Regulatory Submission Information

Here is a document of links pointing to FDA guidance documents and other forms of communication. It was mostly compiled by googling CDRH regulatory buzz words. We hope this document is useful. You might also refer to Figure 2 of this paper: Marble et al. (2020). A regulatory science initiative …” J Pathol Info, 11(1), 22. https://doi.org/10.4103/jpi.jpi_27_20

Caveat to all: You won’t know what’s required for your submission until you ask in a Q-sub.

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Pre-submission (Q-sub) meeting

In CDRH, the best advice is to know about pre-submission meetings.

• Slides: Pre-Submissions and Meetings with FDA Staff.

• Guidance document: Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff.

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IFU: Indications for Use

Part of the definition of your medical device are the indications for use.

• Webpage: Indications For Use.

It’s never to early to start thinking about, researching, and crafting an IFU for your device.

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Comprehensive Regulatory Assistance

• Webpage: Comprehensive Regulatory Assistance.

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Product Codes

• Every device is given a product code.

• Product Classification (product code) database

510(k) Pathway

• Guidance document: The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications 510(k). Guidance for Industry and Food and Drug Administration Staff.

• 510(k) Premarket Notification Database.

• 510(k) devices must comply with general and special controls. Special controls are generally defined in a product code’s corresponding regulations or de Novo device record.

• 510(k) devices are “Cleared”.

A Premarket Notification, also known as a 510(k), is a submission made to FDA to demonstrate that the device to be marketed is safe and effective by proving substantial equivalence (SE) to a legally marketed device (predicate device).

• Guidance document: Deciding When to Submit a 510(k) for a Change to an Existing Device.

• Guidance document: Deciding When to Submit a 510(k) for a Software Change to an Existing Device.

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de Novo Pathway

• Webpage: De Novo Classification Request

• Webpage: Special Controls: Special controls accompany all de Novo classifications and outline device-specific submission requirements.

• De Novo Database.

• de Novo devices are “Granted”.

If you can’t find a de Novo or existing 510k that is a perfect predicate for your device type: Then find and learn about the closest one or two. It’s a way to start.

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PMA Pathway

The Premarket Approval (PMA) regulatory pathway is for medical devices that have a higher risk profile than a 510(k). PMAs are not covered here in depth.

• Webpage: PMA

• PMA database

• PMA devices are “Approved”

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Software as a Medical Device (SAMD)

• Digital Health Center of Excellence.

  • Software as a Medical Device.

  • AI/ML in SAMD.

  • List of AI/ML Enabled Devices.

• Computer aided detection (CADe) guidance - Radiology

  • Webpage: Non-clinical = Stand-alone = No human in the loop.

  • Webpage: Clinical = Reader Study = Human in the loop.

• Guidance document: Off-the-Shelf Software Use in Medical Devices.

• FDA Digital Health and Artificial Intelligence Glossary – Educational Resource

• Machine Learning-enabled Medical Devices: Key Terms and Definitions

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Quantitative Imaging

• Guidance document: Technical Performance Assessment of Quantitative Imaging in Device Premarket Submissions.

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Adaptive Algorithms, continuous learning, Predetermined Change Control Plan (PCCP)

• Webpage: Artificial Intelligence and Machine Learning in Software as a Medical Device.

• DRAFT Guidance document: PCCP.

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Digital Pathology

• Search the digital pathology product codes below in the FDA Product Classification Database. Then click on the Total Product Code Life Cycle (TPLC) Product Code Report to find cleared devices. Make sure to update the scope to “show TPLC since” 2016, when the first scanner device was granted market authorization in DEN160056 to Philips Medical Systems.

  • PSY: whole slide imaging system

  • QKQ: digital pathology image viewing and management software

  • PZZ: digital pathology display

  • QPN: software algorithm device to assist users in digital pathology

  • QYV: digital cervical cytology slide imaging system with artificial intelligence algorithm

• Guidance for Industry and FDA Staff: Technical Performance Assessment of Digital Pathology Whole Slide Imaging Devices.

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CAD Examples

• Device type: Medical Image Analyzer (including breast cancer detection).

  • Secondlook (P010038).

  • Originally a PMA. Downclassified to a 510k on 01/22/2020, Federal Register Ruling.

  • Classification Product Code: MYN

• Device type: Radiological computer-assisted diagnostic (CADx) software for lesions suspicious for cancer.

  • QuantX (DEN170022).

  • Classification Product Code: POK

• Device type: Radiological Computer Assisted Detection and Diagnosis Software” (CADe + CADx).

  • Imagen OsteoDetect (DEN180005).

  • Classification Product Code: QBS

• Device type: Radiological computer aided triage and notification software.

  • Viz.AI ContaCT (DEN170073).

  • Classification Prodcut Code: QAS

• Device type: Retinal diagnostic software device.

  • IDx IDx-DR (DEN180001).

