National Institute for Health and Clinical Excellence

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1 National Institute for Health and Clinical Excellence 269/2 Endoluminal gastroplication for gastro-oesophageal reflux disease Consultation table IPAC date: Thursday 14 th April 2011 Com. 1 Consultee 2 NHS Professional 1 The consultation document provided by NICE refers to several endoscopic anti-reflux technologies that are no longer available or considered effective. It is unfair to consider Transoral Incisionless Fundoplication (TIF) which uses the Esophyx device within this group. The commentary needs to consider TIF in a more focused/separate way including the current data relating to this technology which is qualitatively different to the data reported from the other types of antireflux procedures from the past. Much of the data regarding TIF demonstrates very good medium (rather than short term) outcomes i.e. 3 year follow up measures post-tif, as well as significant improvements in physiological measurements of acid reflux, which have not been shown before. The list of current treatments and alternatives is not intended to be definitive. 1 of 20

2 2 Consultee 1 3 Consultee In review of Section 1.1, it is evident that the statements made regarding efficacy of randomized controlled trials and evidence of sustained improvement in esophageal ph measurements is outdated. Furthermore, the maturity of endoluminal gastroplication in the last three years moves this procedure beyond special arrangements for clinical governance, consent and audit or research and into generally acceptable surgery for the treatment of Gastro-Oesphageal Reflux Disease (GORD). The need for a long-term treatment of GORD has become increasingly apparent as the prevalence and incidence of the disease has grown during the past decade and a half. With evidence from 9 unbiased clinical studies, which have generated 21 peerreviewed US and European publications, Transoral Incisionless Fundoplication (TIF) has proven to be safe and effective. The clinical trial results to date support safety of TIF and its efficacy in eliminating typical and atypical symptoms, reducing daily use of proton pump inhibitors (PPI) and normalizing acid reflux and curing GORD in over 75% of patients. 1.1 GORD is widely recognized as one of the most common clinical disorders observed in developed countries. Although it is not a lifethreatening disease, it can cause serious complications such as esophageal stricture, Barrett s esophagus, or adenocarinoma. i Traditional treatment for GORD has been medical, with surgery reserved for patients with incomplete symptom control or intolerance to medical therapy. However, medical therapy, especially with PPIs, has come under scrutiny because of an associated higher incidence of osteoporosis and hip fractures ii iii, Clostridium difficile colitis iv v, and cardiac events, if used in conjunction with Plavix vi vii. More importantly, PPI therapy does not stop reflux; it merely renders the refluxate less acidic, and up to 40% of patients continue to have symptoms despite reduction in the acid content of the refluxed stomach juice viii ix x xi. Underlying anatomically problems of GORD patients on PPIs showed that 35% of patients experienced a relapse of symptoms at 3 year follow up and required titration with increasing doses of PPIs and later referral for surgery. 2 of 20 The Committee considered this comment but decided not to change the guidance.

3 4 Consultee 1 5 Consultee 1 6 Consultee The current standard of care offers limited treatment options for patients with inadequately controlled symptoms despite high doses of PPIs. 13, 14 Antireflux surgery using laparoscopic Nissen, which represents the comparator for the Transoral Incisionless Fundoplication (TIF) technique, is effective in preventing both acid and nonacid reflux in patients with both typical and atypical GORD symptoms. 15, 16 However, this technique creates super-competent gastroesophageal valves that often lead to new iatrogenic side effects such as bloating and dysphagia. Furthermore, the high prevalence of postoperative complications, poorer outcomes and somatic anxiety makes patients very reluctant to consider surgery. Both the patients who suffer from GORD and the physicians who treat them look for an alternative. 1.1 The TIF Procedure is the latest advancement in the evolution of surgical procedures for the treatment of GORD. It emulates and builds upon the principles of time-proven laparoscopic surgical procedures, and delivers similar benefits: 1) reduces hiatal hernia, 2) recreates the angle of His, and 3) recreates the gastroesophageal valve (GEV). The key differences are that TIF is performed transorally (through the mouth), does not require incisions, and does not dissect any part of the natural internal anatomy. It has been used in more than 5,300 patients world-wide and is gaining popularity because of its high safety profile, good clinical outcomes and minimal invasiveness. 1.1 TIF elongates the esophagus and creates a degree eshophagogastric valve incorporating and tightening the phrenoesophageal membrane. The above table illustrates how TIF is based on and closely emulates the surgical principles of more invasive fundoplication techniques. European studies with the early gastrogastric TIF1 procedure in small series reported reasonable results in treating chronic GORD patients responsive to PPIs. A more recent case study in the U.S. with esophago-gastric TIF2 showed significantly improved subjective and objective outcomes in over 70% of patients with GORD symptoms resistant to PPIs. Barnes (2011) was identified in the updated literature search and its main results presented to the Committee. It will be included in Table 2 of the overview, available on publication of the guidance. The committee saw the full copy of the consultation comments provided by this consultee. 3 of 20

