CLINICAL DATA a) The widely-known experience with the use of mesh over the last 90 years

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1 The clinical evaluation of NAZCA, CALISTAR and SPLENTIS it is based on the compilation of relevant scientific literature that is currently available, so Promedon S.A. considered that clinical investigation of these products was not necessary to demonstrate its safety and effectiveness. This clinical evaluation is divided by: a) The widely-known experience with the use of mesh over the last 90 years... 1 a.1) Introduction... 1 a.2 ) Materials used in the manufacture of mesh... 5 b) The comparison between NAZCA, CALISTAR and SPLENTIS with different medical devices for the treatment of vaginal prolapse... 6 c) The clinical results in surgery verifications... 7 d) Conclusion... 9 a) The widely-known experience with the use of mesh over the last 90 years a.1) Introduction Vaginal prolapse is a disorder similar to a hernia. The vaginal wall looses it strength and the abdominal organ felt over it. This situation can cause an anterior prolapse, a posterior prolapse or it can produce problems in the vaginal dome (apical prolapse). ANTERIOR VAGINAL WALL PROLAPSE OR CYSTOCELE Anterior prolapse occurs when the wall between vagina and bladder looses it strength, causing the bladder drop or sag into the vagina. An anterior prolapse may result from an excessive muscle straining during giving birth, intense straining throughout life or upon exertion during bowel movement (chronic constipation). This condition may cause discomfort and problems with emptying the bladder (an incomplete emptying of bladder could cause infections). The elastic tissues of the vagina may compensate for this tear for some time after the injury occurs. Because the hormone estrogen helps keep the elastic tissues around the vagina strong, an anterior prolapse may not occur until menopause, when levels of estrogen decrease. There are no muscles around the vagina, except the bulbocavernosus muscles at the entrance to the vagina. The levator muscle passes around the vagina and the rectum and inserts into the levator plate, which can elevate rectum, the vagina and the bladder neck together. It is this muscle that is exercised by Kegel exercises. Elevation of the levator plate may partially compensate for the herniation. Page 1 of 11

2 A bladder that has dropped from its normal position may cause two kinds of problems: unwanted urine leakage (heavy work, coughing, sneezing or laughing) and incomplete emptying of the bladder (which may lead to infections). The pubocervical fascia provides back support to the mid urethra, allowing compression when abdominal pressure is increased. This prevents urine loss with sudden increases in pressure, as with coughs, sneezes, laughs, or moves in any way that puts pressure on the bladder. If this compression is lost by tissue tears, then stress incontinence results. If the base of the bladder herniates, then urine will sump down into the inside of the hernia, and bladder emptying will be impaired. Anterior prolapse is classified in grades: An anterior prolapse is mild (grade I) when the bladder droops only a short way into the vagina. With more severe (grade II) anterior prolapse, the bladder sinks far enough to reach the opening of the vagina. The most advanced (grade III) anterior prolapse occurs when the bladder bulges out through the opening of the vagina. A doctor may be able to diagnose a grade II or III anterior prolapse from a description of symptoms and from physical examination of the vagina because the fallen part of the bladder will be visible. The specific treatment for anterior prolapse varies according to several parameters: age, patient s overall health status and medical record, stage of the disease, tolerance to specific medications, procedures or therapies and expectations for the course of the disease. Treatment may be non-surgical for mild cases (grade I) or surgical for more severe anterior prolapse cases (grades II or III). If anterior prolapse is not bothersome, the suggestions include: avoiding heavy lifting and straining, or placing a pessary, a device to hold the bladder in place. In the case of women going through menopause, estrogen therapy to help strengthen the muscles around the vagina may be recommended. Patients should be informed about the possible risks of taking estrogens. POSTERIOR VAGINAL WALL PROLAPSE OR RECTOCELE A protrusion of the visceral content toward the posterior fibromuscular wall of the vagina is called Posterior prolapse. The degree of severity of posterior prolapse may range from a slight bulge of the rectum on the posterior wall of the vagina (Grade I) to a bulge protrusion through the vaginal opening (grade III), witch refer to a portion of the rectum bulging into the vagina and protruding outside the body. The posterior vaginal vault prolapse results from multiple structural support defects. Bulging seems to occur as a consequence of the rupture of the attenuation of the endopelvic structures together with tissue weakness. Vaginal vault prolapse is classified into four grades: Page 2 of 11

