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NICE guidance on sorafenib for treating advanced hepatocellular carcinoma
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NICE guidance on sorafenib for treating advanced hepatocellular carcinoma On Sept 6, 2017, the UK National Institute of Health and Care Excellence (NICE) published guidance that recommends sorafenib (Bayer PLC; Reading, UK), as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade A liver impairment, and only if the manufacturing company provides sorafenib within the agreed commercial access arrangement.1 The appraisal committee’s remit was to assess the clinical and cost effectiveness of sorafenib for advanced hepatocellular carcinoma compared with standard National Health Service (NHS) care. NICE appraised sorafenib, an oral multikinase inhibitor, first in 2009, and then again in 2016 when reconsidering drugs paid for by the Cancer Drugs Fund in England.2 When NICE originally appraised sorafenib, the committee met four times to review the evidence provided by Bayer, the manufacturer, and the critique of Bayer’s submission by the West Midlands Health Technology Assessment Collaboration, the evidence review group (ERG). The evidence centred around one trial, SHARP, 3 designed to compare 400 mg of sorafenib twice daily with best supportive care against placebo with best supportive care in patients with Child-Pugh liver function grade A, with the primary endpoints being time to death or to symptomatic progression. The committee noted that SHARP had shown that sorafenib increased median survival by more than 2·8 months compared with placebo, yet, at the price the company had set, sorafenib was not a good use of limited NHS resources. Thus, the committee did not recommend sorafenib. Bayer appealed the decision, and an appeal panel dismissed all the points. Because NICE issued final guidance not recommending sorafenib,4 it was provided in England
by the Cancer Drug Fund rather than by routine NHS commissioning. To permit the committee to reconsider sorafenib, Bayer submitted additional evidence to support its clinical and cost effectiveness. The committee met three times accompanied by clinical experts, representatives from Bayer, the ERG (NICE Decision Support Unit, University of Sheffield) and the public. The committee concluded that doxorubicin, local resection, ablation using radiofrequency, and chemoembolisation were not usual treatment for first-line treatment of advanced hepatocellular carcinoma, and that best supportive care was still the only relevant treatment with which to compare sorafenib. The committee recognised that between 2010 and 2016, there were no new comparators available for first-line treatment of hepatocellular carcinoma in the NHS, no new randomised controlled trial comparing sorafenib with best supportive care, and no further analyses of SHARP reflecting longer follow-up. For the committee’s first meeting, Bayer submitted: a Commercial Medicines Unit price lower than the price in the original appraisal; data from two observational studies used to validate the company’s extrapolation of overall survival beyond the end of SHARP (GIDEON,5 in which patient characteristics were unmatched to the characteristics of the SHARP participants, and a study by Palmer and colleagues, 6 in which patient characteristics were also unmatched); an estimate of the duration of treatment from SHARP based on time to disease progression; costs based on the committee’s preferences from the original appraisal; and updated estimates of resource use costs. The committee discussed Palmer and colleagues’ study, recognising it as
a small unpublished retrospective UK study comparing patients with hepatocellular carcinoma who were funded for (and received) sorafenib with those who did not receive funding or sorafenib, and considered that the study’s reported association between sorafenib funding and outcomes may have been confounded. The committee noted that the population in GIDEON, a Bayer-sponsored multinational post-marketing uncontrolled safety study of over 3000 people, differed from that in SHARP; for example, only 62% of participants in GIDEON had Child-Pugh grade A liver function at baseline whereas nearly all did in SHARP. The committee stated that it would have been appropriate for the company to modify the GIDEON population to reflect the characteristics of the population enrolled into SHARP. For the committee’s second meeting, Bayer’s submission included: a price for sorafenib lower than that provided at the first meeting; evidence from GIDEON, now matched to the SHARP population, using propensity scores for patient characteristics that might influence mortality; and an estimated duration of treatment using data on time-to-treatment discontinuation from SHARP. At the committee’s third meeting, Bayer’s submission included: a price for sorafenib lower than that provided at the second meeting; UK audit data for treatment for hepatocellular carcinoma; and an estimated duration of treatment using data on time-to-treatment discontinuation from GIDEON matched to the SHARP population. In discussing the appropriate patients for sorafenib, the committee noted that people with Child-Pugh grade A liver function were the only patients specified in the inclusion criteria for SHARP, comprised the majority of patients contributing
www.thelancet.com/gastrohep Published online September 6, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30283-2
