Yazarlar : Linda J Landells Email Address, Carl Prescott , Nicola Hay , Frances Sutcliffe , Andrew Stevens

Yayın : The Lancet Oncology

Yayın Yılı : 2014

Pubmed Linki : http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70089-0/fulltext

Konu : Lenfoma

Literatür İçeriği : On Feb 26, 2014, the National Institute for Health and Care Excellence (NICE) published guidance recommending pixantrone monotherapy as an option for treatment of multiply relapsed or refractory aggressive non-Hodgkin lymphoma in adults who have previously been treated with rituximab and who are receiving third-line or fourth-line treatment, as long as the manufacturer provides pixantrone with the discount agreed in a patient access scheme.1 Although the evidence base for pixantrone was small— particularly for patients previously treated with rituximab—NICE's independent appraisal committee concluded that the evidence as a whole was in favour of pixantrone and that the price agreed in the patient access scheme meant that the drug was an acceptable use of National Health Service (NHS) resources. Pixantrone was appraised under the Single Technology Appraisal process. The appraisal's remit was the assessment of the clinical effectiveness and cost-effectiveness of pixantrone monotherapy within its licensed indication for the treatment of relapsed or refractory aggressive non-Hodgkin lymphoma in people for whom treatment with single-agent chemotherapy is being considered. Pixantrone's manufacturer (CTI Life Sciences, UK) submitted clinical evidence and a health economic model,2 which was critiqued by the BMJ Technology Assessment Group (an independent academic Evidence Review Group).3 An independent NICE appraisal committee met four times to develop guidance. Clinicians who were specialists in treatment of non-Hodgkin lymphoma attended the first meeting along with patient experts; the manufacturer attended all four meetings. A patient access scheme was agreed between the manufacturer and the Department of Health in England, meaning that the manufacturer will provide pixantrone to the NHS at a confidential discount to the list price. The key clinical evidence was from a randomised controlled trial (PIX301),4 in which pixantrone was compared with treatment of physician's choice in adults (aged ≥18 years) with aggressive de-novo or transformed non-Hodgkin lymphoma that had relapsed after two or more chemotherapy regimens, including at least one standard anthracycline-containing regimen with a response that had lasted at least 24 weeks. Patients were randomly assigned to pixantrone (n=70) or treatment of physician's choice (n=70, of whom 67 patients went on to receive a comparator [11 received vinorelbine, 30 oxaliplatin, 12 ifosfamide, nine etoposide, four mitoxantrone, and one gemcitabine]). Aggressive histological features were identified on site in all patients before treatment started. Pixantrone (85 mg/m2) was given on days 1, 8, and 15 of a 28-day cycle for up to six cycles. Comparators were given at predefined standard doses for up to six cycles. Patients were followed up for 18 months after completing study treatment. The primary outcome was complete and unconfirmed complete response in the intention-to-treat population; secondary outcomes were overall survival, response lasting at least 4 months, and progression-free survival. The investigators did a prespecified secondary analysis in the histologically confirmed intention-to-treat population (patients whose lymphoma had been retrospectively assessed by independent central pathological review). More patients in the pixantrone group than in the comparator group had achieved a confirmed or unconfirmed complete response at the end of treatment (14 [20·0%] vs four [5·7%]; p=0·021) and at the end of the study (17 [24·3%] vs five [7·1%]; p=0·009). Median progression-free survival was significantly longer in the pixantrone group (5·3 months) than the comparator group (2·6 months; hazard ratio [HR] 0·60, 95% CI 0·42—0·86; p=0·005). However, median overall survival did not differ significantly between the pixantrone and comparator groups (10·2 months vs 7·6 months; HR 0·79, 95% CI 0·53—1·18; p=0·251). The manufacturer submitted a de-novo semi-Markov economic model in which the cost-effectiveness of pixantrone was compared with treatment with physician's choice in patients with aggressive B-cell lymphoma. Because the intention-to-treat population of PIX301 was broader than pixantrone's European marketing authorisation, clinical effectiveness was derived from a post-hoc subgroup analysis of patients with aggressive B-cell lymphoma confirmed by on-site pathological review who were receiving third-line or fourth-line treatment. The manufacturer's model contained three health states: stable or no progression, progressive or