How to convert FDA approval to CE marking
Hardian collaborated with Koios to convert their FDA regulatory technical file to MDR format, successfully gaining them a class IIa CE mark.
The global healthtech market is huge, with an estimated $40billion+ alone being invested over the past decade. Most Western companies target two main global regions, the USA and Europe, usually starting off in their own backyard before aiming their sights across the North Atlantic.
These two markets have many similarities, but the deeper you look, the more the differences become apparent. Not only are the healthcare systems themselves uniquely complex, the populations they serve also have different characteristics and different needs, not to mention languages and laws. So, being successful in one market doesnât necessarily mean you will succeed in another - and you wonât even be able to enter your second market until you have regulatory approval to do so.
The US FDA and the EU MDR, while ostensibly serving the same purpose of vetting and clearing novel medical devices, do so in subtly different ways. Both expect compliance, rigour, transparency and clarity, but ask for this to be presented in their own preferred manner, taking into account local factors and regulations. Converting a CE mark to an FDA clearance, or vice versa, is not as simple as filling in another form - do not be fooled! You will need to put in just as much work for one regulatory approval as the other.
Koios Medical (âKoiosâ), a New York based start-up in the AI radiology sector, has been making waves with their AI-driven ultrasound analysis technology, having recently been awarded an RSNA Quality Improvement Reports Award. Koios know what they are doing when it comes to picking a solid use-case for AI, and getting FDA clearance, which they achieved both in late 2016 and again in 2019. Of course, being a rocketship start-up means only one thing - market expansion! Koios quickly turned their attention to the EU, and approached Hardian Health for regulatory support to help them gain a CE mark. Weâve been working extremely closely over the past months, and it was with great excitement that Koios recently announced a successful class IIa CE mark for their flagship AI-driven solution, Koios DS for Breast (the DS stands for Decision Support in case you hadnât guessed!).
I sat down (virtually) with their CEO, Chad McClennan to discuss the lessons we both learned in taking an already FDA-cleared product into the EU market.
Q: First of all - congratulations on the CE marking! Can you explain the significance of this to Koios, and what it means for clinicians and patients in Europe?
Thank you, Hugh. Absolutely!
Mammography is known to most and promoted as the breast cancer detection modality solution of choice. However, in most regions of the world over 40% of women require an ultrasound exam in conjunction with mammography due to the density of their breast tissue; mammography simply doesnât work well to see cancers when hidden inside dense tissue, it all looks the same. The profession understands and willingly admits this limitation, and thatâs why breast ultrasound is the next step in the care pathway after mammography. However, variability in ultrasound interpretation is massive. Until now we have been doing the best we can with the tools at our disposal. Now, with AI and computer vision software working directly inside the normal systems used for scanning patients, viewing images and interpreting exams as decision support, the âKoios Owlâ as we call it, helps each physician more accurately interpret what he or she is seeing, allowing them to predict the likelihood of cancer and recommend the best treatment path.
Our results in the US have been extremely exciting. Clinicians improve cancer detection rates by upwards of 5% while at the same time recommend fewer, sometimes cutting down by half, the number of biopsies that return a normal, benign or negative result. This avoids the painful experience and anxiety, not to mention time away from work and family. All of this can now be improved upon across Europe as well.
The significance to Koios? We could not be more energized to help European physicians and patients reap these positive results, tackling a hard problem and improving care, saving lives along the way. The CE Mark makes our simple-to-deploy technology available to a population twice of the US, and in areas where the need for expertise is dire. Specialized radiologists are in short supply. The AI software is a true expert opinion on par with, and certainly more consistent, than physicians from leading academic medical centres at the very top of the field of breast imaging. Think about it, we can now literally expand access to the highest possible quality care using technology. Thatâs an amazing feeling for our team. Incredibly motivating.
Q: Your FDA clearance was in July 2019, and the CE mark was received in March 2021. Looking back, does this timeline surprise you at all, knowing what you know now?
