Extrapolation of time-to-event data from clinical trials is commonly used in decision models for health technology assessment (HTA). The objective of this study was to assess performance of standard ...parametric survival analysis techniques for extrapolation of time-to-event data for a single event from clinical trials with limited data due to small samples or short follow-up.
Simulated populations with 50,000 individuals were generated with an exponential hazard rate for the event of interest. A scenario consisted of 5000 repetitions with six sample size groups (30-500 patients) artificially censored after every 10% of events observed. Goodness-of-fit statistics (AIC, BIC) were used to determine the best-fitting among standard parametric distributions (exponential, Weibull, log-normal, log-logistic, generalized gamma, Gompertz). Median survival, one-year survival probability, time horizon (1% survival time, or 99th percentile of survival distribution) and restricted mean survival time (RMST) were compared to population values to assess coverage and error (e.g., mean absolute percentage error).
The true exponential distribution was correctly identified using goodness-of-fit according to BIC more frequently compared to AIC (average 92% vs 68%). Under-coverage and large errors were observed for all outcomes when distributions were specified by AIC and for time horizon and RMST with BIC. Error in point estimates were found to be strongly associated with sample size and completeness of follow-up. Small samples produced larger average error, even with complete follow-up, than large samples with short follow-up. Correctly specifying the event distribution reduced magnitude of error in larger samples but not in smaller samples.
Limited clinical data from small samples, or short follow-up of large samples, produce large error in estimates relevant to HTA regardless of whether the correct distribution is specified. The associated uncertainty in estimated parameters may not capture the true population values. Decision models that base lifetime time horizon on the model's extrapolated output are not likely to reliably estimate mean survival or its uncertainty. For data with an exponential event distribution, BIC more reliably identified the true distribution than AIC. These findings have important implications for health decision modelling and HTA of novel therapies seeking approval with limited evidence.
While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to ...assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC.
A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations.
In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib.
Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.
For novel cancer treatments, effectiveness in clinical practice is not always aligned with clinical efficacy results. As such it is important to understand a treatment's real-world effectiveness. We ...examined real-world population-based comparative effectiveness of second-line ipilimumab versus non-ipilimumab treatments (chemotherapy or targeted treatments).
We used a cohort of melanoma patients receiving systemic treatment for advanced disease since April 2005 from Ontario, Canada. Patients were identified from provincial drug databases and the Ontario Cancer Registry who received second-line ipilimumab from 2012 to 2015 (treated) or second-line non-ipilimumab treatment prior to 2012 (historical controls). Historical controls were chosen, to permit the most direct comparison to pivotal trial findings. The cohort was linked to administrative databases to identify baseline characteristics and outcomes. Kaplan-Meier curves and multivariable Cox regression models were used to assess overall survival (OS). Observed potential confounders were adjusted for using inverse probability of treatment weighting (IPTW).
We identified 329 patients with metastatic melanoma (MM) who had received second-line treatments (189 treated; 140 controls). Patients receiving second-line ipilimumab were older (61.7 years vs 55.2 years) compared to historical controls. Median OS were 6.9 (95% CI: 5.4-8.3) and 4.95 (4.3-6.0) months for ipilimumab and controls, respectively. The crude 1-year, 2-year, and 3-year OS probabilities were 34.3% (27-41%), 20.6% (15-27%), and 15.2% (9.6-21%) for ipilimumab and 17.1% (11-23%), 7.1% (2.9-11%), and 4.7% (1.2-8.2%) for controls. Ipilimumab was associated with improved OS (IPTW HR = 0.62; 95% CI: 0.49-0.78; p < 0.0001).
This real-world analysis suggests second-line ipilimumab is associated with an improvement in OS for MM patients in routine practice.
Background
In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab‐paclitaxel (GnP) have been publicly funded for first‐line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic ...pancreatic cancer (mPC) since April 2015. We examined the real‐world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC.