relapsed disease, and death. The stable or no progression health state had two subpopulations: patients receiving treatment, and those who had discontinued treatment and not experienced progression. All patients entered the model in the on-treatment subpopulation within the stable or no progression health state. During every cycle, continuation or discontinuation of treatment, disease progression, or death could be recorded. It was assumed that patients received different treatment or palliative care after disease progression. Adverse events were captured by applying a utility decrement, and utilities data were identified from published sources. The appraisal committee deemed that the most appropriate population was the subgroup of patients who had aggressive B-cell lymphoma confirmed by central independent pathological review and were receiving at least third-line treatment. It had concerns that many patients in PIX301 had not previously received rituximab, which is given as part of standard first-line treatment of aggressive B-cell non-Hodgkin lymphoma, because pixantrone's conditional marketing authorisation was subject to future confirmation of benefit in patients who had previously received rituximab. The uncertainty surrounding clinical benefit, especially in patients who had previously received rituximab, combined with a high incremental cost-effectiveness ratio (ICER) were key considerations. On the basis of evidence reviewed at its first meeting in March, 2013 (when no patient access scheme was included), the committee concluded that pixantrone for treatment of multiply relapsed or refractory aggressive non-Hodgkin lymphoma would not be a cost-effective use of NHS resources. In response to the first consultation, the manufacturer provided clinical data from subgroups of patients who had previously received rituximab to show how the PIX301 trial population could be generalised to clinical practice in England. The manufacturer updated its economic model to align it more closely to the committee's preferences (including source of utilities and drug costs). At the second meeting in July, 2013, the committee considered responses to its preliminary guidance5 from consultees, commentators, the general public, and the manufacturer. It was persuaded that assessment of only patients receiving third-line or fourth-line treatment was appropriate because this group would mirror the population in clinical practice in England: subsequent treatment would typically be palliative care or participation in a clinical trial. After the second meeting, the manufacturer submitted a patient access scheme, agreed by the Department of Health, which applied to the subgroup of patients who had aggressive B-cell lymphoma confirmed by central independent pathological review, had previously received rituximab, and were receiving third-line or fourth-line treatment.6 At the third meeting in September, 2013, the committee concluded in its preliminary guidance7 that although the patient access scheme improved the cost-effectiveness of pixantrone, the ICER was too high and too uncertain for it to be able to recommend pixantrone as a cost-effective use of NHS resources. In response to the second consultation, consultees, commentators, and the general public submitted further comments.8 The manufacturer's consultation response included a request to include a revised patient access scheme approved by the Department of Health and clarification about the uncertainty associated with the survival estimates generated by its economic model, which was accepted by NICE. At the fourth meeting in November, 2013, the committee concluded that the limited, non-robust evidence showing that pixantrone is more clinically effective than are other treatments for multiply relapsed or refractory aggressive B-cell non-Hodgkin lymphoma, together with the price agreed in the revised patient access scheme, means that the probability of pixantrone being cost effective when compared with other treatments was acceptable. The most plausible ICER for the comparison of pixantrone and treatment of physicians' choice was likely to be less than £22 000 per quality-adjusted life-year gained in patients with aggressive B-cell lymphoma confirmed by central independent pathological review who had previously received rituximab and were now receiving third-line or fourth-line treatment. NICE issued a final appraisal determination stating the committee's decision, and stakeholders were given the opportunity to request corrections of factual inaccuracies or to appeal against the committee's recommendations. NICE received no appeals. One request for factual amendment was received from a clinical specialist, and the final guidance was published on Feb 26, 2014.

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