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Endoscopic development framework

ASGE/ASMBS task force publishes EBT white paper

Paper establishes framework for the development of new endoscopic therapies

A joint task force from the American Society for Gastrointestinal Endoscopy (ASGE) and the American Society for Metabolic and Bariatric Surgery (ASMBS) has recently published a white paper concerning endoscopic bariatric therapies (EBTs). Specifically, the white paper is intended to provide a framework for, and a pathway towards, the development, investigation, and adoption of safe and effective EBTs.

“The two societies formed a joint task force to identify opportunities where endoscopic treatments may play a role in improving patient outcomes and reducing costs,” said Dr Gregory G Ginsberg, ASGE president and Chair of the ASGE/ASMBS taskforce on EBTs. “The white paper establishes the criteria for success as new technologies and procedures are developed.”


The white paper, entitled ‘A Pathway to Endoscopic Bariatric Therapies’, states that EBTs may have various roles in the treatment of the obesity epidemic, including primary therapy, early intervention, bridge therapy, and metabolic therapy. They will also have varying degrees of intensity, durability, and repeatability and therefore should be evaluated based on intent of therapy and their overall risk/benefit, stated the white paper.


“Endoscopic therapy has the potential to be applied across the continuum of obesity and metabolic disease,” said Dr Bipan Chand, Chairman, ASMBS Emerging Technology and Procedure Committee, and co-chair of the ASGE/ASMBS taskforce. “However, it is generally expected that endoscopic modalities achieve weight loss superior to that produced by medical and intensive lifestyle interventions, have a favourable risk/benefit profile and have scientific evidence to support its use.”


The white paper addresses a number of issues including endoscopic bariatric therapy treatment classification, potential indications, efficacy endpoints (threshold for weight loss and study design, etc) and secondary efficacy endpoints (reduction in obesity-related co-morbidities, changes in quality of life, safety, durability and repeatability, etc), the adoption of EBTs in the context of global patient care, training and credentialing, cost effectiveness and government and industry relations.


The white paper emphasises that any new surgical, endoscopic or nonsurgical weight loss intervention should include a defined threshold of efficacy, balanced with risks of the intervention. EBT potentially offers an ambulatory weight loss procedures with a superior safety and cost profile compared to bariatric surgery, and if it is shown to be feasible, safe, and effective, EBT therapy could be appropriate for intervention to individuals with lower classes of obesity (ie, Class I).


Treatment mechanism


Several EBTs are currently in different stages of development, and include a variety of methods to induce weight loss and reduce obesity-related co-morbidities. EBT technologies can be categorised broadly according to the intended mechanism of action: gastric restriction or manipulation, malabsorption, neuro-hormonal alterations, or some combination.


Some EBTs attempt to decrease effective stomach capacity. These technologies include space-occupying devices and those that alter gastric anatomy. According to the white papers, these space-occupying devices most commonly take the form of temporarily placed prosthetic balloons, which effectively restrict intake, thereby enhancing satiety and instigating weight loss. 


Weight loss and improvements in metabolic comorbidities after malabsorptive surgical procedures are more profound than after purely stomach altering restrictive operations, and have prompted the development of endoscopic devices to induce malabsorption. These therapies are designed to create a physical barrier between food, the intestinal wall and biliopancreatic secretions.

One such device is the duodenal-jejunal barrier sleeve, which may be placed temporarily or left in-situ indefinitely. These impermeable fluoropolymer sleeves open at both ends, are placed endoscopically, and anchor in the proximal duodenum or at the gastroesophageal junction. They prevent chyme from contacting the proximal intestine while bile and pancreatic secretions pass along the outer wall of the liner and mix with chyme in the distal jejunum.


Other EBTs, still in early stage development, aim to modulate satiety and food intake through neuralhormonal mechanisms. Evidence suggests that gut hormones act in conjunction with the complex enteric nervous system to coordinate and regulate gastrointestinal satiety signals, motility, and digestive processes.

Novel endoscopic devices seek to take advantage of this interaction by manipulating neural-hormonal signals to induce satiety. Their intended mechanism of action is to interfere with vagal signals between the brain and gastrointestinal tract, through a variety of techniques such as gastric stimulation or pacing, neuromodulation, and vagal resection.


Intent of endoluminal therapies


The primary goal of EBT is to induce enough weight loss to decrease obesity related metabolic co-morbidities and improve quality of life. Compared to current surgical interventions, EBTs are expected to yield substantial improvements and achieve a favourable risk/benefit profile.

However, while a lower risk EBT must achieve this primary goal, its threshold for efficacy should be lower than a higher risk intervention. With this concept in mind, endoluminal therapies have many potential applications as primary, adjunctive or revisionary bariatric procedures.


