Preferred Endpoint Research Articles

Real-world correlation of RFS and OS in early-stage hepatocellular carcinoma treated with curative intent: A retrospective analysis of SEER-Medicare data.

451 Background: Curative intent therapy with resection or ablation for early-stage HCC is associated with high incidence of recurrence. Effective adjuvant therapy is needed to improve outcomes. While OS is the preferred endpoint for demonstrating efficacy of new adjuvant therapies, recurrence-free survival (RFS) may better reflect the benefits associated with adjuvant therapy due to being independent of subsequent therapies upon recurrence. Additionally, RFS may provide insights into patient (pt) outcomes while OS data are immature. We assessed the correlation between OS and RFS in pts with early-stage HCC after treatment with curative intent. Methods: This study used the SEER-Medicare database (2007–2017). RFS was defined as time from curative intent therapy, by local ablation or surgical resection, until death or disease recurrence (first of: new HCC treatment, liver transplant, metastatic disease). OS was defined as time from curative intent therapy until death. Kaplan-Meier analyses were used, censoring on end of Medicare Parts A/B/D continuous eligibility or end of data availability. RFS/OS were summarized overall and by type of prior local therapy and risk of recurrence. Pts with a solitary tumor with histologic grade 3 or 4, solitary tumor >3cm, or multiple tumors were classified as high to very high risk. Pts with a solitary tumor not histologic grade 3 or 4 or a solitary tumor ≤3 cm were classified as low to intermediate risk. Correlation between RFS and OS was assessed using the Kendall’s τ rank correlation. Results: 611 HCC pts met the inclusion criteria (mean follow-up 3.3 years; mean age 73.3 years). Average (median) primary tumor size at diagnosis was 4.8 (4) cm. 91.6% of pts had a solitary tumor at diagnosis. 66.1% of pts experienced death or recurrence (Table). Median [IQR] OS and RFS post-curative intent therapy were 4.6 [1.8, NR] and 1.8 [0.8, 6.3] years, respectively. OS and RFS were poorer for those in the ablation (median OS 3.2 years; RFS 1.2 years) and high to very high risk of recurrence group (median OS 4.3 years; RFS 1.4 years). Kendall’s τ rank correlation model in the overall group demonstrated a statistically significant positive correlation between RFS and OS (τ = 0.66; 95% CI: 0.60–0.70; P < 0.001). Conclusions: Based on real-world data, a significant positive correlation between RFS and OS supports RFS as an efficacy marker and appropriate endpoint for pts in adjuvant HCC setting when OS data are immature. [Table: see text]

Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.

The effects of aneurysmal subarachnoid hemorrhage on cerebral vessel diameter and flow velocity

BackgroundTranscranial Doppler flow velocity is used to monitor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Generally, blood flow velocities appear inversely related to the square of vessel diameter representing local fluid dynamics. However, studies of flow velocity-diameter relationships are few, and may identify vessels for which diameter changes are better correlated with Doppler velocity. We therefore studied a large retrospective cohort with concurrent transcranial Doppler velocities and angiographic vessel diameters. MethodsThis is a single-site, retrospective, cohort study of adult patients with aneurysmal subarachnoid hemorrhage, approved by the UT Southwestern Medical Center Institutional Review Board. Study inclusion required transcranial Doppler measurements within </= 24 hours of vessel imaging. Vessels assessed were: bilateral anterior, middle, posterior cerebral arteries; internal carotid siphons; vertebral arteries; and basilar artery. Flow velocity-diameter relationships were constructed and fitted with a simple inverse power function. A greater influence of local fluid dynamics is suggested as power factors approach two. Results98 patients were included. Velocity-diameter relationships are curvilinear, and well fit by a simple inverse power function. Middle cerebral arteries showed the highest power factors (>1.1, R2>0.9). Furthermore, velocity and diameter changed (P<0.033) consistent with the signature time course of cerebral vasospasm. ConclusionsThese results suggest that middle cerebral artery velocity-diameter relationships are most influenced by local fluid dynamics, which supports these vessels as preferred endpoints in Doppler detection of cerebral vasospasm. Other vessels showed less influence of local fluid dynamics, pointing to greater role of factors outside the local vessel segment in determining flow velocity.