4 7 Consultee 1 8 Consultee 1 9 Consultee The following data provides evidence that the TIF procedure appears to be safer than the Lap Nissen surgery. TIF Intra-, post and long-term complication rates are significantly lower than those of the Lap Nissen. TIF results in 61% normalization of esophageal acid exposure and 89% normalization of reflux episodes. Additionally, evidence supports that TIF eliminates the need for daily medical therapy in up to 97% of patients. Furthermore such evidence shows that discontinuation of daily PPIs after TIF is associated with significantly increased lower esophageal sphincter (LES) pressure, reduced acid reflux episodes and reduced proximal extent of refluxate. 1.2 We feel that TIF is a safe and efficacious procedure, and that there is sufficient peer-reviewed data to show this. We feel that NICE should permit the TIF to be part of the freely available armamentarium of options for trained surgeons to use in cases of GORD. 1.3 Any further studies should report long term outcomes. Both published and unpublished clinical results showed that the TIF procedures using the EsophyX system with SerosaFuse fasteners was effective in eliminating symptoms, decreasing the need for daily PPIs, normalizing esophageal acid exposure, increasing LES resting pressure, and promoting healing of esophagitis in patients with chronic GORD. The obtained improvement in clinical and pathophysiologic outcomes correlated significantly with the quality of the anatomic reconstruction. When applied to the appropriate patients, TIF resulted in a durable reduction of hiatal hernias and effective reconstruction of the antireflux competency of the gastroesophageal junction. The Committee considered this comment but decided not to change the guidance. The Committee considered this comment but decided not to change the guidance. The Committee considered this comment but decided not to change the guidance. 4 of 20

5 10 Consultee TIF1 Results: Two studies were conducted in Europe to evaluate the safety and long-term efficacy of the TIF gastro-gastric procedure: The first one was a single-center study with 19 patients; and the second was a multicenter study with 86 patients. Both studies demonstrated the safety of the TIF procedure and provided the first long-term efficacy results. The committee saw the full copy of the consultation comments provided by this consultee. 11 Consultee 1 12 Consultee 1 The following table represents 9 European studies of which 6 have completed and 3 are in progress. The primary objective of the trials was to evaluate clinical outcomes in GORD patients who underwent TIF. 1.3 In addition to the European TIF1 clinical trial results, the TIF2 esophago-gastric procedure was introduced in late 2008 and the initial U.S. results report excellent objective and subjective outcomes. The following table represents 12 US studies of which 5 have completed and 7 are in progress. The primary objective of the trials was to evaluate clinical outcomes in GORD patients who underwent TIF. 1.3 The following overview of published literature is based on approximately 500 patients from 9 non-randomized retrospective studies evaluating GORD in patients who underwent TIF. The committee saw the full copy of the consultation comments provided by this consultee. The committee saw the full copy of the consultation comments provided by this consultee. 5 of 20