Lancet Gastroenterol Hepatol 2017 Published Online September 6, 2017 http://dx.doi.org/10.1016/ S2468-1253(17)30283-2
1
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data to the observational studies, and were those that professional groups and NHS England had commented would benefit most from sorafenib. The committee concluded that people with Child-Pugh grade A liver function reflected the appropriate population for its recommendations. To validate projections about anticipated gains in life expectancy beyond the end of follow-up of SHARP, the committee concluded that the matched GIDEON data were the best available because GIDEON followed patients longer than did SHARP, or than did any other observational studies presented. The committee remained concerned that the company did not have data from SHARP and GIDEON reflecting risk factors for death (eg, viral hepatitis), which, if different in frequency between the two studies, would cause problems in generalising extrapolations from GIDEON to SHARP. The committee noted that the company-preferred way to extrapolate GIDEON data was using a log normal curve, because, according to Bayer, it provided a better statistical fit than a Weibull curve. However, the committee observed that beyond about 600 days of follow-up, where sparse or no data existed, the Weibull curve fit better than the log normal curve. The committee understood from the ERG that a log normal function would overestimate overall survival in patients taking sorafenib, whereas a Weibull function would underestimate it. The committee concluded that the true average gain in life expectancy with sorafenib over best supportive care was likely to be closer to a log normal curve. The committee discussed whether an estimate of treatment duration should come from SHARP, or from another
2
study, and agreed that costs should come from the source of the clinical effectiveness data, that is, SHARP. The company preferred to estimate duration of treatment using the proxy measure of disease progression, but the committee did not agree. The committee concluded that to estimate an average time on sorafenib, it was reasonable to extrapolate actual SHARP data measuring time to treatment discontinuation using a log normal distribution. The committee discussed costs, recognising that sorafenib would come off patent in approximately 5 years, but concluded that it could take into account only the current price of sorafenib. The committee decided it was appropriate to account for drug wastage, and to use the estimates of resource use (eg, whether patients are treated in oncology or hepatology clinics, and frequency of hospitalisations) that combine the company’s original estimates and more recent values it provided for the reconsideration meetings. The committee discussed the most plausible incremental costeffectiveness ratio (ICER) for sorafenib compared with best supportive care for treating advanced hepatocellular carcinoma. The committee considered that there was still uncertainty associated with extrapolating overall survival from SHARP. After the committee’s third meeting, the company proposed a new commercial access agreement to NHS England. The committee was aware that using this latest price, the most plausible ICER fell below £50 000 per quality-adjusted life year (QALY) gained (based on the ERG’s weighted average results: 75% log normal and 25% Weibull distribution to extrapolate overall survival).
The committee considered that this reflected a cost-effective use of NHS resources taking into account the extra weight applied to QALYs at the end of life, having agreed that sorafenib met the criteria for a life-extending, end-of-life treatment. The committee recommended sorafenib as a treatment option only for people with Child-Pugh grade A liver function, and only if the company provides sorafenib to the NHS within the agreed commercial access arrangement.
Amanda I Adler, Frances Sutcliffe Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK (AA) and National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK (FS) [email protected] AA and FS receive salary support from NICE. We thank Linda Landells (Associate Director— Technology Appraisals [Cancer Drugs Fund]). 1
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National Institute for Health and Clinical Excellence. Sorafenib for treating advanced hepatocellular carcinoma: NICE technology appraisal guidance TA474. www.nice.org.uk/ guidance/TA474 (accessed Sept 6, 2017). National Institute for Health and Clinical Excellence. Rapid re-consideration of drugs currently funded through the Cancer Drugs Fund. https://www.nice.org.uk/about/whatwe-do/our-programmes/nice-guidance/nicetechnology-appraisal-guidance/ cancer-drugs-fund (accessed Sept 1, 2017). Llovet JM, Ricci S, Mazzaferro V, et al, for the SHARP Investigators Study Group. Sorafenib for advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–90. National Institute for Health and Clinical Excellence. Sorafenib for the treatment of advanced hepatocellular carcinoma. NICE technology appraisal guidance 189. https://www.nice.org.uk/guidance/ta189 (accessed Sept 1, 2017). Bayer. Bayer CSR- GIDEON: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib. Data on file, 2013. Palmer DH, Hussain SA, Smith AJ, et al. Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom. Br J Cancer 2013; 109: 888–90.