The Jim Croce Question

The Jim Croce Question

Abstract IA15: Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge

Abstract Trial Design and Endpoint Definition in general is more complex in hepatocellular carcinoma compared to other solid tumors. It took decades of research until the first systemic treatment was defined in 2007 as a result of the SHARP and the ASIA-Pacific trials. The demonstration of Sorafenib’s anti-tumor efficacy in advanced HCC to a large extend was owing to the concentration on patients with good liver function, avoiding the confounding impact of liver cirrhosis. In intermediate stage HCC trial design is even more challenging: intermediate stage HCC is a heterogeneous disease with a broad spectrum of tumor burden, variable liver function, and radiological intervention with transarterial chemoembolization (TACE) as a standard procedure which is far beyond standardization. Several trials have been launched either combining TACE with systemic therapy or comparing TACE vs. systemic therapy. Several issues in this setting are questioning overall survival as preferred endpoint: with an expected survival in excess of 2.5 years and several systemic therapies available, the competing risks of death (liver disease) and the contribution of post-trial treatments are increasingly impacting OS and obscuring the effectiveness of the trial-specific intervention. This is exemplified by the TACTICS trial, comparing TACE + Sorafenib with TACE, where a solid PFS benefit for the combination (HR: 0.661) did not translate into OS (HR: 0.861), possibly because of a more than 20% higher rate of post-treatment medication in the TACE-only group. Thus, there is an obvious need for surrogate markers, indicative of increased survival time but shifting overall survival analysis into secondary endpoints. We recently started the ABC-HCC trial, a phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma. Here we are using a pragmatic and real-life endpoint, Time to failure of treatment strategy (TTFS) as primary endpoint. TTFS is defined as Time from randomization until failure of strategy, i.e. radiologic progression or lack of radiologic response AND any of the following: the loss of clinical benefit OR unacceptable toxicity OR liver function deterioration OR therapy not further applicable for other reasons Secondary endpoints comprise OS, Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to loss of systemic treatment options (TTSYS), Progression free survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to deterioration of liver function, Safety, and QoL (Patient Reported Outcome; PRO). The trial includes an exploratory biomarker analysis. The ABC-HCC and other trials will give us information on the role of systemic therapy in intermediate stage HCC in the upcoming years. Citation Format: Peter R Galle. Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA15.

Chlorophyll Fluorescence Imaging-Based Duckweed Phenotyping to Assess Acute Phytotoxic Effects.

Duckweeds (Lemnaceae species) are extensively used models in ecotoxicology, and chlorophyll fluorescence imaging offers a sensitive and high throughput platform for phytotoxicity assays with these tiny plants. However, the vast number of potentially applicable chlorophyll fluorescence-based test endpoints makes comparison and generalization of results hard among different studies. The present study aimed to jointly measure and compare the sensitivity of various chlorophyll fluorescence parameters in Spirodela polyrhiza (giant duckweed) plants exposed to nickel, chromate (hexavalent chromium) and sodium chloride for 72 h, respectively. The photochemistry of Photosystem II in both dark- and light-adapted states of plants was assessed via in vivo chlorophyll fluorescence imaging method. Our results indicated that the studied parameters responded with very divergent sensitivity, highlighting the importance of parallelly assessing several chlorophyll fluorescence parameters. Generally, the light-adapted parameters were more sensitive than the dark-adapted ones. Thus, the former ones might be the preferred endpoints in phytotoxicity assays. Fv/Fm, i.e., the most extensively reported parameter literature-wise, proved to be the least sensitive endpoint; therefore, future studies might also consider reporting Fv/Fo, as its more responsive analogue. The tested toxicants induced different trends in the basic chlorophyll fluorescence parameters and, at least partly, in relative proportions of different quenching processes, suggesting that a basic distinction of water pollutants with different modes of action might be achievable by this method. We found definite hormetic patterns in responses to several endpoints. Hormesis occurred in the concentration ranges where the applied toxicants resulted in strong growth inhibition in longer-term exposures of the same duckweed clone in previous studies. These findings indicate that changes in the photochemical efficiency of plants do not necessarily go hand in hand with growth responses, and care should be taken when one exclusively interprets chlorophyll fluorescence-based endpoints as general proxies for phytotoxic effects.

