Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. METHODS: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study. RESULTS: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. CONCLUSION: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study.

BACKGROUND: CARTITUDE-1 is a phase 1b-2 study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma. Primary efficacy outcomes have previously been reported. Here, we report health-related quality of life (HRQOL) secondary outcomes evaluated using patient-reported outcomes. METHODS: This single-arm, open-label, phwase 1b-2 study was done at 16 centres in the USA. Patients were aged 18 years or older with diagnosis of multiple myeloma and Eastern Cooperative Oncology Group performance status of 1 or less with three or more previous lines of therapy, or were double refractory to a proteasome inhibitor and immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR+ T cells per kg) was administered 5-7 days after lymphodepletion. Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30-item, pre-specified items from the EORTC myeloma module, and EuroQol five-dimensional descriptive system questionnaire. Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. This trial is registered with ClinicalTrials.gov, NCT03548207. This trial is completed but feeding into a long-term follow-up study. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 78 patients were enrolled and underwent apheresis in phase 2 of the study. 68 patients were treated (43 [63%] male, 49 [72%] White), and their patient-reported outcomes assessed (median follow-up 16·9 months, IQR 15·7-17·5). After infusion, a transient decline was observed, followed by improvements in global health status (mean change from baseline to day 464 +8·0 points, SD 20·9), physical (+4·6 points, 21·1), and emotional functional scales (+1·9 points, 23·7) over time, and declines for symptom-based scores (-14·1 pain, SD 31·5 and -15·4 fatigue; SD 29·5), indicating improved patient HRQOL following treatment with cilta-cel. INTERPRETATION: These durable HRQOL improvements are consistent with clinical findings, in which a single cilta-cel infusion led to substantial and durable responses in heavily pre-treated patients with relapsed or refractory multiple myeloma. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma. FUNDING: Janssen Research & Development and Legend Biotech USA.

Digital recruitment and enrollment in a remote nationwide trial of screening for undiagnosed atrial fibrillation: Lessons from the randomized, controlled mSToPS trial.

OBJECTIVES: The advent of large databases, wearable technology, and novel communications methods has the potential to expand the pool of candidate research participants and offer them the flexibility and convenience of participating in remote research. However, reports of their effectiveness are sparse. We assessed the use of various forms of outreach within a nationwide randomized clinical trial being conducted entirely by remote means. METHODS: Candidate participants at possibly higher risk for atrial fibrillation were identified by means of a large insurance claims database and invited to participate in the study by their insurance provider. Enrolled participants were randomly assigned to one of two groups testing a wearable sensor device for detection of the arrhythmia. RESULTS: Over 10 months, the various outreach methods used resulted in enrollment of 2659 participants meeting eligibility criteria. Starting with a baseline enrollment rate of 0.8% in response to an email invitation, the recruitment campaign was iteratively optimized to ultimately include website changes and the use of a five-step outreach process (three short, personalized emails and two direct mailers) that highlighted the appeal of new technology used in the study, resulting in an enrollment rate of 9.4%. Messaging that highlighted access to new technology outperformed both appeals to altruism and appeals that highlighted accessing personal health information. CONCLUSIONS: Targeted outreach, enrollment, and management of large remote clinical trials is feasible and can be improved with an iterative approach, although more work is needed to learn how to best recruit and retain potential research participants. TRIAL REGISTRATION: Clinicaltrials.govNCT02506244. Registered 23 July 2015.

Systematic Literature Review of the Methods Used to Compare Newer Second-Generation Agents for the Management of Schizophrenia: A focus on Health Technology Assessment.

