Consultation Protocol
to guide the
assessment of a
duodenal jejunal
bypass liner for the
treatment of clinically
severe obesity, with
or without
uncontrolled type-2
diabetes mellitus
February 2014
Table of Contents
MSAC and PASC ......................................................................................................................... 4
Purpose of this document ........................................................................................................... 4
Primary questions for public consultation ..................................................................................... 4
Purpose of application ............................................................................................................. 6
Background .............................................................................................................................. 6
Current arrangements for public reimbursement........................................................................... 7
Regulatory status ....................................................................................................................... 7
Intervention ............................................................................................................................. 7
Description................................................................................................................................. 7
Delivery of the intervention ......................................................................................................... 8
Prerequisites .............................................................................................................................. 9
Co-administered and associated interventions .............................................................................. 9
Listing proposed and options for MSAC consideration ..........................................................10
Proposed MBS listing ................................................................................................................ 10
Clinical place for proposed intervention ...................................................................................... 12
Patients with uncontrolled type 2 diabetes mellitus and clinically severe
obesity ................................................................................................ 14
Patients with clinically severe obesity who are not suitable for bariatric
surgery................................................................................................ 19
Patients with clinically severe obesity who are suitable for bariatric surgery. ............ 20
Proposed clinical management algorithm .............................................................. 20
Comparator ............................................................................................................................21
Patients with uncontrolled type 2 diabetes mellitus and clinically severe
obesity ................................................................................................ 21
Patients with clinically severe obesity who are not suitable for bariatric
surgery ............................................................................................... 23
Patients with clinically severe obesity who are suitable for bariatric surgery. ............ 23
Clinical claim ..........................................................................................................................23
Outcomes and health care resources affected by introduction of proposed
intervention ..............................................................................................................25
Outcomes ................................................................................................................................ 25
Weight loss ........................................................................................................ 25
HbA1c levels ...................................................................................................... 25
2
Adverse events................................................................................................... 26
Other outcomes.................................................................................................. 26
Health care resources ............................................................................................................... 27
Resources
Resources
Resources
Resources
to deliver proposed intervention ........................................................... 27
provided in association with the proposed intervention........................... 27
provided to deliver comparator ............................................................ 28
provided in association with the comparator (SOC) ................................ 28
Proposed structure of economic evaluation (decision-analytic) ...........................................29
Primary questions for public funding .....................................................................................31
References .............................................................................................................................33
3
MSAC and PASC
The Medical Services Advisory Committee (MSAC) is an independent expert committee appointed by
the Australian Government Health Minister to strengthen the role of evidence in health financing
decisions in Australia. MSAC advises the Commonwealth Minister for Health on the evidence relating
to the safety, effectiveness, and cost-effectiveness of new and existing medical technologies and
procedures and under what circumstances public funding should be supported.
The Protocol Advisory Sub-Committee (PASC) is a standing sub-committee of MSAC. Its primary
objective is the determination of protocols to guide clinical and economic assessments of medical
interventions proposed for public funding.
Purpose of this document
This document is intended to provide a draft protocol that will be used to guide the assessment of an
intervention for a particular population of patients. The draft protocol that will be finalised after
inviting relevant stakeholders to provide input to the protocol. The final protocol will provide the basis
for the assessment of the intervention.
The protocol guiding the assessment of the health intervention has been developed using the widely
accepted “PICO” approach. The PICO approach involves a clear articulation of the following aspects of
the research question that the assessment is intended to answer:
Patients – specification of the characteristics of the patients in whom the intervention is to be
considered for use;
Intervention – specification of the proposed intervention
Comparator – specification of the therapy most likely to be replaced by the proposed
intervention
Outcomes – specification of the health outcomes and the healthcare resources likely to be
affected by the introduction of the proposed intervention
Primary questions for public consultation
1. PASC agreed with the Department that there are 3 subgroups to the primary population of
patients with clinical severe obesity and that these should be taken into consideration as part of
this application, particularly regarding the economics analysis.
Does the general public have any comments regarding the following subpopulations. Are there
any others that should be considered?
a) with uncontrolled type 2 diabetes mellitus;
b) who are not suitable for bariatric surgery (including patients that are contra-indicated for
surgery and “bridge” patients); and
c) who are eligible for bariatric surgery but have a preference for EndoBarrier.
2.
Is a HBA1c level equal to or greater than 7% an appropriate level to define uncontrolled type 2
diabetes mellitus or is this threshold too low in the MBS proposed descriptor?
4
3. Is the wording “despite optimised pharmacological therapy” appropriate as per the MBS
proposed descriptor (page 11)?
4. Should EndoBarrier be delivered by a physician with training for endoscopy who is recognised
by the Conjoint Committee for the Recognition of Training in Gastrointestinal Endoscopy?
5. How does the 12 month timeframe for removal of Endobarrier affect patients who may not be
able to have the surgery within the recommended timeframe?
5
Purpose of application
A proposal for an application requesting the Medicare Benefits Schedule (MBS) listing of a duodenal
jejunal bypass liner (EndoBarrier®) was received from GI Dynamics by the Department of Health in
September 2013. The proposal relates to a new intervention for the treatment of patients with
clinically severe obesity, with or without uncontrolled type 2 diabetes mellitus.
It is proposed that this protocol should guide the assessment of the safety, effectiveness and costeffectiveness of EndoBarrier in the requested populations to inform MSACs decision-making regarding
public funding of the procedure.
Although GI Dynamics is not seeking branded MBS listing, the protocol frequently refers to the
EndoBarrier brand name for clarity and simplicity. If implemented, the proposed MBS item descriptors
would apply to all duodenal jejunal bypass liners registered for use in Australia; however, to the
Sponsor’s knowledge, the EndoBarrier is the only currently available product that fits this description.
Background
This Protocol for EndoBarrier requests reimbursement for a duodenal jejunal bypass liner that is
temporarily implanted in patients to treat clinically severe obesity, with or without uncontrolled type 2
diabetes mellitus.
For implantation, it is proposed by the applicant that the service will be available to patients with
clinically severe obesity in the below subpopulations:
a) with uncontrolled type 2 diabetes mellitus;
b) who are not suitable for bariatric surgery (including patients that are contra-indicated for
surgery and “bridge” patients); and
c) who are eligible for bariatric surgery but have a preference for EndoBarrier.
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may
have an adverse effect on health and result in reduced life expectancy. Excess weight is a risk factor
for a range of serious diseases, including type 2 diabetes, osteoarthritis, cardiovascular disease, and a
variety of cancers (Preventative Health Taskforce, 2009). Direct benefits of weight loss include an
increase in insulin sensitivity, improvement in glycaemic control, improved lipid profiles, decreased
triglycerides and LDL cholesterol and improved blood pressure, mental health and quality of life (Wing
et al., 1991; Maggio and Pi-Sunyer, 1997; Pi-Sunyer, 2000).
Type 2 diabetes mellitus is a related metabolic disorder that is characterised by high blood glucose in
the context of insulin resistance and relative insulin deficiency. Long-term complications from high
blood sugar can include heart disease, strokes, diabetic retinopathy where eyesight is affected, kidney
failure which may require dialysis, and poor circulation of limbs leading to amputations. The
6
development of type 2 diabetes mellitus is caused by a combination of lifestyle and genetic factors,
with obesity as a major risk factor (Ripsin et al., 2009; Riserus et al., 2009).
In Australia, obesity and diabetes have become increasingly prevalent over the last 50 years and are
responsible for a substantial burden on the healthcare system. The health and economic
consequences are so concerning that both diseases have been listed as National Health Priority Areas
(NHPAs) by the Federal Government. As obesity is a risk factor for type 2 diabetes, and both
conditions share common lifestyle-related causes, there is considerable overlap between populations
affected by these two conditions. It is in a subgroup of this overlapping population that EndoBarrier
will primarily be used, that is patients with uncontrolled type 2 diabetes mellitus and clinically severe
obesity.
Current arrangements for public reimbursement
Currently, the implantation of EndoBarrier is not reimbursed through Medicare or subject to public
funding by any other means. Patients who would like access to treatment must currently pay for the
device, implantation and removal of the device out of their own pocket. In most cases, EndoBarrier is
delivered in private hospitals and obesity clinics, with the service provided by a physician trained in
endoscopy.
GI Dynamics has initiated an application to have the EndoBarrier device included on the Prostheses
List. If the current MSAC application is successful, it is expected the gastrointestinal liner and the
associated delivery and removal systems for EndoBarrier will be included on the Prostheses list and
funded by private health insurance companies.
In Australia, EndoBarrier is available at a number of medical centres and has been used in over 100
patients.
Regulatory status
EndoBarrier was approved by the Therapeutic Goods Administration (TGA) in July 2011. The TGAapproved indication for the liner is as follows:
“The gastrointestinal liner system is used for the treatment of type 2 diabetes and obesity. It is
provided sterile and consists of an implant (anchor and liner), preloaded in a catheter that delivers
the implant to the proximal intestine”.
