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Picot J, Cooper K, Bryant J, et al. The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Dec. (Health Technology Assessment, No. 15.41.)

Appendix 7SHTAC data summary of manufacturers' submissions of clinical effectiveness

SHTAC peer review of clinical effectiveness in Celgene's submission for bortezomib and thalidomide for MM

Comprehensiveness of ascertainment of published studies

Clinical effectiveness

  • The MS contains a narrative summary of trials, with the methods and results of each trial presented separately. Tabulation of details on study design and methodology, baseline characteristic of participants, efficacy outcomes, subgroups, second-line therapy, and AEs is presented in Appendix 2 of the MS (pp. 134–9).
  • There is no formal systematic review of clinical effectiveness evidence in the main body of the MS. However, a systematic review was conducted to identify clinical effectiveness evidence for the Bayesian meta-analysis that is reported in Appendix 4 of the MS, which was presented as a separate document.

    Were databases and dates of searches specified?

    Appendix 4 of the MS clearly reports search dates, search strategies and databases searched.

    Were search strategies supplied?

    Yes.

    Was enough detail provided to be reproducible?

    Sufficient detail was provided in Appendix 4 of the MS for the searches to be reproducible.

    Did they search/report on ongoing studies?

    No searches for ongoing studies are reported.

    Did they search for conference proceedings?

    Conference proceedings were included in the searching.

    How much of the data is CIC/AIC?

    The submission contains little CIC information and no AIC information. CIC information is located only on p. 54 and pp. 84–6 of the submission and all relates to the same clinical study report (CSR).

Cost-effectiveness

The MS economic evaluation section states that a literature search was conducted to identify cost-effectiveness models, but no search strategy is presented. There does not appear to have been a search for QoL data.

Searches identified

The systematic review conducted as part of the MTC and reported in Appendix 4 included the following RCTs (the references are as cited in Celgene's submission116):

  • IFM 99/06 (Facon 2007 and Facon 2004 abstract); IFM 01/01 (Hulin 2009, three Hulin 2007 abstracts); GIMEMA (Palumbo 2008, Palumbo 2006, and Palumbo abstracts of 2004–8); Nordic study (Gulbransen 2008 abstract, Waage 2007 abstract, and Nordic Myeloma Study Group PowerPoint slide presentation 2009); HOVON 49 (two Wijermans 2008 abstracts, Wijermans 2008 ASH PowerPoint presentation ‘Final analysis. The HOVON 49 study’); VISTA (San Miguel 2008, San Miguel 2008 abstracts, San Miguel 2007 abstract; Palumbo 2008 abstract; Harousseau 2008 abstract). The studies identified in the systematic review are the same as those reported on in the main submission document. The submission document also recognises the Myeloma IX study is ongoing but the study was not included as complete data were not available.
  • What study types (X RCTs, X cohort studies, etc.)?

    The included studies were RCTs.

  • Did any meet our inclusion criteria that we have not already included?

    The identified studies published as full papers (IFM 99/06, IFM 01/01, GIMEMA and VISTA) are included in the SHTAC systematic review. As the GIMEMA study included maintenance therapy with thalidomide, the SHTAC review only includes outcomes reported for the period prior to the start of maintenance therapy. SHTAC also identified abstracts reporting on the Nordic myeloma group study, and the HOVON 49 study but the powerpoint presentations had not been identified. Owing to the limited reporting of methodological details and outcome data these studies were not included in the SHTAC systematic review but have been briefly mentioned as ongoing studies.

Clinical analysis

  • Any major differences in evidence reported?

    The MS includes a narrative summary for individual trials, with tabulation of the studies' characteristics and results located in MS Appendix 2. There was no quality assessment of the trials. AEs are also presented separately for each trial.

  • Are their conclusions are similar to ours?

