In re: Coloplast Corp., Pelvic Support Systems Products Liability Litigation

Southern District of West Virginia, wvsd-2:2012-md-02387

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6 PageID #: 20036 IN THE UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF WEST VIRGINIA CHARLESTON DIVISION IN RE: COLOPLAST CORP. PELVIC SUPPORT SYSTEMS Master File No. 2:12-MD-02387 PRODUCTS LIABILITY MDLNo.2387 LITIGATION JOSEPH R. GOODWIN U.S. DISTRICT JUDGE RULE 26 EXPERT REPORT OF DR. MANISH PATEL As an experienced, board-certified urologist and board-certified female pelvic reconstructive surgeon, and a clinician who uses the Aris® ("Aris") and Supris® ("Supris") devices in my own clinical practice, I have been retained in this case by Coloplast Corp. to offer my opinions on the safety and efficacy of these devices for treatment of female patients with stress urinary incontinence. I have implanted the Aris and Supris slings in my patients for well over a decade and have personally witnessed their benefits and evaluated the potential incidence and severity of adverse events. In my opinion, to a reasonable degree of medical and scientific certainty, both the Aris and Supris are safe and effective for treatment of stress urinary incontinence when properly implanted in the appropriate patient. I. BACKGROUND AND QUALIFICATIONS My name is Manish Patel, M.D, RPh, FACS, FPMRS. I am a medical doctor licensed in the states of North Carolina and South Carolina. I have practiced Urology and Male and Female Reconstructive Urologic Surgery for the past 17-plus years. I am the Medical Director of the Urology and Women's Health Department for Lifepoint Hospitals for two of its South Carolina Hospitals. I accepted this position in December of 2015; before that time I served as Chief Medical Officer and Director of Female Pelvic Medicine and Reconstructive Surgery at the Carolina Continence Center in Charlotte, North Carolina. I currently have an active hospital-based practice and I also frequently collaborate with universities in clinical trials. I am currently pending appointment to the Medical University of South Carolina. 1 6 PageID #: 20037 Today, 70% of my clinical practice is in women's health and 30% in men's health. I am a tertiary referral source for many of my colleagues in North and South Carolina. I perform numerous complex reconstructive surgeries, including multi-stage urethral reconstruction, kidney reconstructions, complex ureteral surgeries, creation of new bladders from bowel, creation of new vascular flaps for new drainage systems after severe injury, birth defects or cancer; repair of conditions that have occurred due to injury such as fistulas, scars, contraction, pain syndromes or persistent disease progression. I routinely treat patients for their previously operated upon conditions and recurrences, including previous anti-incontinence surgeries. I routinely treat patients suffering from pelvic organ prolapse, urinary and bowel incontinence, and pelvic floor disorders. I have treated these conditions for many years. Throughout my career, I have performed a range of surgical options including the Burch Procedure, Harvested Pubovaginal Sling (PVS) and the Mid-Urethral Sling (MUS). I am an active member of SUFU (Society of Urodynamics, Female pelvic medicine and Urogenital reconstruction), AUA (American Urological Association), ICS (International Continence Society) and the ACS (American College of Surgeons). All these organizations share my passion for women's health and the advancement of surgical training and skill for all our peers. They are collaborative and unified in their desire to improve the lives of patients. These are my personal goals as well. I have been named several times as one of Charlotte's Top Doctors, a peer-nominated honor from my colleagues across multiple specialties. I was also inducted as a Fellow of the American College of Surgeons, another peer-selected organization consisting of all surgical fields. I have researched, published, and presented on urologic issues, with a focus on the treatment of the female pelvic floor, including stress urinary incontinence, on numerous occasions. In 2013, the American Board of Urology created a new board exam in female pelvic medicine and reconstructive surgery, and required physicians to apply for eligibility. Eligibility included a case log of surgeries performed in the field, assessment and management of complications, office visits and procedures, and sufficient peer review. Although this is only a portion of what a reconstructive urologist does in practice, the board certification is an acknowledgement of a comprehensive understanding of complex pelvic floor disorders in women. I passed this board exam on my first attempt in 2013, and was one of only roughly 100 2 6 PageID #: 20038 doctors who were eligible to sit for the exam based on the stringent eligibility criteria set forth by the American Board of Urology. I graduated from Rutgers University in New Jersey, where I received a degree in pharmacy and pharmacology in 1992. I worked as a registered pharmacist before graduating first in my class from Wright State University School of Medicine in 1997. I then completed my residency in the Department of General and Specialty Surgery, Division of Urologic Surgery, at the University of North Carolina Hospital, where I was selected as Resident of the Year in 2000. My compensation in this matter is $450 per hour for records review and document preparation and $600 per hour for time spent having to provide testimony and depositions. I have not testified as a retained expert in litigation in the previous four years. A more thorough recitation of my qualifications, including my list of publications, is set forth in my curriculum vitae, which is attached as Exhibit A. A list of materials I have considered in connection with my opinions is attached as Exhibit B. All of my opinions in this report are expressed to a reasonable degree of medical and scientific certainty. In formulating these opinions, I have relied upon my education, training, and experience, and also the materials listed in the endnotes and my reference list. I reserve the right to supplement this report should additional facts, data, or observations become available. II. OVERVIEW OF STRESS URINARY INCONTINENCE Urinary incontinence is a bothersome and complicated condition that results from many causes, and affects a significant percentage of women during their lifetimes. All incontinence is not alike. To successfully treat the patient, her doctor must first accurately diagnose the type and cause or causes of her urinary incontinence. Many treatment failures result from improper diagnosis. Stress urinary incontinence (SUI) is an involuntary loss of urine upon exertion, such as through sneezing, coughing, laughing, or physical activity. SUI can exist as a single condition or can occur in association with urge urinary incontinence (UUI), which is an involuntary leakage accompanied by or immediately preceded by a sudden, compelling desire to pass urine (urgency). If a patient has both SUI and UUI, her condition is referred to as 3 6 PageID #: 20039 mixed urinary incontinence. Treatment of mixed incontinence often requires additional treatment-often medication-after stress incontinence surgery due to the urgency incontinence component. The treatment of SUI surgically can unmask pre-existing UUI. In addition, any surgical treatment for SUI can cause urinary retention and urgency if the surgical treatment, whether a mid-urethral sling, pubovaginal sling or Burch procedure, is too tightly tensioned. III. THE ANATOMY OF STRESS URINARY INCONTINENCE Successful surgical treatments for SUI require that skilled surgeons have a comprehensive understanding of the relevant anatomy. This includes not only where organs are located, but also how the nerves, blood vessels, and muscles work together, ensuring the organs function properly. The woman's lower urinary system consists of the bladder and urethra (the tube that urine passes through during urination). The function of the bladder is to store and void urine (urinate) in a safe and controlled manner. In order to perform these functions, the body has a complex system of checks and balance controls. Lack of coordination, anatomy changes, or injury to the controls will lead to altered functions. The lower urinary tract function is quite complex. However, its surgical anatomy is quite predictable and safe in the hands of a skilled surgeon. The lower 1/3 of the vagina provides support to the urethra. This area is different from the upper 2/3 of the vagina in its supportive anatomy. These structural differences account for the different physical movements of the vagina. In the standing position, the lower 1/3 of the vagina is aligned vertically (north to south) and the upper 2/3 of the vagina nearly horizontal (from east to west direction). Structural support differences between the lower 1/3 and upper 2/3 of the vagina account for treatment differences between the mid-urethra compared to other conditions such as pelvic organ prolapse. More specifically, mechanical support for the urethra benefits from less elasticity than that required for pelvic organ prolapse support. Dr. Victor Nitti described these properties in his textbook, Vaginal Surgery for the Urologist. He notes the following regarding the lower 1/3 of the vagina where support is a significant component of continence, "This distal (lower) 1/3 is firmly attached to the posterior aspect of the urethra 4 6 PageID #: 20040 providing an inelastic "backboard" for continence support. "1 The bladder operating normally can perform two main functions: 1) It can hold urine without abnormal sensation or discomfort until it is an appropriate time to urinate; and 2) When it is time to urinate, it can do so without difficulty, at normal pressures, with consistent flow and to completion without straining or discomfort. In order to maintain its urine storage function, the bladder relies on a functional urethral closure. Each component of urine storage must be normal in its anatomy, function, and nerve control, or leaks can occur. Put differently, the storage function of the female urethra is dependent on its multiple components working well in coordination with each other. Stress and urge symptoms may in part derive, for different reasons, from anatomic changes in the vaginal wall. The laxity may be caused by defects in the vaginal wall itself, or in the ligaments and muscles that support it. 2 The coordination of the structures involved, as well as the effects of age, hormones, and surgical tissue wound healing, are all integral to maintaining urinary control. Urethral closure depends on three mechanisms, each of which normally contributes roughly one third to urethral closing: 1) the internal urethral sphincter (IUS); 2) the external urethral sphincter (EUS); and 3) a non-muscular component that allows the tissues to stay closed. Failure at one or more of these three mechanisms can lead to stress incontinence. Loss of the IUS function is often called internal or intrinsic sphincter deficiency (ISD). Loss of the EUS can manifest itself as urethral hypermobility, or excess movement of the urethra. Decrease in the non-muscular component reduces urethral lining closure, as a result of conditions such as loss of vaginal estrogen. "In an ideally-supported urogenital tract, increases in intra-abdominal pressure are equally transmitted to the bladder, bladder base, and urethra. In women who are continent, increases in downward-directed pressure from cough, laugh, sneeze, and valsalva maneuver are countered by supportive tissue tone provided by the levator ani muscle and vaginal connective tissue. In those with a weakened supportive 'backboard,' however, downward forces are not countered. This leads to funneling of the urethrovesical junction, a patent urethra, and in tum, urine leakage." 3 Changes in the bladder anatomy and nerve function can also result in 5 6 PageID #: 20041 incontinence. If the patient's incontinence is bladder-based, SUI-focused treatment options will be ineffective and may increase symptoms or result in additional complications, highlighting the importance of the proper diagnosis when selecting treatment options. IV. THE IMPACT OF STRESS URINARY INCONTINENCE ON QUALITY OF LIFE Incontinence has an enormous impact on quality of life in women of all ages. It is a highly bothersome condition that in its most severe form can lead to significant problems, among them infections and irritation of the skin and vaginal canal, infection in the urinary system from urine pooling into pads, loss of self-esteem, depression, isolation, nursing home placement for care, and need for permanent catheter placement. Adult diapers or pads can help prevent some urine leakage or staining of clothing, but can be uncomfortable, bulky, retain urine odor and are insufficient or unacceptable for many women. Additionally, women with incontinence spend time out of work and may self-isolate from family or social situations. They limit activities they enjoy such as exercising, jumping or physical activities with their children. Many women with incontinence avoid sexual activity due to fear of leakage, furthering their isolation from social activity. Patients pursue treatments for various reasons. In my practice, we ask why a patient is choosing to seek treatment at this specific time. Many of my patients report a desire for treatment beyond failed medicines or attempts at performing Kegel exercises at home or with a physical therapist. The patient simply is tired of the embarrassment, anxiety, social disruption, or uncomfortable feeling of urinary leakage. Studies assessing patients' reasons for seeking treatment are lacking. Many studies look at the severity of the patient's condition or impact on quality of life once they have presented or once they have chosen a treatment. However, few studies actually evaluate the timing or impetus for the patient's presentation. Many women are silent about their incontinence for various reasons, such as misperceptions regarding treatment options, being told it is a "normal" part of aging, being unclear as to with whom to discuss the condition, embarrassment, availability of care or specialist, incorrect diagnosis, and so on. In my own clinical experience, many women have reported suffering for years without seeking treatment. Often, they are misdiagnosed and given incorrect treatment-or no treatment options at all. Interestingly, one of the biggest reasons primary care physicians decline to refer patients to a 6 6 PageID #: 20042 specialist is their own beliefs and experiences regarding treatment failures. In my practice, I use questionnaires that often act as a platform to facilitate discussion of SUI and other quality-of-life-related conditions that many women would otherwise have a difficult time discussing with their physicians. Patients are given the opportunity to express their symptoms or their degree of pain, discomfort or bother. Then, we tailor the treatment options to meet their needs. V. DIAGNOSING STRESS URINARY INCONTINENCE The diagnosis of SUI can include the patient's presenting symptoms (history), a physical examination, her objective demonstration of SUI, post- void residual volume (PVR), and/or urinalysis. Various tools can be used in order to inform the treatment plan including videourodynamics (VUDS), urodynamics (UDS), cystoscopy, frequency-volume charts (FVC) or voiding diaries, urine culture, pad testing and imaging. The complexity of the patient's presenting symptoms often guides the utility of additional testing. Indications for further testing include, but are not limited to, the following: • An inability to make a definitive diagnosis based on symptoms and the initial evaluation • Concomitant overactive bladder symptoms • Prior lower urinary tract surgery, including failed anti- incontinence procedures • Known or suspected neurogenic bladder • Negative stress test • Abnormal urinalysis such as unexplained hematuria or pyuria • Excessive residual urine volume • Grade III or greater pelvic organ prolapse • Any evidence for dysfunctional voiding The AUA describes an index patient for the purposes of general education and guideline review, but the patient in the guideline is uncomplicated in her presentation. Although the guideline serves to set forth minimum standards of evaluation in a patient presenting with SUI, it does not reflect the reality of many patients who present with SUI, and therefore, additional evaluation and testing may be required to further inform the diagnosis prior to recommending treatment for a particular patient. 7 6 PageID #: 20043 This is because most patients present to the urologist with more complex conditions than the "guideline patient". Patients often present with associated symptoms such as overactive bladder, incomplete emptying, straining, weak stream, feeling of a vaginal bulge or vaginal pressure, and difficulty with bowel function. These symptoms, in conjunction with the physical examination, mean there are several possible diagnoses for the patient's complaints. In order to select an appropriate treatment course, the specialist must take the patient's complete circumstances and health history into account. Failure to identify associated diagnoses will lead to a failed anti- incontinence procedure or subsequent complications. In other words, if a surgeon operates on a patient without first identifying concomitant conditions, he or she will not have a successful outcome and/or ultimately have a dissatisfied patient. Some examples of conditions that often go undiagnosed or are omitted from a patient's diagnosis are: 1) Increased or Reduced Bladder Sensation 2) Increased or Reduced Cystometric Capacity 3) Detrusor Overactivity or Underactivity 4) Increased or Reduced Bladder Compliance 5) Incompetent Urethral Closure Mechanism The bottom line is that the surgeon must have complete information in order to successfully counsel and treat each individual patient. VI. TREATMENT OPTIONS Once the proper diagnosis is made, different treatment options exist. Each treatment option has different reported success rates, side effects, and durability. Treatment options include both non-surgical and surgical approaches. The surgeon must have all options present in his/her "toolbox" in order to customize the best treatment plan for each individual patient. Surgeons must have an understanding of the risk factors for surgical failure in order to educate patients regarding long-term continence rates. 4 A. Non-Surgical Options Physicians routinely offer non-surgical management as part of their treatment algorithm. The non-surgical SUI options can range from simple to complex. 