3 - Grade I, the vault goes beyond the inferior half of the vagina, without reaching the hymen. - Grade II, the vault reaches the hymen. - Grade III, the vault goes beyond the hymen, but the vagina is not completely inverted. - Grade IV, there is a complete vaginal eversion. Posterior prolapse and apical prolapse are caused by different factors, including constipation, obstetric trauma, prolonged delivery or following a hysterectomy. Non-surgical treatments, such pessaries to elevate the uterus or colpocleisis, can be used with a reduced group of women who are not eligible for surgery, but they are not adequate for women with potential sexual activity. Another way to revert the prolapse of the rectum is to sacrospinous fixation, but it could damage the neurovascular structure adjacent to the vagina. Vaginal prolapse repair with mesh: The concept of biosurgery, a term coined by Hubert Manhes in France in the 1990s, was highly significant in the advance of minimally invasive laparoscopic surgery using meshes for tissue reinforcement as well as in the development of transobturator procedures. Manhes support the idea that surgeons leave aside the clearly mechanical concept of surgeries since they work on live tissues that have their own healing and repair laws. Biosurgery values the principles of traditional surgery, associated to tissue reinforcement induced by biomaterials, and it is characterized by the following principles: 1- Minimally invasive approach. 2- Research of anatomical and physiological planes. 3- Minimum trauma. 4- Respect for tissue engineering and its specific ecosystems. 5- Gives its own solutions, that stimulates and divert body reactions where necessary. 6- No fixation (sutures lead to necrosis and infection). 7- Immediate anatomical and functional results. Surgical procedures using a mesh offer better expectations of a permanent vaginal prolapse repair. There are two types of surgical approaches: vaginal and abdominal (laparoscopic). Laparoscopic procedures require highly skilled professionals, specialized training and hospital stay of 2-7 days. Vaginal approach has the advantage of being minimally invasive, decreasing postoperative pain and reducing morbidity associated to Page 3 of 11

4 abdominal processes. These surgical procedures are used since the 1960s, such as the prepubic approach, which started en Several studies demonstrated that these surgical implantation techniques are safe, effective and minimally invasive. Moreover, they offer many advantages such a short postoperative period, a short sick leave, simplicity in procedure and a short learning curve 19. At present, a growing number of surgeons are implanting meshes from different companies using the anterior and posterior intravaginal approaches. These techniques are minimally invasive due to the use of needles that facilitate the passage of mesh arms through the tissues. These techniques are also highly recommended for obese patients or for those patients who had previously undergone vaginal surgeries 23. NAZCA and CALISTAR mesh for vaginal prolapse repair: NAZCA consists of a mesh and disposable surgical instruments to easy the implantation by intravaginal approach. Mesh arms have silicone connectors at the ends that allow threading of the needles and introducing the arms through the tissues. Connectors are then cut and discarded. CALISTAR consists of a mesh and disposable surgical instruments to easy the implantation by intravaginal approach. Mesh arms have polypropylene columns at the ends that allow threading of the needles and anchor the mesh. The mesh is made of monofilament polypropylene (same of SAFYRE and OPHIRA sling) and it is placed on the bladder or rectum with no tension. Interconnective tissue grows through its pores and holes, allowing for good implant integration and no loss of vascularization between the vagina and the bladder in the case of anterior prolapse treatment, and between the vagina and the rectum in the case of posterior prolapse treatment or apical prolapse. There are holes in the center of the mesh in order to reduce the amount of synthetic material implanted and to make the mesh softer and more flexible, while allowing a fast growth of connective tissue between both walls. Promedon has four mesh models: 1- A mesh for anterior vaginal wall prolapse repair, which consists of a mesh with four arms. At surgeon s discretion, these arms can be placed tension free, two in each obturator foramen, or two prepubic and the other two in each obturator foramen. The set includes two disposable transobturator needles and one disposable prepubic needle. Page 4 of 11