Patients and general practitioners assessment of the main outcomes employed in the acute and preventive treatment of migraine: a cross sectional study

BackgroundWe aim to describe and compare patients and general practitioners’ opinions about the different variables related to acute and preventive treatment for migraine.Patients and methodsAn observational descriptive study was performed. Patients with episodic migraine and general practitioners, from our healthcare area, were invited to answer a survey about the different variables related to migraine treatment. They were asked for their opinions on the different variables, and to consider the desired efficacy in percentage terms and the desired action times of treatment.ResultsFifty-five patients and fifty-five general practitioners were selected. Effectiveness was considered the most important variable for symptomatic and preventive treatment. Cost was considered the least important variable. Patients desired percentage of efficacy was 84.0% (±16.7%) for symptomatic treatment and 79.9% (±17.1%) for preventive treatment. General practitioners desired percentage of efficacy was 75.0% (±14.0) for symptomatic treatment and 70.4% (±14.3) for preventive treatment. For symptomatic treatment the desired action time for pain cessation was selected as 27.5 min (±13.8) for patients and 24.0 min (±18.3) for GPs. For preventive treatment the desired action time for effect was 7.1 days (±4.5) for patients and 13.9 days (±8.9) for general practitioners.ConclusionThe most important endpoints were, for acute: effectiveness, a short action time and a persistent effect. For prophylactic: effectiveness, sustained effect and tolerability. Both patients and general practitioners agreed on the most and least preferred endpoints. Desired percentage of efficacy was above 75% for both symptomatic and preventive treatment; and the desired action time was below 30 min for acute treatment and 2 weeks for preventive treatment.

Deep learning for classification of pediatric chest radiographs by WHO's standardized methodology.

The World Health Organization (WHO)-defined radiological pneumonia is a preferred endpoint in pneumococcal vaccine efficacy and effectiveness studies in children. Automating the WHO methodology may support more widespread application of this endpoint. We trained a deep learning model to classify pneumonia CXRs in children using the World Health Organization (WHO)'s standardized methodology. The model was pretrained on CheXpert, a dataset containing 224,316 adult CXRs, and fine-tuned on PERCH, a pediatric dataset containing 4,172 CXRs. The model was then tested on two pediatric CXR datasets released by WHO. We also compared the model's performance to that of radiologists and pediatricians. The average area under the receiver operating characteristic curve (AUC) for primary endpoint pneumonia (PEP) across 10-fold validation of PERCH images was 0.928; average AUC after testing on WHO images was 0.977. The model's classification performance was better on test images with high inter-observer agreement; however, the model still outperformed human assessments in AUC and precision-recall spaces on low agreement images. A deep learning model can classify pneumonia CXR images in children at a performance comparable to human readers. Our method lays a strong foundation for the potential inclusion of computer-aided readings of pediatric CXRs in vaccine trials and epidemiology studies.

Goals of endoscopic eradication therapy in Barrett’s esophagus: a narrative review

: Barrett’s esophagus is a premalignant condition, and endoscopic eradication therapy is indicated upon development of early neoplasia. Therapy consists of endoscopic resection for visible lesions, if present, followed by endoscopic ablation for remaining flat Barrett’s epithelium. Since Barrett’s esophagus with early neoplasia in itself is asymptomatic disease, the ultimate goal of endoscopic eradication therapy is to prevent progression to advanced cancer: a disease stage with limited treatment options and a poor prognosis. The preventive nature of endoscopic treatment may give rise to debate about the preferred endpoint to pursue. Establishment of a careful balance between the benefits of endoscopic eradication therapy against its risks, such as complications and other adverse events, may help to define the optimum endpoint for each individual patient. To date, various endpoints have been used in regular practice and different endpoints are used in clinical studies. The most important differences between these endpoints are whether all visible Barrett’s epithelium is eradicated or all dysplasia and cancer; and whether the endpoint is assessed on endoscopic examination only or with histologic confirmation. In this narrative review, we aim to evaluate these different endpoints of endoscopic eradication therapy with potential advantages and limitations, and present three clinical vignettes each with a different suggestion for an appropriate treatment endpoint.

