The MOVIE. Currently VP, Regulatory Affairs, MCRA Former Orthopedic Devices Branch Chief (2006)

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2 FDA played by Glenn Stiegman Currently VP, Regulatory Affairs, MCRA Former Orthopedic Devices Branch Chief (2006) Managed Orthopedic and Spine groups (Branch split in 2007) Former Orthopedic Reviewer ( ) Spine Team Leader Author of various Spine and Orthopedic Guidance Documents Various Orthopedic ASTM Standards committees BS, MS in Biomedical Engineering For the Part: The MOVIE Playing 25 year old Biomedical Engineer Courses included Biomechanics, Biomaterials

3 What does the FDA do? Mission: The FDA's mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use. Our work is a blending of law and science aimed at protecting consumers. In Not other FDA s words, Mission: FDA The FDA's does mission not consider is to promote cost and protect the public health by helping safe and effective within products their request reach the of market generating in a cost-effective valid way, scientific and monitoring evidence products for proof for continued of safety safety and after they are in use. Our effectiveness. work is a blending of law and science aimed at protecting consumers.

4 Moving on Up Attempting to allow the safest, effective, and innovative devices onto the market. CDRH Medical Device Innovation Initiative New initiatives to better the total product life cycle IOM Evaluation of 510(k) Process 2010 Strategic Goals Met FY 2010 performance target successfully completed 86 percent, 92 of the 107 actions due in FY As of November 30, 2010 successfully completed 91percent, 99 of 109 actions due by the end of November. Priority 1. Fully Implement a Total Product Life Cycle Approach Strategy 1.1. Enhance and Integrate Premarket, Postmarket, and Compliance Information and Functions Priority 2. Enhance Communication and Transparency Priority 3. Strengthen Our Workforce and Workplace Priority 4. Proactively Facilitate Innovation and Address Unmet Public Health Needs FDA Moving on Up to the Government Trickle Down Housing Effect on to the Reviewer: Beltway Minimal

5 The Road Map Center for Devices and Radiological Health (CDRH) Center for Veterinary Medicine (CVM) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Food Safety and Applied Nutrition (CFSAN)

6 Setting the Foundation: Spine Branch Branch Chief Ronald Jean, Ph.D. 15 Reviewers and Scientists 3 Medical Officers Review: Pedicle Screw Systems Anterior Cervical Plates Interbody Cages Total Disc Replacements Interspinous devices Posterior Cervical Devices (OCT Systems) Nucleus Replacements Facet Replacements Do Not Review: Biologics Vertebroplasty/Kyphoplasty Cements Vertebral Body Compression Devices Surgical Meshes

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8 CE Marking versus FDA Process FDA PROCESS Classify devices by complexity and risk (I, II, III) Mandate the implementation of a Quality Management System (QMS) (21 CFR 820) 510(k) paradigm relies on demonstration of substantial equivalence to an existing, FDAcleared medical device. Class II Devices (510(k)): Pedicle Screw Systems Cervical Plates Posterior Cervical Systems Interbody Cages Interspinous Devices (Fusion) Class III (PMA): Total Disc Replacements Interspinous Devices (Non-fusion) Nucleus Replacements Facet Replacements CE MARKING Classify devices by complexity and risk (I, IIa, IIb, III) Mandate the implementation of a Quality Management System (QMS) with the exemption of devices listed under the MDD Class I non-measuring/non-sterile subdivision (MDD outlines compliance) Technical files are prepared in accordance to the MDD for review by a Notified Body. Upon review, a legally-binding Declaration of Conformity is prepared by the manufacturer indicating that the product is in compliance with the MDD. CE Mark confirms the safety of a product CE Mark does not confirm effectiveness of a product CE Mark is not equivalent to FDA approval / clearance Class IIb: All Spinal devices Class III Biologics (Drugs)

9 WHY ARE YOU PICKING ON US???????? Hip Recalls Zimmer, DePuy, Stryker Rengen Biologics MenaFlex ALL ORTHOPEDIC AND SPINE Synthes Spine - Norian MDT Agile DOJ Sen. Grassley Media RELATED

10 PAVING THE HIGHWAY Bound by regulations and precedent Need significant data to demonstrate safety and effectiveness Highest scientific rigor possible Valid Scientific Evidence Valid scientific evidence is evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, welldocumented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use. The evidence required may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use.. Such information may be considered, however, in identifying a device the safety and effectiveness of which is questionable. Side by Side testing Need to characterize device (lower test parameter) No standard to compare It s what goes into the asphalt that makes the road smoother