  • Classification Prodcut Code: PIB

• Device type: Image Acquisition and/or Optimization Guided by Artificial Intelligence.

  • Bay Labs Caption Guidance (DEN190040).

  • Classification Product Code: QJU

• Device type: Software Algorithm Device to Assist Users in Digital Pathology

  • Paige.AI Paige Prostate (DEN200080).

  • Classification Product Code: QPN

    • Presentation and discussion about the Paige.AI decision summary convened by the Pathology Innovation Collaborative Community (June 2022).

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Medical Device Development Tools (MDDT) program

The FDA’s Medical Device Development Tools (MDDT) program is a way for the FDA to qualify tools that medical device sponsors can use in the development and evaluation of medical devices. It is a way for the broader community (academia, health providers, and government scientists, not just industry) can impact the regulatory process.

• Webpage: FDA page, “Medical Device Development Tools (MDDT)”.

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Catalog of Regulatory Science Tools to Help Access New Medical Devices

• Link to Catalog.

• Webpage: FDA page, “iMRMC: Software to do Multi-reader Multi-case Statistical Analysis of Reader Studies”

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Presentations in this Space

• “Tutorial on Reader Study Designs and MRMC Analysis”

  • FDA internal training, April 8, 2022

  • Pathology Innovation Collaborative Community Webinar, August 5, 2022

  • Brandon Gallas, Research Mathematical Statistician, Division of Imaging, Diagnostics, and Software Reliability OSEL, CDRH, FDA

  • Slides: Tutorial on Reader Study Designs and MRMC Analysis by Brandon Gallas

  • Video: MRMC tutorial

• “ROC curves: Receiver Operating Characteristic Curves”

  • FDA internal training, April 8, 2022

  • Pathology Innovation Collaborative Community Webinar, August 5, 2022

  • Brandon Gallas, Research Mathematical Statistician, Division of Imaging, Diagnostics, and Software Reliability OSEL, CDRH, FDA

  • Slides: ROC Curves Tutorial by Brandon Gallas

  • Video: ROC tutorial

• “Regulatory Considerations and Assessment of AI/ML Devices”

  • Yale, January 29, 2020, New Haven, Connecticut

  • Nicholas Petrick, Deputy Division Director, Division of Imaging, Diagnostics, and Software Reliability OSEL, CDRH, FDA

  • Slides: Regulatory Considerations and Assessment of AI by Nicholas Petrick

• “AI and Digital Pathology: Regulatory Perspective”

  • Pathology Visions, October 8, 2019, Orlando, FL.

  • Shyam Kalavar, Senior Scientific Reviewer, Division of Molecular Genetics and Pathology

  • Slides: AI and Digital Pathology Regulatory Perspective by Shyam Kalavar

• “Evaluating Artificial Intelligence Devices at the FDA and Related Collaborations and Initiatives”

  • ACR Informatics Summit, October 5-6, 2019, Washington, DC.

  • Brandon Gallas, PhD, Research Mathematical Statistician, Division of Imaging, Diagnostics, and Software Reliability OSEL, CDRH, FDA

  • Slides: Evaluating Artifical Intelligence Devices at the FDA and Related Collaborations and Initiatives by Brandon Gallas

  • Jennifer Segui, Lead Medical Device Reviewer, Division of Radiological Health, FDA

  • Slides: Evaluating Artificial Intelligence Devices at the FDA and Related Collaborations and Initiatives by Brandon Gallas and Jennifer Segui

• “Evaluation and Regulatory Considerations for AI Methods in Medical Imaging”

  • Society for Imaging Informatics in Medicine Annual Meeting, June 26, 2019, Aurora, Co

  • Berkman Sahiner, Senior Scientist, Division of Imaging, Diagnostics, and Software Reliability OSEL, CDRH, FDA

    • Slides: Evaluation and Regulatory Considerations for AI Methods in Medical Imaging by Berkman Sahiner

• “Digital Pathology Regulatory Considerations”

  • Pathology Informatics Summit 5/9/19

  • Cheng Cui, Senior Scientific Reviewer, Division of Molecular Genetics and Pathology,

  • Slides: Digital Pathology Regulatory Considerations by Cheng Cui

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Mock Submission

• Webpage: MDICx webinar that includes a presentation on mock submissions to FDA/CDRH.

• Slides: Mock Submissions to FDA/CDRH: History and Lessons Learned by Kyle Myers, Director DIDSR/OSEL/CDRH/FDA. This presentation was made as the agency was working with MDIC to pursue a mock submission about, “Augmenting a Clinical Study with Virtual Patient Models.”

  • The mock submission was followed quickly by actual submissions.

  • Virtual Patient Page at MDIC.

• The virtual patients mock submission was preceded by “Protein-Based Multiplex Assays: Mock Presubmissions to the US Food and Drug Administration” , Regnier et al.

  • Supplementary Materials.