5 2- The mesh for posterior vaginal wall prolapse repair has two arms which are placed in the lateral wall of the elevator muscle, according to the sling implantation technique by posterior approach. The set includes two disposable needles for posterior approach. 3- A mesh for anterior vaginal wall prolapse repair, which consists of a mesh with two polypropylene columns with multiple fixation points, and 3 anchors with suture. The set includes one disposable retractable insertion guide. 4- A mesh for posterior vaginal wall prolapse repair, which consists of a polypropylene mesh, and 3 anchors with suture. The set includes one disposable retractable insertion guide. Promedon meshes are permanent implants and they are provided as sterile single-use products. They come in a double pouch-like bag or in a PETG tray, as well as the needles. All content comes in a cardboard box. a.2 ) Materials used in the manufacture of mesh The bibliography mentions different materials used for the construction of mesh, which can be classified in 2 groups: synthetic origin and biological origin. The synthetic materials offer a great mechanical resistance and they do not have risk of transmission of diseases like the biological materials. The biological materials are better accepted by tissues, although they are reabsorbed with time. 9 Biologic Materials: Autologous Cadaveric fascia lata Porcine Small Intestine Poliéster Polyethylene terephthalate Polytetrafluoroethylene Synthetic Materials: Equally the use of the synthetic mesh for repair of genital prolapse has drastically reduced the recurrence rate from 30-50% in the past to the present 3-6% 25. One of synthetic mesh more used in the treatment of vaginal prolapse is made with polypropylene mesh. Page 5 of 11

6 AMS, Sofradim, Tyco, Cousin Biotech, Ethicon, Hi-Tec, Bard are some of the companies that offer mesh for the vaginal prolapse repair. b) The comparison between NAZCA, CALISTAR and SPLENTIS with different medical devices for the treatment of vaginal prolapse As shown below, the characteristics of NAZCA TC and CALISTAR A are compared with 4 of the main devices for the treatment of anterior prolapse: Characters Devices NAZCA TC (Promedon) Perigee (AMS) CALISTAR A (Promedon) Profilt (Gynecare-J&J) Avaulta (Bard- Sofradim) Elevate Anterior (AMS) Mesh Composition with porcine coating Transvaginal Transvaginal Single Incision Single Incision Surgical Approach Transobturator/ Prepubic Transobturator Obturator internous Muscle/ Transobturator Transobturator Obturator internous Muscle/ Sacrospinous Sacrospinous Ligament Ligament Surgical Instruments TOT Needles TOT Needles Rectractable insertion guide Universal Needles TOT Needles Rectractable insertion guide As shown below, the characteristics of NAZCA R and CALISTAR P are compared with 3 of the main devices for the treatment of posterior prolapse: Characters Devices NAZCA R (Promedon) CALISTAR P (Promedon) Apogee (AMS) Profilt (Gynecare- J&J) Elevate Posterior (AMS) Mesh Composition Page 6 of 11

7 Transvaginal Single Transvaginal Single Surgical Approach Posterior Incision/ Sacrospinous Posterior Posterior Incision/ Sacrospinous Ligament Ligament Surgical Instruments Posterior o Transgluteal Needles Rectractable insertion guide Posterior o Transgluteal Needles Universal Needles Rectractable insertion guide As shown below, the characteristics of SPLENTIS are compared with 4 of the main devices for the treatment of prolapse with sacospinous ligament fixation: Devices Characters SPLENTIS (Promedon) i-stich (A.M.I) Capio (Boston Scientific) Fixt (Bard) Surelift (Neomedic) Anchor/Suture Material anchor with PP suture suture suture suture PEEK Surgical Approach SSL fixation SSL fixation SSL fixation SSL fixation SSL fixation Surgical Instruments Rectractable insertion guide Reusable instrument for use with a Loading Unit Reusable Suture Capturing Device Reusable Suturing Device Reusable anchorsure aplicator c) The clinical results in surgery verifications Many papers, posters, videos and presentations about NAZCA and CALISTAR had been publicized in scientific journals and in nationals and internationals congresses. The following abstract are some of them: NAZCA TC: A RANDOMIZED CONTROLLED TRIAL STUDY, TO COMPARE COLPORRHAPHY VERSUS NAZCA TC, MACROPOROUS POLYPROPYLENE MESH, IN SURGICAL TREATMENT TO GREATER ANTERIOR VAGINAL PROLAPSE. ICS/IUGA 2010 Joint Annual Meeting of the International Continence Society and the International Urogynecological Association. 23 rd-27 th. August 2010, Canada Del Roy C1 Page 7 of 11