Intervention
Description
EndoBarrier is a duodenal jejunal bypass liner that achieves the metabolic effects of a surgical gastric
bypass, with reduced risk. EndoBarrier has been implanted in more than 1200 patients worldwide.
The system consists of two components: the EndoBarrier delivery system and the EndoBarrier
7
retrieval system. The EndoBarrier delivery system includes the gastrointestinal liner preloaded on a
custom delivery catheter, while the EndoBarrier retrieval system consists of a Grasper and Retrieval
Hood, used with an endoscope to remove the liner upon completion of therapy. The role of each
component in the placement, mechanism and removal of the GI liner is illustrated in Figure 1 below.
Figure 1: EndoBarrier placement, mechanism and removal
Source: Schouten et al 2010
This EndoBarrier gastrointestinal liner is a fluoropolymer sheath which is placed in the duodenum just
beyond the stomach and stretches into the first part of the small bowel. Its mechanism of action
most closely resembles surgical duodenal jejunal gastric bypass. Both procedures produce an effect
on weight-loss and glucose metabolism through preventing nutrient contact with the proximal
intestinal mucosa. With EndoBarrier, bile and pancreatic secretions pass along the outer wall of the
impermeable 60-cm liner and mix with the chyme as it exits distal to the liner in the jejunum. By
creating a physical barrier to food absorption, EndoBarrier reduces the uptake of nutrients from the
first part of the small bowel and may also have an effect on key metabolic hormones, including
incretin. By modifying normal processes of nutrient absorption, EndoBarrier results in substantial
clinical benefits in terms of weight loss and glycaemic status.
Clinical data suggest that EndoBarrier therapy improves glycaemic levels by affecting key hormones
involved in insulin sensitivity, glucose metabolism, satiety and food intake. EndoBarrier therapy has
also been shown to produce rapid and sustained weight loss, as well as improve cardiometabolic
risks, including blood pressure, LDL and triglycerides. A summary of the effects of EndoBarrier on
metabolic control is provided in Attachment A.
Delivery of the intervention
The EndoBarrier delivery system is provided sterile, and consists of a gastrointestinal liner (anchor
and liner), preloaded in a catheter that delivers the liner to the proximal intestine. The catheter is
inserted through the mouth and guides the gastrointestinal liner through the stomach, and into the
duodenum. A small anchoring device on the liner keeps the liner in place.
Patients require anaesthesia before the device is implanted with endoscopy used to guide its
placement. The endoscopy also serves a diagnostic purpose to determine if a patient is anatomically
suitable for implantation with the EndoBarrier device. If a patient is found to be suitable, implantation
8
of the EndoBarrier can take place immediately. X-ray is used during the procedure to ensure that the
liner is in the correct position.
An experienced physician with training for endoscopy can perform the implantation, usually with the
assistance of a nurse or assistant. In Australia EndoBarrier insertion is typically a (hospital inpatient)
day procedure centre; however in some cases hospitalisation may be required. The EndoBarrier
device is approved for implantation for up to 12 months; however it may be removed earlier at the
patient's request or if it is clinically warranted. Removal of the device is undertaken through another
endoscopic procedure, using the EndoBarrier Liner Retrieval System, consisting of a Grasper and a
Retrieval Hood, which are compatible with standard endoscopes.
The training protocol for EndoBarrier strongly emphasises that the device is indicated for a placement
period of up to 12 months. Any use beyond this duration is unsupported by clinical evidence.
Furthermore, to be eligible for implantation, patients should be screened to ensure they are not
considered at high risk of loss to follow-up.
The “Instructions for Use” for the delivery and removal of EndoBarrier are provided in Attachment B
and Attachment C, respectively.
Prerequisites
It is expected that EndoBarrier will be delivered by a physician with training for endoscopy that is
recognised by the Conjoint Committee for the Recognition of Training in Gastrointestinal Endoscopy.
GI Dynamics currently provides specialists with training on how to implant and remove the device;
however this training is not associated with any formal accreditation.
The insertion of the liner will require the attendance of at least one trained specialist in bariatric
surgery and/or gastroenterology and the assistance of a nurse or assistant. The main infrastructure
needs for the procedure are associated with administering anaesthesia and performing x-ray and
endoscopy. This equipment is already available at most hospitals. Therefore, the use of EndoBarrier
will not require additional resources in terms of capital equipment or infrastructure. Removal of the
device is also not associated with any specific infrastructure requirements other than anaesthesia and
x-ray equipment.
As an elective procedure, patients that do not have close access to a centre with endoscopy facilities
and an appropriate specialist have the option to travel in order to receive EndoBarrier therapy. As
EndoBarrier can be implanted in any centre that currently performs bariatric surgery, access to
treatment will be at least as broad.
Co-administered and associated interventions
To minimise the risk of bleeding, patients receiving treatment with EndoBarrier are required to take a
proton pump inhibitor (PPI) for the duration of therapy (e.g. omeprazole). The recommendation to
use a PPI with EndoBarrier was developed in response to bleeding events observed in early clinical
9
trials using the first generation device; however marked improvements in the bleeding rate have been
observed in recent trials.
The submission will present evidence from clinical trials of EndoBarrier to assess the risk of bleeding,
including the use of PPIs to prevent bleeding, as part of its evaluation of clinical safety. The costs of
PPI therapy will be included in the economic evaluation. Aside from this, patients implanted with
EndoBarrier do not require any co-administered interventions other than anti-diabetic medications
already being taken. In fact, the majority of diabetic patients undergoing treatment with EndoBarrier
experience an immediate improvement in glycaemic status, reducing the need for medications to
control blood sugar (De Jonge et al., 2013). The reduction in use of anti-diabetic medications in
diabetic patients implanted with EndoBarrier was measured in RCTs of the intervention, and will be
included in the economic evaluation.
The implantation of EndoBarrier will require an endoscopy to determine if a patient is physiologically
suitable for treatment; however, this procedure is included in the proposed MBS item for the insertion
of the duodenal-jejunal liner. If no issues are identified during endoscopy, the EndoBarrier will be
implanted in the same visit. A small minority of patients will be excluded from treatment with
EndoBarrier based on the results of endoscopic imaging. These patients will incur an MBS item fee for
diagnostic endoscopy only (MBS item 30473) or the MBS item for discontinued operative procedures
(MBS item 30001).
Listing proposed and options for MSAC consideration
Proposed MBS listing
The proposed MBS item descriptors for the insertion and removal of EndoBarrier are provided in Table
1. Two separate item descriptors are proposed: for the implantation of EndoBarrier and the removal
of the device.
For implantation, it is proposed that the service will be available to patients with clinically severe
obesity in the below subpopulations:
a) with uncontrolled type 2 diabetes mellitus;
b) who are not suitable for bariatric surgery (including patients that are contra-indicated for
surgery and “bridge” patients); and
c) who are eligible for bariatric surgery but have a preference for EndoBarrier.
The EndoBarrier will be delivered to patients once, and will remain implanted for up to a year. At this
stage, patients will be eligible for implantation once per lifetime; however, there is an emerging body
of evidence to support the clinical benefits of re-implantation. It is proposed this emerging body of
evidence be reviewed in a future MSAC submission and/or review at which point the words “to be
claimed once in the patient’s lifetime” could be removed from the item descriptor should the evidence
support this.
10
Alternatively, the submission could include a specific research question asking “what is the
effectiveness and cost-effectiveness of re-implantation of EndoBarrier compared to standard of care
(SOC)/bariatric surgery”? This would provide MSAC with the opportunity to decide if it is appropriate
to limit the use of EndoBarrier to once per lifetime or some other finite timeframe (e.g. 5 years).
Evidence for the clinical effectiveness of re-implantation will be provided in the final submission to
MSAC.
Table 1: Proposed MBS item descriptor for insertion and removal of EndoBarrier
MBS [TBD] (Insertion of device)
Category [category number] – [Category description]
DUODENAL-JEJUNAL BYPASS LINER, implantation of, including diagnostic endoscopy in a patient who has clinically
severe obesity, with or without uncontrolled type 2 diabetes (where patients with uncontrolled type 2 diabetes has a HBA1c
equal or greater than 7% despite optimised pharmacological therapy).
Claimed once per patient’s lifetime.
The service is performed by a specialist with endoscopic training that is recognised by The Conjoint Committee for the
Recognition of Training in Gastrointestinal Endoscopy.
(Anaes.) (Assist.)
Fee: $[TBD]
Note: The term clinically severe obesity generally refers to a patient with a Body Mass Index (BMI) of 40kg/m2 or more, or
a patient with a BMI of 35kg/m2 or more with other major medical co-morbidities (such as diabetes, cardiovascular disease,
cancer). The BMI values in different population groups may vary due, in part, to different body proportions which affect the
percentage of body fat and body fat distribution. Consequently, different ethnic groups may experience major health risks
at a BMI that is below the 35-40 kg/m2 provided for in the definition. The decision to undertake obesity surgery remains a
matter for the clinical judgment of the surgeon.