8 6 PageID #: 20044 1. No Treatment 2. Behavioral Modifications: a. Frequency Volume Chart/Voiding Diary b. Bladder training c. Pelvic Floor Muscle Therapy d. Weight loss 3. Electrical Stimulation 4. Vaginal Weights/Cones 5. Urethral Plugs, inserts or devices 6. Pessary or Incontinence Rings 7. Medications Many women find non-surgical options unacceptable or burdensome for various reasons. The treatment may be too time-consuming or disruptive to their lifestyles, rendering the treatment option ineffective. These options are nonetheless important to consider before proceeding with surgical options. 1. No Treatment The decision to treat is a personal choice. Whether to treat at all is the patient's decision. A patient may opt for no treatment at all. In my practice, this option is rarely chosen-particularly among more active patients-because by the time that they have arrived in my office, they are frustrated or bothered enough to want treatment. 2. Behavioral Modifications a. Frequency Volume Chart/Voiding Diary One non-surgical option is monitoring fluid intake through a frequency volume chart (FVC) or voiding diary (VD), both of which record information about a patient's fluid intake and voiding habits. This is both a diagnostic and treatment modality; the FVC/VD can be a useful tool to help determine the severity of some patients' symptoms and potential causes of their complaints, and to identify possible associated disorders such as decreased capacity, increased urine outputs, associated increased nighttime urination, or nighttime incontinence. The voiding information can assist the clinician in considering other diagnoses or testing needed to inform the treatment plan. For example, a patient with daytime frequency of every 3-4 hours but nighttime urination (without incontinence) every 1-2 hours may 9 6 PageID #: 20045 have a non-urologic diagnosis such as poor heart function, sleep apnea, fluid retention, or new onset diabetes. The FVC/VD information can also help direct initial and future management for the patient based on improvements or regression in symptoms. Both the patient and her clinician can benefit directly from a voiding diary. The patient's awareness of her condition, sources of worsening, and attention to changes in status with or without treatment can be objectively followed. As a treatment modality, however, alteration of a patient's frequency of voiding or changes in her volume of fluid intake often does not fit practically within the patient's lifestyle choices or general medical health. A healthy lifestyle requires adequate water and fluid intake. b. Bladder Training Bladder training therapy requires the patient to void at predetermined intervals, such as every two hours. The idea is to keep the patient's bladder at lower volumes, thus preventing stress incontinence during an exertion because of low urine bladder volume. This therapy has been used for urgency urinary incontinence (UUI) with relatively good success, but it is not practical for most women with an active lifestyle. c. Weight Loss Obesity is an important, independent risk factor for incontinence. 5 The HERS study (Heart and Estrogen-progestin Replacement Study) found that an increase in BMI was associated with an increase in incontinence episodes. Obesity itself was a strong individual risk factor for increases in incontinence as compared to other risk factors. Unsurprisingly then, weight loss is associated with improved continence, but it may not completely eliminate incontinence to patient satisfaction. A short term, 6-month randomized, clinical study of 338 women, all overweight or obese, who leaked urine at least 10 times in a week, revealed clinically significant reductions in frequency of incontinence episodes, SUI episodes, and UUI episodes with weight loss. 6 For many women, weight loss itself presents a difficult hurdle to overcome. Therefore, these women often choose to move toward surgical treatment. 10 6 PageID #: 20046 d. Pelvic Floor Muscle Therapy (PFMT) The classic Kegel exercise is based on the premise that the relationship between pelvic floor disorders such as incontinence, prolapse, and fecal incontinence revolves around the pelvic floor muscles. Exercising or stimulating the tone of these muscles can lessen urine leakage if performed routinely and correctly. Kegel exercises can improve external urethral sphincter control. They require that the patient perform, each day, 45 total reps divided into 3 sets of 15 at different times of day; the patient must hold each rep for a minimum of 2 seconds, up to 10 seconds. Patients need to alter their positions (lying, sitting or standing), in order to maximize efficacy. PFMT is a well-recognized and accepted treatment for reducing urinary stress, urge and mixed incontinence, however, once the patient stops the exercises, then benefits quickly fade and incontinence often resumes. 7 PFMT can be combined with biofeedback, which is a technique in which the participant receives immediate feedback on the exercise being performed with the assistance of an electrical stimulation device inserted into the vagina (perineometer). When the woman contracts the pelvic floor, a pressure gauge records the rise in vaginal pressure. This feedback helps the clinician and patient see that the correct contractions are being performed. PFMT can also be combined with assistance devices such as vaginal weights or electrical stimulation, 8 discussed below, although there is insufficient evidence of additional benefit. In my clinical experience, PFMT is not practical for most women long-term. First, adherence to the program is needed in order to continue to realize the benefits. Second, the improvement is gradual and therefore not likely to lead to consistent, long-term use because patients do not see tangible results quickly. There is no quick solution in behavioral modification using PFMT. Similar to working on improving muscle strength or flexibility of any other region of the body, improvement requires time and effort. Third, many patients are concerned about the cost and time off work that PFMT requires. Most reports provide information on improvement, with cure rates dependent on consistent and ongoing use of PFMT. The patient needs to be counseled appropriately in order to balance treatment outcomes with the patient's expectations for treatment. 11 6 PageID #: 20047 3. Pelvic Floor Electrical Stimulation (PFES) Pelvic Floor Electrical Stimulation (PFES) engages the pelvic floor muscles, using a vaginal or anal electrical stimulation probe that delivers an electric current that causes the pelvic muscles to contract. More specifically, PFES results in contraction of the levator ani, external urethral sphincter (EUS) muscles, and the smooth muscle of the urethra. Similar to Kegel exercises, therapy is performed 3 times per day, and each session typically lasts 10 to 15 minutes. PFES is a passive technique that requires no exertion -- conceptually similar to abdominal muscle belts that exercise a patient's core abdominal muscles while she does something else, such as watching TV or folding laundry. In my opinion, this technique is most useful for a patient who cannot properly identify or engage her pelvic floor muscles during attempts at home-based or therapist-involved PFMT. The patient can be taught to pay attention to the passive contraction, and then attempt to engage the muscles on her own. In 1995, Peter Sand reported the benefits of PFES. However, since that time, there have been conflicting results on its benefits over standard PFMT. 9 Once again, most women find this treatment impractical, including because of the time commitment required and the imposition of using the probe. 4. Vaginal Weights/Cones Vaginal weights or cones have been used in an attempt to strengthen the pelvic floor muscles. These are weights placed into the vagina, which require the patient to use her pelvic floor muscles to hold the device in place, much like working with weights in a gym. In clinical trials, they have been used individually, and in conjunction with PFMT or PFES. The Cochrane database cumulatively addresses over 1800 women in 23 trials, over 700 of whom received cones; however, variations in outcome measures limit the global assessment and utility of the data. 10 Again, the lack of cure, as well as the social impracticality, limits the benefit to many women. Vaginal weights may be of similar effectiveness to PFMT or electrostimulation. Again, most women do not find these treatments practical for their incontinence long term. 5. Urethral Inserts/Occlusion Devices Urethral occlusion devices or urethral inserts have been developed for 12 6 PageID #: 20048 more active women with SUI for short, episodic use. Inserts are one-time-use, silicone tubes encased in a soft sleeve that are inserted into the urethra by the patient herself, in order to block the passage of urine. They are intended for daytime use, particularly during vigorous physical activities. Side effects include discomfort and pain, blood in the urine, bladder irritation, and UTis. The urethral patch is a multi-use device that is applied over the urethra with adhesive gel that forms a watertight seal. Reported success rates vary widely in reduction in urine loss. 11 · I2 In my experience, patients report that adverse effects can be very uncomfortable and painful; they include skin and urethral irritation, due to the suction effect, and UTis. I 3 I4 Other devices used for the management of SUI, such as the contraceptive diaphragm 15, urethral plug 16, continence control pad 17, and intravaginal sponge 18, have demonstrated varying success. Despite the lack of strong evidence supporting the role of mechanical devices in the management of urinary incontinence, 19 some physicians recommend the devices because of their low cost. However, compliance can be an issue with these devices. In my experience, women do not choose these options as a viable long-term solution. 6. Pessary Pessaries are silicone devices that can be inserted into the vagina to provide support to the pelvic organs. Pessaries may treat stress incontinence by increasing urethral resistance in some women. Tampons are thought to work by a similar mechanism as pessaries by providing urethral support, and many women have observed that their stress incontinence improves when a tampon is in place. In a randomized trial, pessaries and tampons have been shown to be helpful in controlling SUI during exercise when compared with no device. 20 In practice, however, many women find long-term use of pessaries unacceptable. In a different study addressing pessary use, only half of women who attempted to use a pessary to treat their stress incontinence continued to use the pessary after 2 years in clinical practice.2 1 A pessary can be offered to women with pelvic organ prolapse (POP) or SUI. Clinical settings where pessary use may be considered include: 1) Patient preference for nonsurgical treatment. 13 6 PageID #: 20049 2) Presence of severe medical comorbidities that make the patient a poor surgical candidate. 3) Need to delay surgery for several weeks or months. 4) Recurrent POP or SUI and patient preference for avoidance of repeat surgery. 5) Vaginal ulcerations caused by severe POP. Reduction of POP through use of a pessary and application of vaginal estrogen cream combined help to promote healing of the ulcers within three to six weeks, which is useful prior to surgical repair. 6) Current pregnancy, to manage POP and cervical insufficiency. 7) Desire for future childbearing. Pessary use is not a viable option in some women due to coexisting factors or conditions, such as: 1) Shortened vaginal length (< 6 cm) 2) Wide vaginal introitus (4 fingerbreadth or more) 3) History of previous pelvic surgery 4) Hysterectomy 5) Coexistence of other urinary incontinence 6) Obesity 7) Sexual activity 8) A patient who has preexisting dyspareunia or vaginal pain. Although pessary use may be an appropriate option to consider for certain patients, in my experience, it has limited success for SUI due to a high discontinuation rate and limited improvement in incontinence. Many women, especially sexually active women and younger women, find the device unacceptable and embarrassing. Equally limiting is the fact that women often find it cumbersome to insert on their own or do not want to visit the doctor frequently for management of the device. Additionally, pessary use can be associated with odors, infections, difficulty voiding, pain, ulcerations and inconvenience, among other complaints. More severe conditions such as fistulas, erosions and epithelial ulcerations can occur from the pessary itself. I have personally seen and treated these complications on several occasions. 7. Medications There are no FDA-approved medications to treat SUI. The only 14 6 PageID #: 20050 approved drugs to treat incontinence are for overactive bladder. Some physicians use medications off-label that may help mild symptoms of SUI. Results are variable and not impressive. Transvaginal application of estrogen has been thought to be beneficial in post-menopausal women by restoring the estrogen-dependent vascular cushions of the urethral sphincter mechanism. By improving the blood supply and "thickening" the cushions, there is an increase in the ability for the urethra to come together to form a seal in the urethra. Closing the seal of the urethra may improve incontinence, especially in post-menopausal women with mild SUI. B. Surgical Options Historically, successful long-term treatment of SUI has been difficult to achieve. Surgical treatments for SUI have developed over time as physicians have sought longer-term improvement for their patients. Early surgical procedures once used to correct SUI, but which are no longer commonly used for SUI because better surgical options are now available, include: • Anterior colporrhaphy - Suturing the patient's own tissue together in order to provide support to treat stress incontinence. The procedure had a low complication rate but a high failure rate. Initial reported success rates were variable, and results deteriorated sooner than expected. • Paravaginal Defect Repair - This procedure involves an open or laparoscopic approach from the abdomen. The retropubic space is opened and sutures are placed in the pelvic muscles and vagina to provide support to the bladder neck and bladder itself. Potential problems include bleeding risk, high failure rate, new apical prolapse, and voiding dysfunction. • Needle Urethropexy - This procedure provides support to the urethra by passing a trocar from the pubic area toward the vagina and suturing into the peri-urethral/vaginal tissue. Potential problems include voiding dysfunction, inconsistent results, and increasing failure rates over time. • Bone anchors - This procedure involved attaching bone screws to the pubic bone to anchor sutures holding either the patient's own tissue or 15 6 PageID #: 20051 a surgical or biosynthetic mesh under the urethra. The approach was either vaginal or retropubic. Complications from the procedure include osteitis pubis (persistent painful bone inflammation and destruction), persistent pain with movement, no improvement in surgical outcome compared to patients not treated with bone anchors, and an increased infection risk. • Use of Gore-Tex or vascular pledgets - These were used to hold sutures in place for a standard PVS or needle urethropexy in an attempt to prevent failures of those procedures due to sutures pulling out, or to attempt to minimize the amount of dissection needed at the time of surgery. Significant complications include infection, discharge, persistent pain, and inflammation. In lieu of the earlier procedures above, today, most physicians may consider four distinct surgical options for SUI, based on a patient's specific presentation: (1) Intraurethral or Periurethral bulking agents (IUBA/PUBA); (2) the Burch Procedure; (3) a graft-augmented procedure, using a Pubovaginal Sling (PVS); or (4) a graft-augmented procedure usmg a synthetic Mid-urethral Sling (MUS). 1. INTRA-URETHRAL OR PERI-URETHRAL BULKING AGENTS (IUBA/PUBA) IUBA and PUBA are treatment options developed for fixed bladder neck positions seen with the classic "lead pipe urethra", meaning that it is fixed or immobile. The technique involves injecting various synthetic materials into the surrounding urethral tissue. These injections, either transvaginal or through the urethra, allow the tissue to coapt (that is, push together), therefore improving the patient's continence. Today, some patients with ISD and hypermobility are also treated with bulking agents. Overall, success rates are unimpressive and repeated injections are often necessary. 22 Once explained, few patients select this treatment, because of the lack of efficacy, need for repeated treatments, and potential long-term risks. 2. BURCHPROCEDURE The Burch colposuspension procedure, first reported in 1961, involves elevating the vaginal tissue around the urethra to a ligament in the pelvis known as Cooper's Ligament. Usually the surgeon places 2-3 sutures on 16 6 PageID #: 20052 each side of the urethra in an effort to raise it. The Burch procedure can be performed a) open, b) laparoscopic, c) robot-assisted, or d) vaginally using a suture-assist device. Whichever method is used, the Burch procedure carries significant potential for adverse events. 3. PUBOV AGINAL SLING (PVS) A Pubovaginal Sling (PVS), also called a native tissue sling, is a sling harvested from the patient's own body tissue and placed under the bladder neck to treat SUI. The most commonly used tissues for PVS are rectus fascia (harvested and removed from the patient's abdominal wall) and fascia lata (harvested and removed from the patient's thigh). Cadaveric grafts can also be used for this procedure. Similar to many surgeries, there is a wide array of outcomes following PVS surgery. Cure rates have varied widely. One multi-institutional, randomized clinical trial in the New England Joumal of Medicine reported on 655 women who underwent either PVS or Burch. This study, authored by Albo, was a comparative trial with 24 months of follow up analyzing patients with pure SUI and patients with stress-dominant mixed incontinence. For pure stress incontinence patients, the PVS had a 66% SUI success rate vs. 49% for the Burch procedure. Treatment satisfaction was reported as 86% for PVS vs. 78% for the Burch procedure. When considering the entirety of the study population, the category of success was actually 47% for PVS vs. 38% for Burch. 23 At five years, the same study group reported overall continence rates for Burch were 24.1 %, compared to 30.8% for PVS. 24 In 2001, Richter reported on telephone interviews in an attempt to assess quality of life in PVS patients and found that 11.8% of patients were regularly performing intermittent self-catheterization (ISC) and another 6.8% had to depend on positional voiding. 