6 13 Consultee Cadiere et al (2008) reported on a study population that consisted of N=84 patients with chronic GORD symptoms (> 6 months) responsive to PPI therapy as judged by the GORD health-related quality of life (HRQL) scores of 12 while on PPI therapy, whose symptoms recurred upon discontinuation of PPI therapy for 14 days (GORD-HRQL) scores 20 or a difference of 10 between scores on and off PPIs). xii Exclusion criteria included an irreducible hiatal hernia > 2 cm. The TIF procedure (n = 84) reduced all hiatal hernias (n = 49) and constructed valves measuring 4 cm (2-6 cm) and 230 degrees (160 degrees -300 degrees). Serious adverse events consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other adverse events were mild and transient. At 12 months, aggregate (n = 79) and stratified Hill grade I tight (n = 21) results showed 73% and 86% of patients with 50% improvement in GORD health-related quality of life (HRQL) scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of esophageal acid exposure; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of patients with Hill grade I tight valves had a normalized cardia circumference. Resting pressure of the lower esophageal sphincter (LES) was improved significantly (p < 0.001), by 53%. EsophyX-TIF cured GORD in 56% of patients based on their symptom reduction and PPI discontinuation. The 12-month results showed that EsophyX-TIF was safe and effective in improving quality of life and for reducing symptoms, PPI use, hiatal hernia, and esophagitis, as well as increasing the LES resting pressure and normalizing esophageal ph and cardia circumference in chronic GORD patients. The Cadiere (2008) study is included in Table 2 of the overview. 6 of 20

7 14 Consultee In 2009 Cadiere et al presented the results on a feasibility study (n = 19) which evaluated the safety and initial efficacy of TIF for the treatment of GORD. The results at 1 year (n = 17) indicated that TIF was safe and had a significant effect on reducing GORD symptoms, PPI usage, acid exposure, and small hiatal hernia. This study was designed to evaluate the long-term safety and durability of TIF. Fourteen patients (50% female; median age, 34 years) completed the 2-year follow-up assessment tests. Three patients were excluded from the study after 1 year because two of them underwent retreatment and one was lost to follow-up. At 2 years, no adverse events related to TIF were reported. A >or=50% improvement in GORD-HRQL scores compared with those at baseline on PPIs was sustained by 64% of patients. TIF was effective in eliminating heartburn in 93% of patients and daily PPI therapy in 71% of patients. Significantly (p < 0.05) more patients were able to consume reflux-causing foods and maintain lifestyle activities without GORD symptoms compared with baseline on PPIs. Fundoplications were durable and maintained their geometric dimensions. TIF was effective in eliminating hiatal hernia in 60% of patients and esophagitis in 55% of patients. Global assessment of all outcomes in each patient revealed that 79% of patients experienced complete cure (29%) or remission (50%) of GORD at 2 years after TIF. The results at 2 years supported the long-term safety and durability of TIF and its sustained effect on the elimination of heartburn, esophagitis, <or=2 cm hiatal hernia, and daily dependence on PPIs. Thanks you for your comment. Cadiere (2009) is included in Appendix A of the overview. 7 of 20

8 15 Consultee A multicenter study currently being prepared for submission to a scientific journal, evaluated the safety and efficacy of TIF for the treatment of study (n=86) evaluated the safety and initial efficacy of TIF for the treatment of chronic GORD. The results after 1 year (n=79) indicated that TIF was safe and had a significant effect on reducing GORD symptoms in 73% of patients and discontinuation of daily proton PPI usage in 85%. Three-year follow-up consisted of symptom evaluation using the GORD Health related Quality of Life (HRQL) questionnaire and medication usage, as well as endoscopy and phmetry for selected patients with normalized ph at 1 year follow-up. Fifty-four patients from all seven sites completed 3-year follow-up visit. No adverse events related to TIF were reported. Median GORD-HRQL score off PPIs was 3 (range 0-32) and improved significantly compared to median scores at baseline off (25, 13-38, P<0.01) and on (9, 0-22, P<0.01) PPIs (see figure below). A 50% improvement in GERD- HRQL scores compared with baseline off PPIs was sustained in 90% of patients. The discontinuation of daily PPIs was sustained in 74% of patients including 9% who used PPIs occasionally. The results at 3 years supported the long-term safety and durability of TIF and its sustained effect on the elimination of heartburn, esophagitis, <or=2 cm hiatal hernia, and daily dependence on PPIs. The IP programme is unable to consider unpublished efficacy data. The committee saw the full copy of the consultation comments provided by this consultee. 8 of 20

