Regulatory_Master_Class.pdf

Transcript

1. Medical Device Approval Pathways in the United States and European Union A master class on how these two systems work and what you should consider early in your start-up journey. Sejal Patel-Tolksdorf
2. Regulatory Pathways Matter! It’s worth strategizing how and where you launch Saves you money Saves you time Appeals to investors Prevents rework
3. Regulatory Pathways Matter! It’s worth strategizing how and where you launch Saves you money Saves you time Appeals to investors Prevents rework Pathways determine whether you’ll pay ~$6,000 versus ~$100,000 for the approval alone You don’t want to lose momentum! An approval can take just 3 months or up to 2 years… Milestones matter! Regulatory approval improves your valuation to investors and acquirers Avoid having to redo clinical trials, validation studies, and documentation
4. Side Bar: Here is my disclaimer: For moderate-risk medical devices, I have a bias toward the FDA’s regulatory pathways. Once you learn about them, you’ll probably favor them as well. They are simply easier, faster, and cheaper.
5. Who is my audience? We developed this course for digital health & medical device startups, particularly those dabbling in SaMD and AI products that are moderate risk Why? Because we feel this group has the most to gain (and to lose) from not having a solid regulatory strategy.
6. Who is my audience? We developed this course for digital health & medical device startups, particularly those dabbling in SaMD and AI products that are moderate risk Why? Because we feel this group has the most to gain (and to lose) from not having a solid regulatory strategy. Is your device considered moderate-risk? So long as your device cannot lead to death or serious injury, consider it moderate-risk for now…
7. Side Bar: Let’s make sure you know what a medical device is… • Any instrument, machine, implant, or software intended by the manufacturer to diagnose, prevent, monitor, treat, or alleviate disease or injury, or to affect the structure or function of the body— excluding tools used solely for general wellness or administrative purposes.
8. Side Bar: If you don’t have a medical device, count your blessings and stop taking this Master Class! • Any instrument, machine, implant, or software intended by the manufacturer to diagnose, prevent, monitor, treat, or alleviate disease or injury, or to affect the structure or function of the body—excluding tools used solely for general wellness or administrative purposes. Ex: An AI-enabled app for assisting doctors with paperwork Ex: An AI-enabled journal for tracking meals and calculating overall nutrition NOT MEDICAL DEVICES!
9. Bird’s Eye View of Medical Device Approval in the US and EU UNITED STATES • Centralized system with the FDA approving devices • Designed to promote incremental innovation and premised on efficiency of review/approval process EUROPEAN UNION • Decentralized system that uses ~50 Notified Bodies across EU to assess compliance (~20 in Germany!) • Designed to reinforce Common Framework principles, i.e., emphasis on consistency across Notified Bodies
10. Evolution of US Medical Device Regulation Prior to 1976 No regs! FDA’s original mandate focused on drugs and food, not devices. Devices were far simpler before 1976 so the need for oversight and approval was not obvious 1993 Medical Device Amendment added Bad IUDs, fracturing heart valves, toxic hip implants put in place Pre-Market Authorization (PMA) processes for high-risk devices and novel devices. 510(K) Path fast- tracked approvals for devices that had existing predicates on the market 1997 De Novo Pathway Manufacturers were annoyed at having to go through PMA for novel low-risk devices, so FDA created an alternative pathway to fast-track lower risk devices and reduce burden
11. Evolution of US Medical Device Regulation Prior to 1976 No regs! FDA’s original mandate focused on drugs and food, not devices. Devices were far simpler before 1976 so the need for oversight and approval was not obvious 1993 Medical Device Amendment added Bad IUDs, fracturing heart valves, toxic hip implants put in place Pre-Market Authorization (PMA) processes for high-risk devices and novel devices. 510(K) Path fast- tracked approvals for devices that had existing predicates on the market 1997 De Novo Pathway Manufacturers were annoyed at having to go through PMA for novel low-risk devices, so FDA created an alternative pathway to fast-track lower risk devices and reduce burden Super important pathway for SaMD and AI- enabled devices
12. Evolution of EU Medical Device Regulation Pre-1993 Each EU country had its own approval system, which stymied cross-border trade Medical Device Directive 1993 New Approach framework based on Essential Requirements and Notified Bodies (NBs), and the introduction of the CE Marking for Medical Devices, enabling cross-border marketing 2017 Medical Devices Regulation (MDR) passed Scandals like the PIP breast implant case uncovered inconsistencies across Notified Bodies and need for their stricter oversight of NBs MDR in effect 2021 EC and Competent Authorities deputized to uphold principles of harmonization and the EU’s Common Framework among NBs
13. Evolution of EU Medical Device Regulation Pre-1993 Each EU country had its own approval system, which stymied cross-border trade Medical Device Directive 1993 New Approach framework based on Essential Requirements and Notified Bodies (NBs), and the introduction of the CE Marking for Medical Devices, enabling cross-border marketing 2017 Medical Devices Regulation (MDR) passed Scandals like the PIP breast implant case uncovered inconsistencies across Notified Bodies and need for their stricter oversight of NBs MDR in effect 2021 EC and Competent Authorities deputized to uphold principles of harmonization and the EU’s Common Framework among NBs Unfortunately, this UP-RISKED many SaMD and AI-enabled devices
14. Side Bar: Why use Notified Bodies and not a centralized authority like the EMA (for drugs) or FDA? • CE marking system existed for other commercial devices; why not extend to medical devices as well? • Fits in well with the EU principle overall notion of a union of sovereign states operating under a common framework • Belief that independent NBs would stimulate competition and thus result in faster review times compared to the FDA.