25 PVS incontinence treatments are simply not risk-free. 4. MID-URETHRAL SLINGS (MUS) Mid-urethral slings, such as the Aris and Supris, represent an advancement in the treatment of SUI. Today, currently-available Type-I polypropylene mesh mid-urethral slings are recognized as the state-of-the-art standard of care for the treatment of SUI. In contrast to the PVS, which uses human tissue, the mid-urethral sling uses a polypropylene mesh. Also, 17 6 PageID #: 20053 where an PVS is placed at the bladder neck, the MUS is, as its name infers, placed at the mid-urethra. Mid-urethral slings utilize one of three approaches: retropubic (RP), suprapubic (SP), or transobturator (TOT). The retropubic approach, or "bottom-up," places the sling on each side of the urethra by entering the vaginal incision and culminating in an exit at the lateral aspect of the pubic bone on each side of the patient, creating an exit site on the right and left. The suprapubic, or "top-down", approach, begins on each side of the lateral aspect of the pubic bone and delivers the needle guide behind the pubic bone to the surgeon's awaiting finger behind the bone, and out through the vaginal incision on each side. Finally, the transobturator approach can be performed in one of two ways: "inside out" or "outside in," defined by where the needle guide originates. The "inside out" approach initiates delivery of the graft from the vagina, exiting the skin after passage through the obturator membrane; "outside in" follows the same course, but in the opposite direction, beginning through the skin and then exiting into the vagina through the incision. Appropriate full-thickness dissection allows the surgeon to ensure the sling material, once placed, lies in an appropriate "U" or hammock formation, while being flat along its width in the vaginal plane. No matter which approach is used, the surgeon's fingers can tactilely trace the path of the needle guides to their appropriate entry and exit points. VII. SAFETY AND EFFICACY OF MID-URETHRAL SLINGS The mid-urethral sling is the most extensively-researched of all surgical treatments for SUI, with the greatest degree of data-collection scrutiny and multi-institutional study designs. The Type 1 polypropylene mesh used in mid-urethral slings (such as the Aris and Supris) represents a tremendous advance in women's pelvic health. Mid-urethral slings are as effective as traditional surgery, but with significantly lower morbidity. Slings are a well-accepted standard for the surgical treatment of female SUI, because of their very positive surgical outcomes and low morbidity. As surgeons, we must consider the patient's desire to return to activity as soon as is practicable. In my clinical experience, many women elect the less invasive approach of the MUS because of their very active lifestyles at work, home and socially. These requirements led to the emergence of less invasive and successful mid-urethral sling procedures. The development of 18 6 PageID #: 20054 the MUS allowed patients to have success in the treatment of urinary incontinence while reducing overall morbidity. Over two decades ago, in 1996, Ulmsten reported on an initial series of patients who underwent a less invasive, out-patient ambulatory procedure, which later became known as the tension-free vaginal tape. 26 The procedure was designed to address the concepts entailed in the Integral Theory, a complex interplay of specific pelvic floor structures involved in maintaining urinary continence in the female patient. 27 Classic distinctions of the MUS from the PVS included the MUS's focus on the mid-urethra instead of the bladder neck, reflecting a different approach to treatment. The MUS procedure also did not pull up on the urethra, but instead was placed loosely against or near the mid-urethra, thereby decreasing the risk of post- procedure voiding dysfunction, or urinary retention. Early slings were elastic, increasing the risk of sling deformation after placement. As compared to PVS, the MUS procedure limits dissection which, in turn, reduces surgical trauma and leads to less edema and pain. Ulmsten et al. followed up their initial study with a prospective 3-year follow up which showed an 86% complete dry rate and a 11 % significantly improved rate, with one failure. They also reported no defective healing or rejection of the tape. 28 In other words, no exposures, erosions, or extrusions occurred. The choice of type 1 (low density) polypropylene mesh led to lower risk of adverse events than other synthetic materials or weaves that had been used in the past. In 2002, Ward and Hilton reported their results on tension-free vaginal tape (TVT) MUS versus Burch Colposuspension. They found the 2 procedures were equivalent at 6 months (TVT MUS 66% vs. Burch 57%); the TVT MUS had a slightly greater incidence of placing the needle guide into the bladder, however this ultimately does not require any surgical intervention. The needle guide is simply removed and replaced in an appropriate position. Meanwhile, Burch had greater incidence of: 1) delayed return to voiding, 2) increased operation time, 3) increased hospital stay, and 4) delayed return to work or normal activity; all of which are clinically relevant. 29 Around this same time, in 2001, a French urologist, Emmanuel Delorme, introduced the TOT procedure30 in an attempt to better recreate the "natural hammock" of the pubourethral ligament support structures. The principal goals of this approach were to create less risk of overcorrection and 19 6 PageID #: 20055 therefore reduce post-operative voiding dysfunction and irritative symptoms such as urgency or dysuria. This anatomic approach would reduce the risk of bladder perforations through a safe, well-studied and well-known passage zone that avoids the internal abdominal pelvic structures, thereby eliminating the major risks of bleeding and bowel injury present in the Burch colposuspension, PVS, and even TVT. The anatomic landmarks of guided passage from the out-to-in position are skin, Gracilis muscle, Adductor Brevis muscle, Obturator externus muscle, Obturator membrane, Obturator internus muscle, Endopelvic fascia behind the ischiopubic ramus and into the vagina to the surgeon's finger, and finally out of the vaginal incision. This route markedly reduces or even eliminates many potential risks or hazards present in other forms of incontinence surgery while maintaining or improving continence rate ranges and creating an anatomic "hammock" reproducing a more natural support. Since the early 2000s, there have been many additional studies supporting the safety, success and durability of the MUS procedure. 31 · 32 In 2011, the Cochrane Review of MUS concluded that the MUS was as effective as the PVS, but significantly, the MUS had shorter operative time, less voiding problems, and less onset of new urgency symptoms. The 2011 Cochrane Review also concluded similarly for Burch, where there was no statistically significant difference between cure rates for the MUS and open Burch in the short-term, but with less overall problems for the MUS; the authors concluded that MUS and laparoscopic Burch share equivalency, but only within 12 months as this was only evaluated short-term. Furthermore, the review concluded that monofilament (that is, type 1 polypropylene) grafts had higher objective cure rates and less exposure than earlier, non- Type 1 materials. 33 A 2017 Cochrane Review addressing laparoscopic Burch noted that the "newer vaginal sling procedures [MUS] appear to offer even greater benefits, better objective outcomes in the short term and similar subjective outcomes in the longer term"; the article also found that the role of laparoscopic Burch in clinical practice was limited by the lack of long-term study results. 34 With regard to approach, transobturator (TOT) vs retropubic (RP), the 2011 Cochrane review concluded that TOT had a lower objective cure rate than RP MUS, but the patient-reported subjective cure rates were equal. The TOT also had less voiding problems, blood loss, and bladder perforations, and shorter OR time when compared to RP slings. A recent meta-analysis 35 20 6 PageID #: 20056 reached a similar conclusion, finding TOT slings had a lower risk of intraoperative bladder or vaginal perforation, pelvic hematoma, UTis, and voiding lower urinary tract symptoms. In clinical studies comparing outcomes after Burch and TOT procedures, the TOT has been demonstrated to be a safe and effective option, with less operative time and shorter in-hospital stay, 36 and fewer unintended functional outcomes such as long-term voiding dysfunction and urinary retention. 37 From a review of 81 trials evaluating over 12,000 women, a subset of whom were treated with a TOT, a 2017 Cochrane review determined that in the short-term (up to one year), the rate of subjective cure of TOT ranged from 62% to 98%. The trials showed that over 80% of women with SUI are cured, or have significant improvement in symptoms, for up to five years after MUS surgery. 38 Today, MUS are considered by the overwhelming majority of experts in the field to be standard of care, myself included. This is due to their higher success and lower potential for adverse events. Success rates in the literature are dependent on the definition of success in a given study. Patient-reported satisfaction is high in the majority of studies. In my practice, we routinely see patients for follow-up for at least five years following a procedure, and we continue to see success, durability, and patient satisfaction with mid-urethral slings. In contrast, we see a 5-year downward success trend with our patients who have undergone a Burch procedure, which is similar to the published data. There are now prospective studies published in the literature including ten-year data on pure stress incontinence showing high satisfaction rates and objective cure rates with both transobturator and retropubic MUS, with very low rate of adverse events. 39 I understand that surgeons who have defended the use of midurethral slings have been criticized in this litigation because they have consulted with medical device companies. As a surgeon, I would expect companies that develop and manufacture medical devices to consult with surgeons in the field who treat patients that may benefit from the device, and believe it would be irresponsible not to do so. Such communications help inform the company and the surgeons about patient experience and assist in the development of optimal devices. Surgeons with active practices, while compensated for their time, are often compensated less for their time 21 6 PageID #: 20057 working with medical device companies than they would be with their daily practice. In my opinion, it is simply inappropriate and misleading to suggest a nefarious motive from doctors who consult with companies in an effort to exchange information for the benefit of patients. The major organizations responsible for evaluating and discerning the medical data and the use of mid-urethral slings are the American Urological Association (AUA) and an affiliated organization of Reconstructive Urogenital Surgeons known as the Society of Urodynamics, Female Pelvic Medicine and Reconstructive Surgery (SUFU), along with the American Urogynecology Society and international organizations like the International Continence Society. These organizations recommend the use of Type 1 Polypropylene Mesh Mid Urethral Slings (MUS) as a primary or secondary surgical option for women with SUI. SUFU recently affirmed this position as follows: "1. Polypropylene material is safe and effective as a surgical implant. Polypropylene material has been used in most surgical specialties (including general surgery, cardiovascular surgery, transplant surgery, ophthalmology, otolaryngology, gynecology, and urology) for over five decades in millions of patients in the US and the world. As an isolated thread, polypropylene is a widely utilized and durable suture material employed in a broad range of sizes and applications. As a woven material, polypropylene mesh is the consensus graft material for augmenting hernia repairs in a number of areas in the human body and has significantly and favorably impacted the field of hernia surgery. As a woven implant for the surgical treatment of SUI, macroporous, monofilament, light weight polypropylene has demonstrated long term durability, safety, and efficacy up to 17 years. (Citations omitted.) 2. The monofilament polypropylene mesh MUS is the most extensively studied anti-incontinence procedure in history. A broad evidence base including high quality scientific papers in medical journals in the US and abroad supports the use of the MUS as a treatment for SUI. There are greater than 2000 publications in the scientific literature describing the MUS in the treatment of 22 6 PageID #: 20058 SUI. These studies include the highest level of evidence in the peer reviewed scientific literature. The MUS has been studied in virtually all types of patients, with and without comorbidities, and with varying clinical presentations of SUI. Multiple randomized controlled trials comparing types of MUS procedures, as well as trials comparing the MUS to other established non-mesh SUI procedures, have consistently demonstrated its clinical effectiveness and patient satisfaction. Among historical SUI procedures, the MUS has been studied with as long a follow-up after implantation as any other SUI procedure and has demonstrated comparable safety and efficacy. No other surgical treatment for SUI before or since has been subject to such extensive investigation. (Citations omitted.) 3. Monofilament polypropylene mesh MUSs are a standard of care for the surgical treatment of SUI and represent a great advance in the treatment of this condition for our patients. With the publication of numerous randomized comparative trials, the MUS became the most common surgical procedure for the treatment of SUI in the US and the developed world. This procedure essentially replaced open and transvaginal suspension surgeries for uncomplicated SUI. There is adequate evidence that the MUS, for many patients, is safe and effective and associated with less pain, shorter hospitalization, faster return to usual activities, and reduced costs as compared to other options that have been used in the past. Accordingly, MUSs remain a leading treatment option for SUI surgery. (Citations omitted.) 4. The FDA has stated that the polypropylene MUS is safe and effective in the treatment of SUI. The midurethral sling was not the subject of the 2011 FDA Safety Communication, "Urogynecologic Surgical Mesh: Update on the Safety and Effectiveness of Vaginal Placement for Pelvic Organ Prolapse. " In this document, it was explicitly stated: "The FDA continues to evaluate the effects of using surgical mesh for the treatment of SUI and will report about that usage at a later date." In 2013, the FDA, in its website, stated clearly that: "The safety and effectiveness of multi-incision slings is well-established in clinical 23 6 PageID #: 20059 trials that followed patients for up to one-year." (Citations omitted.) Conclusion The monofilament polypropylene MUS has helped millions of women with SUI regain control of their lives. The MUS is a simple outpatient procedure that allows these individuals to return to daily life quickly. With its acknowledged safety and efficacy, the MUS has made it possible for more women to have access to treatment. In the past, concerns over failure and invasiveness of existing surgeries resulted in a substantial number of women living their lives without treatment for their incontinence. One of the unintended consequences of the polypropylene mesh controversy relating to pelvic organ prolapse has been the emergence of an obstacle to women seeking treatment for SUI. The MUS procedure has represented the most impactful and important advancement in the treatment of SUI in the last 50 years and has the full support of our organizations, which are dedicated to improving the lives of women with urinary incontinence. Given the substantive evidence cited, the MUS should remain a treatment option for women with stress incontinence desiring surgical therapy. The right to make an informed decision regarding her own treatment should not be taken away from any woman." The first position statement was approved by the AUGS Board of Directors and the SUFU Board of Directors in January 2014, and has been re-approved in June 2016 and February 2018, and SUFU again affirmed in February 2019. I have reviewed and agree with this statement. Similarly, the AUA has also adopted a Position Statement on the Use of Vaginal Mesh for the Surgical Treatment of Stress Urinary Incontinence (SUI), which recognizes its support for the use of synthetic polypropylene mesh slings for the treatment of SUI. The AUA's Board of Directors most recently updated this statement in October 2018. In August 2016, the following organizations, "together representing more than 84,000 urologists, gynecologists and other healthcare professionals that provide care to women with stress urinary incontinence (SUI), reaffirmed 24 6 PageID #: 20060 their collective support for the use of midurethral slings, including synthetic polypropylene mesh slings, for the surgical treatment of SUI": • American Urological Association (AUA); • American Congress of Obstetricians and Gynecologists (ACOG); • American Urogynecologic Society (AUGS); • International Continence Society (ICS); • International Urogynecological Association (IUGA); • Society of Gynecologic Surgeons (SGS); and • Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). VIII. RISK OF ADVERSE EVENTS FROM SURGICAL REPAIR OF STRESS URINARY INCONTINENCE No surgical procedure is without risk. In my experience, as supported by the extensive literature, mid-urethral slings such as the Aris and Supris pose overall lower risks for patients than the earlier Burch or PVS procedures. Each procedure carries its own unique, and non-unique, risk of adverse events. A. Burch Procedure Whether performed laparoscopically, as an open procedure, or robot- assisted, the Burch procedure carries significant risks with comparable or lower efficacy than available alternatives, the PVS 40 and MUS. 41 Serious and morbid adverse events from the Burch procedure are well-documented, 42,43,44 .45 but their true frequency is unknown because we lack a reporting mechanism. 46 For example, adverse events post-Burch procedure are not required to be reported to the FDA or any other reporting body. The Burch procedure carries intra-operative and peri-operative risks inherent to a surgery of its duration and location of operation. The Burch procedure also carries significant risk of post-operative adverse events. Burch procedures typically carry operative times of greater than 60 minutes, as compared to 10 to 20 minutes for a mid-urethral sling. Surgeries of duration greater than 60 minutes carry an increased risk for deep vein thrombosis, pulmonary embolus, and cerebrovascular events, all of which are life threatening. Increased intra-abdominal and intra-thoracic pressures decrease blood flow to major organs including the heart, lungs and kidneys. 