Rivaroxaban for the treatment of deep vein thrombosis and ...

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Appendix 4 Reproduction of Section D of the manufacturer’s clarifications – textual and additional clarifications. D1. Please clarify whether the references to sections 2.9 and 2.10 in section 2.12 are correct, as these sections do not seem to reference appropriate sources of data to answer the question posed by section 2.12 (page 25). Section 2.12 asks for references to support the advantages for rivaroxaban described in previous sections. The draft SmPCs for rivaroxaban (references 2-3) are key references, which describe the circumstances in which rivaroxaban should be delivered to patients to whom it is prescribed. Also relevant are the SmPCs for the LMWHs (37, 39, 40, 41), warfarin (87) and fondaparinux (89), and the PILs (88, 90, 91), which describe the administration requirements and extensive contraindications associated with the current standard of care. Safety issues in relation to LMWH and warfarin have been discussed in references 7, 10 and 13. Increased treatment satisfaction with rivaroxaban in comparison to LMWH/VKA is supported by an analysis described in reference 18. D2. Please confirm that the sentence ‘from these 687 were excluded...’ should read ‘from these, 683 were excluded..’ to match Figure 2 (page 30, section 5.2.2) We confirm that the sentence should read `from these, 683 were excluded’. D3. Please clarify the asterisk attached to the statement ‘treatment period 3, 6, or 12 months’ on page 37, Figure 3. In the internal diagram from which Figure 3 was taken, the asterisk refers to a footnote which describes the selection of treatment duration by investigators, as described elsewhere in the submission (for example in Table 9, page 39). D4. Page 42, states that 53% of patients in EINSTEIN-EXT had participated in EINSTEIN-DVT. However, the figure on Page 38 suggests this figure is 34%. Note that the numbers quoted in Figure 6 (page 51) suggest 53% is the correct value. Please clarify. The study identification numbers within Bayer of EINSTEIN-DVT and EINSTEIN- PE studies are both 11702, and this appears to be associated with some confusion. Figure 4 on page 38 of the submission correctly states the source of patients in EINSTEIN-Ext. This Figure corresponds with the NEJM article, 16 which states: From February 2007 through March 2009, a total of 1197 patients were enrolled in the Continued Treatment Study. Of these patients, 34.1% had completed the Acute DVT Study and 19.1% had completed the Acute PE (Pulmonary Embolism) Study of the EINSTEIN program; the remaining 560 patients (47.5%) were referred from outside both these studies (Fig. 1B). 177 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
A bullet on page 42 states that `53.0% had participated in EINSTEIN-DVT’. This should more accurately read `53.2% had participated in EINSTEIN-DVT/PE’. Figure 6 (the CONSORT flow diagram for EINSTEIN-Ext) on page 51 states that 632 of the 1197 randomised patients were from study 11702 and a further 5 randomised patients had pre-treatment both in and outside study 11702. In total therefore, 637 of 1197 randomised patients, or 53.2%, had at least some pre-treatment in EINSTEIN- DVT or EINSTEIN-PE. See also B11. D5. Table 15 (Page 45) defines “Treatment emergent AEs”, which are not referred to in table 14. Table 14 uses “other adverse events” and “adverse events”. Please clarify the definitions of adverse events by defining the two categories used in table 14. Please note that Table 14 on page 44 is a summary of the outcomes measured and their categorisation as primary, secondary etc. The `other’ in `other adverse events (AEs)’ in column 2 refers merely to the various adverse events monitored in this study besides the safety related endpoints listed above that bullet (vascular events, all cause mortality). We can understand why the bullet may be interpreted in another way, but the intention of this bullet was simply to highlight that there were other outcomes, relating to safety, that were measured and collected in EINSTEIN-DVT besides those already stated. The protocols for EINSTEIN-DVT and EINSTEIN-Ext contain the following identical wording in relation to safety outcomes: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxx This protocol definition of treatment-emergent AEs is reflected in Table 15 of the submission. Therefore we could consider the existing format of presentation of AE data in Table 29 and 30 on pages 81-82 of the submission to be appropriate. D6. Please confirm that the asterisk in the boxes listing ‘excluded from PP’ refer to footnote e and f for the treatment arm and comparator arm, respectively (page 50, Figure 5). We confirm that this is the case. The asterisk aside `n=29 intake of strong CYP3A4 inducer’ refers to footnote e. The asterisk aside `n=21 wrong intake of medication’ refers to footnote f. D7. Unexpected imbalances between drop-outs have been scored “no”. Please clarify why this has been scored “no”, when data in figure 5 (p50) suggest otherwise (total end of study medication (EOSM) in treatment arm = 298, total EOSM in comparator arm = 338. Specifically, withdrawal of consent is very different between groups). Have failure to comply and withdrawal of consent been combined? It is true that fewer patients, both in absolute number and proportionally, withdrew in the rivaroxaban arm than in the comparator arm (298 vs 338, 17.2% vs 19.7%). Put another way, patients randomised to rivaroxaban appeared to have greater adherence 178 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
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Rivaroxaban for the treatment of de
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TABLE OF CONTENTS List of Abbreviat
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Table 12 Time to therapeutic INR (I
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identified in the model). Table 40
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Figures Figure 1 Flow diagram for i
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Figure 23 Exploratory analysis in c
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MS Manufacturer’s submission NE S
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The dose of LMWH used reflects Amer
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The exploratory analysis in cancer