9 16 Consultee The Barnes et al retrospective study evaluated clinical outcomes in 124 consecutive gastroesophageal reflux disease (GORD) patients who underwent TIF at 2 community hospitals. xiii Out of 123 patients treated successfully, 110 gave consent (74% female, median age 60 [range 21-87] years, body mass index 27.5 [ ]). At a median 7-month follow-up (range 5-17), typical and atypical symptom scores were normalized in 75% to80% of patients, proton pump inhibitors (PPIs) were completely discontinued by 93%, and 83% were satisfied with their current health condition. Endoscopy in 53 patients revealed Hill grade I tight valves in 89% of the cases, reduced hiatal hernia in 33/34 (97%), and healed reflux esophagitis in 25/30 (83%). Based on global analysis, 72% of the patients were in remission, 20% improved symptomatically, and only 8% had ongoing GORD. These results supported the safety and efficacy of TIF as well as encouraged its application as an alternative treatment of GORD refractory to PPIs. Barnes (2011) was identified in the updated literature search and its main results presented to the Committee. It will be included in Table 2 of the overview, available on publication of the guidance. 9 of 20

10 17 Consultee In the Bell et al paper, 37 consecutive patients on antisecretory medication and with proven gastroesophageal reflux and limited hiatal hernia underwent TIF for persistent GORD symptoms. xiv Five patients were reoperations for failed laparoscopic fundoplication. Of the 37 treated patients, 57% were female. The median age was 58 (range = 20 81) years and BMI was 25.5 (range = ) kg/m2. Sixty-eight percent indicated GORD-associated cough, asthma, or aspiration as a primary complaint and 32% complained of heartburn or regurgitation. The TIF procedures created tight wraps of extending 3 4 cm above the Z-line. Two complications occurred: one mediastinal abscess treated laparoscopically and one postoperative bleeding requiring transfusion. At 6 (range = 3 14) months median follow-up TIF resulted in a significant improvement of both atypical and typical symptoms in 64% and 70 80% of patients, respectively, as indicated by the corresponding GORD health-related quality of life (HRQL) and reflux symptom index (RSI) score reduction by 50% or more compared to baseline on proton pump inhibitors (PPIs). No patient reported problems with dysphagia, bloating, or excess flatulence, and 82% were not taking any PPIs. Reflux characteristics were significantly improved and normalized in 61, 89, and 56% of patients in terms of acid exposure, number of refluxates, and DeMeester scores, respectively. TIF was effective in treating GORD in 75% of patients among whom 54% were in a complete remission and 21% were improved. The remaining 25% were considered failures, and five (13.5%) patients underwent revision. In conclusion, rotational/longitudinal esophagogastric fundoplication using the EsophyX TIF device significantly improved symptomatic and objective outcomes in over 70% of patients at median 6-month follow-up and post-fundoplication side effects were not reported after TIF Bell (2010) study will be included in Appendix A of the overview, available on publication of the guidance. 10 of 20