    Although the Celgene MS (but not the MTC) included the OS outcome from Palumbo and colleagues,24 which SHTAC excluded due to the use of thalidomide maintenance treatment in the MPT arm, the conclusions (based on narrative summary) on the clinical effectiveness of MPT and VMP are broadly similar. MPT and VMP treatments both show better OS and PFS than MP. The conclusions from the MS MTC were the same. A summary statement on response outcomes from the included trials is not provided. The MS presents an indirect comparison (as noted below), which suggests that MPT provides better PFS outcomes than VMP at 6, 12 and 18 months but the credibility intervals cross 1. The MS finds subgroup data variable and insufficient, so no conclusions have been drawn.

  • Any indirect comparisons?

    The MS included an indirect comparison to enable comparison of MPT and VMP as there are no head-to-head trials for this comparison. Not all of the studies identified by the systematic review were included in the meta-analysis and indirect comparison. The base case excluded the GIMEMA trial (on the basis of a different regimen of thalidomide not consistent with the label, and due to cross over to thalidomide in the MP arm after disease progression), and the Nordic and HOVON 49 trials (insufficient information in abstracts for meta-analysis). These three studies were included in a sensitivity analysis (using information from slide presentations for Nordic and HOVON 49 trials).

  • Any differences in outcome measures?

    The MS reports on the same outcome measures as the SHTAC review. Outcome data were not reported from the studies included in the systematic review presented in MS Appendix 4.

  • Any extra AE info?

    Adverse event information was restricted to that reported in trial publications.

Interpretation

  • Does their interpretation of the clinical data match their analyses?

    Limited analyses in main MS document (mainly just narrative summary) but where analyses are presented, for example MTC, the interpretation of the clinical data broadly matches these.

Questions

  • Any areas of uncertainty/discrepancy compared with the SHTAC review?

    The MS presents a narrative summary of the Palumbo and colleagues24 study as well as the Nordic and HOVON 49 trials (as cited in Celgene's submission116), which have been reported only in abstract form. However, these three studies were not included in the base-case MTC, and therefore the data in the base-case MTC more closely match the data included in the SHTAC review.

    The SHTAC excluded most of the data from Palumbo and colleagues24 because participants in the MPT group received thalidomide maintenance therapy. In contrast, this study was excluded from the MS MTC because the thalidomide regimen was inconsistent with the label and because participants could cross over to thalidomide at disease progression. SHTAC do not believe that on this latter point the study differs substantially from the IFM trials,23,59 where participants received treatment after disease progression that could include thalidomide, and where a greater proportion of participants in the MP groups received thalidomide at this point than in the MPT group.

SHTAC peer review of clinical effectiveness in Janssen–Cilag's submission for bortezomib and thalidomide for MM

Comprehensiveness of ascertainment of published studies

Clinical effectiveness

The MS contains a systematic review of clinical effectiveness evidence in the main body of the report. Summary details on trial size, interventions, inclusion criteria, efficacy end points, and duration of treatment are tabulated. Trials were critically appraised. Results from the included studies were tabulated.

  • Were databases and dates of searches specified?

    The MS briefly summarises the searches and clearly reports search dates, search strategies and databases searched in Appendix 1. Searches were conducted in two phases, before and after the finalisation of the scope of the appraisal.

  • Were search strategies supplied?

    Yes.

  • Was enough detail provided to be reproducible?

    Sufficient detail was provided for the searches to be reproduced.

  • Did they search/report on ongoing studies?

    No searches for ongoing studies are reported.

  • Did they search for conference proceedings?

    Conference proceedings were included in the searching.

  • How much of the data is CIC/AIC?

    The submission contains both CIC and AIC information. CIC data appears on the following pages: 32–4; 60; 61; 67; 70; Appendix 4 (from VISTA); References: all three clinical study reports (J&J, Velcade CSR 1, CSR 2, CSR 3). AIC data appears on pages 2; 3; 33–6; 40–41; 43–47; 59–60; 66; Appendices 7, 8 and 11.

Cost-effectiveness

A review of economic evaluations was conducted, reported in detail in Appendix 9. The review sought to identify any economic evaluations and resource use studies assessing the first-line therapy of patients with MM with regimens included in the NICE scope, as well as others, for example VAD that did not form part of the final scope. The review included studies assessing first-line chemotherapy regimens but also included induction/mobilisation regimens prior to transplantation. Appendix 9 reports on 30 studies, but the MS states that none of these cost-effectiveness studies included bortezomib-based regimens in the patient group of interest. There does not appear to have been a search for QoL data.

