Adjunctive colposcopy technologies for examination of the uterine cervix DySIS, LuViva Advanced Cervical Scan and Niris Imaging System

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1 Appendix 9 Further LuViva analysis Following several requests for clarification and extra information Guided Therapeutics provided two tables on the accuracy of LuViva and colposcopy (personal correspondence with Guided Therapeutics (04/02/12)). One provided data on colposcopic accuracy at a CIN2+ cut-off conditional on the LuViva result where LuViva also had a CIN2+ cut-off (Table A9.1). The other had data on colposcopic accuracy at a CIN2+ cut-off conditional on the LuViva result where LuViva had a CIN1+ cut-off. However, the data provided in these tables contradict one another (for example, LuViva appeared to have a lower sensitivity and higher specificity when the cut-off was CIN1+ than at CIN2+ where sensitivity and specificity was calculated based on histological findings based on CIN2+); given the limited time available we were unable to clarify this with the manufacturer. Despite this, in an attempt to inform the committee, we have used the data based on a LuViva CIN2+ cut-off (presented in the table below) in the cost-effectiveness model which matches the results presented in Section of the main report, although it should be emphasised that major concerns exist regarding the quality of these data (Section ). Table A9.1 LuViva data based on a CIN2+ cut-off Histology CIN2+ Histology Clear or CIN1 LUVIVA (0 threshold) Positive (CIN2+) Negative (CIN2+) positive (CIN2+) (CIN2+) positive (CIN2+) (CIN2+) ** *** * ** ** *** ** *** The authors of the LuViva study stated that the study evaluated the potential of the new technology to effectively triage women at risk for moderate and high grade dysplasia rather than as an adjunct to colposcopy as in the scope for this assessment, although the reporting in the study is not clear. Therefore, in this analysis LuViva was tested using different scenarios: 1

2 i) as a triage to colposcopy; and ii) as a stand-alone replacement for colposcopy. Using LuViva as triage suggests that only patients with positive findings on LuViva would have a colposcopy, but treatment decisions would be based only on the colposcopic and cytological findings (hereby referred to as the LuViva triage analysis). Using LuViva instead of colposcopy suggests patients' treatment can be determined using only LuViva, although colposcopy may be required for biopsy treatment (hereby referred to as the LuViva alone analysis). Given that, in the study, LuViva uses a cut-off of CIN2+ to send patients to colposcopy, it is unclear how this would work in UK practice, where management guidelines are different for patients who are found to be clear or CIN1 at colposcopy. However, for simplicity and for consistency with the other analyses contained in this report, we have assumed that sensitivity and specificity determine the probability of being identified as a particular type of patient and, therefore, on treatment allocation in the same way as for the other devices (i.e. through the use of the Gallwas et al. data). We have also assumed that LuViva and any subsequent colposcopy would be performed at the same appointment; therefore, whether a patient continues on from LuViva to a colposcopy does not impact on the cost. Table A9.2 reports the accuracy statistics based on the data from Table A9.1. Table A9.2 Sensitivities and specificities from LuViva data Parameter Value Sensitivity of LuViva ******** Specificity of LuViva ******** Sensitivity of colposcopy following LuViva at cut-off of CIN2 ******** Specificity of colposcopy following LuViva at cut-off of CIN2 ******** Sensitivity of colposcopy alone ******* Specificity of colposcopy alone ******* For the triage analysis, sensitivities and specificities for the entire diagnostic pathway (LuViva followed by colposcopy when LuViva is positive) have to be calculated based on a 2

3 two stage process. The figures below represent this diagnostic pathway for a patient with CIN2+ (Figure A9.1) and for a patient with CIN1 or less (Figure A9.2). Figure A9.1 Diagnosis of CIN2+ with LuViva P3 positive Luviva P1 P4 False positive patient (CIN2+) P2 False Figure A9.2 Diagnosis of CIN1 or less with LuViva P7 False positive Luviva P5 P8 Negative patient (CIN1 or less) P6 Therefore, the overall sensitivity of the pathway (LuViva followed by colposcopy) is equal to the sensitivity of LuViva multiplied by the sensitivity of colposcopy conditional on a positive 3

4 LuViva result (P1*P3), whilst the specificity of the pathway is equal to the specificity of LuViva (P6) and (1 specificity of LuViva) multiplied by the specificity of colposcopy conditional on a false positive LuViva result (P5*P7). Table A9.3 presents the sensitivity and specificity of the LuViva treatment pathway and the comparator colposcopy alone arm which have been used in the triage analysis. The sensitivity and specificity of LuViva alone are reported in Table A9.2 and are those used in the analysis of LuViva alone versus colposcopy. Table A9.3 Sensitivities and specificities for the model Parameter Value Sensitivity of LuViva diagnostic pathway ******** Specificity of LuViva diagnostic pathway ******* Sensitivity of colposcopy alone ******* Specificity of colposcopy alone ******* All analyses were run using the base case assumptions described in Section 4.5. Results The results of the triage analysis for the different reasons for referral and the overall population are presented in Table A9.4. As can be seen from the results, LuViva is dominated when used as triage in all reasons for referral; that is colposcopy is less costly and more effective than LuViva. The results of the LuViva alone analysis for the different reasons for referral and the overall population are presented in Table A9.5. As can be seen from the results, LuViva dominates in all reasons for referral; that is LuViva is less costly and more effective than colposcopy. Discussion In the study provided by the manufacturers it appears that LuViva was tested as a triage to colposcopy, although it is unclear. Other options are available for the use of LuViva. It may be that some combination of the LuViva and colposcopy results provides the best accuracy, 4

5 or that LuViva will be helpful in locating the most appropriate areas for biopsy or treatment. Nevertheless, from the information available, it appears unclear how LuViva should be used, and how its use should affect treatment decisions. Therefore, a second analysis was undertaken to test the cost-effectiveness of LuViva alone versus colposcopy. It is also unclear from the study how patients reported as by LuViva should be treated. In the analyses, we assumed that patients found by LuViva would be identified as either clear or CIN1 in the same proportion as was found in the Gallwas et al. study, and then treated following clinical guidelines based on their reason for referral and whether they were clear or CIN1. Conclusions No conclusions on the cost-effectiveness of LuViva can be drawn from this analysis without knowing the intended method of use in clinical practice. However, there is also major uncertainty regarding the data which are considered unreliable (Section ). 5

6 for Health and Clinical Excellence - Diagnostics Assessment Report Table A9.4 Results for LuViva triage analysis Reasons for referral Borderline + HPV Mild + HPV Moderate Severe vs. LuViva alone ********* ******** ********* ******* ********* ******* ********* ******* LuViva diagnostic pathway ********* ******** ********* ********* ******* ********* ********* ******* ********* ********* ******* ******** Reasons for referral Possible invasion Possible neoplasia 3 x Inadequate Whole population vs. LuViva alone ********* ******** ********* ******* ******* ******* ********* ******* LuViva diagnostic pathway ********* ******** ********* ********* ******* ********* ******* ******* ********* ********* ******* ******** Table A9.5 Results for LuViva alone analysis Reasons for referral Borderline + HPV Mild + HPV Moderate Severe vs. LuViva ********* ******** ********* ******** ********* ******** ********* ******** LuViva ********* ******** ******** ********* ******** ******** ********* ******** ******** ********* ******** ****** Reasons for referral Possible invasion Possible neoplasia 3 x Inadequate Whole population vs. LuViva ********* ******** ********* ******** ******* ******** ********* ******** LuViva ********* ******** ******* ********* ******** ********* ******* ******** ********* ********* ******** ****** 6