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1 Eloise Saile Technology Appraisal Project Manager National Institute for Health and Clinical Excellence Midcity Place 71 High Holborn London WC1V 6NA 01 November 2007 Dear Eloise, Appraisal of cochlear implants for severe to profound deafness in children and adults - Comments on the Assessment Report for consideration by the Appraisal Committee Thank you for the opportunity to provide comments on the Assessment Report for the above appraisal. Cochlear Europe Limited are appreciative of the work completed by PenTAG in summarising the data in what is a very complex field and is generally supportive of the Report findings regarding the positive clinical benefits of unilateral and bilateral cochlear implants (CIs). In recognising the importance of CIs in adults and children Cochlear Europe support PenTAGs conclusions and are in agreement: That the evidence is strongly supportive of the effectiveness and costeffectiveness of unilateral cochlear implantation versus non technological interventions and hearing aids in adults and children. That within the limitations of the evidence available bilateral implantation has been shown to be of clinical benefit particularly for listening in noise and improving localisation. In considering the value of bilateral implantation we would draw the Appraisal Committee s attention to the fact that these two hearing attributes are indispensable in school, university, work and social settings but that the value of these benefits are not fully addressed by any QALY measure of which we are aware. Certainly for children particular advantages are envisaged from the educational perspective. In addition we ask the Appraisal Committee to consider the importance of bilateral implantation in deaf-blind and post-meningitic children and adults. Each of these groups is small and bilateral implantation is appropriate for specific clinical reasons. Post-meningitic children and adults require bilateral implantation, due to the risk of 1

2 total ossification occurring and rendering re-implantation impossible if a unilateral implant fails (Aschendorff et al. 2005, Dodds et al. 1997, Young et al. 2000). The deaf-blind have a particularly high need from the improved localisation offered by bilateral implantation. Due to the small size of these patient groups, evidence is limited, but the additional benefit resulting from bilateral implantation in these patients is uncontroversial in clinical practice. Key Issues There are however a number of key issues we would like to highlight in order to provide clarification to the Appraisal Committee during their consideration of the evidence and the drafting up of provisional recommendations on 21 st November Our main concerns are: Inconsistency throughout the report regarding PenTAGs classification of the patient population Inconsistency, in some sections, between the actual study populations evaluated and the study population included within the conclusion. Omission of key data The exclusion of patients with severe to profound deafness from the PenTAG cost-utility analysis 1. Classification of deafness The final remit for this appraisal states that the objective of this appraisal is to To appraise the clinical and cost effectiveness of cochlear implants in severe to profound deafness in children and adults. While the population statement of severe to profound is clearly defined and recognised by the PenTAG within their initial decision problem they then incorrectly divide the initial decision problem into two decision problems in the severely deaf and the profoundly deaf populations and into two policy questions for severely deaf or profoundly deaf (see page 34 of the Assessment Report, Section 3.1 Decision Problem). This inconsistency between severe to profound, severe and profound and severely or profound then continues throughout the report. We would highlight to the Appraisal Committee that the interchangeable use of these classifications is incorrect. For the majority of studies, severe to profound hearing loss refers not only to the degree of the hearing loss but the configuration of the loss (i.e. the degree of deafness at different frequencies of sound). Hearing loss can be categorised as mild, moderate, severe or profound based on average threshold values across a range of frequencies. The average hearing threshold does not however, take into account the configuration of the hearing loss which may include profound deafness at some frequencies and severe deafness at other frequencies (BSA recommendations 2