Adjudication Of Cause-specific Endpoints In Heart Failure Trials

Introduction Clinical endpoints are standard outcomes measures used to prove treatment effect in clinical trials. Differences in endpoint definitions and ascertainment of cause-specific clinical events influence the validity of heart failure (HF) trials. Cause-specific clinical events have become preferred endpoints because they separate signals of efficacy from noise (non-related events). Clinical endpoints could be ascertained through case report forms (CRFs) by investigators or through a central adjudication method by a Clinical Endpoint Committee (CEC). Investigator reporting is more efficient and inexpensive but is affected by inaccuracy, geographic variability, and complexity of endpoint definitions. CEC adjudication is a standardized, blind and independent ascertainment process but may be limited by high costs. Aims To analyze cause-specific endpoints, and the need for CEC adjudication in HF trials, comparing HF with reduced versus preserved ejection fraction (EF). Methods We analyzed 10 HF with reduced EF (HFrEF) trials and five HF with preserved EF (HFpEF) trials. For each trial we described and compared the prevalence of all-cause and cause-specific mortality. Results A comparison between all-cause mortality and cardiovascular mortality in 9 selected HFrEF and HFpEF clinical trials is presented in Figure 1. The relative proportion of CV death was significantly lower in HFpEF compared with HFrEF trials. Additionally, in HFrEF, the relative proportion of CV death was significantly lower in recent trials compared with early trials. CV specific endpoints were the primary cause of death in HF trials. Conclusions There are more CV deaths in HFrEF trials, although it is the primary mode of death in both populations. CEC adjudication may be more beneficial in HFpEF vs. HFrEF trials, and in recent HFrEF trials due to the increase in non-CV events which may attenuate the treatment effect.

Impact of Targeted Therapies for Coronary Microvascular Dysfunction as Assessed by the Index of Microcirculatory Resistance.

Coronary microvascular dysfunction (CMD) has emerged as an important therapeutic target in the contemporary management of ischemic heart disease. However, due to a lack of a reliable traditional "gold standard" test for CMD, optimal treatment remains undefined. The index of microcirculatory resistance (IMR) is an intra-coronary wire-based technique that provides a more reliable and quantitative assessment of CMD and has been increasingly used as a preferred endpoint for evaluating CMD treatment strategies in recent studies. IMR can help diagnose CMD in angina patients with non-obstructive epicardial coronary disease, predict peri-procedural myocardial infarction in stable patients undergoing coronary stenting, and predict long-term prognosis after acute myocardial infarction. Studies of IMR in the setting of non-ST-elevation acute coronary syndromes are still lacking. This review critically appraises the current published literature evaluating targeted therapies for CMD using IMR as the assessment tool and provides insights into evidence gaps in this important field. The index of microcirculatory resistance has rapidly evolved from a research tool to being the new "gold standard" test for evaluating coronary microvascular dysfunction.

Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma

It is difficult to demonstrate an overall survival (OS) benefit in trials of immediate therapy vs observation in follicular lymphoma (FL). Time to 2nd treatment (TT2T) may be a preferred endpoint. We identified 584 consecutive patients at our institution with advanced stage FL grade 1–3 A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TT2T, and OS were estimated (subdistribution function). Modified Kendall's tau (mKτ) was used to assess correlation between survival endpoints. Among initially observed patients, median TT1T was 3.3 years, TT2T was 12.1 years, 10-year treatment-free survival was 23%, and 10-year OS was 82%. TT2T was strongly correlated with OS following initial observation (mKτ 0.46, p = .004) or therapy (mKτ 0.53, p < .0001), while duration of observation was not. TT2T is a potential surrogate for OS. Given the outstanding survival in this population, early intervention trials should focus on identifying high risk patients.