25 6 PageID #: 20061 These organs are susceptible to low oxygen conditions and subsequent organ damage and associated risk. In laparoscopic or robot-assisted procedures, carbon dioxide air embolus can be fatal and requires emergency measures for correction, including invasive procedures. Even eye complications and cardiopulmonary compromise have been reported from patient positioning in a Trendelenburg position (where the patient is positioned with her head down and legs up forcing the blood toward the head). Open surgery adds additional risk of wound complications, longer recovery, increased pain, and injury to surrounding organs and nerves. It also creates a significant risk of bleeding/hematoma formation, and urinary tract infection. One study reported the overall incidence of complications associated with the open Burch procedure to be over 40 percent. 47 Laparoscopic Burch procedures are not without their own significant risks. It is worth noting that many patients are not even candidates for prolonged laparoscopic procedures. For instance, patients with existing lung or breathing disorders such as COPD, tobacco use, asthma, congestive heart failure, or reactive airway disease may not tolerate anesthesia. Similarly, patients with a significant history of previous surgery or history of known scar formation will have higher risks for injury to surrounding organs, which can lead to tragic results. Beyond the standard risks of surgery, laparoscopy (both retroperitoneal and transperitoneal) and robotic-assisted surgery also add unique risks. Significant risks from laparoscopic or robot-assisted procedures result from trocar injuries during blind insertion into the abdominal cavity. Reported injuries from pelvic or abdominal surgery include hematoma; umbilical hernias; umbilical wound infection; penetration of the blood vessels; small or large bowel injuries; and major blood vessel injury of the inferior vena cava, left common iliac vein, right common iliac vein and artery, pelvic veins and even the aorta. 48 ·49 · 50 Blood vessel injuries can result in life-threatening hemorrhage. Injuries to the bowel can cause a life-threatening, delayed infection of the abdomen (peritonitis), or necessitate a life-altering stool bag on the abdomen (colostomy). Thermal burns from laparoscopic and robot-assisted approaches are well-documented in the literature. Sustained electrical burns from the cautery device used in surgery can lead to bowel or urogenital injury with severe life-threatening or life-altering implications. Post-operatively, the Burch poses additional risks. There is a risk of 26 6 PageID #: 20062 developing adhesions (scars, or abnormal attachments between tissues and organs), which in abdominal surgeries has been reported as high as 50% or more 51; adhesions develop as a result of wound healing. The risk of adhesions presents a very common complication of abdomino-pelvic surgery. The risk of developing adhesions is comparable for both open and laparoscopic procedures. 52 Complications of adhesions include chronic pelvic pain, bowel obstruction, and infertility. 53 In particular, small bowel obstruction poses the most significant problem. The Burch procedure also increases the risk of new-onset prolapse, including enterocele (where the small bowel herniates into the vagina), posterior, or apical prolapse, thereby creating the need for additional surgery. 54 · 55 To reduce this risk, the patient would require an additional, preemptive surgery to close off the location where the small bowel would herniate-a surgery with its own additional risks and complications. If the patient chose not to proceed with the additional surgery, then she would need to understand that she might develop a symptomatic prolapse in the future due to the Burch procedure. Additional, but not unique, complications are also seen with Burch procedures, among them voiding dysfunction, 56 onset of urgency urinary incontinence, urgency/frequency syndrome, and post-Burch syndrome (pain in one or both groin regions at the site of Burch procedures, which has been reported in up to 12% of patients 57 ·58 ·59 · 60). Other reported complications include the onset of intrinsic sphincter deficiency due to Burch sutures pulling the bladder neck open, stranguria (voiding pain immediately after completion of voiding), ureter injury needing emergency surgical repair, fistula of the bladder to the vagina or to the skin, and foreign body erosion to the bladder or urethra. Nerve pain (neuropraxia), chronic pelvic pain 61, and pain during intercourse (dyspareunia) 62 are also known and reported potential complications of Burch procedures. Erosion is seen from Burch sutures, especially non-absorbable braided sutures. 63 · 64 Burch procedures can also result in unrecognized ureteral injury and subsequent kidney damage, which is more likely in patients with a history of previous surgery. 65 Some patients treated with Burch procedures experience the delayed adverse event of ureteral kinking or obstruction. 66 These patients often present with diminished kidney function. Partial obstruction or strncturing does not cause pain or fistula formation, therefore going undiagnosed as an 27 6 PageID #: 20063 mJLiry. Later, the complication is identified during evaluation for an unrelated condition. In addition, the partial obstruction may not affect blood test results because a one-sided obstruction may not change the overall kidney function if the other kidney is healthy and unobstructed. Over time, patients present to their physicians with variable symptoms including recurrent urinary tract infection, lower abdominal discomfort (not pain), kidney stones, voiding problems, reduction in kidney function, or microscopic blood in the urine. Major surgery is then required to reconstruct the kidney tubes or to remove a non-functioning kidney. The Burch presents all of these risks for an adverse event without offering additional efficacy benefits for treating SUI. A recent (2017) Cochrane review described 55 studies involving 5,417 women who underwent open Burch colposuspension, and the overall findings were consistent with its 2003 iteration. The review found overall cure rates to range between 68.9% and 88.0%. Continence rates at one year were 85-90% but dropped to 70% five years after surgery. 67 In 2012, the E-SISTEr trial concluded, in a five-year prospective evaluation, that the Burch procedure was significantly associated with long-term incontinence. 68 In short, the Burch procedure is no more effective than a mid-urethral sling, but carries significant morbidity and unique risks, many of which are life-threatening or severely life-altering. In large part because of these concerns, physician and patient dissatisfaction with the Burch procedure led to the development and adoption of sling procedures. B.PVS Native tissue slings present numerous potential complications for patients, and an increased rate of adverse events compared to MUS, 69 and perhaps even the Burch procedure, although they are often not reported. 70 Like the Burch procedure, there is no regulatory body that tracks complications with PVS. A randomized clinical trial in the New England Journal of Medicine that compared the Burch procedure against the PVS found that the PVS had more UTis, difficulty voiding, and post-operative urge symptoms. Serious adverse events were similar. Notably, all of the repeat surgical procedures for urinary retention were performed in the PVS group. Post-operative urgency unnary incontinence (UUI) was 27% for PVS and 20% for the Burch group. 71 28 6 PageID #: 20064 This same trial found significant complications with both procedures. Voiding symptoms were higher in PVS. PVS also had a higher rate of UTis (48% vs. 32%), difficulty voiding (14% vs. 2%), and postoperative UUI (27% vs. 20%). However, continence rates were better for PVS. All of the repeat surgical procedures for bladder outlet obstruction (19 of 20) were performed in the PVS group. PVS and MUS are procedurally similar - both use guided passage of small ergonomic guiding devices to place the sling - but differ in the location of the sling placement. The PVS is located at the bladder neck while the MUS is located at the mid-urethra. Because PVS, unlike MUS, is placed at the bladder neck, ureteral injury or obstruction can occur during a PVS, similar to a Burch procedure. The PVS is supported upward, which can kink and obstruct the ureters (the tube draining urine from the kidneys in to the bladder). Ureteral injuries are very serious complications that can lead to infections, decreased kidney function, pain, and potential kidney failure if unrecognized. 72 The PVS and MUS also differ in the sling material implanted. Unique adverse events result from use of the patient's own harvested tissue. Disadvantages of PVS harvested from the rectus fascia of the abdominal wall, as compared to mid-urethral slings, include increased operative time, longer hospital stay, increased post-operative pain, incisional infection, abnormal fluid collections needing drainage, hernia formation through the harvest site, and longer recovery time and return to normal activity. Known adverse events from PVS procedures, regardless of the fascia used, include bleeding, infection, bladder injury, bowel injury, ureteral injury or obstruction, dyspareunia, and erosions. Although PVS and MUS present some common risks, PVS presents additional complications related to the harvest site: bleeding, wound infection and dehiscence, hernia, and pain syndromes. Additionally, neuropathy from entrapment of nerves can occur during harvesting with PVS; this can be long-term and require additional intervention. Similarly, disadvantages of PVS harvested from the thigh include increased operative time, leg pain, infection, abnormal fluid collections needing drainage, bleeding, and longer recovery time and return to normal activity. Dyspareunia after PVS has not been reported on routinely in the literature due to the lack of studies using validated questionnaires on female sexual function (for example, the PISQ-12 questionnaire). The studies 29 6 PageID #: 20065 focused on incontinence cure and voiding function outcomes at the time of their publications, and few addressed sexual function. Accordingly, data is sparse and cannot be adequately compared to MUS data. In my own clinical experience, I have seen dyspareunia from PVS procedures. Although infrequent, erosions into the urethra have been reported with PVS. PVS erosions can occur because the operation requires tensioning under the bladder neck. However, if the PVS erosion is located along the bladder sidewall, this suggests that the sling was likely placed in that location during the original operation. C.MUS Pelvic reconstructive surgeries involving mid-urethral slings are not without potential adverse events, as is the case with any surgical procedure. The most frequently reported adverse events are temporary, transient, and treatable. Mid-urethral slings are safe and effective in the management of SUI when implanted by skilled and knowledgeable surgeons in the appropriate patient. Sufficient data supports this position. Surgical complications are not unique to MUS procedures. Many of the reported events appear to be intraoperative technical errors unrelated to the surgical implant utilized. For instance, delivery of the graft guides into the bladder or inadvertent pass- through of the guide into the sulcus are surgical, technical errors. Voiding abnormalities are commonly reported following MUS, PVS and Burch, however, the TOT MUS approach has the least overall voiding problems. The UITN (Urinary Incontinence Treatment Network) performed a multi-center randomized clinical trial, 73 which concluded that most adverse events resolved without long-term problems. It noted most serious adverse events were greater in the retropubic group (RP) versus the transobturator group (TOT). Although the neurologic symptoms were greater in the TOT group, the authors reported they were usually mild and had resolved by 6 weeks post-surgery. Of the 597 patients treated (299 patients treated with a TOT, and another 298 in the RP group), 4 (0.67%) had unresolved neurologic symptoms at 24 months. Performing additional surgery at the time of the MUS increased the frequency of adverse events. For example, additional prolapse surgery added to risk factors like UTI, which were effectively treated with antibiotics. 30 6 PageID #: 20066 The most common adverse events reported in the study were technical surgical problems attributable to the surgeon's technique. These are easily identifiable and treatable intraoperatively, without long-term consequence. These included bladder perforation in 15 patients (all in the RP approach) and vaginal skin perforation (19 reports). They were reported as SAEs using the benchmark that additional surgical time or procedure was needed to address the condition during the first surgery, but no additional surgery was needed to correct these events. These injuries are not unique to MUS procedures and are also seen in Burch and PVS procedures. We perform cystoscopy routinely in urinary surgery to help identify needed placement corrections and resolve them prior to leaving the operating suite. Overall, the literature reports similar UTI rates after MUS, PVS, and Burch. For any procedure, UTI reporting is not standardized, and UTis are likely overreported. In my experience, UTI should be documented by an appropriately-collected specimen and culture. A population-based retrospective cohort study74 by Gurol-Urganci et al. recently found that, of over 34,000 women treated with a TOT, the rate of sling removal over a 9-year period was estimated to be 2.7%. The reasons for removal were unclear because the data was obtained by relying on procedure coding. The study could not provide insight into the basis for MUS removal, and the study also could not account for relevant clinical and patient characteristics. In my experience, the reasons for sling removal are not mesh-related, but result from other conditions that over time impair voiding such as detrusor underactivity or other changes in continence status. The 2011 Cochrane review addressing MUS (62 trials involving 7101 women undergoing MUS) concluded that MUS was as effective as PVS and Burch colposuspension for the available study period but with less post- operative complications. 75 In a 2017 Cochrane review, the overall adverse event rates from MUS remained low, with high subjective cure rates. Significantly, initial groin pain was reported to be resolved in the short-term. Viewing the data as a whole, exposure rates for both RP and TOT MUSs remained low, at 2.1 % and 2.4%, respectively. 76 If exposure of a surgical implant occurs, the exposure is usually easily treated, including in-office or through a minor outpatient procedure, and without long-term consequences. 77 I have personally been referred these patients in my clinical practice with long-term outcomes being positive. In fact, I have seen foreign body exposures in patients who underwent pelvic 31 6 PageID #: 20067 floor surgery or incontinence surgery without synthetic mesh. Non-mesh exposures that I have seen include native tissue grafts, suture material, xenografts, and allografts. They present similarly, and treatments are similar, with positive outcomes as well. The Lose editorial cited by Plaintiffs' experts contains opinions that are not consensus opinions, and citing the article as such is misleading and inappropriate. Nonetheless, even this opinion piece does not recommend abandoning the TOT approach and instead acknowledges that TOT is often the "preferred" approach. The overwhelming clinical data supports the use of MUS. In my roughly two decades of experience, an aggressive removal of a synthetic MUS has not been necessary to improve the patient's condition or treat her symptoms. If a removal is warranted, removal procedures do not require aggressive intervention and dissection. Guidelines issued by AUGS and ACOG note that, where an exposure occurs, "Excision of the entire mesh usually is not necessary." Moreover, removal procedures require local anesthesia and minimal dissection for removal. These same Guidelines state that "there is no role for intervention" in "women who are not symptomatic," and that well-incorporated mesh should not be removed "unless there is a specific therapeutic indication." 78 D. Importance of Surgical Skill and Experience Surgical skill is an important factor in the success of any surgery. It is also the most variable. Incontinence surgical treatments, like many surgical treatments, can be performed safely and effectively in the hands of surgeons employing appropriate surgical technique. Although opponents of synthetic mesh sling procedures argue that MUS procedures are dangerous because they require the use of "blind trocars," this is an unfair criticism; use of guides is not unique to pelvic surgeries. Many other types of laparoscopic surgery rely upon the use of trocars and are considered standard of care. For instance, in laparoscopy, such as the laparoscopic Burch, surgical cameras and instruments are inserted through trocar-guided ports that are placed "blindly" into the body. Skilled surgeons use trocars to pass through the abdominal wall into the abdomen or pelvis where improper placement could lead to injury to surrounding organs or blood vessels and result in significant morbidity. When first introduced, laparoscopy was deemed "unsafe" by many surgeons 32 6 PageID #: 20068 in the field. Yet laparoscopy first performed roughly four decades ago is now the standard of care in numerous operations, including gallbladder, appendix, bowel, tumor removal, chest surgery, prostate cancer, and hysterectomy. A comprehensive understanding of the anatomy allows a skilled surgeon to safely navigate an operation using trocars. Surgical knowledge is only one aspect of success. Equally critical is the surgeon's technical ability. A surgeon's skillset is influenced in part by controllable factors such as training and the number of surgeries performed. There are also factors that cannot be controlled, like the inherent operational skill of the surgeon. Much like any profession, the skills of the surgeon can vary greatly. Both the surgically skilled and unskilled are knowledgeable and professional, however the skilled surgeon operates with precision. This precision reduces tissue trauma, imparts exactness of the incision, creates accuracy in the dissection, and allows fluidity and control of the operation that is simply superior. The art of surgery is inherent in the surgeon and the visualization of the surgery is often innate to them. Some physicians, despite training, simply do not operate with sufficient precision to become proficient surgeons, even through long residency and fellowship trainings. In addition to surgical skill, surgical volume and experience are an important factor in surgical outcomes. 