TA306 · STA
Pixantrone is recommended only if: the person has previously been treated with rituximab; the person is receiving third- or fourth-line treatment; and the manufacturer provides pixantrone with the discount agreed in the patient access scheme.
Source documents
Intervention
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| physician's choice of single-agent comparators | standard of care | Yes | — |
| vinorelbine | active drug | — | — |
| oxaliplatin | active drug | — | — |
| ifosfamide | active drug | — | — |
| etoposide | active drug | — | — |
| mitoxantrone | active drug | — | — |
| gemcitabine | active drug | — | — |
| treatment of physician's choice | standard of care | Yes | Yes |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| PIX301 | RCT | phase III | Yes |
| PIX203 | RCT | II | — |
Economic model
ICER
Methodological decisions (28)
PIX301 used physician's choice of single-agent comparators (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, gemcitabine) rather than a single standard comparator.
ERG noted lack of consensus on which chemotherapy regimens should be used after second-line treatment fails and concluded that choice of treatment in comparator arm was unlikely to be a key issue, despite small numbers per treatment.
Company: Used treatment of physician's choice
ERG: No consensus on appropriate comparators; small sample sizes preclude reliable analysis
ICER impact: uncertain_direction
Drug costs calculated based on average dose per administration from PIX301 trial. Manufacturer initially used incorrect pixantrone vial price (£343.80) which was corrected to £553.50, with minimal impact on cost-effectiveness estimates
Company: Costs calculated from BNF edition 62 and NHS reference costs based on actual doses used in trial
Drug costs for comparator treatments changed from BNF to NHS Commercial Medicines Unit eMIT database in line with NICE Guide to the methods of technology appraisal (2013).
Company: Updated to use eMIT database
Committee: eMIT database method
ICER impact: uncertain_direction
Semi-Markov model used with partitioned survival approach. Stable/no progression state divided into 2 subpopulations (on treatment vs off treatment). Adverse events modelled as events rather than health states with time-independent occurrence.
Company: Semi-Markov partition approach chosen as particularly suited to progressive conditions with varying risks over time
Model assumed overall survival and progression-free survival were independent, leading to survival curves crossing in probabilistic analysis (30% of simulations affected). Manufacturer provided alternative assuming dependencies using Cholesky decomposition.
Company: Independence assumption with manual adjustment; also provided dependent assumption scenario
ICER impact: increases
Central independent pathological review undertaken retrospectively (after trial), confirming aggressive disease in only 104 of 140 randomised patients. ERG considered this important for evaluating benefit in patients with confirmed aggressive B-cell lymphoma.
Company: Not practical to confirm aggressive disease at enrolment
ERG: Retrospective confirmation creates uncertainty; subgroup analyses should be evaluated separately as they are underpowered
ICER impact: uncertain_direction
Generalisability of PIX301 to NHS population: only 54 of 70 (77%) patients in pixantrone arm had disease confirmed by central independent pathological review; 36 patients had non-confirmed histology with various reasons for non-confirmation.
Company: Manufacturer considered post-hoc subgroup of patients with aggressive B-cell lymphoma confirmed by onsite pathological review to be similar to the population eligible for treatment according to pixantrone's European marketing authorisation
Base case included patients who had received 2 or 3 prior therapies and whose disease was sensitive to anthracyclines, consistent with pixantrone's European marketing authorisation. This focused on 3rd or 4th line treatment, with note that treatment benefit not established for 5th line or greater.
Company: Population restricted to patients consistent with marketing authorisation (2-3 prior therapies, anthracycline-sensitive)
ERG had concerns about generalisability of PIX301 population to English clinical practice, particularly regarding previous rituximab treatment (given as part of standard first-line treatment in UK). About 50% of PIX301 patients had received a biological agent previously.
ERG: Significant concerns about generalisability, especially regarding rituximab-pretreated subgroup
ICER impact: uncertain_direction
Study population definition: whether the ITT population (including ~10% patients without confirmed aggressive B-cell lymphoma) or the subgroup with disease confirmed by central independent pathological review is most relevant to NHS clinical practice and marketing authorisation
Company: Manufacturer submitted multiple subgroup analyses based on onsite and central pathological review
ERG: ERG judged the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review to be most relevant because it excluded patients with irrelevant disease (e.g. indolent disease). ERG noted this subgroup was underpowered and based on post-hoc analysis.
Committee: Committee concluded it would be more appropriate to consider the population with aggressive B-cell lymphoma confirmed by central independent pathological review, particularly those who had received third- or fourth-line treatment, when assessing PIX301 results
ICER impact: increases
Histology determination method: onsite single pathologist review vs central multidisciplinary team pathological review
Company: PIX301 population had tumour histology determined by onsite review by single pathologist
ERG: ERG was advised this was not representative of NHS clinical practice where multidisciplinary team review is routine with examination by 2-3 pathologists. ERG considered population with central independent pathological review more relevant.