FIT: Functional and imaging testing for patients with metastatic cancer.

208 Background: Despite multiple cancer cachexia (CC) trials evaluating novel agents, the FDA has not approved a single drug to date. One key challenge in CC trials is selection of endpoints. The aim of this study was to explore changes in body composition and associations with functional and patient-reported outcomes (PROs) to clarify CC trial endpoint selection. Methods: We identified metastatic solid tumor cancer patients receiving cancer-directed therapies at a single cancer center (2016-2018). Patients completed all assessments at study enrollment and 3 months from enrollment. We analyzed body composition utilizing cross-sectional computed tomography (CT) scans at the third lumbar vertebra. Functional assessments included the 6-minute walk test (6MWT), Timed Up-and-Go (TUG) test, and Short Physical Performance Battery (SPPB). PROs included the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) and Functional Assessment of Cancer Therapy Fatigue (FACT-F). We examined changes in body composition and functional assessments from enrollment to 3 months using paired t-tests. We utilized linear regression models to assess the relationship between changes in body composition and changes in functional assessment adjusting for age and sex. Results: A total of 57 patients completed baseline assessments; 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data (mean age 61.8 years, 47% female, 71% GI malignancy), 50% received chemotherapy, 16% immunotherapy, and 34% combination therapy. From enrollment to 3 months, we observed an increase in total adipose tissue (16.9±52.4 cm2, 95% CI -33.79-0.63; p = 0.059), but not weight or skeletal muscle. Greater losses in skeletal muscle were associated with greater declines in 6MWT (B = 0.036, p = 0.014) and SBBP (B = 2.444, p = 0.002), but not the TUG. We observed no association with change in weight with all functional outcomes or PROs. Moreover, we found no association with body composition and PROs from enrollment to 3 months. Conclusions: In future CC trials, changes in longitudinal body composition rather than weight should be utilized. Furthermore, changes in skeletal muscle and the 6MWT and/or SBBP may be preferred endpoints.

Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration

Background: PF-06412562 is a moderately potent, highly selective oral D₁/D₅ dopamine receptor partial agonist. Objective: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. Methods: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using Kinesia^TM technology (as the primary end point) and change from baseline in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. Results: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of –10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (–inf, –7.44) at 1.5–2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. Conclusions: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D₁/D₅ partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D₁ agonists.

Mucosal Healing in Ulcerative Colitis: A Comprehensive Review.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-α drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNFα drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings.

Implementation of flame optical emission spectroscopy system for converter Fe end-point control associated with Ni-Cu-S-PGM converter mattes

Iron endpoint control in nickel-copper converting operations is critical for optimal operation of subsequent hydrometallurgical extraction and refining operations and has additional impacts where such operations are also associated with platinum group metal (PGM) processing. The identification of the optimal converter iron endpoint, its impact on operations and real time inferential detection are discussed. An evaluation of the thermochemistry was conducted with thermodynamic equilibrium modelling software and validation of the data was performed with actual plant data and operating experience. The impact of iron endpoint on the quality of the matte, from a downstream refining perspective, environmental and safety considerations and the impact on smelter costs were qualitatively evaluated. Different methodologies of end-point control in the converter are discussed with emphasis on flame optical emission spectroscopy as the preferred endpoint monitoring method. While optical emission spectroscopy as a tool to determine the oxidation state in a converter is well established in the Cu industry its application in Ni matte converting is recent. Western Platinum has been the first PGM producer to apply this technology for iron endpoint control. Results achieved after implementation are presented and the current focus/development areas are listed, specifically around the practice in which the converters at Western Platinum Limited finishes the blow before granulation.

Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries

There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used end points in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL), varies, leading to the available evidence being valued differently. This research studies the extent to which the value of end points for cancer medicines differs among European decision makers. We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, The Netherlands, Poland, and Scotland. Anticancer medicines that received marketing authorization in Europe between 2011 and 2013 with at least four available national REAs were evaluated. A total of 79 REAs were included. Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant end points such as OS and QoL above surrogate end points. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant end point. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred end point by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies. European decision-making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited.

Population pharmacokinetic–pharmacodynamic modelling in oncology: a tool for predicting clinical response

In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic–pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.

Time to Second Objective Disease Progression (PFS2): An Emerging Clinical Trial Endpoint with Regulatory and Reimbursement Implications

Introduction: Overall survival (OS) continues to be the preferred endpoint for measuring sustained clinical benefits in oncology trials. In some cases, measuring OS can be problematical due to trial design, multiple lines of treatment (Tx), long survival times, and other factors. In this context, there is growing interest in the time to second objective disease progression (PFS2) for Txs with good toxicity profiles.The European Medicines Agency (EMA) recommends the use of PFS2 to help understand the relevance of meaningful improvements in PFS when OS cannot be measured (e.g. maintenance Tx, increased number of “induction” cycles) (EMA, 2012). PFS2 is defined as “time from randomisation to objective tumour progression on next-line treatment or death from any cause. In some cases, time on next-line therapy may be used as proxy for PFS.”PFS2 is likely to become an important endpoint for regulatory and reimbursement evaluations in Europe and elsewhere as a result of the recent EMA guidance. Therefore there is a need to optimally understand the role PFS2 is likely to play in clinical trial results and their application.Methods: We undertook a search on clinicaltrials.gov for cancer trials that include PFS2 as an endpoint (search terms: cancer AND PFS; cancer AND PFS2). Through mapping of drugs vs. other endpoints, stage of development, likely or current indications, and other factors, we considered whether PFS2 would have a role in a potentially new or changed indication and therefore in regulatory and health technology assessment (HTA) submissions. Based on this, we have identified critical areas where understanding and use of PFS2 data may pose challenges in the submission processes, from the perspectives of the clinical trial sponsor and regulatory agency.Results: As of July 2014, a total of 7,957 cancer trials list PFS as an endpoint; 14 of these include PFS2. In all cases, PFS2 is listed as a secondary endpoint. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. It is being studied in the context of either maintenance (10/14 trials) or sequential Tx (3/14) and has the potential for inclusion in regulatory and HTA submissions in all cases.The types of oncology trials in which PFS2 is being assessed included multiple myeloma (n = 3), prostate cancer (n = 2), breast cancer (n = 2), head and neck cancer (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), and pancreatic cancer (n = 1). There are 6 phase 2 and 8 phase 3 trials that are listed as either not yet recruiting (n = 4), ongoing (n = 4), or recruiting (n = 6).We identified a number of issues for key groups that may arise from the inclusion of PFS2 in clinical trials. For healthcare professionals there is a need to understand the clinical relevance of a new endpoint that may provide additional and complementary information on Tx of progressive disease from both medical and patient (pt) perspectives. For trial sponsors, clear and clinically relevant communication of PFS2 results is needed and data must be included in medical and economic models. Agencies evaluating regulatory or HTA submissions must understand the benefits shown by an improved PFS2, whether or not there is an improvement in OS, and methodologies for evaluating the medical and economic value of PFS2 are required.Restricting our search to clinicaltrials.gov was associated with some limitations. For example, some trials in which PFS2 has been measured could have been missed due to ongoing updates to publically available information. Also, in some cases, post-hoc analyses may have evaluated PFS2 without a change to website details. Trials in which PFS2 has been measured and data published were not part of the search strategy.Conclusions: PFS2 is emerging as a secondary endpoint in a growing number of clinical oncology trials assessing the benefits of maintenance or sequential Tx. Although data are currently limited, the results of trials currently listed on clinicaltrials.gov will help to determine how PFS2 provides additional and complementary information about Tx of progressive disease from both medical and pt perspectives. DisclosuresMbanya:PHMR Associates: Consultancy. Chadda:PHMR Associates: Consultancy.