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Leveraging Data to Develop, Execute and Exceed the Expectations of Your Regulatory Strategy - OMTEC 2018


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Scientific data, homegrown or from published literature, is essential to your regulatory strategy…be it establishing substantial equivalence in FDA 510(k) applications, qualifying a device as a legitimate predecessor in the context of a Technical File for CE Mark, predicting the performance of a device in development, judging a new device in verification and validation testing and, with proper planning, expanding indications for use and identifying new marketable claims of performance (or mitigation of risk and liability). In this session, participants will be exposed to various vital data sources and obtain practical examples for putting them to meaningful use.

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Leveraging Data to Develop, Execute and Exceed the Expectations of Your Regulatory Strategy - OMTEC 2018

  1. 1. Leveraging Data to Develop, Execute, and Exceed Expectations of Your Regulatory Strategy OMTEC 2018, Chicago, IL USA Robert A Poggie, PhD President, BioVera Inc. Notre-Dame-de-L’Ile-Perrot Quebec, Canada
  2. 2. About the Instructor…(Robert A Poggie, PhD) 3  BE mechanical Engineering, MS and PhD in Materials Science & Engineering, Vanderbilt University  Tribology, surface chemistry, metallurgy, mechanical testing…  Employers, large and small companies in orthopaedics  S&N, Zimmer, Implex, Pipeline Orthopaedics  Self employed since 2009, BioVera Inc.  FDA regulatory work dominates time, including development and management of testing; biomaterials expertise  Current clients include Bodycad, AmorChem, NextStep Arthropedix, Biedermann-Motech, Bio-Gate, Acuitive Technologies, AGelity (HSS)… BioVera, Inc. Integrity Expertise Results
  3. 3. Introduction 4 Leveraging Regulatorily Required Data (homegrown and published)  Maximizing claims / statements in marketing application  Scientific and conference publications  Feedback for improved and new products Develop Regulatory Strategy  Rough to detailed plans, metrics, target criteria (‘success’) Execute Regulatory Strategy  Supporting application through to clearance / approval Exceed Expectations = Leveraging as above BioVera, Inc. Integrity Expertise Results
  4. 4. Outline 5  Background  Identifying and using data in FDA submissions  FDA and ISO data requirements for new devices  Industry white papers, top journals, conference abstracts  Establishing substantial equivalence with data  Predicate and reference devices; IFU is ‘king’  Case examples  Reducing risks and increasing efficiency to market  Q&A, discussion, open-forum BioVera, Inc. Integrity Expertise Results
  5. 5. Regulatory Trend, 25 Years 6  Continuously increasing regulations of all devices  Continuously increasing number of required tests  Dramatic increase in consensus standards for pre-clinical tests  Increasing demand for clinical data; especially Europe in 2017  Increasing sophistication of test methods (FEA, sims, wear…)  And in turn cost of regulatory testing has sky rocketed…  Validations of processes and performance  W/r to design specifications and planned surgery  Sterility, cleaning of reusable insts, endotoxins, biocompatibility…  Statistical significance (more devices tested; higher cost of test) BioVera, Inc. Integrity Expertise Results
  6. 6. Regulatory Trend, Today’s News 7 April 2017: European Union issues new medical device regulations (MDRs); 10-fold increase in text  Class 2b required to have significantly more clinical evidence to obtain and maintain CE Mark  Clinical = published scientific data on similar devices, company’s own clinical data, or new clinical trial data  Class 2b products often treated as class 3 products  Rigorous requirements for post market surveillance  Clinical outcomes and AEs  Significantly higher barrier (cost and time) to market for new devices and devices with minor differences  Fewer ‘me-too’ products = higher cost, fewer new products BioVera, Inc. Integrity Expertise Results
  7. 7. Cause and Effect 8 NewCo desires CE Mark for cementless hip in EU  < 2017, Technical file + clinical literature data for safety  2017 / 2020, Clinical data required, 1 or 2 years fu for between 30 and 60 patients; RSA possible  Effect – Fewer NewCo class 2 products in Europe NewCo wants CE Mark for resorbable ACL device  < 2017 and currently, class 3 high risk device requires clinical trial; 60 to 65 patients, RCT, 2 year fu, PMS  Effect – No change in EU and USA companies strategy for class 3 devices; lower cost barrier to large marketBioVera, Inc. Integrity Expertise Results
