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Outside the Lab Technology and innovation, Digital and computational pathology, Regulation and standards

Midas Touch or Fool’s Gold?

The world of healthcare has seen a technological explosion over the past few years – especially with respect to digital medical devices. But despite an estimated global digital health market of $223 billion by 2023 (1), digital pathology’s penetration into the space has been limited. Only a few of the artificial intelligence/machine learning (AI/ML)‐based medical devices approved by the US Food and Drug Administration (FDA) over the past several years have been in the digital pathology sphere (2). Now, the FDA has proposed new regulatory frameworks to account for the expected growth and iterative nature of AI/ML‐based medical devices (3) – and it’s vital that companies stay on top of the new regulatory paradigms so they can gain the necessary regulatory approvals to bring their products to market. After all, until a medical technology reaches the market, it cannot help real patients in real-world clinical settings.

Will digital pathology take advantage of this change and turn all that it touches into gold… or will it lose out on the quarter trillion‐dollar digital future?

Probing precertification

We examined and summarized the FDA’s proposed precertification and software as a medical device (SaMD) regulatory frameworks (4). To do this, we selected three digital pathology companies with publicized AI/ML‐based products that would be categorized as SaMD under the FDA’s frameworks. To perform our mock Excellence Appraisal and review determinations, we examined publicly available company and product descriptions, as well as news releases about the companies and their products obtained from the organizations’ websites (5, 6, 7). Where appropriate, we also gave recommendations as to how these companies might demonstrate the “Excellence Principles” required of them.

It’s vital that companies stay on top of the new regulatory paradigms so they can gain the necessary regulatory approvals to bring their products to market.

The FDA outlines two new approaches: one for organizational precertification that involves five “Excellence Principles” and one for review pathway determination for SaMD product approval that involves four risk categories (see Table 1). In brief, the process begins with an Excellence Appraisal; here, the company must demonstrate a culture of quality and organizational excellence (CQOE), before receiving a precertification level based on its previous experience with SaMD. Next, the SaMD product’s review pathway is determined – a three-step process that involves evaluating its clinical decision significance and clinical severity state, giving it a risk categorization, and combining those factors to select the appropriate premarket review pathway.

The three companies we chose to examine for our mock Excellence Appraisal and review pathway determination were Paige (Modules), Huron Digital Pathology (Index & Search), and Proscia (DermAI). Ultimately, we categorized Modules as Type IV (highest risk) and Index & Search and DermAI as Type III. Under the traditional regulatory model, these products would all require burdensome premarket approval – but if these companies were precertified, even the highest-risk product would be eligible for streamlined premarket review.

From the FDA

“The FDA is encouraged by the interest expressed in our Digital Health Innovation Action Plan, including the Software Pre-Cert Pilot, as we seek to harness the power of real-world data to provide new insights into device performance and accelerate the development of AI/ML-based medical devices and services. Working together, this effort will support device makers in developing and maintaining cultures of quality and organizational excellence, which are fundamental to ensuring that patients have access to safe and effective medical devices, diagnostics, and cutting-edge digital health tools. Digital pathology is uniquely poised to leverage advances in imaging, computing, and information technology to expedite diagnosis and improve quality of care. We welcome feedback and engagement from all stakeholders as we work to build, test, and refine critical new regulatory approaches to address emerging technologies and improve the lives of patients.”

– Sara A. Brenner, Associate Director for Medical Affairs and Chief Medical Officer for In Vitro Diagnostics, U.S. Food and Drug Administration

Opinions and opportunities

Despite the clear advantages, however, none of the organizations we examined were compliant with precertification requirements (see Table 2). Why? Most companies are not aware of the Pre-Cert program; they are instead familiar with the traditional established regulatory pathways, such as the 510(k), De Novo, or Premarket Approval (PMA). Companies have not kept up-to-date with future pathways that are being considered, developed, or even piloted. The Pre-Cert program is still a working model, and the FDA is still actively developing and updating the program. Therefore, there is no clear, finalized guidance on how to become compliant. However, the FDA is actively seeking participation from companies to join its Test Plan, with the goal of finding out more about the obstacles to real-world implementation. If companies are interested in the Pre-Cert program, we recommend joining the Test Plan; by collaborating with the FDA, they can establish the necessary knowledge and experience needed to become precertified once the program is finalized.