3 1988). An individual with severe hearing loss at low frequencies and profound hearing loss at high frequencies may be referred to as having severe to profound deafness. The degree of hearing loss may not correlate directly with speech understanding. In clinical practice the majority of CI programmes use multiple measures to define functional deafness including the audiogram and performance (mainly speech perception) tests. While PenTAG clearly recognise that the degree of hearing loss alone does not correlate directly with speech perception (see page 28, Section 2.3.3) they appear to be unaware that patients can have a hearing loss that is severe to profound in configuration, rather than just severe or profound. This configuration is the typical profile of most sensorineural hearing losses in the severe to profound range (Green 1972). Reflecting the importance of the severely to profoundly deaf classification the current UK candidacy criteria (as per the BAA, BCIG and ENT UK i joint submission) include severe to profound deafness as one of their selection criteria for cochlear implantation (see Assessment Report page.27, Section 2.3.3). In accordance with the appraisal remit it is the severely to profoundly deaf population which is the subject of this appraisal and while the PenTAG have been inconsistent with their use of their terminology it is this population along with the profoundly deaf which have been reviewed within the clinical effectiveness section of the Assessment Report. In the data reviewed half of the subjects ( adults and 472 children) were classified as severe to profoundly deaf (these figures exclude quality of life and education studies). It should be noted that similar efficacy benefits were observed in this group when compared with those subjects classified as profoundly deaf ( adults and 851 children). 2. Inconsistency between effectiveness data sections and conclusions We are also concerned about conclusions of clinical effectiveness sections for both children and adults for unilateral CIs vs.non technological support. While the data considered within both sections of the Assessment Report (pages and ) includes studies of both severely to profoundly deaf patients or profoundly deaf patients with no distinction made between the studies PenTAG, without justification, limit their conclusions to the profound patient population alone (pages 67 and 126). The limitation of the Assessment Groups conclusions to the profoundly deaf for these sections is perverse and not supported by main body of evidence considered and analysed by PenTAG which clearly supports cochlear implantation for severe to profound deafness in adults and children. In addition these conclusions are not reflected in the final discussion (pages ) which accurately reflects the initial appraisal scope/remit, the initial decision problem and the evidence and (for children) relates effectiveness of CIs in the severe to profoundly deaf population. 3

4 3. Omission of data We would draw the Appraisal Committees attention to the omission, from the Assessment Report, of key data from a recent North American Trial. This data strongly supports the clinical efficacy of unilateral CI for adults with severe to profound deafness vs. hearing aids (pre-implant assessment of each subject included assessment in their best acoustic aided condition). While details of the study were provided (on an academic confidence basis) within the Cochlear Europe submission they do not appear to have been considered during PenTAGs review of the Cochlear submission. Furthermore while the study was published in early 2007 (Balkany et al. 2007) it was not identified during PenTAGs July update of their initial systematic review. Given its relevance to the appraisal in we strongly recommend that this study forms part of the evidence considered by the Appraisal Committee. A copy is attached for this purpose. 4. Cost Effectiveness As previously, mentioned the final remit of this appraisal is To appraise the clinical and cost effectiveness of cochlear implants in severe to profound deafness in children and adults. The PenTAG cost-utility analysis presented in the Assessment Report addresses the cost-effectiveness of cochlear implantation in adults and children with profound deafness only. In paragraph 7.7.4, PenTAG report that they were unable to find any reliable published estimates of the utility gain from cochlear implantation [ ] for severely deaf adults and children. We were also not able to identify published evidence of the utility gain for patients with severe to profound deafness receiving CIs. However, as noted above half the patients included in the PenTAG review had severe to profound deafness, and a substantial and consistent body of evidence reports statistically significant gains in speech perception and other hearing measures among these patients. A statistically significant correlation between change in speech perception after implantation and improvement in utility has also been reported (Francis et al., 2002). A mapping, combining these two data sources, was the basis of the estimated utility gain in patients with severe to profound deafness reported in the Cochlear Europe submission and is in adherence with NICE s Guide to the Methods of Technology Appraisal (Section ) which states: There are always likely to be deficiencies in the evidence base available for health technology assessment [ ] Despite such weaknesses in the evidence base, decisions still have to be made about the use of technologies. Therefore, analyses should use the best evidence available, be explicit about data limitations and any attempts to overcome these, and quantify as fully as possible how the limitations of the data are reflected in the uncertainty in the results of the analysis. We would challenge that the PenTAG cost-utility analysis does not address all the patients included in the decision problem and argue that the existence of a significant treatment effect and a published correlation between treatment effect and utility gain 4

5 offers a route to estimate utility gain in patients with severe to profound deafness. We contend that, although not ideal, estimating utility gain using such a mapping is more in keeping with the principles set out in section of the NICE Guide to the Methods of Technology Appraisal than the approach taken by PenTAG who makes no attempt to estimate utility gain in these patients. PenTAG have however recognised the value of mapping from speech perception to utilities including suggesting this as a future research question (Section 1.6.2, page 14 and Section , page 296). By not addressing all patients included within the decision problem we strongly contend that it would not be appropriate for the Appraisal Committee to deny patients with severe to profound deafness access to a clearly beneficial technology on grounds of cost-effectiveness, when the best evidence available to consider the costeffectiveness of the technology in this patient group has not been considered by the Assessment Group. In addition to these main comments further detailed comments from Cochlear Europe Limited are documented in the attached table. Yours sincerely, Brendan Murray Clinical Research Specialist Cochlear Europe Limited 5