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intended treatment duration of 12 m
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VTE therefore has a substantial bur
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indefinite treatment. VTE LMWH, low
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3 Critique of manufacturer’s defi
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Subgroups to be considered Special
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contraindications for the drug (as
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3.1.3 MTC populations The populatio
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3.2.2 Length of treatment As discus
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“No preventative therapy” is th
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It could be argued that poor TTR ma
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3.4.2 Outcomes recommended by EMA r
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4 CLINICAL EFFECTIVENESS 4.1 Critiq
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competitor products were excluded f
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Figure 1 Flow diagram for identifyi
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Table 7: Table showing list of rele
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The approach taken to quality asses
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o EINSTEIN-DVT dose-ranging study 3
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Trial name References, study type E
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4.2.1 Critique of pivotal EINSTEIN-
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However, the study design did not i
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Table 10: Summary of outcomes for E
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Chi-square analyses were undertaken
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clarification on this matter, the m
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Both of these factors are likely to
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It remains unclear why these patien
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leeding may be less suited to longe
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may account for the apparent differ
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Table 13: Criteria used to define a
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DVT and/or PE xxxxxxxxx xxxxxxxxxxx
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There is some doubt about the appro
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Subgroup analyses - EINSTEIN-Ext Su
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o It is clear that bleed events wer
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is likely to be small as the outcom
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depends on the specific parameteris
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4.4.3 Between study standard deviat
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Table 19.2: VTE recurrence (dichoto
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Table 22 Uncertainties in clinical
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The ERG are of the understanding th
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For the primary analysis, the rates
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In the economic model, the manufact
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Finally, in cancer patients, the ma
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Our experts believed that patients
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Similarly, the manufacturer used da
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Table 25: baseline risk of events f
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y intended treatment duration given
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eflect the current long term risk o
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survival of 70% in the 148 non-surg
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Monitoring xxxxxxxxxxxxxxxxxxxxxxxx
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The ERG acknowledges that the monit
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For patients managed in the inpatie
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The searches identified 2,811 poten
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The health state utility value for
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few occasions for both VTEs and ble
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2) the values used in the PSA for t
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5.2.1 Results included in the manuf
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Figure 8: Tornado plot - Net Moneta
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5.2.2.1.2. Results for patients for
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Page 139 and 140: Figure 14: Tornado plot - Net Monet
Page 141 and 142: 5.2.2.2 Subgroup analysis - cancer
Page 143 and 144: Figure 17: Tornado plot - Net Monet
Page 145 and 146: 5.2.3 Comment on validity of result
Page 147 and 148: Table 36: Summary of uncertainties
Page 149 and 150: Summary of uncertainties Has the im
Page 155 and 156: Superseded - See Erratum 6. ADDITIO
Page 157 and 158: Superseded - See Erratum Table 37 S
Page 159 and 160: Superseded - See Erratum Table 38:
Page 163 and 164: Superseded - See Erratum Figure 21:
Page 167 and 168: Superseded - See Erratum 6.3. Proba
Page 173 and 174: 6.5. Exploratory analysis in cancer
Page 175 and 176: Figure 23: Exploratory analysis in
Page 177 and 178: Table 60: Deterministic base case a
Page 179 and 180: The ERG also examined the impact of
Page 181 and 182: days after stopping treatment.(Bull
Page 183 and 184: Both Phase II studies performed ana
Page 185 and 186: Appendix 2 Correction of Tables 29
Page 187: Appendix 3 Definition of `sufficien
Page 191 and 192: Both numbers refer to the placebo a
Page 193 and 194: 9. REFERENCES 1. Bayer PLC. Rivarox
Page 195 and 196: http://www.dh.gov.uk/en/Publication
Page 197 and 198: 51. Department of Health. NHS Refer
Page 199: 77. NICE Guidance. Atrial fibrillat
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