MBS [TBD] (Removal of device)
Category [category number] – [Category description]
DUODENAL-JEJUNAL BYPASS LINER, removal of within 12 months of placement or prior due to medical reasons,
including endoscopy.
(Anaes.) (Assist.)
Fee: $[TBD]
Current MBS item descriptors for the surgical treatment of clinically severe obesity (MBS items 31569
to 31581) define clinically severe obesity as BMI ≥ 40 or between 35 and 40 where there are other
major medical conditions such as high blood pressure and diabetes. However, due to some variability
in the health risks between individuals of the same BMI (especially on the basis of ethnicity), the
definition of clinically severe obesity is accompanied by a note stating that "the decision to undertake
obesity surgery remains a matter for the clinical judgment of the surgeon” (MBS note T8.30).
It is proposed that the item descriptor for the implantation of EndoBarrier should include a note to
define “clinically severe obesity”, similar or identical to the note (MBS note T8.30) currently
associated with bariatric procedures on the MBS (Items 31569 to 31581). This is consistent with the
clinical trial evidence for EndoBarrier in obese patients, which mostly consists of patients with BMI
11
≥40 kg/m2 or 35 kg/m2 with significant co-morbidities. Patients with clinically severe obesity, but who
are unsuitable for treatment with bariatric surgery, have limited treatment options. It is proposed that
this population should be eligible for treatment with EndoBarrier as an alternative to SOC, which has
poor clinical efficacy.
Patients with type 2 diabetes mellitus are generally advised to take oral blood glucose lowering drugs
such as metformin and sulphonamides if lifestyle interventions are not successful. These medications
have an unrestricted listing on the PBS, meaning that eligibility for treatment does not require
patients to reach a specific blood glucose threshold.
For patients who do not respond to treatment (HbA1c levels greater than 7%) clinical practice
guidelines for diabetes (NHMRC, 2009) recommend intensifying treatment. These patients are advised
to commence combination therapy with the addition of one or more drugs from the following classes:
thiazolidines (glitazones), dipeptidyl peptidase 4 (DPP-4) inhibitors, acarbose or insulin. Despite
treatment with multiple drug therapies and insulin, many patients with type 2 diabetes mellitus
continue to experience a deterioration of glycaemic control over time, and remain at high risk of
serious diabetes-related complications.
It is therefore proposed that eligibility for EndoBarrier in this subpopulation should be restricted to
patients with Type 2 diabetes and whose HbA1c is greater than 7% despite treatment with optimised
pharmacological therapy. It should be noted that this is a heterogeneous group of patients, with a
wide range of symptoms and diverse medical histories. It is therefore appropriate that final decisions
about patient management should be made at the discretion of an endocrinologist or other relevant
specialist. This is consistent with the clinical trial evidence for EndoBarrier, which includes diabetic
patients, above a threshold Hba1c level, with a diverse range of medical histories and prior
treatments.
It is therefore proposed that the definition of uncontrolled diabetes should be “Type 2 diabetes
mellitus in a patient whose HbA1c is greater than 7% despite treatment with metformin and a
sulfonylurea or where a combination of metformin and a sulfonylurea is contraindicated or not
tolerated”. In regards to the definition of uncontrolled type 2 diabetes mellitus, PASC was concerned
that >7% HBA1c figure was too low. It was agreed that further comment would be sought during the
public consultation process around the validity of a >7% threshold.
Clinical place for proposed intervention
It is proposed that the population eligible for treatment with EndoBarrier will consist of patients with
clinically severe obesity in the following subpopulations:
a. with uncontrolled type 2 diabetes mellitus;
b. who are not suitable for bariatric surgery (including patients that are contra-indicated for
surgery and “bridge” patients); and
c.
who are eligible for bariatric surgery but have a preference for EndoBarrier.
12
Patients with clinically severe obesity are a subset of patients with obesity, and patients with diabetes
can be obese, severely obese or non-obese. As shown in Figure 2, there is therefore considerable
overlap between clinically severe obesity and type 2 diabetes mellitus. This is the primary population
in which EndoBarrier will be used. Epidemiological data are available for the prevalence of diabetes
and obesity in Australia (ABS, 2013), as well as the distribution of BMIs within these two populations
(South Australian Department of Health, 2003; Thomas and Nestel, 2007). Thus the population of
patients with diabetes and obesity can be determined. These data suggest that the prevalence of
diabetes in Australian adults is 4.0% (ABS, 2013). Based on the BMI profile of diabetics in Australia,
20% of patients with diabetes have BMI ≥ 35 kg/m 2 (Thomas and Nestel, 2007), meaning that the
size of the eligible population of patients with type 2 diabetes and clinically severe obesity is 0.8% of
the adult population. A large proportion of patients with diabetes have HbA1c levels below the
threshold of 7% due to efficacy of current treatments. Therefore, it is likely that the eligible
population for EndoBarrier will comprise a proportion of this group.
In addition, there is a subpopulation of patients with clinically severe obesity who are not suitable for
bariatric surgery. The size of this population will be calculated based on the prevalence of a range of
contraindications for bariatric surgery. Patients with clinically severe obesity who are eligible for
bariatric surgery are essentially the patients with clinically severe obesity that don’t fall into either of
the two previously described populations (i.e. patients with uncontrolled type 2 diabetes mellitus, or
patients that are unsuitable for bariatric surgery). As such, this is a relatively large population that
includes the majority of clinically obese patients.
The clinical place for EndoBarrier in each of the requested populations is discussed separately in the
following sections.
Figure 2 Populations with clinically severe obesity and/or type 2 diabetes
Obesity
(BMI ≥ 30)
Clinically severe obesity
(BMI ≥ 35 + comorbidities
or BMI ≥ 40)
Unsuitable for
bariatric surgery
Type 2
diabetes
Uncontrolled type 2
diabetes
13
Patients with uncontrolled type 2 diabetes mellitus and clinically severe obesity
As described previously, one of the proposed indications for EndoBarrier is in patients with
uncontrolled type 2 diabetes mellitus and clinically severe obesity. While weight-loss is an important
component of care in these patients, standard anti-diabetic treatment targeted and lowering blood
glucose levels remains a cornerstone of treatment. Therefore, standard of care for these patients
includes a combination of guidance from clinical practice guidelines for diabetes and obesity.
The treatment guidelines published by Diabetes Australia and the Royal Australian College of General
Practitioners (RACGP, 2012) are currently the most widely used guidelines in Australia. The treatment
algorithm, shown in Figure 3, was developed based on evidence from the NHMRC guidelines for type
2 diabetes (National Evidence Based Guidelines for the Management of Type 2 Diabetes Mellitus,
2009). Only evidence from drugs with a PBS listing was considered by Diabetes Australia/the Royal
Australian College of General Practitioners while developing this treatment algorithm. A summary of
the recommendations for the treatment algorithm is presented below.
Patients should first modify their lifestyle, which includes changing diet, weight control and increased
physical activity. Pharmacological agents should be used if this does not result in sufficient glycaemia
control over a period of six weeks. The first line pharmacological therapy should be metformin.
Metformin reduces hepatic glucose output and insulin resistance, and has been shown to significantly
reduce the risk of diabetes-related morbidity and mortality in overweight patients. Patients should
continue with lifestyle modification while receiving metformin. If glycaemic control is not achieved
with metformin, a sulfonylurea should be used, either as monotherapy or as combination therapy with
metformin. Sulfonylureas act by increasing insulin release from the beta cells in the pancreas.
If glycaemic control is not achieved with metformin and/or sulfonylurea, third line therapies should be
considered. These include acarbose, a DPP-4 inhibitor, a glitazone or insulin. The guidelines do not
offer specific guidance as to which of these classes should be prescribed. However, drugs from
different classes have varying contraindications and precautions. The decision to use one class of
drug over another should be made on an individual patient basis, taking into consideration the
specific risk and benefit profile for each class.
The RACGP guideline (2012) briefly discusses the different classes of third line therapy. Acarbose is
considered useful when blood glucose values remain high after meals despite dietary modification. It
is necessary to take care in patients with renal impairment or gastrointestinal disease. Liver enzymes
need to be monitored. The DPP-4 inhibitors include linagliptin, sitagliptin, saxagliptin and vildagliptin.
The DPP-4 inhibitors are generally weight neutral and improve post prandial glycaemic control. The
glitazones (thiazolidinediones) include pioglitazone and rosiglitazone. Both glitazones can be used as
dual therapy with metformin or a sulfonylurea via the PBS. Pioglitazone can also be used in triple
therapy with metformin and a sulfonylurea or in combination with insulin. Contraindications include
moderate to severe cardiac failure. There are a number of safety issues associated with rosiglitazone,
including contraindications to moderate to severe cardiac failure, or any history of cardiac failure.
Rosiglitazone is associated with an increased risk of myocardial infarction.