  8. 8. Test Plan (for data for pre-sub and application) 9 First-Order Items to Define and Search  Identify the FDA regulation # and product code  Identify and obtain FDA Guidance Documents (if any) – and draft list of data required for regulatory application.  Identify and obtain consensus test standards (e.g. ASTM, ISO) that govern performance testing  Identify predicate devices and obtain 510k) summaries or PMA documents  Scientific literature using key words regarding your product and performance tests of interest  Company websites for technical / white papers BioVera, Inc. Integrity Expertise Results
  9. 9. FDA Links 10  FDA (class 3, 510(k)s, PMAs, guidance dox, etc…)  andGuidance/Overview/ClassifyYourDevice/ m  pmn/pmn.cfm  calProcedures/DeviceApprovalsandClearances/PMAAp provals/default.htm  /default.htm BioVera, Inc. Integrity Expertise Results
  10. 10. Guidance Document Examples 11 BioVera, Inc. Integrity Expertise Results
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  13. 13. 510(k) Summary Examples 14  Arthrex – Vitamin E UHMWPE, using existing data for new products with common materials.  Zimmer – Vivacit UHMWPE and control data; data aids in planning tests, supporting ‘control’ data for similar products (and IFU).  PorOsteon – Functional animal data for cervical fusion in sheep; data useful for planning tests and for control data (PEEK and porous metal devices) BioVera, Inc. Integrity Expertise Results
  14. 14. Leveraging Data: Arthrex Example 15 Applicability of data for x-linked, vit. E tibial insert for TKR to subsequent uni tibial insert BioVera, Inc. Integrity Expertise Results Tens of thousands / 100K $$ and months saved in using poly insert data from TKR to UKR systems.
  15. 15. How Was This Possible? 16  UKA and TKA have similar kinematics for a given compartment (lateral, medial)  Arthrex likely has same or very similar articulation design for the femoral and tibial surfaces  Therefore, contact mechanics about the same  Tribology about the same  FDA may have required proof via additional contact area and stress maps for both products BioVera, Inc. Integrity Expertise Results
  16. 16. Leveraging Data: Zimmer K120370 17 BioVera, Inc. Integrity Expertise Results 11 performance claims (Vivacit poly) with supporting data!  Mechanical properties (tensile, small punch, lzod, Crack Propagation), physical and chemical characterization (Oxidation Index, Compressive Modulus, Poisson's Ratio, Surface Roughness, Density, Melting Temperature, Degree of Crystallinity, Crosslink Density, Swell Ratio, Molecular Weight, Free Radicals, Vitamin E Elution and Extraction, Trans-vinylene Index…  From Claim #8 of 11: Predicate and subject data statements…
  17. 17. Leveraging Data: PorOsteon K142041 18 BioVera, Inc. Integrity Expertise Results Histology, micro-CT, in-life radiography, CT, biomechanical evaluation of Phusion Metal Cervical Cage devices in the ovine model showed…  100% rate of fusion at 6 months (4 sheep, 2 devices/sheep),  Statistically equivalent fusion at 6 months to the control  Statistically significant, higher percentage of bone contact of the superior and inferior surfaces of devices at 4 and 6 months for Phusion Metal devices as compared to PEEK control devices (23.90% vs. 9.94% at 4 months; 56.09% vs. 27.31% at 6 months). Claims allowed in marketing literature. Claims useful for predicting and planning outcomes of functional modeling of cervical devices.
  18. 18. Scientific Literature Links 19  PubMed   Google Scholar    Useful for planning clinical studies / trials Limited amount of data; sparse BioVera, Inc. Integrity Expertise Results
  19. 19. Orthopaedic Journal Links 20      ; Recommend that one or more people in your organization subscribe to the ‘best’ scientific journals, and at least one trade journal. BioVera, Inc. Integrity Expertise Results
  20. 20. Scientific Literature Examples 21  Peck et. al. (FDA) Data gold mine for cervical fusion devices, no predicate testing needed for strength  Micheli et. al. Data for wear, oxidation, strength of tibial inserts; likely eliminates need for control  Mazzocca et. al. Data for tendon-ligament interference screws; four devices, methods, results; covers predicate BioVera, Inc. Integrity Expertise Results
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  23. 23. BioVera, Inc. Integrity Expertise Results Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 21, No 11 (November), 2005: pp 1296-1306
  24. 24. Judging Quality & Utility of Data 25  Is IFU statement for your product similar to that of the device with published data?  Methods and materials described in sufficient detail to replicate and/or explain differences?  Statistical significance of the data, or same sample numbers in 510(k) summaries or FDA guidance dox?  Consensus standards used? Where none exist, industry ‘norms’ for test methods?  Source from reputable journal or society conf.? BioVera, Inc. Integrity Expertise Results
