a standardized structure, prompts, help text, and validation features. A completed PreSTAR for a CDRH-led submission is submitted through the CDRH portal. FDA has not announced a mandatory transition date for PreSTAR use.

The standardised structure and built-in prompts can help submitters to address applicable content and completeness considerations. The PreSTAR method is intended to improve submission quality and enhance review efficiency by guiding applicants through preparation of a comprehensive submission. 

Pre-Sub request contents

Request content should be tailored to the feedback requested. Depending on the topics to be discussed the Pre-Sub request should include the following:

  • Cover letter
  • Premarket review submission cover sheet (administrative and contact information required by the PreSTAR template)
  • Clearly defined regulatory questions (generally three or four major topics)
  • Detailed device description
  • Rationale for proposed regulatory pathway
  • Clinical and nonclinical performance expectations
  • Target population and intended users
  • Risk analysis and cybersecurity considerations
  • V&V plans and relevant testing protocols (bench, software, usability, AI/ML specific)
  • Draft labelling and proposed indications for use
  • Prior submission history, if applicable

The FDA recommends limiting a Pre-Sub to a small number of substantial topics that can be addressed meaningfully within the available review and meeting time. As a practical planning convention, sponsors often limit the request to approximately three or four major topics. For particularly complex AI/ML systems or topics focusing on one principal topic may support a more substantive discussion. 

Pre-Sub timeline

Plan development timelines according to the FDA timelines, particularly for AI systems requiring iterative FDA interaction. Typical FDA timelines are:

  • Written FDA feedback: FDA generally targets written feedback within 70 calendar days of receipt. When a meeting is requested, written feedback is ordinarily provided before the meeting.
  • Pre-Sub meeting (if requested): The meeting is generally scheduled approximately 70 to 75 calendar days after receipt.

Common Pre-Sub pitfalls

A Pre-Sub meeting is limited to one hour, so it is crucial to plan to maximise your use of time. To ensure a productive meeting manufacturers should avoid:

  • Broad, vague or theoretical questions
  • Addressing too many topics or posing too many questions for a single hour long meeting
  • Inadequate preparation, such as missing documentation or limited team participation
  • Overly long submissions that obscure key issues
  • Failure to review the latest FDA guidance documents
  • Slow responses to FDA follow up requests
  • Lack of internal coordination during the meeting and failure to document FDA positions.

Although preparing a focused Pre-Sub package requires time and careful planning, early FDA interaction can increase the likelihood of receiving clear, actionable feedback and help reduce avoidable regulatory uncertainty. 

This blog is adapted from content in our whitepaper Designing the future: Regulatory readiness for next generation AI in SaMD. 

Download our whitepaper to learn about FDA regulatory requirements for AI-enabled SaMDs.

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