www.thelancet.com/gastrohep Published online September 6, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30283-2
NICE guidance on sorafenib for treating advanced hepatocellular carcinoma On Sept 6, 2017, the UK National Institute of Health and Care Excellence (NICE) published guidance that recommends sorafenib (Bayer PLC; Reading, UK), as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade A liver impairment, and only if the manufacturing company provides sorafenib within the agreed commercial access arrangement.1 The appraisal committee’s remit was to assess the clinical and cost effectiveness of sorafenib for advanced hepatocellular carcinoma compared with standard National Health Service (NHS) care. NICE appraised sorafenib, an oral multikinase inhibitor, first in 2009, and then again in 2016 when reconsidering drugs paid for by the Cancer Drugs Fund in England.2 When NICE originally appraised sorafenib, the committee met four times to review the evidence provided by Bayer, the manufacturer, and the critique of Bayer’s submission by the West Midlands Health Technology Assessment Collaboration, the evidence review group (ERG). The evidence centred around one trial, SHARP, 3 designed to compare 400 mg of sorafenib twice daily with best supportive care against placebo with best supportive care in patients with Child-Pugh liver function grade A, with the primary endpoints being time to death or to symptomatic progression. The committee noted that SHARP had shown that sorafenib increased median survival by more than 2·8 months compared with placebo, yet, at the price the company had set, sorafenib was not a good use of limited NHS resources. Thus, the committee did not recommend sorafenib. Bayer appealed the decision, and an appeal panel dismissed all the points. Because NICE issued final guidance not recommending sorafenib,4 it was provided in England
by the Cancer Drug Fund rather than by routine NHS commissioning. To permit the committee to reconsider sorafenib, Bayer submitted additional evidence to support its clinical and cost effectiveness. The committee met three times accompanied by clinical experts, representatives from Bayer, the ERG (NICE Decision Support Unit, University of Sheffield) and the public. The committee concluded that doxorubicin, local resection, ablation using radiofrequency, and chemoembolisation were not usual treatment for first-line treatment of advanced hepatocellular carcinoma, and that best supportive care was still the only relevant treatment with which to compare sorafenib. The committee recognised that between 2010 and 2016, there were no new comparators available for first-line treatment of hepatocellular carcinoma in the NHS, no new randomised controlled trial comparing sorafenib with best supportive care, and no further analyses of SHARP reflecting longer follow-up. For the committee’s first meeting, Bayer submitted: a Commercial Medicines Unit price lower than the price in the original appraisal; data from two observational studies used to validate the company’s extrapolation of overall survival beyond the end of SHARP (GIDEON,5 in which patient characteristics were unmatched to the characteristics of the SHARP participants, and a study by Palmer and colleagues, 6 in which patient characteristics were also unmatched); an estimate of the duration of treatment from SHARP based on time to disease progression; costs based on the committee’s preferences from the original appraisal; and updated estimates of resource use costs. The committee discussed Palmer and colleagues’ study, recognising it as
a small unpublished retrospective UK study comparing patients with hepatocellular carcinoma who were funded for (and received) sorafenib with those who did not receive funding or sorafenib, and considered that the study’s reported association between sorafenib funding and outcomes may have been confounded. The committee noted that the population in GIDEON, a Bayer-sponsored multinational post-marketing uncontrolled safety study of over 3000 people, differed from that in SHARP; for example, only 62% of participants in GIDEON had Child-Pugh grade A liver function at baseline whereas nearly all did in SHARP. The committee stated that it would have been appropriate for the company to modify the GIDEON population to reflect the characteristics of the population enrolled into SHARP. For the committee’s second meeting, Bayer’s submission included: a price for sorafenib lower than that provided at the first meeting; evidence from GIDEON, now matched to the SHARP population, using propensity scores for patient characteristics that might influence mortality; and an estimated duration of treatment using data on time-to-treatment discontinuation from SHARP. At the committee’s third meeting, Bayer’s submission included: a price for sorafenib lower than that provided at the second meeting; UK audit data for treatment for hepatocellular carcinoma; and an estimated duration of treatment using data on time-to-treatment discontinuation from GIDEON matched to the SHARP population. In discussing the appropriate patients for sorafenib, the committee noted that people with Child-Pugh grade A liver function were the only patients specified in the inclusion criteria for SHARP, comprised the majority of patients contributing
www.thelancet.com/gastrohep Published online September 6, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30283-2