11 18 Consultee 1 19 Consultee 2 NHS Professional 20 Consultee Though heartburn is the most common symptom, GORD sufferers may also experience: Regurgitation Hoarseness or sore throat Frequent swallowing Asthma or asthma-like symptoms Pain or discomfort in the chest Reflux-related sleep disorders Yellow fluid or stains on pillow after sleep Excessive clearing of the throat Persistent cough Burning in the mouth or throat Intolerance of certain foods Bloating Dental erosions or therapy-resistant gum disease or inflammation 2.1 Surgical fundoplication in many instances is like using a sledgehammer to crack a walnut. In addition the side effect profile of anti-reflux surgery is significant and a concern to patients. Alternative therapies (i.e. a non PPI and non-surgical option) such as endoscopic treatment, particularly for the treatment of patients with mild to moderate acid reflux (as well as those intolerant to PPI or averse or unsuitable for surgery) should be an available option. TIF with its low side effect profile and good efficacy data should therefore be considered a 3rd treatment option for patients Gastro-Oesophageal Reflux Disease (GORD) is the reflux of gastric contents back into the esophagus frequently enough to disrupt the quality of life for the patient. GORD occurs when the sling musculature of the Gastroesophageal Junction (GEJ) becomes stretched and loose and the angle of His is lost. The angle of His is the angle at which the base of the esophagus enters the stomach. This section of the guidance is intended to be a summary of the indication. The IP Programme does not have a remit to determine the placement of a procedure in the pathway of care for a disease or condition in its guidance. This section of the guidance is intended to be a summary of the indication. 11 of 20

12 21 Consultee 1 22 Consultee 1 23 Consultee In a healthy individual, the tissue at the base of the esophagus doubles back as it enters the stomach, creating a double-layer of tissue that serves as a valve by resting against the lesser curve of the stomach. This valve opens during swallowing and then remains closed to prevent reflux of gastric contents into the esophagus. Reflux of gastric acid, pepsin and other enzymes and caustic agents irritate the squamous epithelium of the esophagus, and may lead to erosion and ulceration of esophageal mucosa. Eventually, in a subset of about 10% of the refluxing population, the squamous epithelium may be progressively replaced by a columnar or intestinal epithelium. The presence of this columnar or intestinal epithelium in the esophagus is a premalignant condition named Barrett's Esophagus (BE), and yields a ~10% risk of progression to adenocarcinoma of the esophagus, which is much higher than the risk of the general population Current Treatments: Open and laparoscopic surgical procedures are highly effective but are rather invasive and expensive and adverse events like gas bloat syndrome and dysphagia are common. For this reason, less than 1% of the relevant GORD patients choose surgical therapy to treat GORD Nissen fundoplication, introduced in 1951 as an open procedure, demonstrated that reconstructing the natural anatomy of the gastroesophageal junction not only reduces the occurrence of symptoms but also improves the physiological conditions necessary to prevent reflux. In the early 1990's, the Laparoscopic Nissen Fundoplication (LNF) was introduced and became the most widely used surgical procedure for the treatment of GORD.[9, 10] LNF attempts to recreate the natural anatomy of the gastroesophageal junction as well as reduce hiatal hernia. In studies, LNF has been show to be effective in 75 to 90 percent of patients in alleviating heartburn and 50 to 75 percent in alleviating cough, asthma, and laryngitis. This section of the guidance is intended to be a summary of the indication. This section of the guidance is intended to be a summary of the current treatments available. Papers cited do not report on the procedure of interest. This section of the guidance is intended to be a summary of the current treatments available. 12 of 20

13 24 Consultee 1 25 Consultee 1 26 Consultee In addition, anti-reflux surgery has been shown to be superior to drug therapy in preventing Barrett's metaplasia. The etiology of Barrett's metaplasia, a precancerous condition, presents strong evidence linking alkaline duodenogastric reflux to the development of esophageal mucosal damage which can best be prevented by restoring the ARB Nissen Fundoplication, both LNF and open, requires significant changes to the natural anatomy in order to recreate the gastroesophageal valve. During the procedure, the fundus of the stomach, the short gastric vessels, and the phrenoesophageal membrane are typically dissected. The fundus is then wrapped around the esophagus and stitched to the anterior aspect of the stomach creating a loose wrap around the distal esophagus and the GEJ. Complications may include a long-lasting dysphagia, gas bloat syndrome, scarring, and, rarely, achalasia. The fundus is lost and belching may be impossible. In addition, LNF results in permanent anatomical modifications that are difficult to undo Until recently, endoluminal technologies for the treatment of GORD primarily focused on tightening the Lower Esophageal Sphincter (LES) with the aim of improving this component of the compromised antireflux barrier (ARB) through one of three methods: Thermal tissue remodeling by delivering radio frequency Injection/implantation of non-absorbable material Esophageal tissue pleats at the LES level by endoscopic suturing The Interventional Procedures programme at NICE assesses the safety and efficacy of new interventional procedures. The Committee makes recommendations on conditions for the safe use of a procedure including training standards, consent, audit and clinical governance. It does not have a remit to determine the placement of a procedure in the pathway of care for a disease or condition. This section of the guidance is intended to be a summary of the current treatments available. This section of the guidance is intended to be a summary of the current treatments available. 13 of 20