Searches identified

The systematic review included the following RCTs:

  • VMP versus MP VISTA (Dimopoulos et al. 2008;112 Harousseau et al. 2008;113 San Miguel et al. 2008;60 San Miguel et al. 2008;114 San Miguel et al. 200826).
  • MPT versus MP IFM 99/06 (Facon et al. 200723); GIMEMA [Palumbo et al. 2006 (not in MS reference list, presume24) and 200825]; IFM 01/01 (Hulin et al. 200959); HOVON 49 (Wijermans et al. 200864); Gulbrandsen et al. 2008 (Gulbrandsen et al. 200866)].
  • MP versus CTDa (maintenance treatment: thalidomide only) MRC Myeloma IX study (non-intensive arm) (Owen 2009; Morgan 2009, not in MS reference list).
  • What study types (X RCTs, X cohort studies, etc.)?

    The included studies were RCTs.

  • Did any meet our inclusion criteria which we have not already included?

    The identified studies published as full papers (IFM 99/06, IFM 01/01, GIMEMA, and VISTA) are included in the SHTAC systematic review. As the GIMEMA study included maintenance therapy with thalidomide the SHTAC review only includes outcomes reported for the period prior to the start of maintenance therapy. SHTAC also identified abstracts reporting on the Nordic myeloma group study (Gulbrandsen), and the HOVON 49 study. Due to the limited reporting of methodological details and outcome data these studies were not included in the SHTAC systematic review but have been briefly mentioned as ongoing studies. Abstracts for the MRC Myeloma IX study were identified, but not the two cited by the MS, the second of which is not referenced in the MS.

Clinical analysis

  • Any major differences in evidence reported?

    The MS includes a narrative summary and tabulation of the studies' characteristics. The main efficacy results are very briefly summarised and tabulated. Trials were subject to critical appraisal using a modification of the CONSORT Assessment Framework. The VISTA study is additionally presented in more detail including some data that is not in the public domain. A small amount of non-RCT evidence from Phase I/II trials of bortezomib is presented.

  • Are their conclusions are similar to ours?

    Although the Janssen–Cilag MS systematic review included more studies than SHTAC, the conclusions (based on narrative summary) on the clinical effectiveness of MPT and VMP are broadly similar. The results from meta-analysis and indirect comparison are more difficult to compare with the SHTAC results because of additional data used in the MS and the different methodology (MS winbugs MTC, SHTAC pairwise meta-analysis). For the comparisons of MPT versus MP and MPV versus MP the direction of the overall effect is the same, although the magnitude differs. It appears that the MS MTC indicates a greater difference in effect in favour of MPV over MPT than the SHTAC pairwise estimates suggest.

  • Any indirect comparisons?

    The MS included an indirect comparison to enable comparison of MPT and VMP as there are no head-to-head trials for this comparison. The studies identified by the systematic review were included and, in addition, unpublished updated survival data from the VISTA trial were also included in the meta-analysis and indirect comparison.

  • Any differences in outcome measures?

    The MS reports on the same outcome measures as the SHTAC review.

  • Any extra AE info?

    Adverse event information was restricted to that reported in trial publications.

Interpretation

  • Does their interpretation of the clinical data match their analyses?

    The interpretation of clinical data appears to match the analyses that have been undertaken.

Questions

  • Any areas of uncertainty/discrepancy compared with the SHTAC review?

    The MS has included final data from the Palumbo and colleagues24 study, which SHTAC did not include, as well as the Nordic and HOVON 49 trials, which have only been reported in abstract form and were therefore not included by SHTAC (with the HOVON 49 trial designated ‘unclear’ because of the use of thalidomide maintenance therapy). The impact of including these studies within the MTC presented by the MS is uncertain and SHTAC cannot determine what the outcomes would have been had these data been excluded from the MTC.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation
The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.41.
Picot J, Cooper K, Bryant J, et al.
Southampton (UK): NIHR Journals Library; 2011 Dec.

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