79 ·80 ·81 ·82 This is not a concept unique to MUS implant surgery. Across surgical fields, those surgeons who have greater experience performing a particular surgery will have generally better outcomes with lesser complications. 83 ·84,85,86 IX. RISK FACTORS FOR POOR SURGICAL OUTCOMES All surgical procedures carry risks, including the risk of a poor outcome. Pelvic floor reconstructive surgeries that use no surgical mesh implants carry the risk of pain, dyspareunia, bleeding, nerve entrapment, hematoma, infection, abscess, bowel and bladder injury, recurrence, and the need for repeat surgery, and suture exposure and erosion, to name a few. No surgery is without potential complications. There are many factors that put a patient at an increased risk of poor surgical outcome. For example, any condition that impacts a patient's tissue healing can affect surgical outcome. Similarly, implant placement is important~ if an implanting physician places the sling too tightly, or places it in the wrong space, the patient's likelihood of a poor outcome increases. In 33 6 PageID #: 20069 many instances, where a poor outcome occurs, its reasons are multi-factorial, in that a patient has numerous issues that contribute to that outcome. The surgeon selects a particular operation for a specific patient, viewing that patient's medical history in its totality. This is why a surgeon should have a knowledge of multiple approaches to the management of conditions such as urinary incontinence. While it is not possible to identify or list every reason that a complication or adverse event may occur in a particular patient, certain risk factors appear frequently. Although not an exhaustive list, the following are among the risk factors that a surgeon should consider and discuss with an individual patient before performing a surgery implanting a MUS. A. Smoking A smoking history places a patient at an increased risk of poor wound healing, whether or not her pelvic reconstructive surgery utilizes a mesh implant. Although not a direct contraindication to implant surgery, smoking is a known cause of poor tissue healing, poor tissue quality, and long term weakening of tissue structures. 87 Of course, simply because an additional surgery may be required does not mean that the medical device used was defective. Surgeons and their patients should discuss the risks created by smoking during the pre-surgical consent process. I routinely discuss the risks posed by smoking in my practice with my patients. It is generally accepted by surgeons in all surgical specialties that wound healing can be delayed or incomplete in tobacco users, regardless of the surgery or use of an implant. The American College of Surgeons has issued a position statement that directly addresses the role smoking may play in poor surgical outcomes: "Smoking before and after surgery has been associated with increased postoperative complications, increased hospital costs, and more frequent use of medical resources. Tobacco cessation has been prioritized as a quality improvement performance measure by The Joint Commission and the Centers for Medicare and Medicaid Services. Surgeons have an active role in smoking cessation counseling and this series of resources-including the new ACS position statement-support the surgical community with focused 34 6 PageID #: 20070 resources on best practice methods for communicating smoking cessation to patients." 88 Moreover, the Aris and Supris Instructions for Use have long warned that "[t]he risks and benefits of using" Aris and Supris "in patients with compromised immune systems or any other conditions that affect healing should be carefully considered." Cigarette smoking leads to poor tissue healing. Of note, alternative surgical treatments for SUI also carry increased risk for cigarette smokers. No treatment for these patients is risk free, and more morbid procedures are likely to increase a smoker's risk of complications. Decisions about the most appropriate procedure by which to address conditions such as prolapse and stress urinary incontinence must be based on the potential risks and expected benefits of each option for each patient. B. Estrogen status. Post-menopausal women may have compromised vaginal tissue. The degree to which estrogen status may limit the role of a MUS is a clinical decision to be made by the surgeon. It is important to counsel patients who have pre-existing dyspareunia or pelvic floor discomfort from loss of estrogen that the symptoms may continue after pelvic surgery, regardless of the use of a MUS. Dyspareunia can occur in aging women who have not had any pelvic surgery at all. In fact, one-quarter to one-third of post-menopausal women without pelvic surgery report dyspareunia. C. Prior Pelvic Surgery A prior pelvic surgery - whether a hysterectomy, POP repair, previous SUI repair, or other surgery in the pelvic region - puts a patient at increased risk of poor surgical outcome. A recent study found that a previous hysterectomy has a strong association with a need for sling revision or removal. 89 Previous pelvic surgery also creates a risk of pelvic pain and adhesion formation; put simply, scarring from an earlier surgery can complicate the results of a later surgery. 35 6 PageID #: 20071 D. Concomitant POP Surgery In addition to having a prior pelvic surgery, concomitant surgery to repair pel vie organ prolapse has also been determined to present a risk factor for post-operative complications. 90 While these four factors are commonly-reported as independent risk factors, it is important to realize that this is not an exhaustive list. Surgeons must look at the cumulative patient health history to determine the sources of the patient's concerns. X. THE ARIS AND SUPRIS MID-URETHRAL SLINGS I have used mid-urethral slings for nearly two decades. I have evaluated and used various sling implants during my career but ultimately chose Colop last' s Aris as my transobturator mid-urethral sling (TOT) of choice and Coloplast's Supris as my retropubic (RP) mid-urethral sling of choice, because of the grafts' characteristics. In my clinical experience, these implants have provided excellent outcomes for my patients. For the purposes of this report, because the mesh material used in Aris and Supris is the same, and the only difference is the surgical approach, my opinions referencing Aris in this report are equally applicable to Supris with regard to graft integrity and performance. The Aris and Supris are implantable, synthetic mid-urethral medical device grafts indicated for the surgical treatment of SUI. These slings both have many sought-after characteristics that make them superior to previous MUS surgical mesh used to treat SUI. Aris/Supris Favorable Characteristics Pore Size: Aris is a Type 1, macroporous surgical mesh implant. The Aris pore size not only meets, but exceeds the greater than 75 micron pore size that defines an Amid Type 1 macroporous mesh to facilitate adequate tissue in-growth and host response. In fact, the Aris pore size (approximately 374 microns) is approximately five times beyond the threshold determined to be a Type 1 surgical mesh. 91 Aris's pore size allows for tissue ingrowth without impeding macrophage (a type of inflammatory cell that is known to be present during wound healing) activity. Aris's low elasticity prevents pore size deformation, 92 allowing the pore sizes to remain stable for proper in-growth of tissue after the sling is placed. 36 6 PageID #: 20072 Criticisms that the Aris mesh pore size is too small are simply unsupported. The pore size in Aris is more than sufficient to allow tissue in growth and access to macrophages. Density: Density= mass (or weight)/volume. Aris and Supris are the least dense MUS on the market. Aris/Supris mesh has a lower volume per strand with nearly 50 percent less thickness in the graft diameter as compared to other available TOT implants. Comparative Slings Characteristics 112g/m' 114g/m' 108g/m' 113g/m2 94g/m' 0.64mm 0.70mm 0.65mm 0.54mm 0.65mm 540mm/8cm 500mm 445mm/8cm 450mm 510mm 30.1% -30% -30% 25% 51.9% Aris's low mesh volume, due to lower thickness and fiber diameter, reduce foreign body response. Low density Type I mesh has been shown to reduce foreign body response and allow for improved tissue integration and improved wound healing. I prefer the Aris sling due to its low volumetric mass density. Less material is needed to get the required support. While it is generally accepted that low-density meshes improve tissue response, a mesh can become too light to be effective for mid-urethral support. Early attempts at lighter-weight, larger pore, lower-volume, elastic mesh for MUS failed because they were of insufficient tensile strength to provide adequate support under the mid-urethra. As such, the literature addressing optimal characteristics for POP mesh does not apply to MUS due to anatomic and functional differences necessary to provide urethral support versus pelvic organ support. Inelasticity: Aris/Supris also is relatively inelastic, meaning that it does not stretch or deform under load (such as a pelvic floor event-cough, sneeze, laugh, exertion). Inelasticity is different than rigidity. Rigidity typically refers to an inability to bend, as opposed to an inability to stretch. However, Aris is not rigid. While some authors refer to Aris as "stiff', Aris is actually highly flexible. "Stiffness" is simply a scientific measure of how a material responds to force over a surface. This measure indicates how well 37 6 PageID #: 20073 a design can handle a stress (force over an area) load without deformation in order to provide support. This is Young' s modulus principle. While highly flexible, the Aris and Supris have less elasticity than other available MUS. In my experience, this low elasticity provides a clinical advantage because it enables the surgeon to more accurately adjust the support of the sling to ensure the appropriate placement. Further, because the sling will not deform under load, Aris has the advantage of ensuring maintenance of porosity, as the sling does not rope or otherwise change architecture after exposure to the normal forces expected in the pelvic floor. Other slings can deform and experience pore collapse under such forces, as has been demonstrated in the literature 93 and was demonstrated by the bench tests showing decreased surface area of other slings under pelvic floor load as set forth below. Slings Under Pelvic Floor Event Forces Aris/ Supris· Coloplast TVT{TVT·O· Gynecore Monarc/Sparc · ASTORA Obtryx /Lynx - Boston Scientific ~1111111111111~, ======··====:, i§~!! ! !U~l r - -! . l f(,rn •Aris/ Su_pris Sling· maintains integrity under a cough simulation (2lb force) Each sling wast nsio ed from 0 -21bs and photogra~hed; average measurements cha .ges from 3 test ore shown demonstra ing decreos .' surface art:a In my view, the inelasticity in Aris sling mesh recognizes the differences in the front one-third of the vaginal anatomy, as compared to the back two-thirds. The front third is subject to different stresses and serves a different purpose, and the Aris design reflects that difference and explains why it is appropriate to have a different design for mesh used for incontinence versus mesh used for pelvic reconstructive surgery to treat pelvic organ prolapse. Typically, in the continent woman, the native tissue supporting the mid-urethra is firmly attached, providing a backboard for urethral stresses. An inelastic sling provides more consistent support during the tissue in growth process and thus reduces the variability in outcome from 38 6 PageID #: 20074 the procedure. And while the Aris sling's configuration prevents pore collapse, and does not stretch, it is also extremely soft and supple, which assists the surgeon during the implantation process. By contrast, I have observed more elastic slings having recoil properties, creating additional risk to the urethra. In an elastic sling, upon increases in pelvic floor pressure like Valsalva, a propulsive energy can be created when the sling is under stress, and creates the risk of recoiling back at the urethra. This can increase the risk of urethral injury and erosion. In my experience, the Aris sling reduces risk of an injury or erosion to the urethra itself because its shape does not band under stress. Smooth Edges/Sheathless. Not only are Aris and Supris flexible and soft, these mesh slings have smooth edges that allow the sling to pass through the tissue without significant damage to the surrounding issue. The graft easily passes through the intended tissue structures effortlessly without fraying, distortion, or pore disruption. As such, unlike other slings, a sheath is not required. This ensures that the location where the surgeon places the sling is the location where the support stays, without the risk of being altered by the act of removing the sheath. The lack of a sheath also allows the surgeon to assess the sling placement and, if the surgeon felt optimum placement did not occur on first attempt, they can re-pass the graft to a proper positioning. Any assertion that the absence of a sheath increases tissue damage, or leads to an increased risk of erosion, infection, migration, slippage, pain, and encapsulation is misleading, unsubstantiated, and not based in fact. The sheath provided with other slings is necessary to address two characteristics that Aris does not have: tanged/barbed edges and elasticity. The sheath is necessary for slings with tanged/barbed edges because those slings would otherwise unduly damage surrounding tissue during implantation. The decrease in tissue trauma associated with Aris' s smooth edge design appears to reduce damage and the inflammatory response. Further, because of Aris's inelasticity, the Aris graft maintains its pore size and I. I cm width to support the midurethra as intended after placement. Because more elastic slings may permanently deform or band under pressure (such as pulling), the sheath is necessary to reduce the risk of deformation and banding of elastic slings from the pulling forces that occur during the implantation procedure. In elastic slings, when the sheath is ultimately removed, the sheath cannot protect against potential deformation from pelvic forces after implant, a risk inapplicable to Aris mesh. 39 6 PageID #: 20075 The absence of a sheath with Aris slings prevents deformation of the sling from the act of sheath removal. In my experience, the act of sheath removal has a tendency to deform the sling and increase the risk of sling migration. With Aris, unlike other TOT slings, I have not had to go back to the operating room for a sling revision due to loss of urethral support from sling migration or deformation. A sheath travels along the same pathway as any sling without a sheath, and there is no evidence that the absence of a sheath increases the risk of bacteria being present in the surgical route after the sling is in place. Indeed, whether a sling is implanted with or without a sheath, the vagina is cleansed before implantation to minimize the risk of bacterial contamination. The risk of bacterial contamination during vaginal surgery is addressed with appropriate surgical preparation, including prophylactic antibiotics and skin and vaginal mucosa cleansing protocols. In my extensive clinical experience in using Aris/Supris, I have not seen clinical infection along the surgical route. Much of the literature addressing optimal mesh characteristics has been focused on mesh used to treat pelvic organ prolapse, a distinctly different medical condition, and a part of the vagina having a different function and exposed to different forces. The prolapse mesh literature does not address the mesh used for SUI treatments. Nonetheless, of all the available synthetic slings, Aris/Supris mesh is the most flexible, least dense, and softest, with the least amount of material. Initial support is provided by the graft and further augmented by tissue ingrowth to provide efficacious results. It must be noted that Aris/Supris mesh does not "shrink" with implantation in the human body. Tissue ingrowth does and should occur, and is in fact intended. I have seen no clinical evidence of clinically relevant "contracture" or "shrinkage" of Aris or Supris mesh. To the contrary, in my experience, patients I have followed have been treated with Aris and Supris have experienced good tissue ingrowth and maintained their width and length over time. As with all surgical treatments for incontinence, recurrences can occur. In my clinical experience, over time, if there happen to be patients who may develop return of SUI, and they choose to consider repeat surgery, it is my clinical practice to remove the original implant. Based on my experience, it has not been challenging to remove the sling and upon 40 6 PageID #: 20076 examination of the explanted device, there was no evidence of distortion, pore collapse, fraying, cracking, breaking, shrinking, or degradation of the graft. In fact, I have seen appropriate tissue ingrowth without significant chronic inflammation, abnormal fibrosis, or evidence of infection. I have seen no clinical evidence of mesh damage in vivo with Aris mesh. The mesh design of Aris and Supris does not increase the risk of erosion, migration, slippage, tissue damage, granulomas, pain, or encapsulation. There is no evidence supporting the theory that stress shielding occurs in MUS. Having used this graft in well over a thousand patients, any allegation to the contrary is clinically unsupported and misleading. Clinical Data As set forth above, significant clinical data establishes that synthetic, Type I macroporous polypropylene MUS is an effective treatment for stress urinary incontinence. This data alone is enough to support the use of the Aris and Supris which possess the key qualities that allow for an effective and appropriate sling implant, including its material, pore size, density, and function. It is among the cJass of surgical implants recognized by every medical organization that treats patients with incontinence as an appropriate surgical option for surgeons to consider for their patients. While the general sling data establishes the safety and effectiveness of Type 1 MUS, clinical data specific to Aris further establishes that the Coloplast surgical mesh slings are a safe and effective treatment in the hands of skilled surgeons in appropriately-selected patients. Patient experience with Aris has been reported in numerous studies, and physicians analyzing the clinical data consistently conclude that the Aris is a safe and effective treatment for stress urinary incontinence. I have reviewed peer-reviewed literature, including multiple abstracts regarding patient experience presented at conferences as wel1 as studies involving Aris published in manuscript form. The literature relating to Aris which I have reviewed can be sorted into three main categories: (1) a prospective registry collection; (2) the combined clinical trials known as Aris 1 and 2; and (3) additional investigator-initiated studies. While no one study drives my conclusions, the totality of the data informs my decision-making and opinions. I understand that Coloplast acquired the Aris device from another company (Mentor) and that at the time of acquisition, Mentor had initiated 41 6 PageID #: 20077 two clinical trials as well as created a registry of patients in Europe. Coloplast continued these studies and worked with the study investigators to prepare numerous publications reflecting the data. At the same time, other surgeons not involved in either the prospective registry or the Aris 1 and 2 began reporting on their own clinical experience at medical conferences and within the peer-reviewed literature. I have reviewed those publications and the data provides additional support for a favorable safety and efficacy profile for Aris in both the short- and long-term. Aris Registry After Coloplast acquired Aris, the prospective registry continued, with information reported from as many as 16 centers who treated patients using the Aris surgical mesh sling to treat stress urinary incontinence. The published results of the registry concluded that Aris was effective in the treatment of SUI with low occurrences of post-operative complications. As one of the first or sentinel registries of its kind, the surgeons were assessing safety and efficacy. The data from the registry initially was reported in a small patient population that grew over time, with frequent analysis so that patient experience could be monitored over time. As the patient population grew, patient experience remained consistent and positive. 