6 Cochlear Europe Additional Comments on the PenTAG Assessment Report - Appraisal of cochlear implants for severe to profound deafness in children and adults Page Comments Executive Summary 1-2 As previously mentioned in the accompanying letter there is a high degree of inconsistency in terms of the patient population being studied e.g. 1.2 Objectives The purpose of the report, in line with the appraisal scope, is stated as being to assess the clinical and cost effectiveness of cochlear implants for children and adults with severe to profound sensorineural (i.e. abnormality of the cochlea or nerve pathways) hearing loss but PenTAG addressed this by answering to questions on the severely or profoundly deaf Clinical effectiveness systematic review Despite PenTAG devising two policy questions which relate to the severely or profoundly deaf the actual systematic review was conducted using the appraisal scope patient population e.g. those with severe to profound deafness. This inconsistency initiates from a misunderstanding of the classification of deafness. Further details are provided in our comments for Section 3.1, page Summary of cost effectiveness 11 Discussion The paragraphs discussing the Cochlear Europe model should be amended to include patients who were severely to profoundly deaf not just profoundly deaf. The limitation of the Assessment Groups conclusions to the profoundly deaf is perverse and not supported

7 by main body of evidence considered and analysed by PenTAG which considers cochlear implantation for severe to profound deafness in adults and children Strengths and limitations of the analyses and uncertainties 12 (and also page 294) We would challenge PenTAGs statement that the report is up to date on the basis that they have not included (nor listed as excluded) a study of unilateral CI for adults with severe to profound deafness vs. hearing aids (pre-implant assessment of each subject included assessment in their best acoustic aided condition). As stated in the accompanying letter details of the study were provided on an academic confidence basis within the Cochlear Europe submission. Furthermore while the study was published in early 2007 (Balkany et al. 2007) it was not identified during PenTAGs July update of their initial systematic review the paper. Given its relevance to the appraisal in we strongly recommend that this study forms part of the evidence considered by the Appraisal Committee. A copy is attached for this purpose Strengths and limitations of the analyses and uncertainties We would draw the Appraisals Committee attention to the statement The dislocation between assessing severity of deafness from measures of sensitivity to sound (the audiogram), as studies tend to report, from the level of functional hearing, means that these results should be interpreted as relating to those who are both profoundly deaf (AHL >95 db) and also have a low level of functional hearing when optimally acoustically aided". This statement does not consider those who are severely to profoundly deaf and have low levels of functional hearing (and who were included in many of the studies evaluated by PenTAG). We can understand the hesitation of the Assessment Group to overestimate efficacy but given that a high proportion of the subjects included in the report had a severe to profound hearing loss and the body of evidence reports statistically significant gains in speech perception and other hearing measures among these patients the current statement is misleading. In order to recognise this patient group the statement would benefit from the addition of the following text "The dislocation between assessing severity of deafness from measures of sensitivity to sound (the audiogram), as studies tend to report, from the level of functional hearing, means that these results should be interpreted as relating to those who are severely to profoundly deaf and also have a low level of 7

8 Section 2 - Background 32 Table 2: functional hearing when optimally acoustically aided". The last row for Cochlear UK should read Nucleus Freedom with either BTE and BWP option Section 3 Definition of the decision problem Decision Problem As already stated within the accompanying letter there is a high level of inconsistency in the patient population to be studied. This inconsistency initiates from a misunderstanding of the classification of deafness and PenTAGs development of the initial decision problem. Within the Decision Problem section of the report: The purpose of the report is stated as To assess the clinical and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults Two decision problems are defined for the severely and profoundly deaf population Finally the policy questions to be answered incorrectly relate to the severely or profoundly deaf population Each of these populations varies and it is only the severely to profoundly deaf population which is specified within the initial appraisal remit. 35 and 36 Following on from the comments made for page 34 (see row above) PenTAG continue to use different classifications defining the patient population as: then children and adults with severe to profound deafness (Page 35, Section Population including sub-groups) children and adults who have severe or profound deafness (Page 36, Section 3.2 Overall aims and 8