14
Insulin may be required if adequate control has not occurred on maximum doses of oral
hypoglycaemic agents. Insulin may be needed early in the condition when treatment is being started
(the so-called ‘primary’ failure of oral hypoglycaemic agents that suggests the patient actually has
type 1 diabetes) or when the patient has later become refractory to oral hypoglycaemic agents (socalled ‘secondary’ failure consistent with the usual progression of type 2 diabetes).
The recommendations of the International Diabetes Federation were found to be broadly consistent
with the RACGP (2012) guidelines. These guidelines advise that patients should receive lifestyle
interventions followed by metformin and a sulfonylurea. This should be followed by thiazolidinediones
or α-glucosidase inhibitors (such as DPP-4 inhibitors). SGLT inhibitors are not discussed in either
guideline, as these represent a new class of treatment.
Figure 3 Diabetes Australia treatment algorithm for type 2 diabetes
Lifestyle modification:
Diet modification
Weight control
Physical activity
Metformin
Sulphonylurea
Acarbose
OR
DPP-4
inhibitor#
OR
Glitazone*
OR
Insulin†
Source: Diabetes Management in General Practice Guidelines, 2010 page 39.
# Authorised only as dual therapy with metformin or a sulfonylurea where combination metformin and a
sulfonylurea is contraindicated or not tolerated.
* Rosiglitazone is not authorised for triple therapy or for use with insulin but is approved only as dual therapy
with metformin or a sulfonylurea where combination metformin and a sulfonylurea is contraindicated or not
tolerated.
† Insulin is frequently required for glycaemic control in people with type 2 diabetes and can be initiated as basal
therapy or as premixed insulins, usually in combination with oral antidiabetic medications.
15
As discussed previously, weight control is also an important component of care for patients with
diabetes and clinically severe obesity. Most obesity guidelines agree that all patients should initially
attempt behavioural, lifestyle and dietary modifications to lose weight. Despite these interventions, it
is generally agreed that obesity is a chronic disorder with a high likelihood of recurrence. This is
especially true of severely obese patients, who generally require more intensive care strategies to
produce sustainable weight loss (NHMRC, 2013). Table 2 summarises recommendations from some
key evidence-based clinical practice guidelines. Only recommendations relating specifically to the
management of clinically severely obese patients are listed. The guidelines are generally consistent in
their advice that for severely obese patients (i.e. patients with a BMI ≥40 kg/m2, or between 35
kg/m2 and 40 kg/m2 and other significant disease), some form of bariatric surgery is strongly
recommended if behavioural modifications have been unsuccessful.
Table 2 Clinical practice guideline recommendations for morbid (severe) obesity
Guideline
Recommendations for clinically severe obesity
NHMRC (2013) Clinical
Practice Guidelines for the
Management of Overweight
and Obesity in Adults.
Canberra: National Health and
Medical Research Council.
For adults with BMI > 40 kg/m2, or adults with BMI > 35 kg/m2 and comorbidities that may
improve with weight loss, bariatric surgery may be considered, taking into account the
individual situation (Grade A).
NICE (2006) Obesity: guidance
on the prevention,
identification, assessment and
management of overweight and
obesity in adults and children:
National Institute for Health and
Clinical Excellence
Bariatric surgery is recommended as a treatment option for adults with obesity if all of the
following criteria are fulfilled:
For adults with BMI ≥ 30 kg/m2, or adults with BMI ≥ 27 kg/m2 and comorbidities, orlistat
may be considered as an adjunct to lifestyle interventions, taking into account the
individual situation (Grade A).
-
they have a BMI of 40 kg/m2 or more, or between 35 kg/m2 and 40 kg/m2 and
other significant disease (for example, type 2 diabetes or high blood pressure) that
could be improved if they lost weight
-
all appropriate non-surgical measures have been tried but have failed to achieve or
maintain adequate, clinically beneficial weight loss for at least 6 months
-
the person has been receiving or will receive intensive management in a specialist
obesity service
-
the person is generally fit for anaesthesia and surgery
-
the person commits to the need for long-term follow-up
Bariatric surgery is also recommended as a first-line option (instead of lifestyle
interventions or drug treatment) for adults with a BMI of more than 50 kg/m2 in whom
surgical intervention is considered appropriate.
Orlistat should be prescribed only as part of an overall plan for managing obesity in adults
who meet one of the following criteria:
-
a BMI of 28.0 kg/m2 or more with associated risk factors
-
a BMI of 30.0 kg/m2 or more
16
Guideline
Recommendations for clinically severe obesity
Lau DCW, Douketis JD,
Morrison KM, et al., for the
Obesity Canada Clinical
Practice Guidelines Expert
Panel 2006. Canadian clinical
practice guidelines on the
management and prevention of
obesity in adults and children.
CMAJ 2007;176(8 Suppl):
online 1-117
Adults with clinically severe obesity (BMI ≥ 40 kg/m2 or ≥ 35 kg/m2 with severe comorbid
disease) may be considered for bariatric surgery when lifestyle intervention is inadequate
to achieve healthy weight goals (Grade B).
SIGN (2010) Management of
obesity. A national clinical
guideline. Edinburgh
(Scotland): Scottish
Intercollegiate Guidelines
Network
Bariatric surgery should be considered on an individual case basis following assessment
of risk/benefit in patients who fulfil the following criteria:
-
BMI ≥35 kg/m2
-
presence of one or more severe comorbidities which are expected to improve
significantly with weight reduction (e.g. severe mobility problems, arthritis, type 2
diabetes)
Orlistat should be considered as an adjunct to lifestyle interventions in the management
of weight loss. Patients with BMI ≥28 kg/m2 (with comorbidities) or BMI ≥30 kg/m2 should
be considered on an individual case basis following assessment of risk and benefit.
Despite these recommendations, only a small proportion of obese patients in Australia eventually
resort to surgery. Table 3 summarises the various types of bariatric surgery and provides the number
of MBS services provided for each procedure based on Medicare statistics. Until July 2013, the MBS
items under which bariatric surgery procedures were billed included a range of bariatric procedures.
On the basis of recommendations made in the recent MBS review of items for the surgical treatment
of obesity (MBS Review 3), a number of surgical items numbers have been created so that each
specific surgery procedure is associated with an individual item. Therefore, data on the utilisation of
different surgical procedures is only available from the period between July 2013 and December
2013. Based on these data, it appears that currently, the two most common bariatric procedures are
gastric banding and sleeve gastrectomy. Other surgical procedures such as gastroplasty and gastric
bypass surgery are declining due to the advent of less invasive procedures. Relative to the total
number of patients with clinically severe obesity, it is apparent that only a small proportion of patients
receive bariatric surgery, and the vast majority of patients are likely to persist with standard of care.
The NHMRC guideline (2013) observes that in Australia, access to surgery under the public health
system is limited and services for bariatric surgery and necessary follow-up may be even more limited
in rural and remote areas. In addition, it is noted that while bariatric surgery can achieve long-term
weight, the surgery is not always successful and revision is frequently required.
17
Table 3 Summary of different types of bariatric surgery
Surgical procedure
Current Description
MBS
item
Fee
Number of MBS
items
processed
July-Dec 2013
Eligible
population
Gastric reduction/gastroplasty
Adjustable gastric
banding
(AGB)/Laparoscopic
adjustable gastric
banding (LAGB)
31569
A surgical procedure in which a small
silicone band is placed around the top
of the stomach to produce a small
pouch about the size of a thumb,
thereby limiting food intake.
$849.55
1,871
Clinically
severe
obesitya
Sleeve gastrectomy
(SG)
31575
Involves removing the lateral 2/3 of
the stomach with a stapling device. It
leaves a stomach tube instead of a
stomach sack.
$849.55
3,654
Clinically
severe
obesitya
Vertical banded
gastroplasty
(stomach stapling)
(VGB)
31578
The upper stomach near the
oesophagus is stapled vertically to
create a small pouch along the inner
curve of the stomach. The outlet from
the pouch to the rest of the stomach
is restricted by a band.
$849.55
15
Clinically
severe
obesitya
31581
The first two segments of the small
intestine, the duodenum and jejunum,
are bypassed and the stomach pouch
is attached to the ileum.
$1,045.40
7
Clinically
severe
obesitya
$1,045.40
355
Clinically
severe
obesitya
Gastric bypass
Biliopancreatic
diversion (BPD)
Biliopancreatic
diversion with
duodenal switch
(BPD-DS)
Roux-en-Y gastric
bypass (RYGB)
BPD in conjunction with DS is an
additional adaptation where a
proportion of the duodenum remains
attached to the stomach.
31572
A small stomach pouch is created to
restrict food intake. Next, a Y-shaped
section of the small intestine is
attached to the pouch to allow food to
bypass the lower stomach, the
duodenum (the first segment of the
small intestine), and the first portion
of the jejunum (the second segment
of the small intestine).