Methods
Patients receiving first‐line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population‐based databases. Overall survival (OS) was assessed using Kaplan‐Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models.
Results
For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70‐0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia‐related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar.
Conclusion
In the real world, FFX had longer OS, less frequent all‐cause EDV and all‐cause hospitalization, but more febrile neutropenia‐related hospitalization compared to GnP.
In the real world, implementation of universal public funding of FOLFIRINOX for metastatic pancreatic cancer was associated with improved overall survival, less frequent all‐cause emergency department visits, less frequent all‐cause hospitalization, but increased febrile neutropenia‐related hospitalization compared to patients treated with gemcitabine + nab‐paclitaxel. Expanding funding to include unresectable locally advanced pancreatic cancer was associated with a similar trend in benefits, but with improved absolute survival.
The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to ...evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.
The International Extranodal Lymphoma Study Group-32 (IELSG32) randomized patients with primary central nervous system lymphoma (PCNSL) for induction treatment with methotrexate-cytarabine, ...methotrexate-cytarabine-rituximab, or methotrexate-cytarabine-thiotepa-rituximab (MATRix) and reported significantly improved complete remission with the MATRix regimen. This study assessed cost-effectiveness among these three induction strategies for PCNSL. A Markov model was developed based on the IELSG32 trial over a 20 year time horizon from the Canadian health care system perspective. Costs for induction, consolidation, inpatient treatment administration, follow-up, adverse events, relapsed disease, and palliative care were included. Methotrexate-cytarabine-rituximab was subject to extended dominance by the other two strategies. The MATRix regimen compared to methotrexate-cytarabine produced 3.05 quality-adjusted life year (QALY) gains at added costs of $75,513, resulting in an incremental cost-effectiveness ratio of $24,758/QALY gained. The MATRix regimen was the optimal strategy in the majority of simulations (98% probability at willingness-to-pay of $50,000/QALY gained) and results appeared robust across sensitivity analyses.
Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and ...healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8-11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration's Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.
The initial assessment of pertuzumab use for treatment of metastatic breast cancer by health technology assessment agencies suggested that pertuzumab was not cost-effective. In Ontario, Canada, ...pertuzumab became funded in November 2013 based on the substantial clinical benefit. To date, there is a paucity of analysis of pertuzumab using real-world data for cost-effectiveness.
To assess the cost-effectiveness of pertuzumab, trastuzumab, and chemotherapy vs trastuzumab and chemotherapy for patients with metastatic breast cancer.
A population-based retrospective economic evaluation was conducted in Ontario, Canada. Patients who received first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, were identified. Patients were followed up from the start of treatment up to 5 years, with maximum follow-up to March 31, 2019. Patients were identified from the Ontario Cancer Registry and linked to the New Drug Funding Program database to identify receipt of first-line treatment (N = 1158).
Treatment with pertuzumab, trastuzumab, and chemotherapy after public funding (November 25, 2013) compared with treatment with trastuzumab and chemotherapy before funding.
Cost-effectiveness, from a public payer perspective, was estimated from administrative data with a 5-year time horizon, adjusted for censoring, and discounted (1.5%). Incremental cost-effectiveness ratios for life-years gained and quality-adjusted life year (QALY) with bootstrapped 95% CIs were calculated. Sensitivity analysis with price reduction of pertuzumab alone or in combination with trastuzumab was conducted.
A total of 579 pairs of matched patients receiving pertuzumab and controls were included. The mean (SD) age of the matched study cohort was 58 (12.97) years; 1151 were women (99.4%). Pertuzumab resulted in 0.61 life-years gained and 0.44 QALYs gained at an incremental cost of $192 139 (all costs measured in Canadian dollar values, CAD) with an incremental cost-effectiveness ratio of $316 203 per life-year gained and $436 679 per QALY. The main factors associated with cost included the cost of pertuzumab (60%), outpatient cancer treatment delivery (24%), and trastuzumab (15%). With 100% price reduction of pertuzumab, the incremental cost-effectiveness ratio was $174 027 per QALY. When the price of pertuzumab and trastuzumab were both reduced by more than 71%, the incremental cost-effectiveness ratio decreased below $100 000 per QALY.