14 27 Consultee 1 28 Consultee These previously mentioned technologies do not emulate surgery. However, the TIF procedure, performed with the EsophyX device, is the first transoral surgical procedure to provide: Reduction of hiatal hernia Creation of a robust antireflux barrier and valve Procedures that can be customized to the anatomy of the individual The TIF procedure, performed with the EsophyX device, is the latest advancement in the evolution of surgical procedures for the treatment of GORD. It emulates and builds upon the principles of time-proven laparoscopic surgical procedures, and delivers similar benefits: 1) reduces hiatal hernia, 2) recreates the angle of His, and 3) recreates the gastroesophageal valve (GEV). The key differences are that TIF is performed transorally (through the mouth), does not require incisions, and does not dissect any part of the natural internal anatomy. In addition to restoring the GEV, the EsophyX TIF procedure: Constructs a , 3-5 cm omega shaped antireflux valve. Reestablishes the angle of His. Achieves serosa-to-serosa fusion. Lengthens the intraabdominal esophagus. Reduces hiatal hernia. Has been proven safe and effective in clinical studies. No long-term complications have been reported to date. 14 of 20

15 29 Consultee While emulating principles of conventional open or laparoscopic GORD surgery, the TIF procedure is intended to reduce invasiveness, allow for faster recovery, and be more versatile. It is a safe, effective alternative to conventional surgical approaches or pharmaceutical therapies. because it is only minutely invasive, it significantly lowers the hurdle to GORD patients electing to have an anatomical repair done to resolve their condition. The committee saw the full copy of the consultation comments provided by this consultee. 30 Consultee 2 NHS Professional 31 Consultee 1 32 Consultee 1 The evidence provided in the table illustrates that the TIF appears to have lower complications rates that alternative surgical procedures. 2.2 Perhaps the commentary could reference the TIF procedure in greater detail as the other technologies mentioned in the consultation document are no longer performed or commercially available Endoluminal gastroplication for GORD is an endoscopic procedure to avoid the need for surgical fundoplication. The TIF procedure, performed with the EsophyX device, is a surgical procedure for the treatment of GORD. It emulates and builds upon the principles of time-proven laparoscopic surgical procedures, 1) reduces hiatal hernia, 2) recreates the angle of His, and 3) recreates the gastroesophageal valve (GEV) and 4) achieves serosa-to-serosa fusion. The key differences are that TIF is performed transorally (through the mouth), does not require incisions, and does not dissect any part of the natural internal anatomy Patient undergoing the TIF procedure are placed under general endotracheal anesthesia with an emphasis on complete diaphragm relaxation. The EsophyX device is introduced into the stomach transorally over a flexible endoscope. The device enables molding of tissue and placement of polypropylene suture materials in the region of the gastroesophageal (GE) junction. This section of the guidance is intended to be a brief description of the procedure. This section of the guidance is intended to be a summary of the procedure. This section of the guidance is intended to be a summary of the procedure. 15 of 20