Sources: Schouten R., RijsBegg S, Vos T, Barker B, Stevenson C, Stanley L, Lopez AD (2007) The burden of
disease and injury in Australia in 2003, AIHW
Preventative Health Taskforce (2009) Australia: the healthiest country by 2020,
http://www.health.gov.au/internet/preventativehealth/publishing.nsf/Content/E233F8695823F16CCA2574DD008
18E64/$File/obesity-jul09.pdf, accessed 12 April 2013.
a The term clinically severe obesity generally refers to a patient with a Body Mass Index (BMI) of 40kg/m 2 or
more, or a patient with a BMI of 35kg/m2 or more with other major medical co-morbidities (such as diabetes,
cardiovascular disease, cancer). The BMI values in different population groups may vary due, in part, to
different body proportions which affect the percentage of body fat and body fat distribution. Consequently,
different ethnic groups may experience major health risks at a BMI that is below the 35-40 kg/m2 provided for in
the definition. The decision to undertake obesity surgery remains a matter for the clinical judgment of the
surgeon.
18
On this basis, the clinical place for EndoBarrier in patients with uncontrolled type 2 diabetes mellitus
and clinically severe obesity is likely to be in addition to SOC, and as a substitute for bariatric surgery
in a small proportion of patients.
For the treatment of uncontrolled type 2 diabetes mellitus, EndoBarrier may be used in a patient
whose HbA1c is greater than 7% despite treatment with metformin and a sulfonylurea. The MSAC
submission will therefore examine the cost-effectiveness of the intervention after these first-line
therapies. Due to its effect on blood sugar levels, it is expected that a proportion of patients will be
able to cease anti-diabetic medications while implanted with EndoBarrier and beyond.
Patients with clinically severe obesity who are not suitable for bariatric surgery.
Patients who are not suitable for bariatric surgery consist of two subpopulations:
a. Patients with contra-indications for bariatric surgery
b. “Bridge” patients who are currently not suitable for bariatric surgery due to excess weight
and co-morbidities, but may become eligible through significant weight-loss or improvement
of other metabolic outcomes using EndoBarrier
The first group of patients is difficult to define as there are no absolute contraindications to bariatric
surgery. Relative medical contraindications to surgery may include severe gastrointestinal disease,
uncontrolled obstructive sleep apnoea with portal hypertension, and serious blood or autoimmune
disorders, severe heart failure, unstable coronary artery disease, end-stage lung disease, active
cancer diagnosis/treatment or cirrhosis with portal hypertension. Laparoscopic surgery may be
difficult or impossible in patients with giant ventral hernias, severe intra-abdominal adhesions, large
liver, high BMI with central obesity or physiological intolerance of pneumoperitoneum (SAGES, 2008).
In addition, patients must be able to give fully informed consent to bariatric surgery and commit to
post-operative care plans. Therefore, bariatric surgery should not be performed on patients who have
serious psychological or psychiatric disorders such as drug/alcohol dependency, significant intellectual
impairment or active psychosis. These contraindications are supported by a range of international
guidelines (Fried et al., 2008; Dixon et al., 2011).
While most patients with the aforementioned contraindications will never be eligible for bariatric
surgery, another group (“bridge” patients) may become eligible for bariatric surgery after a successful
weight-loss intervention. The intent of this approach is to promote weight loss specifically to reduce
the risk from a subsequent intervention, including bariatric surgery. The American Society for
Gastrointestinal Endoscopy (ASGE) and the American Society for Metabolic & Bariatric Surgery
(ASMBS) Task Force on Endoscopic Bariatric Therapy states in a white paper on the topic that
patients with Class III (BMI >50) 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 >60 where there is a greater risk of morbidity or mortality
than patients with BMI 45-60 (ASGE/ASMBS, 2011).
Both groups of patients follow the same clinical algorithm for weight-loss as outlined in Table 2, that
is to say patients should initially attempt behavioural, lifestyle and dietary modifications to lose
19
weight. If these initial strategies are unsuccessful, bariatric surgery is not an option (by definition). In
these patients, EndoBarrier will provide a treatment option where few alternatives currently exist, and
will prevent many from experiencing substantial deterioration in health outcomes over time.
In the proposed clinical algorithm patients with clinically severe obesity, but for whom bariatric
surgery is not considered suitable, EndoBarrier will be used in addition to SOC. For “bridge” patients,
subsequent bariatric surgery may be considered as a downstream option after successful weight-loss
using EndoBarrier.
Patients with clinically severe obesity who are suitable for bariatric surgery.
In response to the request from the PASC, a third population including patients with clinically severe
obesity who are eligible for bariatric surgery will also be considered. As discussed previously, this
group includes patients with clinically severe obesity that don’t fall into either of the two previously
described populations (i.e. patients with uncontrolled type 2 diabetes mellitus, or patients that are
unsuitable for bariatric surgery). As such, this is a relatively large population that includes the
majority of clinically obese patients.
Initially, patients in this group follow the same clinical algorithm for weight-loss as outlined in Table 2,
that is to say patients should initially attempt behavioural, lifestyle and dietary modifications to lose
weight. If these approaches are not successful, patients may then proceed to one of the bariatric
surgery procedures outlined in Table 3. As discussed previously, only a small proportion of patients
receive bariatric surgery, and the vast majority of patients are likely to persist with SOC. The NHMRC
guideline (2013) observes that in Australia, access to surgery under the public health system is
limited and services for bariatric surgery and necessary follow-up may be even more limited in rural
and remote areas. In addition, it is noted that while bariatric surgery can achieve long-term weight,
the surgery is not always successful and revision is frequently required. It should be noted that in
contrast to the group of patients with uncontrolled diabetes, SOC in this group does not include
pharmacological treatment with anti-diabetic medication.
On this basis, the clinical place for EndoBarrier in patients with clinically severe obesity who are
suitable for bariatric surgery is likely to be in addition to standard of care (SOC), and as a substitute
for bariatric surgery in a small proportion of patients.
Proposed clinical management algorithm
Figure 4 presents the proposed clinical management algorithm for EndoBarrier in the treatment of
patients with clinically severe obesity, with or without uncontrolled type 2 diabetes mellitus patients
with clinically severe obesity in patients who are not suitable for bariatric surgery (including patients
that are contra-indicated for surgery and “bridge” patients), and patients with clinically severe obesity
who are eligible for bariatric surgery but have a preference for EndoBarrier.
In patients with uncontrolled type 2 diabetes mellitus who have clinically severe obesity, EndoBarrier
is an alternative to SOC alone or bariatric surgery plus SOC. As described previously, in type 2
diabetic mellitus patients, SOC consists of a range of oral blood glucose lowering drugs and/or insulin.
In clinically obese patients who are unsuitable for bariatric surgery, EndoBarrier is an alternative to
20
SOC. For this group of patients, SOC consists of behavioural and lifestyle interventions for weightloss.
Figure 4 Clinical management algorithm for type 2 diabetes and clinically severe obesity
Clinically severe
obesity
Uncontrolled
type 2 diabetes
Controlled diabetes
or non diabetic
Suitable for
bariatric surgery
Not currently suitable
for bariatric surgery
Bridge patient
Bariatric
surgery
EndoBarrier
SOC
Bariatric
surgery
EndoBarrier
Removal of
EndoBarrier
Bariatric
surgery
SOC
Removal of
EndoBarrier
SOC
Bariatric
surgery
SOC
EndoBarrier
Removal of
EndoBarrier
SOC
Bariatric
surgery
Contraindicated
for surgery
EndoBarrier
SOC
Removal of
EndoBarrier
SOC
Clinically severely obese: BMI ≥ 40kg/m2 or BMI ≥ 35kg/m2 with co-morbidities
Abbreviations: SOC, standard of care
Comparator
Patients with uncontrolled type 2 diabetes mellitus and clinically severe obesity
Patients who have uncontrolled type 2 diabetes mellitus and clinically severe obesity require
treatment with anti-diabetic medications; however weight loss also remains an important component
of care. Therefore, in this group of patients the clinical place for EndoBarrier is likely to be in addition
to SOC, and as a substitute for bariatric surgery in a small proportion of patients.
Clinical practice guidelines (NHMRC, 2009) recommend that "interventions to achieve target glycated
haemoglobin should begin with lifestyle modification followed by pharmacological options selected on
the basis of individual clinical circumstances, side effects and contra-indications (Grade A). Based on
this advice, the primary comparator in patients with type 2 diabetes mellitus is considered to be SOC,
consisting of lifestyle and dietary changes and/or pharmaceutical interventions with concomitant
insulin. As discussed above, patients with type 2 diabetes mellitus may receive a range of medications
from different drug classes in different combinations, depending on the needs of the patient. The
definition of SOC presented in the submission to MSAC will therefore include a range of medications
considered to be representative of Australian clinical practice. As most anti-diabetic medications are
21
currently reimbursed through the PBS, the composition of the comparator will be based primarily on
Medicare data for the utilisation of these drugs.
In patients with uncontrolled type 2 diabetes mellitus and clinically severe obesity, interventions
targeted at weight loss are recommended in addition to treatment with anti-diabetic medications.