  25. 25. For years, device companies used the Central Limit Theorem (CLT) and its rule of thumb of 30 parts tested. Increasing tolerances and regulatory oversight are two reasons that CLT is no longer relative. For example, FDA now seeks a more analytical approach—justification—for choosing sample size. However, calculating an appropriate minimum sample size is one of the most difficult things to do and is an ongoing challenge for many of us. To complicate things further, a large number of journal articles are devoted to this subject, and their advice is often case-specific or discusses a new and unique way to determine a sample size, leaving us more confused than ever. I am not a statistician, and after reading a dozen or more articles, I’ve come to the conclusion that “everything depends on everything” when it comes to statistics. There are no simple answers. As an example, let’s say you want to determine the sample size if the standard deviation over time has been σ = 0.02 inches from the desired perfect length, but you’re willing to accept an error of 0.005 inches from that number for any given sample mean. Since we’re assuming normal distribution and we know probabilities vary from 0 to 1, the center of your bell curve is 0.5. Thus, you take 0.5 – 0.025 = 0.475 and look up Z = 1.96. Rearranging your equation to solve for n: Thus, for this one measurement, your sample size should be 62. The formula is very sensitive to E, and this is something that you have to decide based on your experience. Note that it’s not necessary to do this calculation for every variable. In fact, you should choose your worst case, most important variables and set the sample size based on them, as all of the other variables will require fewer samples. Practical Information Examining Methods to Determine Sample Sizes Posted in Legal, Clinical & Regulatory | December 05, 2017 | Comments (0) Tags: Editor's Choice, fda, validation, verification, testing, quality management, FDA By: Deborah Munro Reader Question: Larger companies have statisticians on staff to determine the minimum number of samples for given validation and verification (V&V) activities, but for folks who don’t use Minitab and don’t have an extensive stats background, are there guidelines to know the right amount of parts to test?
  26. 26. Consensus Standards 27  ISO standards  ISO stds findable via www search and purchase  ASTM  medical-devices-standards.html Same story as ISO stds; lower cost w/r to ISO BioVera, Inc. Integrity Expertise Results
  27. 27. Company Websites 28   Example: interference-screws One of the white papers: BioComposite™ Interference Screws - A Stronger Turn in ACL/PCL Reconstruction Data to be used for planning regulatory path and tests; i.e. the strategy and tactics for FDA pre-sub and/or 510(k):  2 years animal data for Arthrex and DePuy screws  Torque in / out, strength of screws, Arthrex and DePuy  Solubility and cell tests for two materials… and more… BioVera, Inc. Integrity Expertise Results
  28. 28. BioVera, Inc. Integrity Expertise Results Page 3 of BioComposite™ Interference Screws - A Stronger Turn in ACL/PCL Reconstruction Arthrex white paper Page 1 of Arthrex 7 mm x 23 mm BioComposite Interference Screw vs. DePuy Mitek 7 mm x 23 mm Milagro Screw. Arthrex white paper
  29. 29. Case Examples Ankle Devices TMT Monoblock Cup Patient Specific Knee Device BioVera, Inc. Integrity Expertise Results
  30. 30. Case Example: Ankle Replacement 31  Many 510(k)s  FDA website for PMA dox (includes clinicals) for several products cleared since the early 2000s  Robust literature  Well described tests finable on www BioVera, Inc. Integrity Expertise Results
  31. 31. FDA Resources for Ankle Devices 32 FDA website and Google to start searches as...  mnsimplesearch.cfm  Type in “ankle”, order results from most recent, review 510(k) summary (class 2) for K171004.  On Google, type in “PMA for ankle replacement”  4299s1-01.pdf  ma.cfm?id=P050050  df BioVera, Inc. Integrity Expertise Results
  32. 32. Ankle Devices 33 Top Level Info of Importance…  2-part device is class 2  3-part device is class 3 (cementless and mobile bearing (STAR, p050050)  510(k) summary lists performance tests applicable to both class 2 and 3 devices  FDA guidance documents  ASTM and ISO consensus standards listed BioVera, Inc. Integrity Expertise Results
  33. 33. From K171004… 34 BioVera, Inc. Integrity Expertise Results ASTM F2665-09 FDA Guidance for plasma sprayed coatings… deviceregulationandguidance/guidancedocuments /ucm107699.pdf And more…
  34. 34. From slide deck & p050050 doc. 35 BioVera, Inc. Integrity Expertise Results • Pre clinical testing information, wear testing details, and more... • Detailed information on clinical trial • IFU • Clinical measures, subjective, objective • Patient pop, Statistical methods fm?id=P050050 7f3e813589d1c6e6ea45dd82f.pdf (slide deck)