BACKGROUND: The challenges of comparative effectiveness to support health technology assessment (HTA) agencies are important considerations in the choices of antipsychotic medications for the treatment of schizophrenia. OBJECTIVES: Our aim was to assess the study methods used and outcomes reported in the published literature to address the question of comparative effectiveness of newer antipsychotic agents and the adequacy and availability of evidence to support HTA agencies. DATA SOURCE: A systematic search of the PubMed database from 1 January 2009 to 30 September 2013 was conducted to identify studies evaluating new atypical antipsychotics reporting on comparative effectiveness. STUDY SELECTION: The systematic review comprised of studies on schizophrenia patients where at least two drugs were being compared and at least one treatment group received one of the following second-generation antipsychotics: risperidone, olanzapine, aripiprazole, paliperidone, asenapine, iloperidone, lurasidone, and quetiapine. The included studies were also required to have an efficacy, safety or economic outcome, such as Positive and Negative Syndrome Scale (PANSS) score, weight gain, resource utilization, or costs. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers (BW and GK) independently applied the inclusion criteria. Disagreements between reviewers were resolved by consensus, referring to the original sources. Information on the methodology and outcomes was collected for each included study. This included study description, head-to-head drug comparison, patient population, study methodology, statistical methods, reported outcomes, study support, and journal type. RESULTS: A total of 198 studies were identified from electronic search methods. The largest category of studies was randomized controlled trials [RCTs] (N = 73; 36.9%), which were largely directed at the regulatory endpoint. Fewer studies were undertaken for HTA-purposes cohort studies (N = 53; 26.8%), meta-analyses (N = 32; 16.2%), economic studies (N = 14; 7.1%), and cross-sectional studies (N = 13; 6.6%). Direct head-to-head comparisons preferred by HTA were dominated by the comparison involving olanzapine and risperidone, representing 149 (75.3%) and 119 (60.1%) studies, respectively. RCTs, which are the primary study type for regulatory submissions, showed a lack of bias. Studies aimed at HTA were not as well performed. Cohort studies suffered from bias in the selection of comparison groups, lack of control for confounders, and differential dropout rates. As a group, cross-sectional studies scored poorly for bias, with a primary failure to identify a representative sample. Economic studies showed highly variable bias, with bias in the representation of effectiveness data, model assumptions without validation, and lack of sensitivity analyses. LIMITATIONS: One limitation of this systematic review is that it only included studies from 2009 to 2013, potentially excluding some earlier comparator studies, particularly those involving first-generation antipsychotics. CONCLUSIONS: This review of comparative effectiveness studies of second-generation antipsychotic agents for schizophrenic patients revealed a wide range of study types, study methodologies, and outcomes. For traditional efficacy outcomes and select safety outcomes, there is strong evidence from many well-conducted studies; however, there are fewer studies of types preferred by HTA with limited head-to-head comparisons and a higher risk of bias in the execution of these studies.

Effectiveness versus convenience: patient preferences for an erythropoietic agent to treat cancer-related anemia.

OBJECTIVE: To assess patient preferences across two attributes--effectiveness and convenience--in the selection of an erythropoietic agent to treat chemotherapy-related anemia. METHODS: During 2004, 500 adults with solid tumors and anemia were recruited through 50 oncologists' offices across the USA. Data were collected through self-administered questionnaires, divided into two parts. The first, completed by the provider, captured clinical information and providers' perceptions of patient preferences. The second, completed by the patient, recorded knowledge, experiences, and preferences regarding anemia and its treatments. Patient preferences, the relative importance of effectiveness (time to noticeable relief of fatigue) and convenience (number of provider visits required in an 8-week period), were measured using a choice-based conjoint (CBC) analysis. Each attribute was assessed at three levels (4, 6, or 8 weeks/visits). RESULTS: 467 providers (93%) and 438 patients (88%) completed the preference sections. When choosing a medication to treat anemia, 77% of providers viewed effectiveness as more important to patients than convenience. Similarly, patients had a greater preference for effectiveness than convenience. Relative preference weights were significantly higher for 4- versus 6-week effectiveness (0.61 vs. 0.09, p < 0.001) and 6- versus 8-week effectiveness (0.09 vs. -0.70, p = 0.004). Overall, time to effectiveness was twice as important to patients as the number of visits. LIMITATIONS: Only two attributes were included in the CBC, which did not control for bias from respondent characteristics or experiences. CONCLUSION: When evaluating an erythropoietic agent to treat chemotherapy-related anemia, both providers and patients view effectiveness as more important than convenience.

Early hemoglobin response and alternative metrics of efficacy with erythropoietic agents for chemotherapy-related anemia.

OBJECTIVE: To examine associations between early hemoglobin response and alternative measures of efficacy following treatment with an erythropoietic agent for chemotherapy-related anemia. RESEARCH DESIGN AND METHODS: Preliminary data from an ongoing randomized, multicenter, 16-week, open-label clinical trial of epoetin alfa versus darbepoetin alfa were used to dichotomize patients based on attainment of early hemoglobin response (> or = 1 g/dL increase in hemoglobin level within 4 weeks of treatment initiation). Measures of efficacy were compared between patients with early hemoglobin response and those without. Sensitivity analyses were then performed to evaluate the impact of various methods for handling censored data and hemoglobin values following blood transfusion. MAIN OUTCOME MEASURES: Efficacy measures included: the proportion of patients with a > or = 1 g/dL increase in hemoglobin by 4 weeks or a > or = 2 g/dL increase by 8 weeks; mean hemoglobin levels at 4, 8, 12, and 16 weeks; area under the curve for change in hemoglobin level; proportion of patients who required a blood transfusion after 4 weeks; proportion of follow-up days on which patients had hemoglobin levels within the therapeutic range of 11 g/dL to 13 g/dL; and proportion of patients who never had a hemoglobin level within this range. RESULTS: A total of 274 patients were included (66.1% female, mean age 62.4), of whom 48.9% had an early hemoglobin response and 51.1% did not. Mean duration of follow-up was 10.1 +/- 5.05 weeks. All metrics indicated superior longer-term response among patients with early hemoglobin response compared to patients without early response. The findings were robust across sensitivity analyses. Although the analysis establishes a significant relationship between early hemoglobin response and alternative efficacy metrics, causality cannot be inferred. CONCLUSIONS: Early hemoglobin response is significantly associated with various metrics of clinical response to erythropoietic agents and is an appropriate measure for evaluating treatment effects.