Direct benefits of weight loss in this group include an increase in insulin sensitivity, improvement in
glycaemic control, improved lipid profiles, decreased triglycerides and LDL cholesterol and improved
blood pressure, mental health and quality of life (Wing et al., 1991; Maggio and Pi-Sunyer, 1997; PiSunyer, 2000). In Australia, patients with a BMI greater than 35 kg/m2 and diabetes are eligible for
bariatric surgery based on the current item descriptors for MBS Items 31569 to 31581. Therefore, in
patients with uncontrolled type 2 diabetes mellitus and clinically severe obesity, a proportion will
receive standard anti-diabetic medication (SOC) and bariatric surgery.
Bariatric surgery includes a variety of procedures that aim to reduce the size of the stomach with a
gastric band (gastric reduction), removal of a portion of the stomach (gastroplasty) or by resecting
and re-routing the small intestines to a small stomach pouch (gastric bypass surgery). The choice of
procedure will depend on a patient’s weight-loss goals, resources, and current health. Of the different
types of bariatric surgery, it is expected that gastric banding is most likely to be replaced by
EndoBarrier if it were approved for reimbursement in patients with clinically severe obesity. Like
gastric banding, EndoBarrier has the advantages of no alteration to gastrointestinal tract or
anastomosis, reversibility, and lower operative mortality and morbidity compared with other bariatric
procedures. Although sleeve gastrectomy appears to be widely used, it is relatively radical procedure
that involves dividing the stomach vertically to reduce its size to about 25%. The operation is nonreversible and is usually performed laparoscopically. The mechanism of action of EndoBarrier most
closely mimics surgical duodenal jejunal gastric bypass (Roux-en-Y gastric bypass); however the
number of these procedures performed is relatively low due to an increasing reluctance for
procedures that involve extreme and permanent modification of the anatomy. The MBS item
descriptor for gastric banding is presented in Table 4 below. It should be noted that patients who
undergo gastric banding often require gastric band adjustments (MBS item 31587), and some
patients choose to eventually have the procedure reversed (MBS item 31584).
Table 4: MBS item descriptor for gastric banding
Category 3 – THERAPEUTIC PROCEDURES
MBS 31569
Adjustable gastric band, placement of, with or without crural repair taking 45 minutes or less, for a patient with clinically
severe obesity
Multiple Services Rule
(Anaes.) (Assist.)
Fee: $849.55 Benefit: 75% = $637.20
On this basis, it is expected that patients with uncontrolled type 2 diabetes mellitus and clinically
severe obesity will use EndoBarrier is an alternative to SOC alone or bariatric surgery plus SOC (SOC
consists of a range of oral blood glucose lowering drugs and/or insulin).
22
Therefore, this submission proposes that in this group, the main comparator will be a weighted
comparator comprising SOC and bariatric surgery.
The final weighting given to each intervention included in the comparator (SOC and bariatric surgery)
will be determined on the basis of the relative use of these two approaches in the Australian
population. As discussed previously, the uptake of bariatric surgery is small relative to the size of the
eligible population. The most appropriate form of bariatric surgery to consider in the analysis is most
likely to be gastric banding.
Patients with clinically severe obesity who are not suitable for bariatric surgery
In clinically obese patients who are unsuitable for bariatric surgery, EndoBarrier is an alternative to
SOC. For this group of patients, SOC consists of behavioural and lifestyle interventions for weightloss.
This submission proposes that in patients with clinically severe obesity who are not suitable for
bariatric surgery, the main comparator will be SOC.
It should be noted that both proposed populations, EndoBarrier will always be used in in addition to
SOC. For patients with uncontrolled type 2 diabetes mellitus and clinically severe obesity, SOC
includes a range of oral blood glucose lowering drugs and/or insulin. For patients with clinically severe
obesity who are not suitable for bariatric surgery, SOC consist of behavioural and lifestyle
interventions.
Patients with clinically severe obesity who are suitable for bariatric surgery.
In Australia, patients with a BMI greater than 35 kg/m2 and diabetes are eligible for bariatric surgery
based on the current item descriptors for MBS Items 31569 to 31581; however only a small
proportion of patients receive bariatric surgery, and the vast majority of patients are likely to persist
with SOC. It should be noted that in contrast to the group of patients with uncontrolled diabetes, SOC
in this group does not included pharmacological treatment with anti-diabetic medication.
Therefore, this submission proposes that in this group, the main comparator will be a weighted
comparator comprising SOC and bariatric surgery.
The final weighting given to each intervention included in the comparator (SOC and bariatric surgery)
will be determined on the basis of the relative use of these two approaches in the Australian
population. As discussed previously, the uptake of bariatric surgery is small relative to the size of the
eligible population. As was the case in the population with type 2 diabetes and clinically severe
obesity, the most appropriate form of bariatric surgery to consider in the analysis is most likely to be
gastric banding.
Clinical claim
As described above, the MSAC submission for EndoBarrier will seek reimbursement for the procedure
in patients with clinically severe obesity. Subgroups considered in the evaluation will include patients:
23

with uncontrolled type 2 diabetes,

who are not suitable for bariatric surgery (including patients that are contra-indicated for
surgery and “bridge” patients), and

who are eligible for bariatric surgery but have a preference for EndoBarrier.
The respective comparators for these groups are SOC with or without bariatric surgery, SOC alone,
and a weighted comparator comprising SOC and bariatric surgery. Thus the submission will be based
on different clinical claims for each population and comparator.
In patients for whom bariatric surgery is the main comparator:
-
EndoBarrier is non-inferior to bariatric surgery in terms of clinical efficacy
-
EndoBarrier is superior to bariatric surgery in terms of clinical safety
In patients for whom SOC is the main comparator
-
EndoBarrier plus SOC is superior to SOC alone in terms of clinical efficacy
Note that in the absence of a full analysis of clinical data (to be completed in the final submission) the
Sponsor is pre-empting the results that would form the basis of the economic evaluation. If the
clinical data did not support any of these conclusions, the claims in the final application would be
adjusted to reflect this.
As shown in Table 5, for all populations and comparisons, the most appropriate form of economic
evaluation is a cost-utility analysis; however as discussed previously the comparators for the various
subpopulations will differ. For patients with uncontrolled type 2 diabetes mellutis and clinically severe
obesity, the analysis includes a weighted comparator of bariatric surgery and SOC. The weighting
applied to each comparator will be determined in the final submission on the basis of the relative use
of bariatric surgery and SOC in the proposed population. A similar approach will be applied to patients
with clinically severe obesity who are suitable for bariatric surgery; however SOC in these patients will
not include anti-diabetic medications. Depending on the safety data for EndoBarrier and bariatric
surgery, there is a possibility that the submission could claim a net clinical benefit for EndoBarrier due
to non-inferior clinical efficacy but superior safety.
In patients with clinically severe obesity who are not considered suitable for bariatric surgery, the
main comparator will be SOC alone. The comparison with SOC will be a cost-utility analysis based on
superior clinical efficacy. For patients who are using EndoBarrier as a bridge to bariatric surgery,
patients will proceed to surgery if the intervention is successful. These downstream consequences will
be considered in the economic model.
Comp
arativ
e
safety
versu
s
comp
arator
Table 5: Classification of an intervention for determination of economic evaluation to be presented
Comparative effectiveness versus comparator
Superior
Non-inferior
Inferior
Net clinical benefit CEA/CUA
Comparison with bariatric
Superior
CEA/CUA
surgery
Neutral benefit
CEA/CUA*
CUA
Net harms
None^
24
Non-inferior
Comparison with SOC
CEA/CUA
None^
Net clinical benefit
CEA/CUA
Neutral benefit
CEA/CUA*
None^
None^
Net harms
None^
Abbreviations: CEA = cost-effectiveness analysis; CMA = cost-minimisation analysis; CUA = cost-utility analysis
^ No economic evaluation needs to be presented; MSAC is unlikely to recommend government subsidy of this intervention
Inferior
Outcomes and health care resources affected by
introduction of proposed intervention
Outcomes
The clinical trials for EndoBarrier selected a range of patient relevant clinical efficacy endpoints;
however the most important outcomes for the purpose of this evaluation were considered to be:
weight loss, HbA1c levels and procedure-related adverse events. These outcomes are discussed in
detail in the sections below.
Weight loss
Weight loss is a particularly important clinical outcome for patients with clinically severe obesity
(including patients that are suitable and not suitable for surgery) and is therefore considered the
primary outcome for this group.
As described previously, there is a vast body of literature to support the relationship between excess
weight and the development of long-term health complications including type 2 diabetes,
hypertension,
dyslipidaemia, and
cardiovascular
disease. Although
weight
gain
has been
demonstrated to increase health risks in paediatric and adult populations, it does not necessarily
follow that weight loss can reverse these impacts. The NHMRC systematic review underlying the
current obesity guidelines (NHMRC, 2013) addressed this question and concluded that surgicallyinduced weight loss in adults (gastric banding and gastric bypass) is associated with a reduced risk of
cardiovascular disease, all-cause and global mortality in patients with morbid obesity. Gastric bypass
was reported to be associated with greater reductions in cardiovascular mortality than gastric
banding. The results of this review validate the importance of weight loss as a clinical endpoint.
