1. MICKEY KARRAM MD DIRECTOR OF UROGYNECOLOGY THE CHRIST HOSPITAL CLINICAL PROFESSOR OF OB/GYN & UROLOGY UNIVERSITY OF CINCINNATI Vaginal Insertion of Mesh for Incontinence and Prolapse; How will the Recent FDA Warning Impact our Clinical Practice

2. 1-Review current FDA requirements for approval of a drug or device 2-Discuss the history of industry driven mesh kits for incontinence and prolapse 3-Review prevelance of mesh complications after surgeries for SUI and Pelvic Organ Prolapse 4-Discuss impact of recent FDA warning 5-Future of pelvic floor surgery and medico-legal implications OBJECTIVES

3. FDA Regulatory Process; A DOUBLE –EDGED SWORD WHY IS THE PROCESS REQUIRED BY THE FDA SO DIFFERENT FOR A DRUG VS A DEVICE? 1.Budget differences between CDRH vs CDER 2.1976 ruling on devices that occurred after Dalkon Shield problems 3.Differences between financial status of pharmaceuticals vs device companies

4. Regulatory Approval - Drugs Four phase process I II III IV TIME ( 7 -10 yrs)

5. Regulatory Approval - Drugs Phase I Safety Initial human exposure – healthy volunteers CV, Metabolic, Bioavailability Pharmacokinetics (half life etc) Pharmacodynamics (unique issues with compound )

6. Regulatory Approval - Drugs Phase II Class specific adverse events Safety monitoring Dose ranging Pharmacokinetics Usually 20-80 patients 2-3 year process

7. Regulatory Approval - Drugs Phase III BIG DECISION; REQUIRES HUNDREDS/THOUSANDS OF PATIENTS; RCT – expanded exposure May include active comparator (not absolute) Efficacy / Tolerability / Safety Special patient populations Several year process ;70-90% get approved

8. Recent Drugs that went through Phase III trials and got rejected by FDA DULOXETINE (LILLY) INTRINSA (P&G)

9. Regulatory Approval-Drugs Phase IV Postmarket studies to define additional information including risks benefits, and optimal use

11. FDA Regulations Filing for a new device or material 510(K) Premarket Notification Process PMA Premarket Approval Process

12. Classes of Devices Class I-Low potential for harm (bandages, gloves etc) Class II-May be harmful, requires special controls, labeling requirements, post market surveilence (meshes, instruments etc) Class III-Should require PMA (heart valves,breast implants etc )

13. Examples of 510(k) products that were withdrawn from market TMJ implant Bladder slings Renu moisture/loc Heart valves Orthopedic prosthesis

14. 1-In 1996 Boston Scientific obtained 510(k) approval for the PrtoGen Sling 2-In 1998 Ethicon/Gynecare obtained 510(k) approval for TVT 3-In 2002 Ethicon/Gynecare obtained 510(k) approval for Gynemesh for repair of prolapse HISTORY OF INDUSTRY DRIVEN MESH KITS FOR INCONTINENCE AND PROLAPSE

15. 510 (k) Clearance of Surgical Mesh (1992-2010)

16. 510(k) Clearance of Surgical Mesh by Material Category

17. CURRENTLY AVAILABLE SYNTHETIC SLINGS RETROPUBIC; below to above vs above to below PREPUBIC TRANSOBTURATOR; outside in vs inside out MINI-SLING; urogenital diaphragm vs obturator internus GENERIC SYNTHETIC SLINGS

18. Abdominal Sacrocolpopexy

19. Mesh Overlay Techniques

20. MESH KITS – TROCAR BASED SYSTEMS 1- Prolift (Gynecare) 2- Apogee & Perigee (AMS) 3- Avaulta (Bard)

21. MESH KITS; DIRECT ACCESS SYSTEMS 1-ELEVATE (AMS) 2-UPHOLD & PINNACLE (BSC) 3-PROSIMA (GYNECARE)

22. Manufacturer and User Device Experience Database; Requires mandatory reporting by manufacturer Voluntary reporting by user; most users do not manage their own mesh complications MAUDE DATABASE

23. 1.B etween Jan 1, 2008 & Dec 31, 2010; the FDA received 2874 reports of complications associated with surgical mesh used to repair SUI and POP; with 1503 associated with POP. 2.The most frequent complications reported were erosion through the vagina, pain, infection, bleeding, dyspareunia, organ perforation, and urinary problems. 3.There were also reports of recurrent prolapse, neuromusculsar problems, vaginal scarring or shrinkage, & emotional problems. Recent warning from July 2011; What the FDA said

24. 1-Obtain specialized training for each mesh placement technique 2-Be vigilant for potential adverse events especially erosion and infection 3-Watch for c/o associated with the tools; especially bowel, bladder and blood vessel perforation 4-Inform patients about the potential for serious complications; including pain and narrowing of the vagina 5-Provide patients with a copy of the patient labeling from the manufacturer if available FDA Recommendations to Physicians

25. MESH COMPLICATIONS Vaginal Exposure Vaginal Pain & Dyspareunia Vaginal Scarring and Loss of Vaginal Tissue Visceral Injury Thigh Pain and Referred Pain

26. Extensive review of published data with conclusions that question efficacy of mesh for prolapse repair FDA White Paper

27. Panel will be asked to discuss 1-Risks associated with vaginal mesh for POP repair 2-Based on available data is their adequate assurance of the effectiveness of vaginal mesh used for POP repair 3-Do risks of mesh repair outweigh potential benefits 4-Are more studies needed to document safety and efficacy; if so recommend study design outcome measures etc 5-Does the panel agree with the FDA regarding abdominal mesh repair has been proven to be safe and efficacious 6-SHOULD VAGINAL MESH KITS BE RECLASSIFIED AS CLASS III DEVICES FDA Obstetrics & Gynecology Devices Advisory Committee Meeting; Sept 8 & 9; 2011

28. Mayo Data – Mesh Complications Complications specific to synthetic material use continue to increase Multiple surgeries to address complications may be necessary, and may incompletely resolve symptoms Potential for underreporting – only 14% referred from original treating physician Dyspareunia and recurrent prolapse are common reasons for referral Blandon et al. Int Urogynecol J 2009 Feb10 (EPub)

29. Mesh Complications; How Common are They The BIG QUESTION Severe mesh complications are occurring; but are the majority of them TECHNICAL or WOULD THEY OCCUR IN THE BEST OF HANDS

30. What about Complications with Meshes?

31. Outcomes for Pelvic Organ Prolapse Vaginal anatomy; bulge, pressure, mass Visceral symptoms: Urinary and bowel symptoms Sexual activity and expectations Future surgical procedures or medicines to manage failures or complications

32. Who should ultimately be responsible for training surgeons to utilize new devices or materials? The company that makes and sells the device. The hospital in which the surgeon performs the surgery The medical organization or society that represents the surgeon. A formal credentialling board made up of an expert panel. Certified, trained proctors that have demonstrated competence in this area or device. Other

33. YES 1-How we teach and train 2-How we consent 3-Medico-legal implications 4-Hospital credentialing 5-Reimbursement by third party payers Will this warning have a long term impact on our clinical practice?