Dose conversion and cost effectiveness of erythropoietic therapies in chemotherapy-related anaemia : a meta-analysis.

OBJECTIVE: To estimate a dose-conversion ratio (DCR) between epoetin alfa (EPO) and darbepoetin alfa (DARB) and compare the costs of both drugs at the estimated DCRs using average wholesale prices (AWPs). METHODS: A search of PUBMED, CANCERLIT and references for papers and abstracts reporting on clinical trials of DARB or EPO for chemotherapy-related anaemia (CRA) identified 56 publications. A meta-analysis was conducted on the 12 eligible papers to estimate a DCR at which the two drugs were equally effective as measured by the area under the curve of haemoglobin (Hb) change (Hb AUC) at weeks 4 and 13. The DCR is based on the ratio of the coefficients of DARB and EPO doses in a regression of Hb AUC on those two variables, baseline Hb, Hb change calculation method, tumour type, and dosing frequency. Studies were frequency-weighted by the number of subjects. DCRs with confidence intervals (CIs) were calculated using a Monte-Carlo approach. Results from the regression were used to calculate DCRs for different dosing regimen comparisons - EPO three times weekly (TIW) versus DARB once weekly (QW), EPO TIW versus DARB once every 2 weeks (Q2W), EPO QW versus DARB QW, and EPO QW versus DARB Q2W. Relative cost effectiveness (RCE) was assessed by comparing drug costs at the estimated DCRs at $US 2003 AWPs [RCE = DCR . ($/U EPO)/($/mug DARB)]. RESULTS: The regression results suggest an EPO QW : DARB QW DCR of 187 (95% CI 183, 191). Depending on the assumed starting dose, the DCR ranges from 126 to 137 for EPO TIW : DARB QW; from 128 to 139 for EPO TIW : DARB Q2W; and equals 191 for EPO QW : DARB Q2W. RCE was 2.0 for the main regression. CONCLUSION: The DCR of 330 : 1 estimated for the 2004 Hospital Outpatient Prospective Payment System by the Centers for Medicare and Medicaid Services is greater than the DCRs estimated based on Hb AUC. The DCR estimated in the primary regression suggests that based on AWPs, EPO is 2.0 times more cost effective than DARB.

Cost-minimization analysis of once-weekly versus thrice-weekly epoetin alfa for chemotherapy-related anemia.

BACKGROUND: For individuals with chemotherapy-related anemia, the clinical effectiveness of epoetin alfa (EPO) dosed once weekly ([QW], 40,000 units per dose) has been demonstrated to be indistinguishable from that observed with thrice-weekly dosing ([TIW], 10,000 units per dose). Whether the advantage of less-frequent administration justifies the higher EPO dosage used in the weekly regimen in terms of overall cost of care is unknown. OBJECTIVE: To conduct a cost-minimization analysis comparing QW and TIW EPO dosing from a societal perspective. METHODS: Direct and indirect medical cost data were calculated for a 16-week period for 2 large, prospective, multicenter, community-based studies. Costs measured included EPO, transfusions, laboratory tests, office visits, and opportunity cost of patient time. RESULTS: The average total costs in 2002 (first half) dollars were nearly equivalent across the 2 groups (QW: 9,204 dollars; 95% confidence interval [CI], 9,057 dollars-9,350 dollars. TIW: 9,265 dollars; 95% CI, 9,083 dollars-9,447 dollars. P=0.60). QW incurred mean drug acquisition costs that were 23% higher (QW: 6,725 dollars; 95% CI, 6,611 dollars-6,838 dollars. TIW: 5,474 dollars; 95% CI, 5,350 dollars-5,598 dollars. P<0.001). However, QW patients can avoid the resource use and time cost associated with 2 additional office visits incurred each week (QW: 592 dollars [583 dollars-600 dollars]; TIW: 1,709 dollars [1,678 dollars-1,740 dollars]; P<0.001). Transfusion and laboratory test costs were slightly higher in the TIW group (QW: 1,888 dollars [1,837 dollars-1,940 dollars]; TIW: 2,082 dollars [2,020 dollars-2,144 dollars]; P<0.001). CONCLUSION: Total anemia treatment costs over a 16-week period with EPO QW were similar to those of TIW dosing. In the absence of cost differences between regimens, the noneconomic advantages of less-frequent dosing intervals should make weekly dosing increasingly attractive to patients, clinicians, and payers.