Furthermore, there is clinical evidence to show that only a modest amount of weight loss is required
to achieve substantial clinical benefits (Klein et al., 2004).
HbA1c levels
In diabetes, patient-relevant clinical endpoints such as blindness and amputations are the best
measure of disease control. However, the effectiveness of diabetes management strategies is
consistently improving and clinical endpoints such as amputation occur much less frequently and later
in the course of the disease. Therefore, clinical trials rely on surrogate markers such as HbA1c to
establish the effectiveness of diabetes treatment strategies.
25
The risk of developing microvascular, macrovascular and other complications is closely associated
with glycaemic control, as measured by HbA1c levels. The United Kingdom Prospective Diabetes
Study (UKPDS) prospective study reported that each 1% reduction in mean HbA1c was associated
with a 14% reduction in the relative risk of myocardial infarction, a 37% reduction in the relative risk
of microvascular complications and a 21% reduction in the relative risk of death (Stratton et al 2000).
The Diabetes Control and Complications Trial (DCCT) study randomised patients to intensive or
conventional therapy, who were followed for a mean of 17 years. A decrease HbA1c was significantly
associated with most of the positive effects of intensive treatment on the risk of cardiovascular
disease (DCCT, 2005). A 10% reduction in HbA1c was associated with a 20% reduction in the relative
risk of a cardiovascular event (95 CI 9%, 30% p<0.001). The vast majority (96%) of the reduction in
the risk of retinopathy was explained by the reduction in mean HbA1c level. Similar results were
found for microalbuminuria (99.2% of the risk reduction explained by a reduction in HbA1c) and
albuminuria (96.7% of the risk reduction explained by a reduction in HbA1c).
The validity of HbA1c is thus well established, and this outcome has been accepted by regulatory
authorities worldwide as an appropriate surrogate marker of clinical effectiveness in clinical trials of
new treatments. The change in HbA1c will be used in this submission as the primary measure of
clinical effectiveness in patients with diabetes.
Adverse events
To ensure that EndoBarrier is non-inferior to its comparators in terms of safety, a comparison of
safety in terms of intervention-related adverse events will be undertaken. Clinical trial evidence
suggests that adverse events are generally infrequent, and of low severity. The following symptoms
and adverse effects have been reported from EndoBarrier implantation in some patients:







Nausea
Vomiting
Upper abdominal pain
Bleeding
Device migration
Transient fever
Obstruction with vomiting
Other outcomes
In addition to the outcomes discussed above, clinical trials of EndoBarrier evaluated a range of other
efficacy endpoints associated with safety, resource-use or the risk of diabetes or cardiovascular
disease. These outcomes include, but are not limited to, the following:
26











Change in fasting plasma glucose (FPG) concentration
Postprandial seven-point blood glucose profile
Meal tolerance test (MTT)
Percentage of subjects achieving 10% excess weight loss (EWL)
Change in total body weight
Change in insulin dosage
Oral anti-diabetic drug (OAD) use
Blood lipid levels
Blood pressure
Waist circumference
Metabolic syndrome
In addition to the trial-based outcomes, the economic model will also consider some downstream
health impacts such as cardiovascular events, microvascular events, quality of life and mortality.
Health care resources
Resources to deliver proposed intervention
The cost of the EndoBarrier device, including the liner, insertion and removal systems, is expected to
be reimbursed on the Prostheses List and will be included in the economic evaluation. In addition to
the prostheses costs, patients using EndoBarrier will incur a range of additional professional/clinic
costs while the implantation and removal procedures are being undertaken all of which will be
included in the economic evaluation
As mentioned previously, an experienced physician with training for endoscopy can complete the
implantation process as a (hospital) day-case procedure; however in some cases hospitalisation may
be required. The insertion of the liner will require the attendance of at least one trained specialist and
the assistance of a nurse or assistant. Removal of the device is undertaken through another
endoscopic procedure that is less complex and time-consuming than the implantation procedure.
Insertion and removal of the device will also require anaesthesia.
The MBS item fees for EndoBarrier implantation and removal will be determined in the final
submission with reference to MBS-listed procedures of similar complexity. A full justification of MBS
item fees for the implantation and removal of EndoBarrier in terms of resource-use will be presented
in the submission-based assessment.
Resources provided in association with the proposed intervention
To minimise the risk of bleeding, all patients receiving treatment with EndoBarrier are required to
take a proton pump inhibitor for the duration of therapy (e.g. omeprazole).
As part of SOC, all diabetic patients are assumed to receive conventional anti-diabetic medications
including metformin, sulfonylurea and third-line treatments such as acarbose, a DPP-4 inhibitor, a
glitazone or insulin, depending on a patient’s disease severity and treatment history. Although
EndoBarrier will be used in addition to anti-diabetic medications there will be some reduction in the
use of their use based on a patient’s response to treatment.
27
Resources provided to deliver comparator
As discussed previously, a proportion of patients with diabetes and clinically severe obesity currently
receive gastric banding. Both procedures have the advantages of no alteration to gastrointestinal
tract or anastomosis, reversibility, and lower operative mortality and morbidity compared with other
bariatric procedures. The costs associated with gastric banding include the MBS item fee for gastric
banding (MBS item 31569) plus associated expenses such as hospitalisation and anaesthesia.
Hospitalisation costs and average length of stay associated with AR-DRGs K07Z K04A and K04B.
It should be noted that patients who undergo gastric banding often require gastric band adjustments
(MBS item 31587), and some patients choose to eventually have the procedure reversed (MBS item
31584). The costs of these procedures will be considered in the economic evaluation.
Resources provided in association with the comparator (SOC)
As is the case for patients implanted with EndoBarrier, diabetic patients are assumed to receive SOC
consisting of conventional anti-diabetic medications including metformin, sulfonylurea and third-line
treatments such as acarbose, a DPP-4 inhibitor, a glitazone or insulin, depending on a patient’s
disease severity and treatment history.
Resources used in the delivery of EndoBarrier and the main comparators are summarised in Table 6
The costs of these resources will take a societal perspective incorporating government and private out
of pocket costs (data permitting).
Table 6: List of resources to be considered in the economic analysis
Number of
Proporti
Setting in
units of
on of
Provider of
which
resource per
patients
resource
resource is
relevant time
receiving
provided
horizon per
resource
patient
Resources provided to identify eligible population
No additional testing
required
Resources provided to deliver proposed intervention
Insertion of
Surgeon/special Private
100%
1
EndoBarrier
ist
hospital
Acquisition of liner and Manufacturers
removal system
Private
hospital
100%
1
Anaesthesia
Specialist
Private
hospital
100%
1
Hospital stay or day
procedure centre
Private hospital
Private
hospital
100%
Removal of device
Surgeon/special
ist
Private
hospital
100%
Resources provided in association with proposed intervention
Proton pump inhibitor
PBS
Private
100%
hospital
Anti-diabetic
medications
Other cardiovascular
medications
TBD
1
Disaggregated unit cost
MBS
Safety
nets*
Other
govt
budget
Private
health
insurer
Patient
Total
cost
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
1 (twice daily)
TBD
TBD
TBD
PBS
Private
hospital
TBD
TBD
TBD
PBS and out of
pocket
Private
hospital
TBD
TBD
TBD
TBD
TBD
28
Provider of
resource
Number of
Proporti
Setting in
units of
on of
which
resource per
patients
resource is
relevant time
receiving
provided
horizon per
resource
patient
Resources provided to deliver comparator
Insertion of gastric
Surgeon/special
band
ist
Acquisition of gastric
Manufacturers
band
Anaesthesia
Specialist
Disaggregated unit cost
Safety
nets*
MBS
Other
govt
budget
Private
health
insurer
Private
hospital
Private
hospital
Private
hospital
100%
1
100%
1
100%
1
TBD
TBD
TBD
TBD
Hospital stay
Private hospital
Private
hospital
100%
AR-DRGs
K07Z K04A
and K04B
Gastric Band
adjustment
Private hospital
Private
hospital
TBD
TBD
$637.20
Total
cost
Patient
$212.35 $849.55
$3,300
$3,300
$
$83.50
$14.65
$97.95
Reversal of gastric
banding
Surgeon/special
ist
Private
hospital
Resources provided in association with comparator
Anti-diabetic
PBS
Private
medications
hospital
Other cardiovascular
medications
PBS and out of
pocket
Private
hospital
$384.75 $1,539.1
0
TBD
TBD
$1,154.35
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
TBD
Abbreviations: PBS, Pharmaceutical Benefits Scheme; TBD, to be determined
* Include costs relating to both the standard and extended safety net.
Proposed structure of economic evaluation (decisionanalytic)
Table 7 summarises the population, intervention, comparator and outcomes of EndoBarrier, for
treatment of patients with clinically severe obesity, with or without uncontrolled type 2 diabetes
mellitus.