16 33 Consultee 1 34 Consultee 1 35 Consultee 1 36 Consultee 2 NHS Professional It is composed of a handle, wherein the various controls are located, a chassis of 18 mm in diameter through which the endoscope is inserted and control channels run, side hotels on the distal end of the shaft to which external suction can be applied (the tissue invaginator), a tissue mold, which can be brought into retoflexion pushes tissue against the shaft of the device, a helical retractor, which is advanced into tissue to pull tissue caudally between the tissue mold and the shaft, two stylets, which advance from the shaft of the device through the plicated tissue and then through the plicated tissue and then through eyelets in the tissue mold, and a cartridge containing polypropylene H-shaped fasteners (or plicators), which are deployed over the stylets within the esophageal lumen and the leading leg engages within the gastric lumen Preoperative endoscopy under general anesthesia is necessary to determine (1) the distance (in centimeters) between the incisor teeth and the diaphragmatic hiatus, and (2) the greatest transverse dimension (in centimeters) of the hiatus and the GE junction under full gastric distension and complete diaphragmatic relaxation To the best of our knowledge, the Esophyx device is currently the only device remaining that is commercially available for Endolumenal Fundoplication. It is the only commercially available device in the UK, and as such the data attached represents the sum total of data for this procedure. 2.3 Apart from symptomatic improvement which is good to excellent with TIF, a significant amount of objective (up to medium term) data has now been published, showing cessation or marked reduction in PPI use, reduction of hiatus hernia, improvement of oesophagitis, reduction in proximal extent of refluxate, reduction/normalisation in reflux episodes and importantly a 61% normalisation of oesophageal acid exposure. It would be helpful if this up to date information is included in the revised document as this does not seem to have been considered at present. 16 of 20 This section of the guidance is intended to be a summary of the procedure. The Committee considered this comment but decided not to change the guidance.

17 37 Consultee 1 38 Consultee Efficacy TIF Clinical results to date support the safety of TIF and its efficacy in eliminating typical and atypical symptoms, reducing daily use of medication, normalizing acid reflux and curing GORD in over 75% of patients. With over 5300 cases worldwide performed worldwide, TIF has been evaluated in 9 unbiased clinical studies, which generated 21 peer-reviewed publications. Six additional abstracts with 181 patients have been accepted for presentation at major medical conferences during Additionally three randomized trials in Europe and the U.S. and a 500-patient U.S. Registry are underway. Clinical trials have demonstrated that TIF is safe with a complication rare not exceeding 1% and that TIF restores the anatomy and functions of the gastroesophageal junction. Additionally, clinical trials have demonstrated that efficacy has been proven measuring symptoms and quality of life, use of PPIs, impedance, ph-metry and manometry. TIF improves significantly typical symptoms such as heartburn and regurgitation in 75-89% of patients and eliminates refractory to medical therapy atypical symptoms such as cough and hoarseness in 72-90% of patients. Further clinical evidence supports that TIF eliminates the need for medical therapy, mainly PPIs, mainly in up to 80-90% of patients and results in 61% normalization of esophageal acid exposure and 89% normalization of reflux episodes. Furthermore, long-term published and non-published results support TIF valve durability and their effectiveness in controlling gastroesophageal reflux in over 80% of patients. The following results [in the enclosed document] illustrate safety and efficacy results from published clinical trials performed in Europe and the U.S The TIF technique using the Esophyx device has been shown to provide good controll of acid reflux in the short and medium (3 year) term. 17 of 20 The committee saw the full copy of the consultation comments provided by this consultee.

18 39 Consultee 1 40 Consultee 2 NHS Professional 2.4 Safety: In addition to the above referenced safety and efficacy results, the following represents adverse events and their occurrence rate reported at one week after TIF are listed below. These events were all mild and resolved spontaneously for all cases within 3-4 weeks. 7% Bloating 1-2% Diarrhea 3-4%Dysphagia (temporary) 5% Epigastric pain 7% Nausea 9% Shoulder pain 9% Sore throat 9% Upper abdominal pain 2% Vomiting No mortality or long-term complication such as dysphagia, bloating, etc. Serious Adverse Events that have occurred and may be related to the use of EsophyX are summarized in the table below. Incidence and rate of each SAE are as follows: 8 (0.15%) Perforations/Tear 5 (0.09%) Esophageal leak 4 (0.07%) Intraluminal bleeding 3 (0.06%) Pleural effusion 2 (0.04%) Mediastinal abscess 2 (0.04%) Mediastinitis 2 (0.04%) laceration As of early 2011 the worldwide SAE rate is 0.49%. 2.4 TIF has a very good safety profile with a low incidence of significant complications compared to surgical fundoplication. The Committee considered this comment but decided not to change the guidance. 18 of 20