Lancet Gastroenterol Hepatol 2017 Published Online September 6, 2017 http://dx.doi.org/10.1016/ S2468-1253(17)30283-2
1
News
data to the observational studies, and were those that professional groups and NHS England had commented would benefit most from sorafenib. The committee concluded that people with Child-Pugh grade A liver function reflected the appropriate population for its recommendations. To validate projections about anticipated gains in life expectancy beyond the end of follow-up of SHARP, the committee concluded that the matched GIDEON data were the best available because GIDEON followed patients longer than did SHARP, or than did any other observational studies presented. The committee remained concerned that the company did not have data from SHARP and GIDEON reflecting risk factors for death (eg, viral hepatitis), which, if different in frequency between the two studies, would cause problems in generalising extrapolations from GIDEON to SHARP. The committee noted that the company-preferred way to extrapolate GIDEON data was using a log normal curve, because, according to Bayer, it provided a better statistical fit than a Weibull curve. However, the committee observed that beyond about 600 days of follow-up, where sparse or no data existed, the Weibull curve fit better than the log normal curve. The committee understood from the ERG that a log normal function would overestimate overall survival in patients taking sorafenib, whereas a Weibull function would underestimate it. The committee concluded that the true average gain in life expectancy with sorafenib over best supportive care was likely to be closer to a log normal curve. The committee discussed whether an estimate of treatment duration should come from SHARP, or from another
2
study, and agreed that costs should come from the source of the clinical effectiveness data, that is, SHARP. The company preferred to estimate duration of treatment using the proxy measure of disease progression, but the committee did not agree. The committee concluded that to estimate an average time on sorafenib, it was reasonable to extrapolate actual SHARP data measuring time to treatment discontinuation using a log normal distribution. The committee discussed costs, recognising that sorafenib would come off patent in approximately 5 years, but concluded that it could take into account only the current price of sorafenib. The committee decided it was appropriate to account for drug wastage, and to use the estimates of resource use (eg, whether patients are treated in oncology or hepatology clinics, and frequency of hospitalisations) that combine the company’s original estimates and more recent values it provided for the reconsideration meetings. The committee discussed the most plausible incremental costeffectiveness ratio (ICER) for sorafenib compared with best supportive care for treating advanced hepatocellular carcinoma. The committee considered that there was still uncertainty associated with extrapolating overall survival from SHARP. After the committee’s third meeting, the company proposed a new commercial access agreement to NHS England. The committee was aware that using this latest price, the most plausible ICER fell below £50 000 per quality-adjusted life year (QALY) gained (based on the ERG’s weighted average results: 75% log normal and 25% Weibull distribution to extrapolate overall survival).
The committee considered that this reflected a cost-effective use of NHS resources taking into account the extra weight applied to QALYs at the end of life, having agreed that sorafenib met the criteria for a life-extending, end-of-life treatment. The committee recommended sorafenib as a treatment option only for people with Child-Pugh grade A liver function, and only if the company provides sorafenib to the NHS within the agreed commercial access arrangement.
Amanda I Adler, Frances Sutcliffe Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK (AA) and National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK (FS) [email protected] AA and FS receive salary support from NICE. We thank Linda Landells (Associate Director— Technology Appraisals [Cancer Drugs Fund]). 1
2
3
4
5
6
National Institute for Health and Clinical Excellence. Sorafenib for treating advanced hepatocellular carcinoma: NICE technology appraisal guidance TA474. www.nice.org.uk/ guidance/TA474 (accessed Sept 6, 2017). National Institute for Health and Clinical Excellence. Rapid re-consideration of drugs currently funded through the Cancer Drugs Fund. https://www.nice.org.uk/about/whatwe-do/our-programmes/nice-guidance/nicetechnology-appraisal-guidance/ cancer-drugs-fund (accessed Sept 1, 2017). Llovet JM, Ricci S, Mazzaferro V, et al, for the SHARP Investigators Study Group. Sorafenib for advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–90. National Institute for Health and Clinical Excellence. Sorafenib for the treatment of advanced hepatocellular carcinoma. NICE technology appraisal guidance 189. https://www.nice.org.uk/guidance/ta189 (accessed Sept 1, 2017). Bayer. Bayer CSR- GIDEON: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib. Data on file, 2013. Palmer DH, Hussain SA, Smith AJ, et al. Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom. Br J Cancer 2013; 109: 888–90.
www.thelancet.com/gastrohep Published online September 6, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30283-2