MICKEY KARRAM MD

DIRECTOR OF UROGYNECOLOGY

THE CHRIST HOSPITAL

CLINICAL PROFESSOR OF OB/GYN & UROLOGY

UNIVERSITY OF CINCINNATI

Vaginal Insertion of Mesh Vaginal Insertion of Mesh for Incontinence and for Incontinence and Prolapse; How will the Prolapse; How will the Recent FDA Warning Recent FDA Warning Impact our Clinical Impact our Clinical PracticePractice

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

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

Regulatory Approval - DrugsFour phase process

I II III IV

TIME ( 7 -10 yrs)

Regulatory Approval - DrugsPhase I

Safety

Initial human exposure – healthy volunteers

CV, Metabolic, Bioavailability

Pharmacokinetics (half life etc)

Pharmacodynamics (unique issues with compound)

Regulatory Approval - DrugsPhase II

Class specific adverse eventsSafety monitoringDose rangingPharmacokinetics

Usually 20-80 patients2-3 year process

Regulatory Approval - DrugsPhase IIIBIG DECISION; REQUIRES HUNDREDS/THOUSANDS OF PATIENTS;

RCT – expanded exposureMay include active comparator (not

absolute)Efficacy / Tolerability / SafetySpecial patient populations

Several year process ;70-90% get approved

Recent Drugs that went through Phase III trials and got rejected by FDA

DULOXETINE (LILLY)

INTRINSA (P&G)

Regulatory Approval-Drugs

Phase IV

Postmarket studies to define additional information including risks benefits, and optimal use

FDA Regulations

Filing for a new device or material

510(K) Premarket Notification Process

PMA Premarket Approval Process

Classes of DevicesClass 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)

Examples of 510(k) products that were withdrawn from market

• TMJ implant

• Bladder slings

• Renu moisture/loc

• Heart valves

• Orthopedic prosthesis

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

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

510(k) Clearance of Surgical Mesh by Material Category

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

Abdominal Sacrocolpopexy

Mesh Overlay Techniques Mesh Overlay Techniques

MESH KITS – TROCAR BASED SYSTEMS

1- Prolift (Gynecare)

2- Apogee & Perigee (AMS)

3- Avaulta (Bard)

MESH KITS; DIRECT ACCESS SYSTEMS

1-ELEVATE (AMS)

2-UPHOLD & PINNACLE (BSC)

3-PROSIMA (GYNECARE)

Manufacturer and User DeviceExperience Database;•Requires mandatory reporting by manufacturer•Voluntary reporting by user; most users do not manage their own mesh complications

MAUDE DATABASE

1.Between 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

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

MESH COMPLICATIONS

• Vaginal Exposure

• Vaginal Pain & Dyspareunia

• Vaginal Scarring and Loss of Vaginal Tissue

• Visceral Injury

• Thigh Pain and Referred Pain

Extensive review of published data with conclusions that question efficacy of mesh for prolapse repair

FDA White Paper

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

Mayo Data – Mesh ComplicationsComplications 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)

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

What about Complications with Meshes?

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

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

YES1-How we teach and train 2-How we consent3-Medico-legal implications4-Hospital credentialing 5-Reimbursement by third party payers

Will this warning have a long term impact on our clinical practice?