Appendix C
National Institute for HEALTH AND Clinical Excellence
Health Technology Appraisal
Rimonabant for the treatment of overweight and obese patients
Comments received from Consultees and Commentators on the draft remit and scope
Comments on the draft remit
Consultee Name / Section / Comment / Response /Sanofi-Aventis / Wording / Sanofi-Aventis suggests that the wording of the remit is amended as follows, to more accurately reflect the marketing authorisation of rimonabant as well as the relevant issues of the clinical and cost effectiveness of this product:
"To appraise the clinical and cost effectiveness of rimonabant in its licensed indications as an adjunct to diet and exercise for the treatment of obese patients, and overweight patients with associated risk factors, such as type 2 diabetes and dyslipidaemia, and to provide guidance to the NHS in England and Wales." / The remit states that rimonabant will be appraised within its licensed indication. Further details of the licensed indications are provided in the detail of the scope. No change.
Roche / Wording / The draft remit describes the indication for rimonabant but not in full and could thus be considered incomplete.
We therefore suggest that either:
1) The indication for rimonabant is described in full, as under the description of the technology within the scope
or
2) The remit is simply stated as 'To appraise the clinical and cost effectiveness of rimonabant in its licensed indications (see scope)'. / The remit explicitly states that rimonabant will be appraised within its licensed indications. No change necessary.
Primary Care Cardiovascular Society / Wording / To appraise the clinical and cost effectiveness of rimonabant in its licensed indications as an adjunct to diet and exercise for the treatment of obese and overweight patients. To identify those patients who would benefit the most from treatment with rimonabant taking into account clinical benefit and cost effectiveness. / Under “other considerations” the scope has been amended to state that the appraisal will identify subgroups of patients for whom rimonabant is particularly appropriate if the evidence allows. No change to remit.
NHS QIS / Wording / Yes / No action necessary
ABCD (2) / Wording / Yes / No action necessary
ABCD (1) / Wording / Yes / No action necessary
Royal College of Physicians / Timing issues / A decision is urgent / Comments noted.
Roche / Timing issues / There are already two pharmacological treatments which have received positive NICE guidance for the treatment of obesity (orlistat, TA guidance no.22; and sibutramine, TA guidance no.31). There is also a NICE Clinical Guideline on obesity due to be published in November 2006.
The current availabilty of these proven clinically and cost effective agents to NHS patients might therefore be one factor to consider in determining the relative timing for undertaking this appraisal. / Comments noted.
Primary Care Cardiovascular Society / Timing issues / As soon as is practically possible. / Comments noted.
NHS QIS / Timing issues / Urgent as obesity is a major public health problem and the problem is rapidly 'expanding' GPs are being asked now to prescribe due to the media hype / Comments noted.
Diabetes UK / Timing issues / Of high relevance to the management of people with Type 2 diabetes who are obese/overweight. / Comments noted.
ABCD (2) / Timing issues / Soon - if possible this should be timed to the Obesity Guidelines since these are likely to drive greater involvement in obesity management and rimonabant is now licensed in the UK / Comments noted. The clinical guideline on obesity has been published (CG43) and is available from the NICE website.
ABCD (1) / Timing issues / Urgent. Rimonabant is being forcefully promoted to doctors and nurses who are not familiar with the detailed issues. Inappropriate use is therefore very likely. / Comments noted.
Roche / Additional comments / The remit does not make mention of any of the wider objectives of this appraisal, for example an assessment of NHS resource and budget implications which would be an important component of this appraisal. / The appraisal will consider the clinical and cost effectiveness of rimonabant as per standard NICE methods. A costing template will be made available following publication of the guidance in accordance with standard procedures.
NHS QIS / Additional comments / No mention of duration of licence; reps say 9-15 months? / The marketing authorisation does not specify the appropriate length of treatment, although it is noted that the safety and efficacy of rimonabant have not been evaluated beyond 2 years.
Diabetes UK / Additional comments / Appears in keeping with previous reviews on orlistat and sibutramine. / No action necessary
ABCD (2) / Additional comments / No / No action necessary
ABCD (1) / Additional comments / No / No action necessary
Comments on the draft scope
ABCD (1) / Background information / Satisfactory / No action necessary /
ABCD (2) / Background information / Fair resume. / No action necessary /
Diabetes UK / Background information / Guidance needs to be in line with current NICE guidance. The draft document 'Obesity:the prevention, identification,assessment and management of overweight and obesity in adults and children' due to be completed November 2006 differs in content to the background information given in this draft scope.
Figures given to define somebody as overweight differs for Asian adults (1.2.2.8) ie 23 or over and these lower figures are already nationally accepted.
In the draft scope different figures are given for older people. Overweight is classified as a BMI of 27 or more in the age range 65-74 and a BMI of 28 in the age range of 75 plus. / Comments noted. The scope has been amended to recognise that the definitions of obese and overweight differ for Asian adults and older adults. /
Consultee Name / Section / Comment / TL suggested action /
Diabetes UK / Background information / Background information regarding sugery-again needs to be in line with the NICE guidelines. For example it is proposed that in people with a BMI over 50 bariatric surgery is viewed as a first line treatment option if surgical intervention is appropriate. / Comments noted. The information on surgery has been removed from the scope as although surgery is an option for some obese people, it is not considered to be a direct alternative to rimonabant. /
NHS QIS / Background information / Latest figures for 2003 state that 22% males and 26% females in Scotland are obese not 21% as mentioned / Comments noted. The figures in the scope have been updated to reflect information from the Health Profile of England 2006. /
Primary Care Cardiovascular Society / Background information / Those at risk of developing diabetes should be considered separately. / The prevention and control of diabetes will be considered. In addition, the appraisal will identify subgroups of patients for whom rimonabant is particularly appropriate if the evidence allows. No change. /
Roche / Background information / The Background section appears to be accurate but not necessarily complete or balanced - within the section describing obesity sequelae and risk-factors in particular.