94.95 .96.97.98.99 By the time the Aris registry ceased, follow-up data had been collected on a large patient set for a relatively longer term. For example, Grise ct al. and Saussine et al. both analyzed the post-operative outcomes of hundreds of patients with follow-up of at least 2 years (with some patients up to 54 months) from 16 and 11 centers, respectively, finding that efficacy was maintained over that period. 100 101 In Grise, efficacy was measured analyzing the subjective reports of urine leakage, whether leakage was absent (cure), decreased (improved), or unchanged/worse. Available data was analyzed at six, twelve and twenty-four months, a standard timcframe for clinical evaluation in that era. At six months, 96.5% of patients analyzed were cured or significantly improved, which remained relatively consistent at 12-24 months (92.7 %) and 24-54 months (88.3%). 102 Saussine used physician assessment to determine whether a patient was "cured," "improved," or "failed." There, 453 patients had a least 12 months of follow-up, with 97% deemed cured or improved. At 24 months, 95% were assessed as cured or improved, based on follow-up data from 390 patients. 103 These investigators determined that the results showed the Aris sling 42 6 PageID #: 20078 demonstrated clinical efficacy from both a physician and patient perspective after 2 years. Additional publications analyzing the registry data at different time points consistently identify favorable subjective and objective outcomes. 104 105 106 Regardless of whether efficacy was measured subjectively or objectively, Aris was shown to be effective in treating SUI. Further, at least one center analyzed its results after 3 years and concluded that its efficacy was sustained over time. Castaings et al. analyzed data from one of the registry centers, where all of the 185 patients included in the study were implanted at the same center. Follow-up data of at least 36 months was available for 68 patients and showed 85.3% were cured and 91.3% of patients with continued follow-up were cured or improved. Castaings compared the cure and improved rates at 3 months (87.5%, 97.2%) with those at 36 months (85.3%, 91.2%) and found that the difference was not statistically significant. As such, the Castaings authors concluded that there was no degradation of urinary incontinence results over time. 107 Data relating to adverse events was collected from the registry centers and reported in the various publications. Erosion/extrusion rates ranged from 0% to 1.2% with the rate described as low, few, or minimaI. 108 109 110 111 112 113 Where treatment information was provided, the erosions/extrusions were noted to have been treated by local excision with no repercussions. 114 115 Castaings, the single-center analysis of the registry, reported "no cases of late-onset serious complications (urethral or vaginal erosion)." The authors noted that "[i]t has been demonstrated that the macroporous, knitted, polypropylene mesh prostheses are more effective at preventing vaginal erosion" - than, for example, multifilament polypropylene - and that "Erosion prevention is conditioned by the type of sling used, but also by the technical quality of the surgical gesture." 116 These observations are consistent with my clinical experience. Aris 1 and 2 Next, the clinical trials known as Aris 1 and 2 were multi-center prospective studies designed to evaluate the safety and efficacy of Aris in the treatment of SUI. Each study involved patients prospectively enrolled at four centers in the United States, for a total of eight centers. Due to slow 43 6 PageID #: 20079 enrollment, the data from the two studies ultimately was combined to provide a larger dataset for analysis. From 2007 to 2010, five abstracts were published from Aris 1 and 2 (one from Aris 2 alone and four from the combined dataset), each of which I have reviewed. The Aris 1 and 2 studies demonstrated similar efficacy in the treatment of mixed and stress urinary incontinence on both the objective and subjective measures. 117 · 118 • 119 · 120. Aris 1 and 2 also reported data relating to post-operative adverse events. Later analyses, as reported by Klutkc 121 and Ghoniem 12 2, found 7/117 patients with vaginal exposure of the sling. All of the reported exposures were treated successfully with local excisions. In each instance, the authors of the Aris 1 and 2 publications concluded that Aris was safe and effective in the treatment of stress urinary incontinence and mixed incontinence. Investigator-Initiated Studies The last group of studies involving Aris - those initiated by independent investigators - range considerably in design, patient population size, length of follow-up time (ranging from 3 months to 9 years), and demonstrate variable surgeon proficiency. Nevertheless, on the whole, these studies consistently report successful efficacy and safety findings consistent with those identified by investigators participating in the Aris Registry and Aris 1 and 2 studies. These additional investigator-initiated studies provide further support for long term safety and efficacy of Aris in the treatment of stress urinary incontinence. Several investigator-initiated studies supported efficacy outcomes of Aris after 1 and 3 years. Consistent with the Aris Registry, early studies reported on smaller patient populations. These studies also reported success/cure rates of approximately 90%. For example, in one of the earlier published studies, Ghoniem (2006) followed 20 patients for 12 months and found that 90% had a negative cough test and 100% were very satisfied or satisfied with their outcomes. Elrnardi et al. (2007) similarly reported high cure rates of 95-96% in 43 consecutive women at 6 months and 85% at one year. In a larger patient population, Bortollini et al. (2009) reported on 250 patients and found objective (negative cough test) and subjective (lack of SUI symptoms) cure rates for 1 year of 92.6% and 86.6%, respectively. Shaker (2011) examined a smaller patient set after a mean of 16 months and 44 6 PageID #: 20080 found positive objective (negative cough test and no urinary leakage during urodynamics) and subjective (patient satisfaction) success (95.83% and 91.67% (complete satisfaction)). Longer term results were repo11ed by Juma, who followed 234 patients with a mean follow-up time of 23.34 months, with 41 % of the patients having follow-up for more than 24 months. SUI cure was reported for 90.61 % of patients. Juma identified three patients (1.3%) with vaginal tape extrusions (which healed completely with excision of the extruded portion), and two (2.5 %) with de novo urge symptoms. These rates were considered low and consistent with other literature. Juma concluded that "[t]he safety, functional efficacy and patient satisfaction with the procedure are sustained at intermediate follow up." 123 The Evaluation for Transobturator Tapes (E-TOT) study has resulted in numerous publications since 2010 (both abstracts and manuscripts), assessing outcomes over nearly a decade. Nine-year data published by Karmakar, et al. establishes the long-term safety and efficacy data of Aris. The E-TOT study, which included patients not only with SUI, but also mixed incontinence, establishes that the efficacy of the Aris procedure holds up over time. 124 In that study, the investigators conducted a long-term prospective, randomized trial to compare the inside-out approach using the TVT-O with the outside-in approach using Aris. The most recent publication reported results after a median of 9.2 years (range 81 to 119 months) of follow-up gathered from 208 patients who were implanted between April 2005 and April 2007, half of whom were implanted with the Aris sling. After 9 years, there was a 71.6% overall patient-reported success rate - with another 14% reporting improvement, for a total of 85.6%, with no significant differences between the Aris and TVT-O groups. Also, this efficacy was consistent with the same mixed incontinence patient population efficacy rates at 3-years. (73.1%). 125 Adverse event rates remained low, with 4% of patients reporting groin or thigh pain, with equal distribution between Aris and TVT-O. The total erosion/extrusion rate (both Aris and TVT-O) over the course of the study was 4.5% (14/314). 126 All were successfully treated with local excision. Consistent with my own experience, the clinical data establishes that the benefits of treating incontinence with the Aris sling appear to hold up over time. While some patients rep01ted complications over time, it must be noted that late complications also exist with non-mesh continence 45 6 PageID #: 20081 treatments. When they occur, exposures are often addressed through a minor, office-based procedure, and treated successfully and without incident. The Aris clinical data viewed as a whole establishes success and complication rates consistent with non-mesh incontinence repairs, with Aris having the added benefit of lower post-operative morbidity than non-mesh incontinence treatments. Looking at the data as a whole, the Aris mid- urethral sling, in the hands of a competent surgeon, can provide outstanding results, remarkable post-surgery recovery times, and remains a superior potential treatment for stress urinary incontinence. The peer-reviewed medical literature and professional organizations of urology and urogynecology support the use of mid-urethral slings. As discussed above, it is generally accepted among urology and urogynecology professional organizations that all currently available mesh mid-urethral slings are well supported as an appropriate standard of care for the treatment of stress urinary incontinence. In my opinion, there are not "safer alternative designs" to the Aris or Supris slings. Any claim of safer alternatives is unsupported. As set forth in detail above, I have personally seen complications resulting not uncommonly from the surgical alternatives suggested-including suture repairs, autologous repairs, and allografts. Allografts fell out of favor due to higher failure rates than their harvested (autologous) counterparts, as well as their unique infection risks, including serious and irreversible infections of the brain, as well as other viral infections associated with biologic tissue. Further, they have been associated with higher recurrence rates. With regard to UltraPro, SUI is not contemplated in UltraPro's indication for use. UltraPro is not indicated for the treatment of SUI. I have not seen clinical data establishing that UltraPro is a safer treatment option than Aris or Supris for SUI. I am routinely asked to repair complications from alternative, non- polypropylene mesh incontinence surgeries involving absorbable and non- absorbable sutures, allografts, xenografts and native tissues. I have personally repaired complications from these non-polypropylene mesh surgeries, including vaginal shortening, vaginal contracture, severe dyspareunia, scarring, erosions, exposures, extrusions, and voiding and defecatory dysfunction. I have also treated patients having surgeries using no polypropylene graft who have nerve pain and pain-related issues. The litany of complications that can occur from surgeries in the absence of mesh 46 6 PageID #: 20082 include everything from voiding dysfunction to loss of a kidney. I reserve the right to expand upon all of the complications that can result from the alternatives suggested. I have implanted the Aris and Supris slings for many years in my patients and have personally witnessed their benefits and lack of adverse events. In my opinion, to a reasonable degree of medical certainty, Aris and Supris are safe and effective for treatment of stress urinary incontinence. There is simply no reliable basis to conclude that either the Aris or Supris sling is defective. In reaching these opm1ons, I have relied upon my expenence, education, trammg, communications with colleagues, conference presentations and materials, and review of the medical and scientific literature, and I hold each of these opinions to a reasonable degree of medical and scientific certainty. I reserve the right to supplement, modify, or amend my opinions upon receipt of additional information, including but not limited to additional documents, reports, testimony, new medical or scientific literature, or other information or documentation that I may receive after the date of this report. In connection with my testimony, I may use documents that I su:;;~c21;:repMe reviewed, pelvic floor models/illustrations, samples of mesh devices, and Manish Patel, MD, RPH, FACS, FPMRS March 31, 2019 47 6 PageID #: 20083 Endnotes 1 Nitti, V, Rosenblum N, Brucker B. Vaginal Surgery for the Urologist (1st ed., 2012). 2 Petros PE, Ulmsten UI. An Integral Theory of Female Urinary Incontine nce: Experimental and Clinical Considerations. Acta Obstet Gynecol Scand 1990;69 Suppl.153:7-31. 3 Magon N, Kalra B, Malik S, et al. Stress urinary incontine nce: What, when, why, and then what? J Mid- life Health 2011;2:57-64. 4 Richter HE, Brubaker L, Stoddard AM, et al. Patient Related Factors Associated with Long-Term Urinary Continence After Burch Colposuspension and Pubovaginal Fascia) Sling Surgeries. J Urol 2012; 188:485-489. 5 Subak LL, Richter HE, Hunskaar S. Obesity and Urinary Incontinence: Epidemiology and Clinical Research Update. J Urol 2009; 182 (6 Suppl): S2-S7. 6 Subak LL, Wing R, West DS, et al. Weight Loss to Treat Urinary Incontinence in Overweight and Obese Women. N Engl J Med 2009; 360:481-490. 7 Dumoulin C, Cacciari LP, Hay-Smith EJC. Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Co chrane Database of Systematic Reviews 2018, Issue IO. Art. No.: CD005654. DOI: I0. 1002/14651858.CD005654.pub4 .. 8 Ayeleke RO, Hay-Smith EJC, Omar Ml. Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD0I0551. DOI: I0. 1002/14651858.CD00I0551.pub3. 9 Stewart F, Berghmans B, Bo K, et al. Electrical stimulation with non-implanted devices for stress urinary incontinence in women. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD0l2390. DOI: IO. 1002/14651858.CD012390.pub2. 10 Herbison GP, Dean N. Weighted vaginal cones for urinary incontinence. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD002114. DOI: I0. 1002/14651858.CD002114.pub2. 11 Versi, E, Griffiths, DJ, Harvey, M. 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Br J Obstet Gynaecol 1999; I 06: 345-350. 29 Ward K, Hilton P. Prospective multicentre randomised trial of tension-free vaginal tape and colposuspension as primary treatment for stress incontinence. BMJ 2002;325: 1-7. 30 Delorme E. Transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women. Prog Urol 200 l; I I: 1306- I 313. (Article in French, but abstract available in English.) 31 Schimpf MO, Rahn DD, Wheeler TL, et al. Sling surgery for stress urinary incontinence in women: a systematic review and metaanalysis. Am J Obstet Gyneco/ 2014;21 l:7l.el-e27 32 Fusco F, Abdel-Fattah M, Chapple CR, et al. Updated Systematic Review and Meta-analysis of the Comparative Data on Colposuspensions, Pubovaginal Slings, and Midurethral Tapes in the Surgical Treatment of Female Stress Urinary Incontinence. Eur Uro/ 2017;72:567-591. 33 Ogah J, Cody DJ, Rogerson L. 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Int Urogynecol J 1999; I 0: 15-21 ("Persistent pelvic pain has been reported to occur in 12% and 27 % of women following Burch colposuspension"). 62 Galloway NTM, Davies N, Stephenson TP. The Complications of Colposuspension. Br J Ural 1987; 60: 122-124. 63 Shapiro R, Hajiran A, Zaslau S. Delayed Presentation of Suture Erosion following Burch Colposuspension. Case Rep Obstet Gynecol 2017;2017:8178361. 64 Dwyer PL, Carey MP, Rosamilia A. Suture Injury to the Urinary Tract in Urethral Suspension Procedures for Stress Incontinence. Int Urogynecol J 1999; I 0: 15-21 ("Surgical injury to the lower urinary tract occurs in 3%-4% of Burch, I %-7% of needle and 1.6% of MMK procedures, and is probably underreported."). 65 Shehata NA, de Courcy-Wheeler RHB, Sim DA. Ureteric kinking after colposuspension: a case report and review of the literature. Ulster Med J 2000; 69:74-75 (describing ureteral complications). 66 Demirci F, Petri E. Perioperative Complications of Burch Colposuspension. 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Common and Uncommon Complications of Autologous Pubovaginal Sling. Ann Clin Case Rep 2016;1:1055. 73 Brubaker L, Norton PA, Albo ME, et al. Adverse Events over Two Years after Relropubic or Transobturator Midurethral Sling Surgery: Findings from the Trial of Midurethral Sling (TOMUS) Study. Am J Obst et Gynecol 2011;205:498e l-498e6. 7 ~ Gurol-Urganci I, Geary, RS, Mamza JB, et al. Long-term Rate of Mesh Sling Removal Following Midurethral Mesh Sling Insertion Among Women with Stress Urinary Incontinence. JAMA 2018;320: 1659-1669. 75 Ogah J, Cody DJ, Rogerson L. Minimally Invasive Synthetic Suburethral Sling Operations for Stress Urinary Incontinence in Women: A Short Version Cochrane Review. Neurourol Urodyn 2011;30:284-291. 76 Ford AA, Rogerson L, Cody JD, et al. Mid-urethral sling operations for stress urinary incontinence in women. Cochrane Database of Sys Rev 2017, Issue 7. Art No.: CD006375. 77 Gebhart J, Trabuco E. 