9 objectives of assessment) Section 4 Assessment of clinical effectiveness 46 Section Number and type of studies included Table 5 The figures for the total number of children and total groups are incorrect and should read 1532 and 2912 respectively Section 5 Systematic review of the evidence for children Summary Effectiveness of unilateral cochlear implants vs. non technical support children Overall conclusions In light of the evidence considered by PenTAG, of which half the study population (472 children) are severely to profoundly deaf, reaching conclusion for profoundly deaf children is perverse. Within the relevant effectiveness sections (pages 57 67) studies on both the profoundly deaf and severely to profoundly deaf are discussed with no distinction made between the studies and/or the results. In discussing the patient populations together in terms of effectiveness it is then perverse to single out the profound population without any justification. It is more perverse in light of the: Summary of clinical effectiveness section (page 114) which correctly reflects the evidence stating in point 6 that all studies irrespective of the patient population (severe to profound or just profound)... found in favour of sensitivity to sound outcomes, speech perception and speech understanding..of one cochlear implant over acoustic hearing aids or non-technological support and bilateral implants over unilateral implants with or without a contralateral acoustic hearing aid. Discussion (page 283) which reflects the initial appraisal remit population, the initial decision problem and the data considered and states The review of clinical effectiveness studies for children indicates that unilateral implantation in severely to profoundly deaf children consistently produces better outcomes than acoustic hearing aids or non technological support... 9

10 Summary of quality of life studies - children As above, in light of the evidence considered by PenTAG the statement The results show that in comparison to pre-implantation, cochlear implants improved children s quality of life and that profoundly deaf children with cochlear implants has a higher parent-rated quality of life than those without is perverse. At least 2 of the 4 studies considered were assumed (by PenTAG) to include patients with severe or profoundly deafness and at no point during the analysis did PenTAG distinguish between the two groups. To then limit their conclusion to the profoundly deaf alone is perverse and at odds to the data considered. Section 6 Systematic review of the evidence for adults 118 Section Type and quality of studies Table 36 The Mawman et al and Parkinson et al studies included patients with post lingual severe to profound hearing not severe or profound alone Summary: Unilateral cochlear implants vs. non technical support - adults Overall conclusions Restricted the conclusion to profoundly deaf adults alone is perverse in light of the evidence considered. Within the relevant effectiveness sections (pages ) studies on both the profoundly deaf alone and severely to profoundly deaf are discussed with no distinction made between the studies and/or the results, with the exception of duration of deafness. In discussing the patient populations together it then seems perverse to single out the profound population without any justification. 164 Summary of adults studies of clinical effectiveness For accuracy point 1 should read There were 1275 adults who were severely to profoundly or profoundly deaf, with ages ranging from years. Section 7 Assessment of cost-effectiveness 10

11 Cost effectiveness analyses from Cochlear Europe Ltd The Assessment Report notes correctly that the costs related to assessment of patients referred but not implanted were not included in the Cochlear Europe model. Figure 10 on page 222 of the Assessment Report however suggests that the contribution of the cost of screening individuals who were not subsequently implanted to the overall expected cost per patient is very small. We suspect that, due to this structural difference, the PenTAG model reports costs and outcomes per patient screened, not cost per patient implanted, which may explain part of the lower expected cost per patient in the PenTAG model when compared to manufacturer submissions reported in Tables (pages ). Initial inspection of the model suggests that this is the case Cost effectiveness analyses from Cochlear Europe Ltd Estimation of utility gains In reviewing the economic model submitted by Cochlear Europe PenTAG describes the use of the correlation reported in Frances et al as most questionable. We note in our accompanying letter that this method of estimating utility gain in patients with severe to profound deafness is not ideal, but contend that it is more in keeping with the principles set out in the Institutes Guide Methods of Technology Appraisal than the current Assessment Report, which makes no attempt to estimate utility gain in these patients. In the estimation of utility gains the Assessment Report contains inaccuracies: 1. The best line fit in the Cochlear Europe analysis uses the monosyllabic words test, not CID sentences as stated. 2. The line of best fit for monosyllabic words was an increase of 0.73 in utility associated with a 100% increase in speech perception, not 0.47 as stated 3. The sample size Francis et al. was 47: we are unable to identify the source of the statement in the Assessment Report that the sample size was 22. The sample size was in any case sufficient to demonstrate a statistically significant correlation between the change in monosyllabic word test and 11