We therefore suggest that paragraph 2 could be strengthened by:
1) Stating that since obesity itself is an important precursor and risk-factor for a wide range of co-morbidities (including CVD already mentioned), weight loss is the primary aim of treatment.
2) Stating that obesity is also an important factor in the development of hypertension specifically.
3) Outlining the inter-relationships between obesity and mental health (eg; depression).
In a letter to JAMA there is a suggestion that there may be insufficient safety evidence from the RIO trials for rimonabant for obese patients with mild depression (ref 1).
Furthermore, a recent study indicated that up to half of all obese patients may suffer from depression (ref 2).
4) Highlighting certain patient populations (eg; ethnic sub-groups) that are at increased risk.
Refs:
1. JAMA. 2006;296:649-650
2. A.Tuthilll et al ‘Psychiatric co-morbidities in patients attending specialist obesity services in the UK’ Q J Med 2006; 99:317-325 / 1) This is reflected throughout the scope.
2) The scope has been amended to note the association between hypertension and obesity.
3) These issues should be considered as part of the assessment of the evidence.
4) The background section has noted that the definition of obesity differs in Asian adults. Recommendations for specific subgroups will be considered if the evidence allows. /
ABCD (1) / Technology/
intervention / OK / No action necessary /
ABCD (2) / Technology/
intervention / Fair resume. Note that license/spc does not have such draconian therapy termination rules as sibutramine and orlistat. / Comments noted /
NHS QIS / Technology/
intervention / Needs more expansion on when contraindicated e.g. eplieptics and drug interactions / This level of detail is not usually provided within the scope, but will be considered within the appraisal. Rimonabant will be appraised in accordance with its marketing authorisation. /
Roche / Technology/
intervention / The description of the technology appears to be accurate but not necessarily complete - within the section describing the mode of action of rimonabant.
We suggest that this could be strengthened by highlighting that rimonabant has CB1 activity at both CNS and peripheral sites, as indicated in section 5.1 of the SPC; this aspect of the mode of action is important, since it explains the different adverse event profile of rimonabant relative to comparator pharmacological treatments. / The technology section has been amended to note that the endocannabinoid system is a physiological system present in brain and peripheral tissues /
ABCD (1) / Population / OK / No action necessary /
ABCD (2) / Population / Reflects clinical trial data and licence. NICE may wish to consider (lack of) evidence in super-obese especially in the light of suggested bariatric surgery guidance and whether or not it is appopriate to treat the super-obese with rimonabant. / Comments noted. The recommendations, including those for specific subgroups of patients, will be based on a consideration of the available evidence. /
Diabetes UK / Population / Please see above comments with regard to categorising people according to their BMI / See above response. /
NHS QIS / Population / Yes although effect on ethnic minorities needs clarity as risk of Western normal BMI of 25 in Indians is same as BMI of 30 in Caucasians / Comments noted. The background section has been amended to reflect the different definitions of overweight and obese for Asian adults. The text in the technologies section reflects the marketing authorisation of rimonabant. /
Roche / Population / The population is defined correctly in terms of rimonabant's indication. However, there are sub-groups that should be considered separately:
1) Black patients, since the SPC indicates evidence of reduced efficacy in this group.
2) Oriental/asian patients and patients over 75 years old, since the SPC indicates a lack of evidence in these groups.
3) Patients who may have depression (diagnosed or not), since depressive disorders have been reported in patients receiving rimonabant
4) Women of childbearing age, since the rimonabant SPC indicates that animal studies with rimonabant show teratogenic effects at levels similar to clinical exposure.
There is also also evidence of a link between cannabinoid activity and unwanted effects in pregnancy, eg; ectopic pregnancy (ref 3), which has resulted in concerns being expressed about the possible effects of rimonabant in pregnancy (ref 4)
Refs:
3. Wang et al ‘Fatty acid amide hydrolase deficiency limits early pregnancy events’ J Clin Invest 2006; 116:8, 2122-2131
4. http://www.pharmatimes.com/news/9319-Acomplia-pregnancy.aspx?src=ActivityBenchmark&fr=1 / The scope has been amended to state that the appraisal will identify subgroups of patients for whom rimonabant is particularly appropriate if the evidence allows. /
ABCD (1) / Standard comparators / OK / No action necessary. /
ABCD (2) / Standard comparators / Yes. Not comments on licence subtleties above. It would be useful to have a homogenous view of therapy duration in the light of availabel data (i.e. 2 yr for rimonabant and sibutrmaine, and 4 yr for orlistat) / Comments noted. /
Diabetes UK / Standard comparators / It should be noted that the medication metformin will also cause minor weight loss and has been shown to prevent and control Type 2 diabetes. / No change.
The licensed indication for metformin states that it is to be used for the ‘Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control’. Furthermore, the licensed indication also states that ‘A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure (see 5.1. Pharmacodynamic properties)’. The consultation on the draft scope has not resulted in sufficient information to suggest that metformin should be considered as a standard treatment in the NHS used in the population for whom rimonabant would be appropriate. However, if such evidence becomes available, consideration should be given to metformin as an alternative treatment for overweight people with type 2 diabetes as a risk factor. The manufacturer of rimonabant and non-manufacturer consultees are requested to clarify the role of metformin in treatment of overweight people with diabetes type 2 as a risk factor in their respective submission and statements. The final scope allows for this consideration by specifying ‘pharmacological treatments, including …’. /