15. Side Bar: Are NBs more efficient than the FDA in reviewing and approving medical devices? • Review bottlenecks formed as many NBs lost designation due to stricter requirements following the MDR (we’ll stick with certifying toasters, thank you) • Stricter regs slow NBs down further, e.g., National competent authority and EC now review NBs themselves • FDA, in contrast, is beholden to strict review timelines, which is why approval timelines for low- and moderate-risk devices is so fast. Nope, not really
16. How Do the US and EU Approach Device Safety?
17. In a nutshell: The riskier your device, the greater your burden to prove safety They ask: “Does this company follow strict safety and quality procedures to make sure all their devices are reliable?” It looks at the company’s overall risk management, documentation, and long-term compliance. But there are fundamental differences in how the FDA and Notified Bodies approach safety FDA focuses on the device itself NBs focus on the manufacturer’s process. It asks, “Is this specific product safe and effective? Does it work like similar products already on the market?” It reviews technical details, test results, and comparisons to existing devices.
18. In a nutshell: The riskier your device, the greater your burden to prove safety They ask: “Does this company follow strict safety and quality procedures to make sure all their devices are reliable?” It looks at the company’s overall risk management, documentation, and long-term compliance. But there are fundamental differences in how the FDA and Notified Bodies approach safety FDA focuses on the device itself NBs focus on the manufacturer’s process. It asks, “Is this specific product safe and effective? Does it work like similar products already on the market?” It reviews technical details, test results, and comparisons to existing devices. As you’ll see later, this difference is responsible for why NBs require far more documentation and reporting than the FDA.
19. Side Bar: A good analogy: if the FDA and Notified Bodies were inspecting restaurants… FDA focuses on the final dish—it would taste it, compare it to similar meals, and make sure it's safe to eat. NBs would check the restaurant's kitchen—it would review sanitary practices of the whole staff, check how often equipment undergoes maintenance, inspect how food is prepared, etc. FDA inspects the food NBs inspect the kitchen
20. Side Bar: A good analogy: if the FDA and Notified Bodies were inspecting restaurants… FDA focuses on the final dish—it would taste it, compare it to similar meals, and make sure it's safe to eat. NBs would check the restaurant's kitchen—it would review sanitary practices of the whole staff, check how often equipment undergoes maintenance, inspect how food is prepared, etc. FDA inspects the food NBs inspect the kitchen Again, this is why the documentation requirements are so intense!
21. How Do You Determine Your Devices Risk Class? This is the very first step in determining your best regulatory pathway
22. FDA Risk Classification FDA classification is based on Device type identification (i.e., what other similar devices have been classed at) along with intended use, indications for use, and risk to the patient/public health if the device fails Class I Low Risk Minimal potential harm to users; does not sustain or support life Bandages, tongue depressors, exam gloves Class II Moderate Risk Requires special controls to ensure safety and efficacy Infusion pumps, powered wheelchairs, pregnancy test kits Class III High Risk Sustains or supports life, is implanted, or poses significant risk of harm Pacemakers, implantable defibrillators, deep brain stimulators
23. MDR Risk Classification MDR classifies devices based on 23 rules outlined in Annex VIII, which consider duration of use, invasiveness, body interaction, and special risks Class I Low Risk Non-invasive devices or low-risk instruments Surgical instruments, stethoscopes Class IIa Low to Moderate Risk Devices with a short-term invasive use or used in the bloodstream/central circulatory system Dental fillings, contact lenses Class IIb Moderate to High Risk Devices used for longer-term invasive applications or life-supporting Ventilators, infusion pumps Class III High Risk Implantable or life-sustaining devices; serious health risks if malfunctioning Heart valves, implantable defibrillators
24. Determining Risk Class: FDA
25. Side Bar: Determining your FDA risk class using predicates (devices similar to your own that the FDA has already approved) Step 1 Search the FDA regs for the medical specialty associated with your device Yup, it’s literally a list of medical specialties listed in 21 CFR Parts 862 through 892, which you can find easily here: https://www.fda.gov/medical-devices/classify-your-medical-device/device- classification-panels