  35. 35. Online Searching… 00027 releases/Pages/2009%20Press%20Releases/Results-of-Controlled- Clinical-Study-Presented-at-Annual-Summer-Meeting.aspx
  36. 36. Case Example: Hedrocel (TM) Cup 37  Monoblock with UHMWPE direct-molded into porous tantalum shell (K964509)  Unique design & material; regulatory consultant advised that IDE-PMA was only path (R&D/we rejected advice)  Porous coated, metal backed, factory interference fit monoblock used as predicate (K932923).  Testing / Data Planning for Regulatory & Marketing  ORL ‘push-out and lever-out’ test data (and subcontract)  U Iowa FEA of 3D stress state of cup & bone  Basis for metrics in clinical outcomes studies (BMD; lysis) BioVera, Inc. Integrity Expertise Results
  37. 37. BioVera, Inc. Integrity Expertise Results RA Poggie, R Cohen, RG Averill, "Characterization of Porous Tantalum Metal, Direct Compression Molded UHMWPE Junction", 44th ORS, March 16-19, 1998, pp 777. JD Bobyn, "UHMWPE: The Good, Bad, & Ugly; Fixation and Bearing Surfaces for the Next Millennium", Orthopaedics, Sep, 1999, Vol. 22 No 9, pp 810-812. DR Pedersen, TD Brown, RA Poggie, "Finite Element Analysis of Peri-Acetabular Stress of Cemented, Metal-Backed, and Porous Tantalum-Backed Acetabular Components”, The 45th Orthopaedic Research Society Meeting, Anaheim, CA, Feb 1-4, 1999. Alan S. Litsky, “Elimination of Cup-Liner Micromotion in Acetabular Components”, 25th Annual Transactions of the Society for Biomaterials Meeting, Providence, RI, 1999. JB Stiehl, Kenneth St. John, Richard Affilitto, Robert Poggie, ”The Trabecular Metal Monoblock Acetabular Cup Biomechanical Characterization & Hip Simulator Wear Results”, 68th Annual Meeting of the AAOS, Scientific Exhibit, Feb 28-Mar 4, 2001. David G. Lewallen, “Use of Porous Tantalum In Total Hip Arthroplasty”, Harvard Hip Course, Boston, MA, September 8-10, 2003. R Lewis, A Unger, TJ O’Keefe, “Monoblock Trabecular Metal Acetabulum: 2 to 5 Year Results”, Abstract and Poster, 70th AAOS, "New Orleans, LA", Feb. 5-9, 2003, poster 45 . T Gruen, A Hanssen, D Lewallen, “Radiographic Evaluation of a Monoblock Acetabular Component – A Multi-Center Study With 2 To 5 Year Results”, The Journal of Arthroplasty, Vol. 20, No. 3, April 2005, pp 369-378. George A. Macheras, et. al., “Survivorship of a Porous Tantalum Monoblock Acetabular Component in Primary Hip Arthroplasty With a Mean Follow-Up of 18 Years”, The Journal of Arthroplasty 32 (2017) 3680-3684.
  38. 38. Zimmer Sales Training 2006
  39. 39. Case Example: Bodycad Uni-Knee 40  Patient specific Uni-Knee w/unique features. FDA deficiency letter stated clinical study likely necessary.  Unique Features: bone resection method; FEA-calculated contact area/stress for each implant; ancillary fixation on femur…  Planning, Literature, Data to establish substantial equivalence and in turn aid marketing  Bone Resection – Literature and homegrown data to establish SE of method and performance relative to perf reqs  Screw Fixation and Bodycad Software – Literature + homegrown data to establish similar or better accuracy of implant position  ORL + Biomechanics R&D for validation of Bodycad FEA of articulation contact data (Fuji film), and relative to ZUK BioVera, Inc. Integrity Expertise Results
  40. 40. K163700, Summary 41 The results of testing showed:  The fatigue strength of the Bodycad UKS tibial and femoral components withstood worst case physiological loading.  ROM testing showed the Bodycad UKS to possess substantially equivalent motion characteristics as the predicate devices and reported in the scientific literature for UKA devices.  Comparison of the tibial and femoral articular surfaces of the Bodycad UKS to the predicate devices, and analyses of constraint, ROM, and contact stress/area of the Bodycad UKS, established substantial equivalence to the predicate devices.  The screw trajectories for the femur and tibia were within the envelope of bone and not at risk of perforation of bony surfaces. Evaluation and testing of femoral and tibial ancillary fixation in cadaver knees and Saw Bones demonstrated substantial equivalence to the predicate and reference devices.  The UHMWPE material used in the manufacture of the tibial inserts was found to be in conformance with ASTM F648.  Cadaver laboratory testing and evaluation of surgical fit to the plan (surgeon input and software) showed the implants to fit and surgery to be completed to the patient-specific, prescribed plan. The cadaver studies performed for the Bodycad UKS showed without exception that the patient specific implants and instruments to fit as planned by the surgeons and Bodycad software.  The single-use cutting guides met the performance criteria and were validated for their intended use.