The findings of this population-based study suggest that pertuzumab may increase survival for patients with metastatic breast cancer but would not be considered cost-effective, even after 100% price reduction, under conventional thresholds.
The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration was established to develop a framework for generating and using real-world evidence (RWE) to inform the ...reassessment of cancer drugs following initial health technology assessment (HTA). The Reassessment and Uptake Working Group (RWG) is one of the five established CanREValue Working Groups. The RWG aims to develop considerations for incorporating RWE for HTA reassessment and strategies for using RWE to reassess drug funding decisions. Between February 2018 and December 2019, the RWG attended four teleconferences (with follow-up surveys) and two in-person meetings to discuss recommendations for the development of a reassessment process and potential barriers and facilitators. Modified Delphi methods were used to gather input. A draft report of recommendations (to December 2018) was shared for public consultation (December 2019 to January 2020). Initial considerations for developing a reassessment process were proposed. Specifically, reassessment can be initiated by diverse stakeholders, including decision makers from public drug plans or industry stakeholders. The reassessment process should be modelled after existing deliberation and recommendation frameworks used by HTA agencies. Proposed reassessment outcome categories include maintaining status quo, revisiting funding criteria, renegotiating price, or disinvesting. Overall, these initial considerations will serve as the basis for future advancements by the Collaboration.
Importance In response to an increase in COVID-19 infection rates in Ontario, several systemic treatment (ST) regimens delivered in the adjuvant setting for breast cancer were temporarily permitted ...for neoadjuvant-intent to defer nonurgent breast cancer surgical procedures. Objective To examine the use and compare short-term outcomes of neoadjuvant-intent vs adjuvant ST in the COVID-19 era compared with the pre–COVID-19 era. Design, Setting, and Participants This was a retrospective population-based cohort study in Ontario, Canada. Patients with cancer starting selected ST regimens in the COVID-19 era (March 11, 2020, to September 30, 2020) were compared to those in the pre–COVID-19 era (March 11, 2019, to March 10, 2020). Patients were diagnosed with breast cancer within 6 months of starting systemic therapy. Main Outcomes and Measures Estimates were calculated for the use of neoadjuvant vs adjuvant ST, the likelihood of receiving a surgical procedure, the rate of emergency department visits, hospital admissions, COVID-19 infections, and all-cause mortality between treatment groups over time. Results Among a total of 10 920 patients included, 7990 (73.2%) started treatment in the pre–COVID-19 era and 7344 (67.3%) received adjuvant ST; the mean (SD) age was 61.6 (13.1) years. Neoadjuvant-intent ST was more common in the COVID-19 era (1404 of 2930 patients 47.9%) than the pre–COVID–19 era (2172 of 7990 patients 27.2%), with an odds ratio of 2.46 (95% CI, 2.26-2.69;P < .001). This trend was consistent across a range of ST regimens, but differed according to patient age and geography. The likelihood of receiving surgery following neoadjuvant-intent chemotherapy was similar in the COVID-19 era compared with the pre–COVID-19 era (log-rankP = .06). However, patients with breast cancer receiving neoadjuvant-intent hormonal therapy were significantly more likely to receive surgery in the COVID-19 era (log-rankP < .001). After adjustment, there were no significant changes in the rate of emergency department visits over time between patients receiving neoadjuvant ST, adjuvant ST, or ST only during the ST treatment period or postoperative period. Hospital admissions decreased in the COVID-19 era for patients who received neoadjuvant ST compared with adjuvant ST or ST alone (Pfor interaction = .01 for both) in either setting. Conclusions and Relevance In this cohort study, patients were more likely to start neoadjuvant ST in the COVID-19 era, which varied across the province and by indication. There was limited evidence to suggest any substantial impact on short-term outcomes.
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