Somewhat yes, but thanks to you and the folks at Hardian the timeline surprise was minimal given the circumstances. You prepared us well and kept our expectations in check. The timeline was a bigger surprise to some of partners and investors who assumed since we have FDA clearance, CE marks should be immediately forthcoming. Thatâs not how things work. As our internal regulatory lead, Patricia Setti-Laperch says: US FDA 510(k) requirements for market clearance are more different from CE Marking that one might assume going into the clearance process - neither better nor worse, just different. Do not underestimate the need for clinical feedback in new markets prior to submission. Implementation of a company-wide ISO 13485 certified QMS is ~6 month project, and if you are a new startup, plan for 9-12 months minimum for an MDR CE mark. We were certainly hopeful for approval sooner, a few months earlier, but Covid delayed on-site audits and the differences in the two approval processes translated into more time required to prepare and address them all in detail, thoroughly. Both are rigorous processes but not in the same ways. It makes for a lot of hard work, long days and late evenings, but we recognized the effort reaps dividends making us a better company while ensuring the safety and efficacy of our software for our users and their patients.
Q: What was the biggest pain point in the whole CE marking journey, and how has handling it changed your internal regulatory processes?
Being in the business of Software as a Medical Device, or SaMD as we all refer to it, is the root cause of the biggest pain point in our whole regulatory journey. First, we crowdsource physician input into our system design. Our users are sources of insights for continuous improvement, a great thing. However, when it comes to regulators approving a dynamic platform and applying all of the ISO standards and guidelines primarily aimed at manufacturing, it was painstaking at the time adjusting to fit both our business and the needs and ideas of our customers. Hardian ensured our design and development process outputs Verification/Validation testing documentation were in accordance with the recognized global standards (ISO, IEC, etc). Aligning best practices for dynamic, agile software development and upgrade release management practices with the regulatory guidelines is new for everyone. I suspect we will all evolve together in the interest of what is best for patient care.
Q: The FDA often mandates clinical study data based on the US population, due to its unique demographics, and vice versa in the EU. Koios did a lot of work in sub-stratifying their data to demonstrate clinical effectiveness in EU populations. What lessons would you take from this process?
Data quality remains paramount. A point we hear over and over but often lacking the required clarity in terms of what quality means. Going through the regulatory rigor amplifies the importance labelling, breadth, diversity and detail in your dataset; both training and validation. Accuracy across a diverse population of patients or what the industry calls âgeneralizabilityâ is critical for any AI solution hoping to cross borders. Each regulatory body and even local customers want reassurance software will perform well on their patients. Both the rigor of the FDA and CE Marking are designed to give that reassurance to users under their jurisdictions. Since both regulators require and customers demand breadth of performance, our models are built on an ever-expanding dataset sourced from nearly 60 institutions across ten countries and four continents. The CE Marking process did not disappoint and we were asked to provide the analysis that the software is effective broadly across Europe. We modelled for essentially the entire population of Europe, by region and in many cases by country. No small task! Local validation helps with physician buy-in, but when someone is considering purchasing an AI software they can rest assured both CE Mark reviewers and the FDA make passing these diversity tests a requirement for approval and clearance in the first place.
Q: One important lesson learned was how picky regulatory auditors can be when it comes to human factors and usability studies and making sure the software is appropriate for its intended local audience.
I know that during this process there was a lot of work done to ensure that the US BI-RADS categorisation for breast lesions would be recognised in the EU, and ultimately we proved it could be mapped safely and clearly to different scoring systems. How will you approach this regulatory factor with your future products, like Koios DS for Thyroid?
Yes, the regulatory auditors can be quite particular, but we often find it is ultimately rightly so. They highlight details about local practices we are well served to address within our software, training or labelling. Take the time to secure usability input from target customers in at least several of the European markets. Multi-language translations are not the only local challenges you will encounter! We define success through the eyes of our customer users. We expect to continue enlisting local physicians that represent the various incumbent local practice guidelines as early as possible in our interface design. While the core work of âthe engineâ is similar, how information is displayed goes beyond simply language translations. We find that specific word usage such as âsuspiciousâ and âindeterminateâ is critical to understanding and adoption so we must study guidelines and ask physicians, âWhat do you think? What do you prefer to see?â and take that input into consideration as a critical design element. Thyroid classification guidelines vary not only by region, but institution. We must incorporate attributes that are universally applicable as well as what may be unique to a particular rating system. Working backwards from what customers need and expect has always been our mantra, so with thyroid this will be no different.
Q: Finally, if you could give one hot tip to American companies attempting the CE marking process, what would it be?
It may seem obvious, but Europe is not the US so get help! Donât think you can possibly know it all or what was successful for approval in one area will suffice for the other. The breadth of information and insight required is immense. Do not go it alone. As the saying goes: "What got you here, won't get you there."
Hardian Health is clinical digital consultancy focussed on leveraging technology into healthcare markets through clinical strategy, scientific validation, regulation, health economics and intellectual property.