8 1. Federal University of Sao Paulo MONOPROSTHESIS FOR SIMULTANEOUS CORRECTION OF STRESS URINARY INCONTINENCE AND CYSTOCELE: A MULTICENTRIC PROSPECTIVE STUDY European Association of Urology 22nd Congress March 21 to Palma P.1, Riccetto C.1, Müller V.1, Paladini M.2, Adile B.3, Cianci A.4, Contreras O.5, Barthos P.6 1Unicamp, Urology, Campinas, Brazil, 2Universidad de Cordoba, Urology, Cordoba, Argentina, 3Hospedale Santa Sophia, Gynecology, Palermo, Italy, 4University Of Catania, Gynecology, Catania, Italy, 5University of Buenos Aires, Gynecology, Buenos Aires, Argentina, NAZCA R: APICAL LIGAMENT SPECIFIC REPAIR WITH NAZCA-R ICS (International Continence Society Meeting) 2009, of April Adile B1, Adile G1, Gugliotta G2, Pitarresi M2, Lo Piccolo S2, Palma P3, Amico M L1, Cucinella G1, Abbate A1 1. Gynecology and Obstetrics Unit Policlinico P.Giaccone Hospital Palermo-Italy, 2. Urogynecology Unit Villa Sofia C.T.O. Hospital Palermo- Italy, 3. Urogynecology Unit Campinas Hospital University San Paulo Brazil Transcoccígeal colpopexy with polyprolylene mesh with helper orifices for the treatment of posterior vaginal wall prolapse: anatomical and functional results. ACTAS UROLÓGICAS ESPAÑOLAS 2009;33(4): Vitor Pagotto, Paulo Palma, Cassio Riccetto, Miguel Bigozzi* Servicio de Urología de la Facultad de Ciencias Médicas de la Universidad Estatal de Campinas. Brasil. *Servicio de Ginecología, Hospital Santojanni, Buenos Aires, Argentina. CALISTAR A: A SINGLE INCISION MONOPROSTHESIS FOR CONCOMITANT MANAGEMENT OF APICAL, ANTERIOR PROLAPSES AND STRESS URINARY INCONTINENCE ICS/IUGA 2010 Joint Annual Meeting of the International Continence Society and the International Urogynecological Association. 23 rd-27 th. August 2010, Canadá Page 8 of 11

9 Palma P1, Riccetto C L Z1, Salgado J R1, Dias F G F1, Herrmann V1 1. University of Campinas - UNICAMP CALISTAR P: TRANSVAGINAL SINGLE INCISION IMPLANT FOR APICAL AND POSTERIOR PROLAPSES. ICS/IUGA 2010 Joint Annual Meeting of the International Continence Society and the International Urogynecological Association. 23 rd-27 th. August 2010, Canadá Riccetto C L Z1, Palma P1, Tcherniakovsky M1, Barreiro T M1, Souza R1, Lopez F C1, Herrmann V1 1. University of Campinas UNICAMP PRELIMINARY FINDINGS WITH TRANSVAGINAL SINGLE INCISION IMPLANT FOR APICAL AND POSTERIOR PROLAPSES. CAU (Confederacion Americana Urologia) Chile 8 to 11 September 2010 Authors: Paulo Palma, Cássio Riccetto, Marcos Tcherniakovsky, Sebastian Altuna, Juan Sardi, Marta Ledesma. d) Conclusion The bibliography and the clinical results demonstrate that the mesh product is safe and effective. Complications detected were minimal. The risks are not different from other similar products and the benefit with regard to the simplicity of the surgical technique is clearly remarkable. The results are acceptable and reproducible, simultaneously that stand out that the product is an excellent alternative to the use of vaginal prolapse repair. Eng. Ivan Maiorov made the investigations and conclusions regarding Prolapse Repair Devices clinical data. Eng. Osvaldo Griguol made the review of it. A copy of him Curriculum Vitae are attached to the present document. References 1.- White GR (1909) Cystocele. JAMA 853: Page 9 of 11