Specifically, the indications for EBT include primary therapy, early intervention/pre-emptive therapy, bridge therapy, and metabolic therapy. For each of these indications, the white paper considered the minimum threshold for efficacy, risk profile, durability and repeatability.


Primary therapy


An EBT with morbidity and mortality comparable to laparoscopic adjustable gastric banding should hold similar efficacy, with the potential to achieve approximately 40% excess weight loss. Alternatively, lower efficacy is acceptable for an EBT with a lower risk profile. Such treatments would be considered for patients with severe obesity


Early intervention/preemptive obesity therapy patients with Class I and II obesity are at risk for disease progression, have a higher cardiovascular risk profile, and have a substantially increased relative risk of all-cause mortality.

There is evidence that patients with Class I obesity respond well to surgical intervention. Prospective trials of both sleeve gastrectomy and adjustable gastric banding in patients with Class I obesity have demonstrated significant weight loss and resultant improvement in or resolution of many obesity related co-morbidities. Several other non-randomized studies have confirmed similar results. 


As a result, the FDA recently approved the use of gastric banding for patients with Class I obesity and at least one associated obesity related co-morbidity. The durability or repeatability of an EBT will be important. For a procedure to be repeatable, the patients’ anatomy must have minimal permanent alteration and be amenable to future intervention.


Bridge therapy


The intent of bridge therapy is to promote weight loss specifically to reduce the risk from a subsequent intervention, including bariatric surgery. Patients with Class III obesity and those with metabolic co-morbidities present greater technical challenges and surgical risk than less obese, healthier patients. Furthermore, these effects are more pronounced in patients with BMI over 60 where there is a greater risk of morbidity or mortality than patients with BMI 45-60. 


Metabolic therapy


EBT may be justified in patients with less severe obesity (Class I), where improvement in metabolic illness is the primary concern. In particular, co-morbidities such as type II diabetes, hyperlipidemia, and hypertension, may improve or resolve with even modest weight loss.


Procedures which aim to effect metabolic disease should have a lower risk profile and greater durability compared to therapies which specifically aim to induce massive weight loss. Substantial weight loss may not be necessary in order to achieve metabolic benefits in less severely obese individuals.

Obese patients who lose 5% of their total body weight benefit from significant reductions in diabetes and cardiovascular risk factors including hypertension and dyslipidemia. Therefore, The taskforce advocates using 5% of total body weight lost as the absolute minimum threshold for any non-primary EBT (eg, early intervention, bridging or metabolic therapy).


Comparison of nonsurgical and operative interventions is limited by differences in the primary outcome measure: nonsurgical interventions typically use actual weight lost or percentage of total body weight, whereas operative therapies traditionally use %EWL. 


Threshold for weight loss for endoscopic therapies


The weight loss threshold for the adoption of any new endoscopic procedures should be balanced against the risk of that procedure. Currently there are no established thresholds for endoscopic bariatric interventions. However, in general it is expected that endoscopic modalities should achieve weight loss superior to that anticipated with medical and intensive lifestyle interventions.


Pharmacologic agents such as orlistat have been FDA approved despite their modest effects because lifestyle interventions have even lower efficacy and poor durability/compliance, and small amount of lost weight (5% of total body weight or less) can lead to significant reductions in obesity-related co-morbidities.

Therefore, based on available evidence and expert opinion, the taskforce recommends that an EBT intended as a primary obesity intervention should achieve a mean minimum threshold of 25% EWL measured at 12 months. This goal will vary depending on the category or intent of endoscopic bariatric procedure.

EBT should also be compared to a second treatment group, not necessarily a sham. Sham groups in comparative trials evaluating the efficacy of bariatric therapies have shown considerable variability in weight loss (3-13% EWL).


In addition to the absolute threshold of weight loss, the mean %EWL difference between a primary EBT and control groups should be a minimum of 15% EWL, and be statistically significant. For other categories of EBT, the amount of EWL and durability of the effect may vary by type and intent of the EBT.

As previously described, EBT may be performed for early intervention, bridge therapy, and as a metabolic therapy. In these instances, the primary endpoint may include, but not be limited to, an improvement or resolution in metabolic illness, decreasing the risks associated when performing another planned intervention, and preventing the progression to greater severity of obesity with its associated risks.


Study design


As a device is designed and modified to address a specific clinical need various types of studies are typically required as part of the regulatory process. Following rigorous preclinical evaluation, a feasibility study in humans is often the appropriate next step.

The concept of such feasibility studies is well described in the FDA guidance documents. These are typically small studies performed in a limited number of subjects to confirm design and operating specifications. The emphasis is on technical feasibility and safety.

Device modification is often necessary in this phase and flexibility is emphasised. There are typically no efficacy targets and the final results are generally used to calculate sample size and establish parameters for a larger pivotal trial.