The FDA has taken the forward‐thinking step of proposing new regulatory pathways to embrace the world of digital health.

We are entering an era of “high‐performance medicine” (8) in which advanced technologies, including AI, could dramatically amplify our natural human abilities to diagnose, treat, and manage patients. The FDA has taken the forward‐thinking step of proposing new regulatory pathways to embrace the world of digital health. These pathways should allow companies to gain regulatory approval faster, enter the market faster, and ultimately increase and improve the digital diagnostic and therapeutic options available to patients.

But this is not a one-sided advance; digital pathology companies must also be proactive. The FDA sought public comments on the two proposed regulatory frameworks (9, 10) – and yet, although these regulatory frameworks have a direct future impact on digital pathology, it is a field that is severely underrepresented in the public comments. When the Pre‐Cert program first launched in 2017, the FDA’s pilot program involved nine companies (11) – almost none of whom were in the pathology sphere. Now, the FDA is actively soliciting new companies to join their Pre‐Cert Test Plan (12) – and we strongly encourage digital pathology companies to take advantage of this opportunity by volunteering test cases. If digital pathology is to thrive in the booming digital health market, companies need to be at the forefront of adapting to new regulatory changes.

Table 1. FDA SaMD Pre-Cert process.
Table 2. Mock Pre-Cert Excellence Appraisals and review pathway determinations.

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  1. MarketWatch, “Global digital health market is expected to attain a size of $223.7 billion by 2023” (2018). Available at: on.mktw.net/34jdbSk. Accessed October 31, 2019.
  2. The Medical Futurist, “FDA Approvals For Smart Algorithms In Medicine In One Giant Infographic” (2019). Available at: bit.ly/2NsrOvJ. Accessed October 31, 2019.
  3. S Gottlieb, “FDA Announces New Steps to Empower Consumers and Advance Digital Healthcare” (2017). Available at: bit.ly/2JBw9vB. Accessed October 31, 2019.
  4. US FDA, “Developing a Software Precertification Program: A Working Model” (2019). Available at: bit.ly/2JDZFAL. Accessed October 31, 2019.
  5. Huron Digital Pathology, “Huron Digital Pathology” 2019. Available at:  bit.ly/2N5l6Nf. Accessed October 31, 2019.
  6. Paige, “Paige” (2019). Available at: bit.ly/2qc5vCI. Accessed October 31, 2019.
  7. Proscia, “Proscia” (2019). Available at: bit.ly/2Py4aRa. Accessed October 31, 2019.
  8. EJ Topol, “High‐performance medicine: the convergence of human and artificial intelligence”, Nat Med, 25, 44 (2019). PMID: 30617339.
  9. Regulations.gov, “Fostering Medical Innovation: A Plan for Digital Health Devices; Software Precertification Pilot Program” (2019). Available at: bit.ly/32zxqKi. Accessed November 11, 2019.
  10. Regulations.gov, “Proposed Regulatory Framework for Modifications to Artificial intelligence/Machine Learning (AI/ML)‐Based Software as a Medical Device (SaMD) – Discussion Paper and Request for Feedback” (2019). Available at: bit.ly/2qG6yel. Accessed November 11, 2019.
  11. FDA, “FDA selects participants for new digital health software precertification pilot program” (2017). Available at: bit.ly/2oyk96C. Accessed October 31, 2019.
  12. FDA, “Digital Health Software Precertification (Pre-Cert) Program: Participate in 2019 Test Plan” (2019). Available at: bit.ly/2N6IEkZ. Accessed October 31, 2019.

About the Authors

Richard Huang

Clinical Informatics Fellow in the Department of Pathology at Massachusetts General Hospital and at Harvard Medical School, Boston, Massachusetts, USA.


Veronica Klepeis

Assistant Professor in the Department of Pathology at Massachusetts General Hospital and an Instructor in Pathology at Harvard Medical School, Boston, Massachusetts, USA.

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