Committee: Committee agreed that central independent pathological review population was more generalisable because it reflected NHS practice and excluded considerable proportion of patients with confirmed indolent disease
ICER impact: increases
Committee appropriateness of using third- or fourth-line subgroup rather than intention-to-treat population
Company: Intention-to-treat analysis of all 305 enrolled patients
Committee: Use subgroup of patients receiving third- or fourth-line treatment and who had previously received rituximab
ICER impact: decreases
Relevance of tumour histology determination method (onsite single pathologist vs central independent review)
Company: Onsite review by single pathologist
ERG: Central independent pathological review more relevant to NHS practice
Committee: Population with tumour histology confirmed by retrospective central independent pathological review by consensus
ICER impact: decreases
Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making, rather than the intention-to-treat population which included patients ineligible under marketing authorisation terms
Company: intention-to-treat population
Committee: subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review, third- or fourth-line treatment, prior rituximab exposure
ICER impact: decreases
Choice of primary endpoint in PIX301: complete or unconfirmed complete response vs overall survival/progression-free survival
Company: Manufacturer designed PIX301 with primary endpoint of complete or unconfirmed complete response
ERG: ERG concerned about statistical power. European regulators prefer overall survival or progression-free survival. Unconfirmed complete response is now considered obsolete in modern trials.
Committee: Committee noted this was a fundamental concern about trial design and concluded the endpoint choice meant considerable uncertainty in validity and robustness of results. Clinical specialists stated they prefer studies powered to detect differences in overall survival.
ICER impact: uncertain_direction
Manufacturer used log-normal distribution for both progression-free survival and overall survival to extrapolate beyond PIX301 data (around 2 years follow-up)
Company: Log-normal parametric curve fitted to patient-level data from PIX301
Treatment of survival modelling uncertainty in probabilistic analysis
Committee: Mean probabilistic ICER of £22,000 may overestimate uncertainty; true value likely lower; median probabilistic ICER £14,700; ICER reduced to £10,000 when assuming PFS and OS not independent
ICER impact: decreases
Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with survival modelling and that the true ICER might be lower
Committee: true value of ICER likely lower than probabilistic estimate
ICER impact: decreases
Line of therapy eligibility: Pixantrone's European marketing authorisation notes reduced benefit when used as fifth line or greater, and benefit not established in patients refractory to last therapy. Economic model and manufacturer's analyses focus on third- or fourth-line treatment.
Committee: third- or fourth-line treatment
Which line of therapy (third, fourth, or fifth+) is appropriate for pixantrone use within its marketing authorisation
Company: Not explicitly stated in this section
ERG: ERG viewed patients with aggressive B-cell lymphoma confirmed by central independent pathological review who had previously received rituximab and were receiving third- or fourth-line treatment as most relevant population
Committee: Committee concluded pixantrone would most likely be used as third- or fourth-line treatment in clinical practice and noted that fifth-line patients would likely receive palliative care or clinical trials. Marketing authorisation does not restrict to specific lines but fifth-line benefit not established.
ICER impact: increases
Manufacturer used utility data from published sources for similar disease areas including diffuse large B-cell lymphoma, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, renal cell carcinoma and melanoma. Specifically selected self-reported quality of life in older patients with aggressive diffuse large B-cell lymphoma (pre-progression 0.81, post-progression 0.60) without providing rationale.
Company: Utility values selected from published sources for similar patient populations with similar expected survival, disease progression and quality of life characteristics
Original model used self-reported quality of life in older patients with aggressive DLBCL (0.81 pre-progression, 0.60 post-progression). Revised model changed to utilities for second- and subsequent-line treatment of renal cell carcinoma (0.76 pre-progression, 0.68 post-progression) in response to Committee concern that original values overestimated quality of life.
Company: Original utilities from DLBCL population
Committee: Utilities from renal cell carcinoma population
ICER impact: decreases
Source of health-state utility values for aggressive non-Hodgkin's lymphoma
Company: Manufacturer used utility values from a population of patients receiving first-line treatment for aggressive non-Hodgkin's lymphoma
ERG: ERG considered these utility values potentially inappropriate because they were from first-line patients (not relapsed/refractory) and derived from a study initially rejected by the manufacturer. ERG noted values were higher than those for healthy older UK patients. ERG explored alternative utility values from chronic lymphocytic leukaemia patients receiving third- or later-line treatment.
ICER impact: increases
Choice of utility values for health states
Company: Utility values for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 pre-progression, 0.68 post-progression)
ERG: Utility values for final-line treatment for chronic lymphocytic leukaemia (0.428 pre-progression, 0.279 post-progression)
Committee: Manufacturer's utility values acceptable; ERG's values likely to underestimate quality of life
ICER impact: uncertain_direction
Committee aware that utility value used by manufacturer for pre-progression health state was similar to that expected for an older UK population, whereas quality of life for patients receiving third- or fourth-line treatment could be lower. However, Committee concluded the manufacturer's utility values were appropriate for decision-making
Committee: manufacturer's revised model utility values are acceptable despite uncertainty
ICER impact: uncertain_direction
Manufacturer assumed no difference in baseline health-related quality of life between patients on treatment vs discontinued treatment within stable/no progression state, and no difference between complete response, partial response or stable disease
Company: All stable/no progression patients assumed to have similar quality of life regardless of treatment status or response type
ERG's exploratory adverse-event disutilities were incorporated into manufacturer's revised model. Any grade 1-4 adverse event occurring in less than 5% of trial population assumed to have no impact on quality of life.
Company: Conservative approach; manufacturer-determined disutilities from literature
ERG: Provided exploratory adverse-event disutilities
Committee: ERG's exploratory disutility values
ICER impact: uncertain_direction
Evidence gaps
Commercial arrangement
Special considerations
Cross-references