19 41 Consultee 1 42 Consultee 2 NHS Professional 43 Consultee To the best of our knowledge, the devices also evaluated in the NICE guidance on Endolumenal Gastroplication are now no longer commercially available. The TIF procedure, using the Esophyx device has proved durable and is currently freely sold in the EU per approved application of the CE mark. It has selective insurance coverage and reimbursement in the USA following FDA clearance. 2.5 It is unfair to group Transoral Incisionless Fundoplication (using the Esophyx device) with the other (older) endoscopic anti-reflux technologies/procedures, particularly as the latter are no longer available or performed. Data relating to the efficacy and follow up of TIF patients is of a far higher standard compared to previous data from these other technologies. This should be considered if possible to avoid biasing the final recommendations. Thank you for considering these comments. General The BSG also submitted an additional abstract describing our one year data in children with Esophyx. The Committee considered that the guidance should be generic for all these techniques, other devices may also be introduced in the future. The Committee considered this comment but decided not to change the guidance. " received in the course of consultations carried out by NICE are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that NICE has received, and are not endorsed by NICE, its officers or advisory committees." i Dean BB, Crawley JA, Schmitt CM, Wong J, Ofman JJ. The burden of illness of gastro-oesophageal reflux disease: impact on work productivity. Aliment Pharmacol Ther. 2003;17: ii Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (2008). Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 179: iii Kahrilas PJ, Shaheen NJ, Vaezi M. AGAI technical review: management of gastroesophageal reflux disease. 2008;135;135: iv Cadle RM, Mansouri MD, Logan N, Kudva DR, Musher DM (2007). Association of proton-pump inhibitors with outcomes in Clostridium difficile colitis. Am J Health-Syst Pharm 64: of 20

20 v Kahrilas PJ, Shaheen NJ, and Vaezi M in collaboration with the AGAI Medical Position Panel on GERD management. AGAI medical position statement: management of gastroesophageal reflux disease. 2008;135: vi Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Runsfeld JS (2009). Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. Jama 301: vii Laine L. Proton Pump Inhibitor Co-therapy with Clopidogrel: Is There GI Benefit or Cardiovascular Harm? Jan 22. [Epub ahead of print] viii Carlsson R, Dent J, Watts R, Riley S, Sheikh R, Hatlebakk J, Haug K, de Groot G, van Oudvorst A, Dalvag A, Junghard O, Wiklund I (1998). Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group. Eur J Gastroenterol Hepatol 10: ix Castell DO, Murray JA, Tutuian R, Orlando RC, Arnold R (2004). Review article: the pathophysiology of gastro-oesophageal reflux disease - oesophageal manifestations. Aliment Pharmacol Ther 20 Suppl 9:14-25 x Fass R (2007). Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure. Drugs 67: xi Hunt RH, Yuan Y, Yaghoobi M (2007). GERD: new strategies and new failures. J Clin Gastroenterol 41 (Suppl 2):S72-S80 xii Cadière GB, Buset M, Muls V, Rajan A, Rösch T, Eckardt AJ, Weerts J, Bastens B, Costamagna G, Marchese M, Louis H, Mana F, Sermon F, Gawlicka AK, Daniel MA, Devière J. Antireflux transoral incisionless fundoplication using EsophyX : 12-month results of a prospective multicenter study. World Journal of Surgery 2008; 32: xiii Barnes WE, Hoddinott KM, Williams M, Mundy S. Transoral incisionless esophago-gastric fundoplication offers high patient satisfaction and relief of therapy-resistant typical and atypical symptoms of GERD in community practice. Surgical Innovation (published Fedruary 8, 2011). xiv Bell RCW, Freeman K. Clinical and ph-metric outcomes of transoral esophago-gastric fundoplication for the treatment of gastroesophageal reflux disease (GERD). Surgical Endoscopy (published online on December 13, 2010). 20 of 20