12 the change in utility (P<0.005, Francis et al. Figure 2) Cost of treatment failures (& Appendix 10) The base case used the in Cochlear Europe model assumed that the proportion of failures receiving subsequent implants was zero, an assumption the Assessment Report described as highly implausible. In the Cochlear Europe model these patients also receive no benefit from the failed implant. In sensitivity analyses presented in the submission the proportions of re-implanted patients after failure were varied between 0 and 100% and the impact on cost-effectiveness was small. See Appendix 9 of the Cochlear Europe submission Failure and replacement of Cochlear Implant internal components In considering reliability of CIs PenTAG pooled reliability data from Conboy et al. (n=377) with data from the Cochlear Europe submission (n>60,000). Although considerable effort has been exerted pooling data from different devices, the pooling of such data has ignored clear differences between devices in failure rates. More modern devices are associated with substantially better cumulative survival as technology improves (See Figures 4 and 5, pages 170 and 171). Section 9 Results of cost-effectiveness in pre-lingually implanted profoundly deaf children 241 & Analysis of uncertainty Figure 28 (page 241) and Threshold Analysis Figure 49 (page 265) PenTAG reports the cost per QALY for different implant systems in bilateral implantation in Figures 28 and 49. However, the calculations are based on pooled assessment of the effectiveness, reliability and adverse events for the different systems. If the objective of the analysis was to compare different devices, it would have been necessary to separately assess effectiveness and reliability for each device. This was not done and as a consequence these figures are misleading and should not be considered by the Appraisal Committee. Section 10 - Results of cost-effectiveness in adults 12

13 Comparison of industry-submission with PenTAG cost-utility analyses Table 111 While the table heading refers to profoundly deaf children alone it should be noted that the Cochlear model considered severely to profoundly deaf children Absence of Budget Impact Section 12 - Discussion The NICE remit requested a budget impact analysis, which was absent from the Assessment Report Summary of industry-submitted economic evaluation Table 115 While the table considers profoundly deaf children alone it should be noted that the Cochlear model considered severely to profoundly deaf children PenTAG health economic model Model We were unable to fully review the economic model as it was not provided until 26 October The model was briefly reviewed on 29 October for final comments. 13

14 References Aschendorff A, Klenzner T, Laszig R Deafness after bacterial meningitis: an emergency for early imaging and cochlear implant surgery. Otolaryngology - Head & Neck Surgery. 2005; 133(6): Balkany T, Hodges A, Menapace C, et al. Nucleus Freedom North American Clinical Trial. Otolaryngology - Head & Neck Surgery 2007; 136: British Society of Audiology recommendations. Descriptors for pure-tone audiograms. British Journal of Audiology 1988; 22:123. Conboy PJ, Gibbin KP. Paediatric cochlear implant durability: The Nottingham experience. Cochlear Implants International 2004; 5(4): Dodds A, Tyszkiewicz, Ramsden R. Cochlear implantation after bacterial meningitis: the dangers of delay. Archives of Disease in Childhood 1997; 76 (02): Francis HW, Chee N, Yeagle J, Cheng A, Niparko JK. Impact of cochlear implants on the functional health status of older adults. Laryngoscope 2002; 112(8 Pt 1): Green DS. J. Chapter 5 Pure Tone Thresholds In Katz, Ed., Handbook of Clinical Audiology. Pages Williams and Wilkins Baltimore,MD Mawman DJ, Bhatt YM, Green KMJ, O'Driscoll MP, Saeed SR, Ramsden RT. Trends and outcomes in the Manchester adult cochlear implant series. Clinical Otolaryngology 2004; 29(4): National Institute for Health and Clinical Excellence. Guide to the Methods of Technology Appraisal London, NICE. Parkinson AJ, Arcaroli J, Staller SJ, Arndt PL, Cosgriff A, Ebinger K. The nucleus 24 contour cochlear implant system: adult clinical trial results. Ear & Hearing 2002; 23(1 Suppl):41S-48S. Young NM, Hughes CA, Byrd SE, Darling C.. Postmeningitic ossification in pediatric cochlear implantation. Otolaryngology - Head & Neck Surgery. 200;122(2): i BAA- British Academy of Audiology, BCIG British Cochlear Implant Group, ENT UK British Association of Otorhinolaryngologists