TY - JOUR
T1 - Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab
T2 - a critique of the submission from GSK
AU - Hoyle, M
AU - Crathorne, L
AU - Garside, R
AU - Hyde, C
N1 - Copyright Queen’s Printer and Controller of HMSO 2011. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2011
Y1 - 2011
N2 - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic
lymphocytic leukaemia (CLL), based upon the manufacturer’s submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal
process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence
for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p<0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progressionfree survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections,
which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine
and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer’s estimates of
effectiveness based on evidence from a single-arm, non-randomised study. An ‘area-underthe-curve’ or ‘partitioned-survival’ model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: ‘alive pre-progression’, ‘alive post progression’ and ‘dead’. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the
Hx-CD20-406 study who did not respond to ofatumumab treatment – ‘non-responders’ – and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further
uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of
the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG’s review of the published and submitted evidence, the revised base-case incremental costeffectiveness ratio for ofatumumab increased to £81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf).
AB - This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic
lymphocytic leukaemia (CLL), based upon the manufacturer’s submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal
process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence
for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p<0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progressionfree survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections,
which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine
and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer’s estimates of
effectiveness based on evidence from a single-arm, non-randomised study. An ‘area-underthe-curve’ or ‘partitioned-survival’ model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: ‘alive pre-progression’, ‘alive post progression’ and ‘dead’. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the
Hx-CD20-406 study who did not respond to ofatumumab treatment – ‘non-responders’ – and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further
uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of
the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG’s review of the published and submitted evidence, the revised base-case incremental costeffectiveness ratio for ofatumumab increased to £81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf).
U2 - 10.3310/hta15suppl1/07
DO - 10.3310/hta15suppl1/07
M3 - Article
C2 - 21609654
SN - 1366-5278
VL - 15
SP - 61
EP - 67
JO - Health Technology Assessment
JF - Health Technology Assessment
IS - Suppl. 1
ER -