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BJOG 2018; 126:419-426. 88 American College of Surgeons (ACS) Statement on the Effects of Tobacco Use on Surgical Complications and the Utility of Smoking Cessation Counseling. August I, 2014. Accessed Mar. 29, 2019 from https://www.facs.org/about-acs/state ments/7 I-tobacco-use/. 89 Clancy AA, Gauthier I, Ramirez FD, et al. Predictors of sling revision after mid-urethral sling procedures: a case-control study. BJOG 20 I 8; 126:419-426. ° 9 Clancy AA, Gauthier I, Ramirez FD, et al. Predictors of sling revision after mid-urethral sling procedures: a case-control study. BJOG 20 I 8; 126:419-426. 91 Amid PK. Classification of biomaterials and their related complications in abdominal wall hernia surgery. Hernia 1997:1:15-21. 92 Moalli PA, Papas N, Menefee S, et al. Tensile properties of five commonly used mid-urethral slings relative to the TVFM. Int Urogyn J 2008; 19:655-663. 93 Moalli PA, Papas N, Menefee S, et al. Tensile properties of five commonly used mid-urethral slings relative to the TVFM. Int Urogyn J 2008; 19:655-663. 51 6 PageID #: 20087 9~ Delorme E, Pasquale J, Trakoen G, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. February 2005. 95 Delorme E, Pasquale J, Trakoen G, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. May 2005. 96 Ballanger P, Barbe Y, Costa P, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. August 2005. 97 Ballanger P, Barbe Y, Costa P, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. October 2005. 98 Ballanger P, Costa P, Delmas V, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. March 2006. 99 de Tayrac R, Hermieu JF, Delmas V, et al. Trans-Obturator Tape Procedure for Female Stress Urinary Incontinence with the New Tape Aris. Int Urogynecol J 2006: l 7(Suppl. 2):S292-S293; abstract 429. 100 Grise P, Serme nt G, Costa P, et al. Efficacy and Safety of a Low Elasticity Polypropylene Transobturator Midurethral Sling in the Treatment of Female Stress Urinary Incontinence in a Large Multi- Center European Registry with Mid-Term Follow-Up. Presented at the annual meeting of International Continence Society; San Francisco, CA. September 29-October 3, 2009; abstract 567 101 Saussine C, Delorme E, Roumeguere T, et al. Efficacy and Safety of a Transobturator Polypropyle ne Sling for Female Stress Urinary Incontinence. Presented at annual meeting of International Continence Society and the International Urogynecological Association; Toronto, Canada, August 23-27, 2010. Int Urogynecol J 2010;21:S225-S227; abstract 157. 102 Grise P, Serment G, Costa P, et al. Efficacy and Safety of a Low Elasticity Polypropylene Transobturator Midurethral Sling in the Treatment of Female Stress Urinary Incontinence in a Large Multi- Center European Registry with Mid-Term Follow-Up. Presented at the a nnual meeting of International Continence Society; San Francisco, CA. September 29-October 3, 2009; abstract 567 103 Saussine C, Delorme E, Roumeguere T, et al. Efficacy and Safety of a Transobturator Polypropylene Sling for Female Stress Urinary Incontinence. Presented at annual meeting of Internati onal Continence Society and the International Urogynecological Association; Toronto, Canada, August 23-27, 2010. Int Urogynecoll 20 I 0;21:S225-S227; abstract 157. 10 ~ Roumeguere T, Serment G, Grise P, et al. Transobturator Tape Aris for Stress Urinary Incontinence: A Multicenter Tracker Study. Presented at annual meeting of International Continence Society. 2007; abstract 498; Available at: https://ics .org/ Abstracts/Publish/45/000498.pdf (Reporting on follow-up data for 134 patients at one year, using a definition of cure that required the absence of subj ective complaint of urine leakage and the absence of leakage on cough stress test. At I year, 82. 1% of patients were cured and an additional 10.4% were improved for a total of 92.5%). 105 Delorme E, Saussine C, Costa P, et al. Efficacy and safety of Aris midurethral tape in the treatment of female stress urinary incontinence in a large patient population. Int Urogynecol J 2008; I 9(Suppl I):S28; abstract 170. (95 .6% of patients were either cured or improved (85.6% cured) at 6-12 months, and 94.3% maintained cured or improved status (80.3% cured) at 12-18 months). 106 Delmas V, Ballanger P, Grise P, et al. Transobturator suburethral tape ARIS in the treatment of stress urinary incontinence: one year evaluation. Urology 2007;70(Suppl A):74-75; abstract MP-07. 13 (at I year, 81.3% of patients were cured (no pads) and 12.5% were improved, for a total of 93.8 %). 107 Castaings T, Abello, N, Delorme E. Prospective study on 185 femal es with urinary incontinence treated by an outside-in transobturator suburethral sling. Pelviperineology 2012;3 I: 18-23. 108 de Tayrac R, Hermieu JF, Delmas V, et al. Trans-Obturator Tape Procedure for Female Stress Urinary Incontinence with the New Tape Aris. Int Urog ynecol J 2006; 17(Suppl 2):S292-S293; abstract 429. 109 Roumeguere T, Serment G, Grise P, et al. Transobturator Tape Aris for Stress Urinary Incontinence: A Multicenter Tracker Study. Presented at annual meeting of International Continence Society. 2007; abstract 498; Available at: https://ics.org/Abstracts/Publish/45/000498.pdf 110 Delmas V, Ballanger P, Grise P, et al. Transobturator suburethral tape ARIS in the treatment of stress urinary incontinence: one year evaluation. Urology 2007;70(Suppl A):74-75; abstract MP-07 .13. 111 Delorme E, Saussine C, Costa P, et al. Efficacy and safety of Aris midurethral tape in the treatment of female stress urinary incontinence in a large patient population. Int Urogynecol J 2008; l 9(Suppl I):S28; abstract 170. 112 Grise P, Serment G, Costa P, et al. Efficacy and Safety of a Low Elasticity Polypropylene Transobturator Midurethral Sling in the Treatment of Female Stress Urinary Incontinence in a Large Multi- 52 6 PageID #: 20088 Center European Registry with Mid-Term Follow-Up. Presented at the annual meeting of International Continence Society; San Francisco, CA. September 29-October 3, 2009; abstract 567. 113 Saussine C, Delorme E, Roumeguere T, et al. Efficacy and Safety of a Transobturator Polypropyl ene Sling for Female Stress Urinary Incontinence. Presented at annual meeting of International Continence Society and the International Urogynecological Association; T oronto, Canada, August 23-27, 2010. lnr Urogynecol J 2010;21:S225-S227; abstract 157. 114 Roumeguere T, Serment G, Gri se P, et al. Transobturator Tape Aris for Stress Urinary Incontinence: A Multicenter Tracker Study. Presented at annual meeting of International Continence Society. 2007; abstract 498; Available at: https://ics.org/ Abstracts/Publi sh/45/000498.pdf 115 Delmas V, Ballanger P, Grise P, et al. Transobturator suburethral tape ARIS in the treatment of stress urinary incontinence: one year evaluation. Urology 2007;70(Suppl A):74-75; abstract MP-07. I 3. 116 Castaings T, Abello, N, Delorme E. Prospective study on 185 females with urinary incontinence treated by an outside-in transobturator suburethral sling. Pelvip erineology 2012;3 I: 18-23. 11 7 Stanford E, Ghoniem G, Klutke J, et al. Two prospective clinical trials of transobturator midurethral tape for stress urinary incontinence: Interim analysis of merged outcome data. Int Urogynecol J 2008; I 9(Suppl 2):S260; abstract 349. 11 8 Klutke J, Ghoniem G, Stanford E, et al. Efficacy Outcomes of a Low Elasticity Polypropylene Transobturator Midurethral Sling for the Treatment of Female Stress Urinary Incontinence: Final Data Combined from Two Multi-Center Prospective Clinical Studies. J Pelvic Med & Surgery 2009;12(Suppl 5):309-3 IO; abstract. 11 9 Ghoniem G, Stanford E, Klutke J, et al. Efficacy Outcomes of a Low Elasticity Polypropylene Transobturator Midurethral Sling for the Treatment of Stress Urinary Incontinence: Final Data Combined from Two Multi-Center Prospective Studies. Presented at annual meeting of International Continence Society; San Francisco, California; September 29-October 3, 2009; abstract 783. 120 Stanford E, Klutke J, Ghoniem G, et al. Two Prospective Clinical Trials of Transobturator Midurethral Tape for Stress Urinary Incontinence: Analysis of Final Merged Outcome Data. J Minim Inva sive Gynecol 2010;17:S64. 121 Klutke J, Ghoniem G, Stanford E, et al. Efficacy Outcomes of a Low Elasticity Polypropylene Transobturator Midurethral Sling for the Treatment of Female Stress Urinary Incontinence: Final Data Combined from Two Multi -Center Prospective Clinical Studies. J Pelvic Med & Surgery 2009; I 2(Suppl 5):309-310; abstract. 122 Ghoniem G, Stanford E, Klutke J, et al. Efficacy Outcomes of a Low El as ticity Polypropylene Transobturator Midurethral Sling for the Treatment of Stress Urinary Incontinence: Final Data Combined from Two Multi-Center Prospecti ve Studies. Presented at annual meeting of International Continence Society; San Francisco, California; September 29-October 3, 2009; abstract 783. 123 Juma S, Brito G. Aris Trans-Obturator Tape: Three Years Follow Up. Int Urogynecol J 2008; 19 (Suppl I):SI 9-S20; abstract 110. 124 Karmakar D, Mostafa A, Abde l-Fattah M. Long-term outcomes of transobturator tapes in women with stress urinary incontinence: E-TOT randomised controlled trial. BJOG 2017; 124:973-981. 125 Karmakar D, Mostafa A, Abdel-Fattah M. Long-term outcomes of transobturator tapes in women with stress urinary inco ntinence: E-TOT randomised controlled trial. BJOG 2017; 124:973-98 1. 126 Karmakar D, Mosta fa A, Abdel-Fattah M. Long-term outcomes of transobturator tapes in women with stress urinary incontinence: E-TOT randomi sed controlled trial. BJOG 2017;124:973-981. 53 6 PageID #: 20089 Exhibit A 6 PageID #: 20090 MANISH P. PATEL, M.D, RPh, FACS, FPMRS Board Certified 2004, 2011 Urology Board Certified 2013, Female Pelvic Medicine and Reconstructive Surgery (FPMRS) Active North Carolina Medical License Active South Carolina Medical License uropatelmd@gmail.com 704-616-9430 EXPERIENCE: 2002-2019– Urology, General and Specialty Female Pelvic Medicine and Reconstructive Urogenital Surgery. Former Chief Medical Officer. EDUCATION/APPOINTMENT: Director of Urology and Women's Health Department 2015 – present Chairman Physician Leadership Council Medical Executive Committee LifePoint Hospitals - Medical University of South Carolina Affiliation Reconstructive Urogenital Surgery Kershaw and Carolina Pines Facilities, S.C. Chair – Department of Urology Maintenance of Certification up-to-date 2015, 2017 Director of Reconstructive Urogenital Surgery, 2002 - 2015 Pelvic Organ Prolapse, Incontinence CITI Certified Carolina Continence Center University of North Carolina Hospitals - Chapel Hill, N.C. University of North Carolina Hospital, Main Campus Dept. of General and Specialty Surgery Division of Urologic Surgery Wright State University School of Medicine – Dayton, OH Degree – Medical Doctor 6/97 Alpha Omega Alpha Status – Valedictorian Rutgers University – New Brunswick, N.J. Degree- Pharmacy/Pharmacology 5/92 Status- Magna Cum Laude Graduate Registered Pharmacist – State of New Jersey 1992-1997 6 PageID #: 20091 Previous Appointments: Chief Medical Officer 2011 - 2015 Director of Research 2011 - 2015 HONORS/AWARDS: Best Doctors in Charlotte NC – 2011/2012/2013 Society of University Urologists – National Chief Resident UNC Hospitals Resident of the Year 2000 Wright State University School of Medicine Valedictorian Alpha Omega Alpha Lange Medical Publication Award- National Recognition American College of Surgeons- Silver Scalpel Award Academy of Medicine – Excellence Award (1995, 1996 & 1997) Carl Jelenko III Excellence in Emergency Medicine Excellence in Pharmacology- Basic Science Scholar Award Excellence in Pathology –Basic Science Scholar Award WSUSOM Academic and Leadership of Medical Training Rutgers University Phi Lambda Sigma – Leadership and Academic Excellence Governing Council Elect PODIUMS: Two-Year Effectiveness of the Altis Sling Incision Sling for Women with Stress Predominant Mixed Urinary Incontinence Ty Erickson1, Jon Crockford2, Manish Patel3, Lori Rusch4 AUGS 2015 The Impact of Obesity on Two-Year Outcomes for the Altis Sling Incision Sling for Women with Stress Urinary Incontinence Ty Erickson1, Jon Crockford2, Manish Patel3, Lori Rusch4 AUGS 2015 Kojancik,E, Tu, ML, Patel M, Erikson T, et al: Investigational Device Application 12/2010 to 2013. A new single incision sling using a helical trans- vaginal delivery for the treatment of urinary stress incontinence. A multi-center national trial. SUFU 2013. Alinsod R, Patel MP, Erickson T: Durability and Complications of an Ultra Light-weight Transvaginal Mesh in the Treatment of Symptomatic Pelvic Organ Prolapse. 41st Annual AAGL Global Congress of Minimally 6 PageID #: 20092 Invasive Gynecology, Nov 5-9, 2012, Las Vegas, NV Alinsod R, Patel M, Erickson T. Durability and complications of an ultra light-weight transvaginal mesh in the treatment of pelvic organ prolapse. International Urogynecology Society, Sidney, IUGA 2012 Patel M, Arendt K Patient based evaluation and management of USI, TOT vs RP Presented AUA May – June 2010 Patel M, Lukban JC, Wrooves JT, Moore RD, Maine C, Layne R, Liedle B A Prospective Multi-Centered study evaluating the Elevate Apical and Posterior for treatment of apical and or posterior vault prolapse a twelve month follow up. Presented at the International Continence Society / International Urogynecological Association Toronto, Canada August 23-27, 2010 Patel M, Arendt K: Considering Patient Risk Factors for SUI Sling Repair To Achieve High Success Rates. Abstract 2010, PRESENTED MAY 2010 AUA Lukban JC, Patel M, Wrooves JT, Moore RD, Maine C, Layne R, Liedle B A Prospective Multi- Centered study evaluating the Elevate Apical and Posterior for treatment of apical and or posterior vault prolapse at six Month follow up. Presented at the American Urogynecology Society Long Beach, CA September 30th – October 2nd, 2009 Davila GW, Flaherty JF, Lukban JC, Patel M, Byer R, Moore RD: Retrospective Analysis of Efficacy and Safety of Perigee and Apogee In Patient's Undergoing Repair for Pelvic Organ Prolapse. Presented at the Global Congress of Minimally Invasive Gynecology at the 35th Annual Meeting of the American Association of Gynecologic Laproscopists. Las Vegas, Nevada November 6-9, 2006. Lukban JC, Patel M, Erickson T, Virelles M, Van Dire D, Weprin S, Flaherty J, Zylstra S, Beyer R, Moore R, Vera R, Nguyen J, Hodroff M: A Prospective Multi-Center Clinical Trail Evaluating the Apogee System For the Treatment of Posterior Vaginal Wall and Apical Prolapse Presented at the 2008 Annual Meeting of the American Urological Association. Orlando, Florida, May 16-22, 2008. Lukban JC, Patel M, Van Drie D, Weprin S. et al: A prospective multi-center trial Ecaluating the apogee system for the treatment of posterior vaginal wall 6 PageID #: 20093 And apical prolapse: A sub-analysis of Apical Extrusions with or without Concomitant hysterectomy. Presented at the 33rd Annual meeting of the IUGA, Taipei, Tiawan. 2008 Davila GW, Lukban JC, Patel M, McCammon K: Efficacy and safety of Porcine Dermal Grafts in patients undergoing Pelvic Organ Prolapse Repair. Presented at the Global Congress of minimally Invasive Gynecology at The 35th Annual meeting of the American Association of Gynecologic Laparoscopists. Las Vegas, NV, Nov. 2006 Patel M: A Reconstructive Option for Large Vaginal Mesh Exposures Using a Porcine Small Intestinal Sub mucosa Graft. Presented at the 2008 SUFU, Las Vegas, NV MODERATED POSTERS: The Impact of Obesity on Two-Year Outcomes for the Altis Sling Incision Sling for Women with Stress Urinary Incontinence Ty Erickson1, Jon Crockford2, Manish Patel3, Lori Rusch4, AUGS, 2015; Seattle, WA Two-Year Effectiveness of the Altis Sling Incision Sling for Women with Stress- Predominant Mixed Urinary Incontinence Ty Erickson1, Jon Crockford2, Manish Patel3, Lori Rusch4 AUGS, 2015, SEATTLE WA Alinsod R, Patel MP, Erickson T: Durability and Complications of an Ultra- Light- weight Transvaginal Mesh in POP. Presented Western Section AUA, 2012. Big Island Hawaii. Lukban JC, Van Drie D, Beyer R, Erikson, T, Patel M, Nguyen J, Moore R: Long term results of Elevate Apical and Posterior for Vaginal Wall Prolapse repair. Presented at the 32nd AUGS Scientific Meeting Providence, RI, 9/20011 Lukban JC, Van Drie D, Beyer R,, Erikson, T, Patel M: A prospective Multicenter Study Evaluating Elevate Apical and Posterior (A&P) for The treatment of posterior and/or Apical Vaginal Wall Prolapse: One year follow up. Presented at the 31st Annual Scientific Meeting AUGS Long Beach, CA, 9/2010 McCammon K, Davila G, Patel M, Flaherty JF, Lukban JC, Moore Rd: 6 PageID #: 20094 Trial Phase Study SITE Date Initiated Enrollment Period Principal Principal Investigator/ Investigator Medical Monitor Retrospective Analysis of Efficacy and Safety of Perigee and Apogee In Patients Undergoing Surgery for Pelvic Organ Prolapse. Presented at the 64th Annual Meeting of the Mid- Atlantic Section of The American Urological Association. Washington, DC, October 12-15, 2006. Lukban JC, VanDrie D, Patel M,WeprinS, ZylstraS, Vera R, Nguyen J, Moore R: A Prospective Multi-Centered Clinical trial Evaluating the Apogee System for the Treatment of Posterior Vaginal Wall and Apical Prolapse: A Sub-Analysis of Apical Extrusions With or Without Concomitant Hysterectomy. Presented at the 29th Annual Scientific Meeting of the American Urogynecology Society. Chicago, Illinois, September 4-6, 2008. Patel M: Management of Vaginal Mesh Extrusion with Porcine Small Intestinal Submucosa Graft Presented at the 35th Annual Scientific Meeting of the Society of Gynecologic Surgeons, New Orleans, Louisiana, March30-April 1, 2009 POSTERS: Davila GW, Flaherty JF, Lukban JC, Patel M, Beyer R, Moore RD Retrospective Analysis of Efficacy and Safety of Perigee and Apogee in Patients Undergoing Repair for Pelvic Organ Prolapse Presented at the 31st Annual Meeting of the International Urogynecological Association Athens, Greece, September 6-9, 2006. Lukban JC, Van Drie D, Patel M, Weprin S, Zylstra S, Vera R, Nguyen J, Erickson T, Virelles M, Flaherty J, Beyer R, Moore R, Hodroff M: A prospective Multi-Center Clinical Trial Evaluating the Apogee System for the Treatment of Posterior Vaginal Wall and Apical Prolapse: A Sub- analysis of Apical Extrusions With or Without Concomitant Hysterectomy Presented at the 29th Annual Scientific Meeting of the American Urogynecologic Society Chicago, Illinois, September 4-6, 2008. PENDING PUBLICATIONS/PRESENTATIONS: 6 PageID #: 20095 Altis 522- Single Incision sling system vs Post Patel (NC) June 2015 2 years transobturator or retropubic mesh sling Market Willard (SC) in the treatment of female stress urinary incontinence 522 G Eure, S Gange, W Walter, M Patel et al: Real-world evidence of prostatic urethral lift confirms pivotal clinical study results: 2-year outcomes of a retrospective multicenter study; J of Endourology- submission: Patel M: Abdominal Myofascial Pelvic Pain Syndromes – Diagnosis and Initial Management of a common but Underdiagnosed Chief Complaint. A Review of the Literature – Urology Today Central Sensitization Syndrome – What Does it mean RESEARCH Genomic Evaluation and Antibiotics Resistance in Recurrent Cystitis (GEAR Trial): Understanding Heterogeneity in Recurrence or Persistence. Vikor Labs, Charleston, S.C.; 2019. Ecoin Trial – Pivotal Study of Subcutabneous Tibial Nerve Stimulation; eCoin for Urgency Urinary Incontinence; Valencia Technologies Valencia, CA; 2018 Patel, MP, Wu, J; ALTER Trial – Prospective Randomized Control Trial Evaluating SIS Helical MUS versus Retropubic Slings; Patient's Perspective of RTNAand Success.2018 Roerborn C, Eure,G, Patel, M; Real World Retrospective Review of Transurethral Prostatic Lift Procedure; Comparative Evaluation Between Clinical trial and Post-Market Use.2018 Patel M, Memelo M: The utilization of MRI to determine submucosal tissue Quality prior to reconstructive urethral surgery. Can it predict Improved surgical tissue quality and outcome. 