Table 7: Summary of extended PICO to define research question that assessment will investigate
Patients
Patients with
uncontrolled type 2
diabetes and clinically
severe obesity
GID will present a
sensitivity analysis
modelling costeffectiveness in patients
with BMI>30 kg/m2 (i.e.
obesity and
uncontrolled type 2
diabetes).
Intervention
Comparator
duodenal jejunal
bypass liner
(EndoBarrier®)
Comparator 1:
Bariatric surgery
Comparator 2:
Standard of care
Outcomes to
be assessed
HbA1cWeight
loss
Adverse
events/compli
cations
Quality of life
Mortality
Early removal
of device
Healthcare resources to be considered
HbA1c
Weight loss
Adverse
EndoBarrier device (including liner)
Insertion and removal of EndoBarrier
Professional/clinic visits
EndoBarrier device (including liner)
Insertion and removal of EndoBarrier
Professional/clinic visits
Anaesthesia
Hospital stay
Gastric banding device
Gastric banding adjustment and removal
Management of adverse
events/complications
29
Patients
Intervention
Comparator
Outcomes to
be assessed
events/compli
cations
Quality of life
Mortality
Early removal
of device
Patients with clinically
severe obesity who are
not suitable for bariatric
surgery (including
“bridge” patients and
patients with
contraindications for
surgery)
duodenal jejunal
bypass liner
(EndoBarrier®)
Standard of care
Weight loss
Adverse
events/compli
cations
Quality of life
Mortality
Early removal
of device
Patients with clinically
severe obesity who are
suitable for bariatric
surgery
duodenal jejunal
bypass liner
(EndoBarrier®)
Comparator 1:
Bariatric surgery
Weight loss
Adverse
events/compli
cations
Quality of life
Mortality
Early removal
of device
Comparator 2:
Standard of care
Weight loss
Adverse
events/compli
cations
Quality of life
Mortality
Early removal
of device
Healthcare resources to be considered
Anaesthesia
Hospital stay
Management of adverse
events/complications
Anti-diabetic medication
Costs associated with CV, macrovascular
and microvascular events
Subsequent bariatric surgery
EndoBarrier device (including liner)
Insertion and removal of EndoBarrier
Professional/clinic visits
Anaesthesia
Hospital stay or day bed
Management of adverse
events/complications
Anti-diabetic medication
Costs associated with CV, macrovascular
and microvascular events
Subsequent bariatric surgery
EndoBarrier device (including liner)
Insertion and removal of EndoBarrier
Professional/clinic visits
Anaesthesia
Hospital stay
Gastric banding device
Gastric banding adjustment and removal
Management of adverse
events/complications
EndoBarrier device (including liner)
Insertion and removal of EndoBarrier
Professional/clinic visits
Anaesthesia
Hospital stay
Management of adverse
events/complications
Anti-diabetic medication
Costs associated with CV, macrovascular
and microvascular events
Abbreviations: AEs, adverse events; SOC, standard of care
a In diabetic patients, SOC consists of anti-diabetic medications including metformin, sulfonylurea and third-line
treatments such as acarbose, a DPP-4 inhibitor, a glitazone or insulin, depending on a patient’s disease severity
and treatment history.
The comparisons of EndoBarrier plus SOC versus SOC alone in patients with Type 2 diabetes mellutis
will require an economic model to calculate the cost-effectiveness of the addition of EndoBarrier to
the treatment algorithm for diabetes. The economic model is to be based on the UKPDS outcomes
model (Clark et al., 2002). The UKPDS outcomes model is a simulation model for type 2 diabetes that
estimates the incidence of 7 major diabetes-related complications. Risk equations used to estimate
the probabilities of these complications are derived from the UKPDS dataset, and are a function of
patient characteristics and prior complications. The efficacy of Endobarrier compared to its
comparator(s) will be modelled via changes in weight loss and/or Hb1AC and/or other cardiovascular
risk factors. The model predicts the risk of a range of mircovascular and macrovascular events. The
incidence of these events will decrease with EndoBarrier treatment, leading to a reduction in costs
and an increase in quality of life. A summary of the UKPDS risk model is provided in Figure 5.
30
Figure 5 Summary of UKPDS risk model
The structure of the proposed decision analytic model is presented in Figure 6
Figure 6 Decision analytic model structure for EndoBarrier in patients with uncontrolled diabetes
and clinically severe obesity
EndoBarrier plus SOC
IHD/MI/CHF/Stroke,
Amputation/Blindness/Renal
failure (risk is a function of
HbA1c and weight loss etc.)
Death
Survive
Death
Free of events
Survive
Uncontrolled type 2
diabetes and
clinically severe
obesity and OR
clinically severe
obesity and not
suitable for bariatric
surgery
Bariatric surgery or
SOC
Same structure as
above
Primary questions for public funding
6. What is the proportion of people in Australia with clinically severe obesity, with or without
uncontrolled type 2 diabetes, and how many would be eligible for the proposed service?
31
7. What is the safety of EndoBarrier in patients clinically severe obesity, with or without
uncontrolled type 2 diabetes compared to SOC with or without bariatric surgery?
8. What is the effectiveness of EndoBarrier in patients clinically severe obesity, with or without
uncontrolled type 2 diabetes compared to SOC with or without bariatric surgery?
9. What is the cost-effectiveness of EndoBarrier in patients clinically severe obesity, with or
without uncontrolled type 2 diabetes compared to SOC with or without bariatric surgery?
32
References
ASGE/ASMBS Task Force on Endoscopic Bariatric Therapy. A pathway to endoscopic bariatric
therapies. Surg Obes Relat Dis. 2011 Nov-Dec;7(6):672-82
Standards of medical care in diabetes--2010. Diabetes Care. 2010 Jan;33 :S11–S61.
Clarke P, Gray A, Holman R. Estimating utility values for health states of type 2 diabetic patients using
the EQ-5D (UKPDS 62). Med Decis Making. 2002 Jul-Aug;22(4):340-9
de Jonge C, Rensen SS, Verdam FJ, Vincent RP, Bloom SR, Buurman WA, le Roux CW, Schaper NC,
Bouvy ND, Greve JW. Endoscopic duodenal-jejunal bypass liner rapidly improves type 2 diabetes.
Obes Surg. 2013 Sep;23(9):1354-60
Department of Health, Population Research and Outcome Studies: Brief Report, Number 2003-03,
[cited at November 2013]
URL: http:// http://health.adelaide.edu.au/pros/docs/reports/BR2003_03_severe_obese.pdf
Dixon JB, Zimmet P, Alberti KG, Rubino F; International Diabetes Federation Taskforce on
Epidemiology and Prevention. Bariatric surgery: an IDF statement for obese Type 2 diabetes. Diabet
Med. 2011 Jun;28(6):628-42
IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes: recommendations for
standard, comprehensive, and minimal care. Diabet Med. 2006 Jun;23(6):579-93
Fried, Martin, et al. Interdisciplinary European guidelines on surgery of severe obesity. Obesity facts
1.1 (2008): 52-59.
Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH; American Heart
Association Council on Nutrition, Physical Activity, and Metabolism. Clinical implications of obesity with
specific focus on cardiovascular disease: a statement for professionals from the American Heart
Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College
of Cardiology Foundation. Circulation. 2004 Nov 2;110(18):2952-67.
Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity. Application to type 2 diabetes.
Diabetes Care. 1997 Nov;20(11):1744-66
Pi-Sunyer FX. Weight loss and mortality in type 2 diabetes. Diabetes Care. 2000 Oct;23(10):1451-2
Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam
Physician. 2009 Jan 1;79(1):29-36.
Risérus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res. 2009
Jan;48(1):44-51
33
SAGES Guidelines Committee. SAGES guideline for clinical application of laparoscopic bariatric
surgery. Surg Endosc. 2008 Oct;22(10):2281-300
Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery vs intensive medical therapy in obese
patients with diabetes. N Engl J Med. 2012;366(17):1567-1576
Snow V, Barry P, Fitterman N, Qaseem A, Weiss K; Clinical Efficacy Assessment Subcommittee of the
American College of Physicians. Pharmacologic and surgicalmanagement of obesity in primary care: a
clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005 Apr
5;142(7):525-31
Stratton IM, Adler AI, Neil AH, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC and Holman
RR on behalf of the UK Prospective Diabetes Study Group.
Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective
observational study. British Medical Journal 321: 405-412.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research Group.Intensive diabetes treatment and cardiovascular
disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-2653.
Thomas MC, Nestel PJ: Management of dyslipidaemia in patients with type 2 diabetes in Australian
primary care. Med J Aust 2007, 186(3):128-130
Wing RR, Marcus MD, Salata R, Epstein LH, Miaskiewicz S, Blair EH. (1991) Effects of a very-low
calorie diet on long-term glycemic control in obese type 2 diabetic subjects. Arch Intern Med 151(7):
1334-40
34