11 Class II: Pedicle Based Systems Dynamic Systems Cleared 5 Systems within 2 years FDA getting innovative devices on the market 364 MDRs since 2005 (search criteria NQP) Problem: ASTM F1717 did not predict the failures seen clinically. Agile Recall Breaking in Shear (not part of ASTM F1717) Solution: 522 Studies Rigid Systems Blackstone Medical ICON Recall Unpredicted with mechanical testing ASTM F1717 meant to compare across devices, not mimic clinical environment Lack of evidence validating the loads and parameters from ASTM F1717 tell the clinical story Concept, Prototype, Preclinical Important

12 Bone GRAFT (Extenders) Bone Void Fillers ( Extenders ) Currently cleared posterolaterally with supplemental fixation Can t market BVF intradiscally Still 510(k) Need clinical data Allograft Cages Only indicated with autograft Allograft would need clinical data WHY? Provide valid scientific evidence of substantial equivalence Use of autograft still standard of care Show Us the DATA Bad to the Bone Graft

13 Bumps in the Road? Surgeons? Use a screwdriver as a rod? 5-level total disc replacement? Wear and Tear? Extensive mechanical testing, devices still break Did they compare to older weaker predicate Patients? Endplate failure Extrusion of device Did the patient follow the correct postoperative regiment? FDA Does Not Regulate Practice of Medicine

14 The 510(k) Predicament Planning and Knowledge Predicate may not be a predicate Old devices may not be viable predicate No split predicates Use of one predicate for material, one for mechanical results Clear and thorough risk analysis What are the differences (i.e., risks ) and how risk mitigated Possible side by side testing Early FDA interaction to manage timing and expectations Expect additional data needed Side by Side testing Animal data Clinical data Don t Get Yourself Stuck

15 STOP INNOVATION Just Kidding Barrier to Entry is Substantial Equivalence with a safety and effective device Technology outpaces scientific evidence to demonstrate safety and effectiveness Need that evidence to make decisions May be generated with standardized testing Significant limitations Limited applicability to new designs, materials, and treatment methods Limited precedent, limited ability to extend beyond regulations Industry s burden, not FDA s, to demonstrate substantial equivalence

16 Class III Examples TDRs Heterotopic Ossification Facet disease Out of ODE s hands: Manufacturing, IP Best study design = Right time, right patient Nucleus Replacements Issues with expulsion Feasibility study needed to evaluate safety Stopping rules regarding expulsions Avoided moving possible risky device into pivotal study Biologics INFUSE AMPLIFY OP-1 Off-label use, Study design, Risk/benefit profile

17 US Market versus CE Mark TDRs (Charite) CE Mark approximately 1998 Clinical study 1999, US market 2004 Interspinous Devices (X-STOP) CE Mark 2002 Clinical study 2000, US Approval 2005 BMP (OP-1, Infuse) Market Authorization 2001 (OP-1) Clinical study 1997, US Approval 2002 (INFUSE) EU is increasing level and amount of data for CE marking, while FDA closing the gap

18 PMA Success PMA success correlated to DESIGN and EXECUTION of the IDE study What does that mean?? Need to pick right indication Need to pick right endpoints Need to pick right sites Need to eliminate bias Valid statistical parameters FDA CAN HELP WITH THESE Means FDA is awesome

19 PMA Success Sequel (Execution) Patient Follow-up Adjudication of Adverse >85% events Independent Compliance Binding Surgeon/company Use of CEC/DSMB Site training Mechanism of Action Minimal study Why does the device work violations/deviations Radiographic Per Protocol Understanding failures Strict training program What went wrong Methods of correction (training, labeling, etc) FDA After Highest Scientific Rigor

20 Basic Ingredients Recipe for Success 2 Cup: Demonstration of non-inferiority Adequate statistical parameters 1 Cup: >85% patient accountability 1 Cup: Positive risk/benefit profile 2 Tbsp: Limited unexpected adverse events/observations 1 Tsp: Clear demonstration of mechanism of action 1 Tsp: Elimination of bias Add: Valid Manufacturing Process, Adequate Preclinical testing, IP Result: Nice Piping Hot Ready to Market Approved Device

21 Bullying or Common Sense Goal: Protect the public health Decisions based on science Preclinical testing Side by side testing Animal data Level 1 Clinical Evidence Prospective, randomized controlled study Timing often set by company, not FDA Approval timeliness based on data Address FDA s concerns There are ways not to provide side by side testing, clinical data, etc Justify response! Winning!

22 End of the Road Initiatives in place to add layer of transparency and streamline premarket process Regulatory precedent prevents quicker regulatory pathways Need to streamline reclassification petition process Clinical precedent guides review stringency Dynamic Stabilization Systems Clinical study design and execution is critical Don t forget manufacturing is important Always plan for a worst case timeframe and worst case budget Know your end goal Have the foresight to know what the market and landscape will be in 4-5 years Work with FDA or at least someone who knows what they re doing

23 Thank you