26. Side Bar: Determining your FDA risk class using predicates (devices similar to your own that the FDA has already approved) Step 1 Search the FDA regs for the medical specialty associated with your device Yup, it’s literally a list of medical specialties listed in 21 CFR Parts 862 through 892, which you can find easily here: https://www.fda.gov/medical- devices/classify-your-medical-device/device-classification-panels
27. Side Bar: Determining your FDA risk class using predicates (devices similar to your own that the FDA has already approved) Step 2 Find your device in the FDA regs for that medical specialty This will tell you: 1) the device risk class and 2) What special controls you may need for getting FDA approval for this type of device
28. Side Bar: Determining your FDA risk class if you have no predicates Risk-Based Classification (No Predicate Exists) Need to weigh your device against the following criteria: ➢ Intended Use ➢ Indications for Use ➢ Risk to Health (if device fails) Difference between a blood pressure measure device (indication for use) that is used at home for daily monitoring (indications for use) versus used in an ICU for critically ill patients. Risk to health is greater for the second indication of use, hence a higher risk score. For more information, see: 21 CFR Part 860 – Medical Device Classification Procedures
29. Side Bar: Determining your FDA risk class if you have no predicates Risk-Based Classification (No Predicate Exists) Need to weigh your device against the following criteria: ➢ Intended Use ➢ Indications for Use ➢ Risk to Health (if device fails) Difference between a blood pressure measure device (indication for use) that is used at home for daily monitoring (indications for use) versus used in an ICU for critically ill patients. Risk to health is greater for the second indication of use, hence a higher risk score. For more information, see: 21 CFR Part 860 – Medical Device Classification Procedures
30. Determining Risk Class: MDR
31. Determining Risk Class: MDR You must use the classification rules to determine risk class for ALL medical devices. That’s right. MDR doesn’t use the concept of predicates like the FDA.
32. Side Bar: MDR’s 23 classification rules are based on 1) duration of use 2) invasiveness, 3) body interaction 4) special risks Annex VIII Will guide you through how to apply the 23 rules to determine device risk
33. Side Bar: MDR’s 23 classification rules are based on 1) duration of use 2) invasiveness, 3) body interaction 4) special risks Annex VIII Will guide you through how to apply the 23 rules to determine device risk This is just one page. It’s a long flow chart, totaling 9 pages!!
34. What does your risk class mean in practice? Your risk class determines which approval pathways you can take and the level of reporting you will need
35. Risk Class and the MDR For Europe, your risk class determines the need for notified bodies, technical documentation requirements, and clinical trials Notified Body review Annex II & III Technical Docs PSURs & SSCPs Clinical trials Risk Class I Risk Class Ia Risk Class Ib Risk Class III
36. Risk Class and the MDR For Europe, your risk class determines the need for notified bodies, technical documentation requirements, and clinical trials Notified Body review Annex II & III Technical Docs PSURs & SSCPs Clinical trials Risk Class I Risk Class Ia Risk Class Ib Risk Class III Note that the technical documentation burden is high across all risk classes! May need a cursory notified body review to assess sterility, reusability, and measurement…
37. Side Bar: What are the technical documentation requirements in Annex II & III? • Device Description & Specification • Labeling & Instructions for Use (IFU) • Design & Manufacturing Information • General Safety and Performance Requirements (GSPRs) Checklist • Benefit-Risk Analysis & Risk Management • Product Verification & Validation • PMS Plan • PSUR or PMS Report • Post-Market Clinical Follow-up (PMCF) Plan and Reports Annex II Core Technical Documentation Annex III Post-Market Surveillance These two account for a roughly 10x higher burden than a similar device approved by the FDA!
38. Risk Class and the FDA Risk Class determines need for special controls and clinical trials FDA Review? General Controls Special Controls Clinical trials Risk Class I Risk Class II Risk Class III
39. Risk Class and the FDA Risk Class determines need for special controls and clinical trials FDA Review? General Controls Special Controls Clinical trials Risk Class I Risk Class II Risk Class III Unlike the MDR, the FDA reviews all devices, including low-risk class I devices. No self-certification!