10 2.- Weber AM, Walters MD (1997) Anterior vaginal prolapse: review of anatomy and techniques of surgical repair. Obstet Gynecol 89: Shull BL, Benn SJ, Kuehl TJ (1994) Surgical management of prolapse of the anterior vaginal segment: An Analysis of support defects, operative morbility, and anatomic outcome. Am J Obstet Gynecol 171: Julian TM (1996) The efficacay of Marlex mesh in the repair of severe, recurrent vaginal prolapse of the anterior midvaginal wall. Am J Gynecol 175: Debodnance P, Berrocal J, Clavé H, et al. Evolution des idées sur le traitement chirurgical des prolapse génitaux. J Gynecol Obstet Biol Reprod. 2004;33: Pre-pubic TVT: an alternative to classic TVT in selected patients with urinary stress incontinence. Eur J Obstet Gynecol Reprod Biol Apr 25: Iglesia CB, Fenner DE, Brubaker L. The use of mesh in gynecologic surgery. Int Urogynecol J. 1997;8: Rosengren A, Bjursten LM, Pore size in implanted polypropylene filters is critical for tissue organization. J Biomed Mater Res. 2003,67A: Amid PK. Classification of biomaterials and their related complications in abdominal wall hernia surgery. Hernia 1997;1: Caputo RM, Benson JT (1993) Vaginal paravaginal repair with mesh placement for cystocele. American Urogynecologic Sicuety Annual Meeting, 1993, San Antonio, TX Leanza V., Gasbarro N., Caschetto S.: New technique for correcting both incontinence and Cystocele: T.I.C.T. Urogynaecologia International Journal 15;3:133-14, Paulo Palma, Cássio Riccetto, Viviane Herrmann, Alejandro Trazona, Nelson Rodriguez Netto Jr. Correccion transobturatriz de los cistoceles. Disciplina de urología y ginecología, Universidade Estadual de Campinas, UNICAMP, Sao Paulo, Brasil 13.- B.N. Farnsworth Posterior Intravaginal Slingplasty (Infracoccygeal Sacropexy) for Severe Posthysterectomy Vaginal Vault Prolapse A Preliminary Report on Efficacy and Safety. International Urogynecology Journal (2002) 13: Stuart L. Stanton and Philippe E. Zimmern (Eds) Female Pelvic Reconstructive Surgery - pag: Marchionni M, Bracco GL. Checcucci V, et al. True incidence of vaginal vault prolapse: thirteen years of experience. J Reprod Med. 1999, Robinson DB. Advances in pelvic floor reconstructive surgery. As presented Smajda S, Vanormelingen L, Vandewalle G, Ombelet W, Jonge ED, Hinoul P. Translevator posterior intravaginal slingplasty: anatomical landmarks and safety margins. Int Urogynecol J Pelvic Floor Dysfunct Jan Jacquetin B, Caquant F, Collinet P, Debodinance P, Rosenthal C, Clavé H, Cosson M, Prolene Soft (Gynecare) Mesh for Pelvic Organ Prolapse Surgical Treatment: A Prospective Study of 264 Patients Macer, G.A.: Transabdominal repair of cystocele, a 20 year experience, compared with the traditional vaginal approach. Am J Obstet Gynecol, 131: 203, Flood CG et al. Anterior colporraphy reinforced with Marlex mesh for the treatment of cystoceles. Int UroGynecol J Pelvic Floor Dysfunct 1998;9:200-4 Page 10 of 11

11 21.- Migliari R et al. Tensión-free vaginal mesh repair for anterior vaginal wall prolapse. Eur Urol 2000;38: Barber MD et al. Psychometric evaluation of 2 comprehensive condition-specific quality of life instruments for women with pelvic floor disorders. Am J Obstet Gynecol 2001; 185: Tayrac R, Eglin G, Ugytex French Study G, Prolapse repair by vaginal route using a new protected low-weight polypropylene mesh: Preliminary results of a prospective multicentre study, Abstract 617 IUGA-ICS Meeting - Paris United Stetes Patent Application Publication, Inventor: Mauro Cervigni, Rome (IT) Pub.Nº: US2005/ A1, Pub.Date: Jun.6, Evolution of surgical routes in female stress urinary incontinence. Gynecol Obstet Fertil Dec;32(12): Hom D et al Pubovaginal sling using polypropylene mesh and Vesica bone anchors Urology 1998 May; 51 (5): Prolift Mesh (Gynecare) for pelvic organ prolapse treatment using the TVM Group Technique: A retrospective study of 687 patients. Abstract 121, ICS Montreal Cystocele repair utilizing anterior wall mesh graft placed via double trans-obturador approach (Perigee System), Moore R, Miklos J. Abstract 595 ICS Montreal Restoration of vaginal apical and posterior wall support with the Apogee System, Davila G W, Beyer R, Moore R, Del Rio S, Lukban J. Abstract 597 ICS Montreal Sexuality and quality of life in women with genital prolapse: Impact of vaginal surgery with low-weight protected polypropylene mesh. Tayrac R, Eglin G, Pelvitex Study Group G. Abstract 273 ICS Montreal 2005 Page 11 of 11