Clinical studies have shown that sustained moderate weight loss achieved through dietary and lifestyle intervention lowers blood pressure, improves glucose control, prevents diabetes, and improves dyslipidemia, haemostatic and fibrinolytic factors. Obese patients who lose 5% of their total body weight benefit from significant reductions in diabetes and cardiovascular risk factors including hypertension and dyslipidemia.


Therefore, the taskforce advocates using 5% of total body weight lost as the absolute minimum threshold for any EBT intended for anything but a primary bariatric intervention (eg, early intervention, bridging or metabolic therapy).

Given that weight has significant metabolic effects, a 5% reduction could result in an improvement in or resolution of obesity-related co-morbidities such as diabetes mellitus, hypertension, obstructive sleep apnea and non-alcoholic fatty liver disease. If an endoscopic intervention proves to have a significant impact on one or more of these co-morbidities with a negligible risk profile, the threshold for intervention may extend to Class I obese individuals (BMI 30-35).


In addition to lowering the prevalence of co-existent obesity-related metabolic illnesses, there is potential for an EBT to primarily prevent these comorbidities by promoting weight loss in mildly obese individuals. In this population, it is important that improvement/resolution of comorbidities be significantly better for endoscopic therapies compared to that of control groups, given the risks associated with any intervention despite how minimal they may be. Improvement and resolution of comorbidities should be defined using objective and standardised criteria.


The safety of an EBT at a moderate intensity level implies a higher incidence of bleeding, perforation and other complications, similar to that observed with interventional endoscopic procedure such as therapeutic endoscopic retrograde cholangio-pancreatography with sphincterotomy. The safety of EBT at a high intensity level would be similar to that seen perioperatively with low risk operative procedures such as the adjustable gastric band. They would typically employ general anaesthesia (endotracheal intubation) as well as extended observation periods.


Durability and repeatability


The goal of primary bariatric surgical therapies is to induce substantial and sustainable weight loss with associated metabolic benefits. These same expectations apply to EBT, as a primary weight loss therapy. However, an EBT with reduced durability may be offset by repeatability of the intervention; EBT is particularly suited to this approach.

Low risk EBT may be repeated at varying intervals to achieve durable effect, whilst remaining cost effective compared to surgical alternatives or a lengthy period of pharmacological agents and supervised lifestyle interventions.


Training/credentialing 


Evidence demonstrates that higher quality patient care is associated with high volume bariatric units. Recognition of this prompted the process of credentialing Centers of Excellence in bariatric surgery.

he white paper stresses that training and skill acquisition with EBT techniques and technology are mandatory before clinical application is undertaken, and must include didactic as well as hands–on practical education. In addition, any practitioner who is interested in performing an EBT should also be educated in the clinical management of obese patients. The duration and type of training is likely to depend on the complexity of a particular EBT. 


The ASGE Interactive Training & Technology center (ITT) and Masters Series courses represent appropriate venues for focused training in the procedural aspects of EBT. EBTs of greater complexity may also require proctoring during the first several clinical applications by a new practitioner.

EBTs of the highest complexity may require a focused training programme (a ‘mini-fellowship’), or longer. For all EBTs, early studies should evaluate its learning curve in order to guide the subsequent training and credentialing process. These procedures should be included as a part of a comprehensive obesity programme and not performed in isolation.


Cost effectiveness


The costs of bariatric surgery and its associated complications may be offset by consequential reductions in weight and obesity-related co-morbidities. However, there are also data to support surgical intervention among Class II and Class I obese individuals with concomitant type II diabetes. Therefore, the taskforce suggests that elements of a cost effectiveness analysis in EBT include the direct cost of a proposed device and the associated health care utilisation required for its implementation (eg, sedation requirements, time of hospitalisation, physician fees). 


An EBT which decreases obesity-related co-morbidities for a sustained period of time is likely to reduce long term health care consumption; therefore, accurate data on this secondary outcome are paramount. Additional measures of indirect costs include consequential improvements in quality of life and work productivity secondary to weight loss from an EBT.

Therefore, the white paper states that cost effectiveness studies in EBT require long term data on weight loss, obesity-related co-morbidities, impact on quality-of-life, and the possible need for repeated EBT in order to sustain these outcome measures. For these reasons, studies evaluating the cost effectiveness of EBT are expected to be phase III or IV clinical trials.


Government and industry relations


The white paper also states that the development of EBT should be done in collaboration with government regulating agencies (eg, FDA) to establish thresholds for safety and efficacy (primary and secondary endpoints). While this is a complex process for new devices with widely different risk and efficacy profiles, a clear and transparent process is needed to stimulate development of innovative EBT. 


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