  41. 41. Published Data Used for SE 42 References, precision and accuracy of UKR, TKR devices (robots, CAS) Smith, J. and Philip E. Riches. 2013. Accuracy of a freehand sculpting tool for uni-condylar knee replacement, Int. J Med Robotics Comput. Assist Surg. Clarius, M., et al. 2009. Saw cuts in unicompartmental knee arthroplasty: An analysis of sawbone preparations. The Knee. 16: 314 -316. Otani, T, et al. 1993. Cutting errors in preparation of femoral components in total knee arthroplasty. J Arthroplasty. 8, (5): 503-10. Ohmori, T., et al. 2015. The Accuracy of Initial Bone Cutting in Total Knee Arthroplasty. Open Journal of Orthopedics. 5: 297 -304. Mason, B. J., et al. 2007. Meta-analysis of alignment outcomes in computer assisted total knee arthroplasty surgery. The Journal of Arthroplasty. 22, (8): 1097-1106. Martinez-Carranza, N. et al. 2012. Deviation between navigated and final 3-dimensional implant position in mini-invasive unicompartmental knee arthroplasty: a pilot study in 13 patients. Acta Orthopaedica. 83, (6): 625-628. Karia M. et al. 2013. Robotic Assistance Enables Inexperienced Surgeons to Perform Unicompartmental Knee Arthroplasties on Dry Bone Models with Accuracy Superior to Conventional Methods. Advances in orthopedics.
  42. 42. Published Data Used for SE 43 S&N Visionaire White Paper … Salehi, A. and C. Moore. 2011. Debris Testing of Visionaire Patient Matched Cutting Blocs. Bone & Joint Science. 02, (9). From Bodycad test report used for SE of this performance metric: “A similar study was conducted on S&N’s Visionaire instrumentation [1]. The Visionaire instrumentation is also patient-specific are made of the same material as the Bodycad Knee cutting guides, and are manufactured using the same equipment and raw material (EOS system and medical grade Nylon 12). The authors of the study reported an average weight loss of 0.0062g, which is 34% more than that measured with the Bodycad cutting guides. Salehi et al. concluded that a weight loss of 0.0062g was negligible [1].”
  43. 43. BioVera, Inc. Integrity Expertise Results Poster / Abstract ORS 2018
  44. 44. BioVera, Inc. Integrity Expertise Results SOFCOT 2017; Surgeon Education
  45. 45. Recap BioVera, Inc. Integrity Expertise Results
  46. 46. Recap, Identify the ‘Data’ 47 1. Identify same or similar devices to your product 2. FDA Website to ID 510(k) summaries, PMA dox, and guidance documents as applicable a. FDA website and search engines; FDA 510(k) summaries w/data; scientific publications recap PMA data b. Draft / list required data for your product 3. ISO and ASTM standards to define tests 4. Company Websites for papers and reference lists 5. Scientific Literature – PubMed, Google Scholar, specialty-specific journals and websites 6. Homegrown plans and data; think beyond regulatory BioVera, Inc. Integrity Expertise Results
  47. 47. Recap, Judging Utility of Data 48  Methods and Materials clearly stated?  Based on consensus stds or industry / scientific norms?  Reputable journal or source? Publicly available?  Scientific publication of PMA data?  Product IFU and clinical function same or similar?  Statistical validity? In-synch with FDA-OK numbers?  White papers that appear obviously related to regulatory testing to clear product?  Metrics / Performance – Did your product outperform completion? W/statistical proof? BioVera, Inc. Integrity Expertise Results
  48. 48. Recap, Data Value to Your Work 49  Project Planning – Testing plans (cost & time) for:  Regulatory applications  Design and process validations  Scientific publications  Marketing  Published Data - Reducing cost and scope of testing  Alternative to testing predicate devices  Target values for device performance & regulatory  Marketing and Scientific Publicity BioVera, Inc. Integrity Expertise Results
  49. 49. Q & A Discussion Open Forum BioVera, Inc. Integrity Expertise Results
  50. 50. Thank You