6 PageID #: 20096 ARGOS- Tumor Collection Registry from Registry Neal Shore, MD Waterhouse December 2 years Routine Nephrectomy for Subjects with Patel 2013 Advanced Stage Renal Cell Carcinoma (RCC) ARN- 509 Spartan- Multicenter, Phase 3 Isan Chen, MD Willard May 2014 2 years Randomized, Double-Blind, Placebo- Patel Controlled, Phase III Study of ARN-509 in Men with Non-Metastatic (M0) Castration- Resistant Prostate Cancer CertNDx- Preliminary Validation of N/A Patel November Open until anticipated CertNDx Bladder Cancer Assay (CertNDx - 2014 enrollment reached 010) GENOMIC HEALTH Registry Haluk Tezcan, White July 2014 Open until anticipated Bladder CA- Genomic Markers in MD Patel enrollment reached Transitional Cell Cancer of the Bladder, Renal Pelvis and Ureter: Methods development and Genomic discovery in Bladder Cancer to improve surveillance and inform risk of progression of non- muscle invasive bladder cancer GENOMIC HEALTH Registry Bela Denes, Waterhouse August 2 years Oncotype Dx- To Assess the MD Patel 2014 Persistence on Active Surveillance when using the Oncotype DX Prostate Cancer Assay 6 PageID #: 20097 GMA-OAB- Multicenter, Double Blind, Phase 4 Irma Patel October Open until anticipated Randomized, Placebo-controlled trial to Yushmanova, 2013 enrollment reached evaluate the Responder Rates for MD Achieving Complete Continence Using BOTOX® (Botulinum Toxin Type A) treatment in Overactive Bladder Patients with Urinary Incontinence: NeoGenomics- Clinical Evaluation For Registry Maher Albitar, White February Open until anticipated Plasma and Urine Test for Predicting MD Patel 2015 enrollment reached Prostate Cancer and Prostate Biopsy Results PHI- A Prospective, Observational Study Registry Mark A. White April Up to 15 months of the Clinical Decision Impact of the Reynolds, Patel 2015 Prostate Health Index Test in a Urology Practice Setting PhD PRO-IMPACT- PROspective Study of Registry Daniel Lin, MD Waterhouse August Open until anticipated the IMPACT of Patel 2014 enrollment reached Decipher® Prostate Cancer Classifier on Physician and Patient Treatment Consideration and Decisions following Radical Prostatectomy [PRO- IMPACT] 6 PageID #: 20098 PRIME- Registry for Immune Phase 4 Andrew Waterhouse August Open until anticipated Monitoring Protocol in Men with Prostate Sandler, MD Patel 2013 enrollment reached Cancer Enrolled in a Clinical Trial of Sipuleucel-T PREDICTS- A Study to Evaluate Registry Candice Waterhouse January 2 years Characteristics Predictive of a Positive McCoy, MD Patel 2014 Imaging Study for Distant Metastases in Patients with Castration-Resistant Prostate Cancer ROSE REGISTRY- Real-time Phase 4 Cohen April Open until anticipated Observation of Safety and Effectiveness Patel 2014 enrollment reached in the treatment of female stress urinary incontinence XENFORM- A Prospective, Non- Post Peter L. Patel Septembe 12 to 18 months Randomized, Parallel Cohort, Multi- Market Rosenblatt, r 2014 Center Study of Xenform vs. Native Tissue M.D. for the Treatment of Women with Anterior/Apical Pelvic Organ Prolapse PUBLICATIONS AND PRESENTATIONS: RESEARCH: Patel, MP: Physiologic Alterations Occurring in the Female Pelvic Floor with Various Exercise Programs – Risk Benefit Evaluation Nutrition and Exercise BOOK CHAPTERS: Published Chapters: Patel M, Lukban JC, Editors: Salchel K, Abouhamad A: A Practical guide to 6 PageID #: 20099 Office Procedures in Gynecology and Urogynecology. Neuromodualtion. Publisher: Jay Pee Brothers, New Deli, India 2012 Patel M, VanDrie D, Lukban JC, Editors: Salchel K, Abouhamad A: A Practical Guide to Office procedures in Gynecology and Urogynecology. Treatment of Urinary stress incontinence. Publisher: Jay Pee Brothers, New Dehli, India 2011. Lukban JC, Davila W…Patel M, et al: Prospective, Multi-Center Study To Assess the XXX Pelvic Floor Repair System Devices for Prolapse Repair, Phase I Lukban, Davila W…Patel Met al: Prospective, Multi-Center Study To Assess the XXX Pelvic Floor Repair System Devices for Prolapse Repair, Phase II Lukban, Davila W, …Patel M et al: Prospective, Multi-Center Study To Assess the XXX Pelvic Floor Repair System Devices for Prolapse Repair, Phase III Patel MP: Management of Vaginal Mesh Extrusion with Porcine Small Intestinal Submucosa Graft. Tech., in Urologic Surgery. 3rd quarter 2007 Lukban, Davila W, …Patel M et al: Prospective, Multi-Center Study To Assess the XXX Pelvic Floor Repair System Devices for Prolapse Repair, Phase IV Lukban, Davila W, …Patel Met al: Prospective, Multi-Center Study To Assess the XXX Pelvic Floor Repair System Devices for Prolapse Repair, Phase V Patel MP, Montesinos C, et al: Multicomponent Phyotherapy In The Treatment of Mild To Moderate EP with Luts J. Nutr, 3/2007 Patel MP, Carson CC: Epidemiology, Antatomy, Phyotherapy and Treatment Of Erectile Dysfunction in Chronic Renal Failure. Adv Ren Repl Ther. 6:296, 1999 Patel MP: Efficacy and Safety of Porcine Dermal Grafts in Patients Undergoing Pelvic Organ Prolapse Repair, Supplement to The Journal Of Minimally Invasive Gynecology, September/October 2006 Patel MP: Retrospective Analysis of Efficacy and Safety of Perigee And Apogee in Patients Undergoing Repair for Pelvic Organ Prolapse Supplement to The Journal Of Minimally Invasive Gynecology, September/October 2006 6 PageID #: 20100 Patel MP, Chun J, Shaban SF: Evidence Based Medicine In Urology. Contemporary Urology 2000 Patel MP, Zenn MR, Carson CC: Replantation Of The Penis: A Patient Report. Annual Of Plastic Surgery 2000 Patel MP, Carson CC" Implications Of Renal Insufficiency on Erectile Dysfunction. Klin Nephrology 2001 Patel MP, Bukowski TP; Ureterovesical Junction Obstruction And Megaureter: Epidemiology, Physiology and Management, Web M.D. Patel MP, Vick RN. Benevedies M, et al: The Efficacy, Safety and Tolerability Of Intracavernosal PNU-93757 in The Treatment of Erectile Dysfunction. Journal Of Urology, 2001 Patel MP, Benevedies M, Vick RN, et al: Intracavernosal Injection Of A Potassium Channel Operator to Treat Erectile Dysfunction. Journal Of Urology, 2000. Patel MP, Carson CC: Management Of Erectile Dysfunction. Mediguide To Urology, 2001. GUEST LECTURES AND SURGICAL LABS: Pelvic Organ Prolapse: Surgical Management, Clinical Pearls and Complex Conditions. March, 2019. William Beaumont Dept. of Urology, Detroit, MI, Feb 2016 Stress Urinary incontinence: Surgical Management of Treatment and Complications William Beaumont Dept. of Urology, Detroit, MI, Feb 2016 Current Evaluation and Surgical Management of POP and USI; A Systematic Review of the Literature; Stanford University, Dept. of Urology Palo Alto, CA, May 2016 Pelvic Floor Disorder and Surgical Management of Treatment and Complications William Beaumont Dept. of Urology, Detroit, MI, Feb 2016 Minimally Invasive Surgery for POP and SUI, Which Graft and When? University Health Network, Toronto, CA, April 2016 Utilization of Ultra-lightweight Transvaginal Grafting for POP; Universitat, Wurzburg, Wurzburg, Germany, June 2014 6 PageID #: 20101 Stress Incontinence Surgery Treatments and Compliations; Istanbul Facility of Medicine, Istanbul, Turkey, May 2014 POP Treatment Options, Understanding the Anatomy and Goals of Corrective Surgery in 2015, Dept. of Urology, Virginia Mason Medical Center, Seattle, WA, April 2014 Graft Augmentation in the Management of POP and SUI; University of Aberdeen School of Medicine and Dentistry, Aberdeen, Scotland November 2013 Surgical Complications of Laparoscopy and TVM in the Management of POP; Leiden University Medical Center, Leiden, Netherlands, October 2013 Immunobiology and Host Responses to Surgically Implanted Graft Materials – Transvaginal and Transperitoneal Approaches; Italian National Congress Meeting, Catania, Italy, November 2013 Overview of Synthetic Materials in the Human Physiology; The Italian Urology And Urogynecology National Meeting, June 2013 Variations in Surgical Mesh Composition and Their Immunobiologic Behaviors In the Implanted Host; University of Paris, Paris, France, Sept. 2013 Lightweight Surgical Graft Implantation Technique for POP and SUI; Universite Rene Descartes, Paris, France, November 2012 Surgical Implantation of SIMUS using Push versus Helical Introduction; Graft Material Review; School of Medicine, Manchester, UK, November 2012 Surgical Technique for Surgical Mesh Implantation for Corrective POP Surgery; Universite Rene Descartes, Paris, France, September 2012 Complications of POP and SUI Surgery, Evaluation and Management; University Hospital, Hostial Sainte Marguerite, Marseielle, France, Feb. 2012 Current management of the Overactive Bladder. Medical Assoc. of Physician's Assistants, Charlotte, NC. Oct. 2011 The use of Neuromodulation for the treatment of voiding dysfunction. U. South Carolina Med. Columbia, SC. Apr 2010 Voiding Function and Dysfunction – Management strategies Florida Urological Association. Orlando, FL. Aug. 2010 6 PageID #: 20102 Pelvic Organ Prolapse – Surgical use of prosthetic and biologic interpositions. Minneapolis, MN 8/2011 The uses of ultra-light weight prosthetic implants for surgical correction of POP. New York City, NY. Multi-hospital educational seminar. 8/2011 Fixation points and suture delivery systems for the treatment of pelvic organ Prolapse. From the Miya hook to the Capio and Digitex. May, 2011 Neuromodulation for the treatment of OAB, UI, NOR and Fecal Incontinence. Charlotte, NC. July, 2011. Urology and Urogynecology. Guest Surgeon – Naples, Italy – trained surgeon in the use of prosthetic implants In the management of SUI and POP. 3 cases. Surgical Techniques for the treatment of USI. Naples hospitals. Naples, Italy Apr. 2009 Guest Surgeon – Munich, Germany. Urinary and Bowel function implantation Of Lower Pelvic function Neurostimulators. 3/2008 Center for Neuromodulation training: Carolina Continence Center, Charlotte, NC Over 25 courses in the use of neuromodulation – Theory, Techniques & Surgical Management. 2004 – present. GRAND ROUND AND MEDICAL SOCIETY LECTURES: International: Toronto Western Hospital/University Health Network Universite De Paris Facvite de Medicine, Paris, France Universite De Marsailles - Professor De Terayak, France Medical University Manchester, Manchester, UK University Medica De Napoli, Napoli, Italy University hospitals Brussels, Brussels, Belgium University Hospital Wurzburg, Wurzburg, Germany University of Amsterdam, Amsterdam Medical Center, Netherlands Medical Hospital Caicos, Turks and Caicos, British VA United States: Stanford University Dept. of Urology, Palo Alto, CA William Beaumont Dept. of Urology, Detroit, MI Carolinas Medical Center, Charlotte, NC Caromont Health Systems, Gastonia, NC Morton Plant Hospital, Clearwater, FL 6 PageID #: 20103 Tampa General, Tampa Bay, FL New York Hospital, New York, NY Regional Medical Center, Memphis, TN Palmetto Health System, Columbia, SC Onslow Memorial Hospital, Jacksonville, NC Carolina East Medical Center, New Bern, NC University of Minnesota, Minneapolis, MN Jackson Health System Miami, Miami, FL Orlando Regional Hospitals, Orlando, FL Johnson City Regional Medical Centers, Tri-Cities, TN Wake Forrest Baptist Medical Center, Winston-Salem, NC Novant Health Systems, Charlotte, Winston, NC St Francis Health System, Greenville, SC Northside Hospital Area, Canton, Atlanta, GA Boca Raton Regional Med Center, Boca Raton, Fl NCH Health Systems, Naples, FL MEDIA INTERVIEWS: Patel, MP: MDNews. Innovative Treatment Options for Urinary Incontinence: Dec 2011 Patel, MP: MDNews. Advances in Robotic Reconstructive Urologic Surgery March 2012. Patel,MP: MDNews. Innovative treatments in urology, Your Urology Home Dec Patel MP: Sign and Symptoms of Pelvic Organ Prolapse in Women NBC News Charlotte, NC (Recorded – pending airtime) October 2011 Patel, MP: Hypogonadism and it impact of men and their families FOX NEWS Charlotte, NC, October 2010 Patel MP: What You Need to Know About Your Pelvic Floor. HealthNewsDigest.Com, 2009 Patel MP: Pelvic Floor Disorders after Childbirth. Pregnancy Today, 2009 Patel MP: What You Need to Know About Your Pelvic Floor. Empowher.com, 2009 Patel MP: The Gender Gap of Growing Old: Top Health Risks of Aging Men and Women. The New York Daily News, 2009 Patel MP: Pelvic Organ Prolapse and Urinary Incontinence. 6 PageID #: 20104 SheKnows.com, April 2009 Patel MP: Comprehensive information on Pelvic Organ Prolapse and Vaginal Reconstruction. Lifescript Women's Journal.com, 2009 Patel MP: Pelvic Organ Prolapse and Urinary Incontinence the Future. Wall Street Journal/Health-Women's Health, 2008 PROFESSIONAL ORGANIZATIONS: International Continence Society American Urogynecology Society American Urological Association Society of Urodynamics and Female Urogenital Reconstructive Surgery Southeast Section of the American Urological Association North Carolina Medical Society CONTACT INFORMATION: Mobile – 704-616-9430 Email – uropatelmd@gmail.com 6 PageID #: 20105 Exhibit B 6 PageID #: 20106 EXHIBIT B REFERENCE LIST Selected Literature References Abdel-Fattah M, Ramsay I, Pringle S, et al. Evaluation of transobturator tapes (E- TOT) study: randomised prospective single-blinded study comparing inside-out vs. outside-in transobturator tapes in management of urodynamic stress incontinence: Short term outcomes. Eur J Obstet Gynecol Reprod Biol 2010;149:106-111. Abdel-Fattah M, Ramsay I, Pringle S, et al. Randomised prospective single- blinded study comparing 'inside-out' versus 'outside-in' transobturator tapes in the management of urodynamic stress incontinence: I-year outcomes from the E-TOT study. BJOG 2010;117:870-878. Abdel-Fattah, M, et al. Evaluation of transobturator tension free vaginal tapes in management of women with stress urinary incontinence and previous failed incontinence surgery. Int Urogynecol J 2010;21:S223-S225; abstract 156. Abdel-Fattah M, et al. Impact of Transobturator Tension Free Vaginal Tapes on Quality of Life and Sexual Function in Women with Mixed Urinary Incontinence. Int Urogynecol J 2010;21(Suppl 1):S140-S41; abstract 28. Abdel-Fattah M, Familusi A, Ramsay I, et al. A Randomised Prospective Single- Blinded Study Comparing "Inside-Out" versus "Outside-In" Transobturator Tapes in the Management of Female Stress Urinary Incontinence (E-TOT Study); 3 Years Follow-Up. 2010; abstract 18. Abdel-Fattah M, Ramsay I, Pringle S, et al. Evaluation of Transobturator Tension- free Vaginal Tapes in Management of Women with Recurrent Stress Urinary Incontinence. Urology 2011;77(5):1070-1075. Abdel-Fattah M, Mostafa A, Familusi A, et al. Prospective Randomized Controlled Trial of Transobturator Tapes in Management of Urodynamic Stress Incontinence in Women: 3-year Outcomes from the Evaluation of Transobturator Tapes Study. Eur Urol 2012;62:843-851. 1 6 PageID #: 20107 Abdel-Fattah M, et al. Evaluation of Transobturator Tension-Free Vaginal Tapes in the Surgical Management of Women with Mixed Urinary Incontinence: 3-Year Outcomes of a Randomized Controlled Trial. J Urol 2014;191:1-6. Abrams P, Cardozo L, Khoury S, et al. (Eds). (2005) Surgery for Urinary Incontinence in Women. In: Incontinence Management. Health Publications Ltd., pp. 1297-1370, Paris, France. AbuRahma AF, Stone PA, Srivastava M, et al. The effect of surgeon's specialty and volume on the perioperative outcome of carotid endarterectomy. J Vasc Surg 2013;58:666-672. Albo ME, Richter HE, Brubaker L, et al. Burch Colposuspension versus Fascial Sling to Reduce Urinary Stress Incontinence. N Engl J Med 2007;356:2143-2155. Amid PK. Classification of biomaterials and their related complications in abdominal wall hernia surgery. Hernia 1997;1:15-21. Amid PK, Shulman AG, Lichtenstein IL, et al. Biomaterials for abdominal wall hernia surgery and principles of their applications. Langenbecks Arch Chir 1994;379:168-171. Amid PK. Classification of biomaterials and their related complications in abdominal wall hernia surgery. Hernia 1997;1:15-21. Andraska E, Santiago-Lastra Y, Stoffel JT. Common and Uncommon Complications of Autologous Pubovaginal Sling. Ann Clin Case Rep 2016;1:1055. Aoki Y, Brown HW, Brubaker L, et al. Urinary Incontinence in Women. Nat Rev Dis Primers 3, 17042 (2017). Asicioglu O, Gungorduk K, Besimoglu B, et al. A 5-year follow-up study comparing Burch colposuspension and transobturator tape for the surgical treatment of stress urinary incontinence. Int J Gynaecol Obstet 2014;125:73-77. Athanasopoulos A, Gyftopoulos K, McGuire EJ. Efficacy and preoperative prognostic factors of autologous fascia rectus sling for treatment of female stress urinary incontinence. Urology 2011;78:1034-1038. Ayeleke RO, Hay-Smith EJC, Omar MI. Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD010551. DOI: 10.1002/14651858.CD0010551.pub3. 2 6 PageID #: 20108 Ballanger P, Barbe Y, Costa P, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. August 2005. Ballanger P, Barbe Y, Costa P, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. October 2005. Ballanger P, Costa P, Delmas V, et al. Short Term Results of Aris Trans-Obturator Tape Implantation. March 2006. Bandarian M, Ghanbari Z, Asgari A. Comparison of transobturator tape (TOT) vs Burch method in treatment of stress urinary incontinence. J Obstet Gynaecol 2011;31:518-520. Bellin P, Smith J, Poll W, et al. Results of a Multicenter Trial of the CapSure (Re/Stor) Continence Shield on Women with Stress Urinary Incontinence. Urology 1998;51:697-706. Birkmeyer JD, Stukel TA, Siewers AE, et al. Surgeon Volume and Operative Mortality in the United States. N Engl J Med 2003;349:2117-2127. Bobyn JD, Wilson GJ, MacGregor DC, et al. Effect of pore size on the peel strength of attachment of fibrous tissue to porous-surfaced implants. J Biomed Mater Res 1982;16:571-584. Bortolini MA, et al. Transobturator tape for the treatment of stress urinary incontinence: effectiveness and predictors of outcome. Int Urogynecol J 2009;20:S372-S373; abstract 380. Braga A, Caccia G, Sorice P, et al. 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