40. Side Bar: Wait… what are special controls and general controls again? General Controls establish baseline safety for all risk classes Special Controls manage moderate-risk devices Device registration & listing; labeling requirements; Good Manufacturing Practices (GMP) / Quality System Regulation (QSR); prohibitions against misbranding/adulteration; records & reports (e.g., adverse events) Performance standards, post-market surveillance, patient registries, specific labeling requirements, clinical data or testing guidelines…
41. Side Bar: Wait… what are special controls and general controls again? General Controls establish baseline safety for all risk classes Special Controls manage moderate-risk devices Device registration & listing; labeling requirements; Good Manufacturing Practices (GMP) / Quality System Regulation (QSR); prohibitions against misbranding/adulteration; records & reports (e.g., adverse events) Performance standards, post-market surveillance, patient registries, specific labeling requirements, clinical data or testing guidelines… guidance documents covering special controls – they are essentially created every time a De Novo approval happens! yes, there are over 90 discrete FDA
42. What are the different pathways for approval? Both the FDA and the MDR allow for different approval pathways based on the risk class of your device
43. Which FDA Pathway Should You Use? Is your device Risk Class III? No Do you have a predicate?? Yes 510 (k) No De Novo Yes PMA
44. Side Bar: What do these FDA Pathways mean? PMA (Pre-market Authorization De Novo Pathway Required for Class III devices and involves clinical trials to prove safety and effectiveness Used for Class I or II devices that are novel with no predicate but are low to moderate risk and do not require clinical trials 510(K) Pathway Used for Class I and II devices that have predicates and require proof of substantial equivalence, and that the devices are as safe and effective as the predicates
45. Side Bar: What do these FDA Pathways mean? PMA (Pre-market Authorization De Novo Pathway Required for Class III devices and involves clinical trials to prove safety and effectiveness Used for Class I or II devices that are novel with no predicate but are low to moderate risk and do not require clinical trials 510(K) Pathway Used for Class I and II devices that have predicates and require proof of substantial equivalence, and that the devices are as safe and effective as the predicates Most commonly used for moderate- risk devices
46. Side Bar: What FDA approval pathways are typical for SaMD and AI/ML products? De Novo Pathway This is by far the most common pathway for SaMD and AI/ML products, in part because they tend to be NOVEL and low- to moderate-risk 510(K) Pathway As more SaMD and AI/ML products are cleared through the De Novo pathway and can serve as predicates, the 510(k) pathway will become more commonly used For instance, there have been 5 follow-on 510(k)s to Apple’s ECG App. Because you can use several predicates for a 510(k) application, there’s great potential in leveraging this pathway for SaMD that combine existing predicate capabilities.
47. Fast Track for Similar Low-Moderate Risk Devices 510(k) Pathway • Timeline: ~3-6 months; Cost: ~$6,000 • Must show "substantial equivalence" to one that’s already FDA-cleared • No need for big clinical trials, but you must provide lab data proving safety and function (think: FDA is inspecting the food, not the kitchen) Fast Track for New, Low- to Moderate-Risk Devices De Novo Pathway • Timeline: ~6-12 months; Cost: ~$33,000 • If your device is unique, but still low or moderate risk • You may need some clinical trial data Drug-like review for high-risk devices Pre-Market Approval • Timeline: 1.5 -3 years; Cost: ~$150,000 • Requires clinical trials, safety data, and long-term studies to prove the device is safe and effective • FDA treats your device effectively as it would a new drug Summary of FDA Approval Pathways
48. Which MDR Pathway Should You Use? Is your device Risk Class I? Yes! Self- certify! No Notified Body Always used for moderate- risk devices
49. Which MDR Pathway Should You Use? Is your device Risk Class I? Yes! Self- certify! No Notified Body Note: If your device is high-risk or an implant, you will require clinical trials and, ultimately, approval from an expert panel from the EC in addition to the NB review
50. Choosing where to launch…
51. Many things to consider beyond regulatory pathways
52. Many things to consider beyond regulatory pathways The key question is whether there’s a better market for your product in the US versus the EU. And where you have networks and relationships can go a long way too, because your patients and providers have to trust your product.
53. But in terms of REGULATORY cost, burden, and time, the take-home is: If your product is low-to-moderate risk and has a predicate, take the FDA 510(K) pathway. If your product is a novel moderate-risk device, strongly consider the FDA’s De Novo pathway. If your device is high-risk, other factors will carry more weight as the cost, burden, and time is probably equivalent between FDA PMA pathway and MDR Notified Body + clinical trial pathway If your device is low-risk and does not have a predicate, take the MDR self-cert pathway.
54. Tips for early start-ups Establish early if your device qualifies for FDA’s 510(k) or DeNovo approval pathways Build your device to align with existing US-approved predicates if you can This opens the door to the easier, cheaper 510(k) pathway Knowing if these pathways are available to you can increase your product’s valuation (the US is, after all, a much larger market!)
55. Tips for early start-ups Establish early if your device qualifies for FDA’s 510(k) or DeNovo approval pathways Build your device to align with existing US-approved predicates if you can This opens the door to the easier, cheaper 510(k) pathway Knowing if these pathways are available to you can increase your product’s valuation (the US is, after all, a much larger market!) Set up a ‘pre-submission’ meeting with the FDA, which will leave you with clear guidance on which pathway you can use and which special controls will apply. Great way to know for sure if a pathway is a possibility!
56. Other important considerations
57. Other important considerations All good reasons to launch in the US