Assessment Of Clinical Benefit Research Articles

Assessing the benefits of digital health solutions in the societal reimbursement context

For anumber of reasons, achieving reimbursability for digital health products has so far proven difficult. Demonstrating the benefits of the technology is the main hurdle in this context. The generally accepted evaluation processes, especially parallel group comparisons in randomized controlled trials (RCTs) for (clinical) benefit assessment, are primarily intended to deal with questions of (added) medical benefit. In contrast to drugs or classical medical devices, users of digital health solutions often profit from gaining autonomy, increased awareness and mindfulness, better transparency in the provision of care, and improved comfort, although there are also digital solutions with an interventional character targeting clinical outcomes (e. g. for indications such as anorexia, depression). Commonly accepted methods for evaluating (clinical) benefits primarily rely on medical outcomes, such as morbidity and mortality, but do not adequately consider additional benefits unique to digital health. The challenge is therefore to develop evaluation designs that respect the particularities of digital health without reducing the validity of the evaluations (especially with respect to safety). There is an increasing need for concepts that include both continuous feedback loops for adapting and improving an application while at the same time generate sufficient evidence for complex benefit assessments. This approach may help improve risk benefit ratio assessments of digital health when it comes to implementing digital innovations in healthcare.

OP163 European Network for Health Technology Assessment Joint Action 3 Relative Effectiveness Pilots: Pharma Company Experience

Introduction:More than 50 HTA agencies evaluate the clinical value of medicines in Europe, resulting in duplication of work for HTA agencies and manufacturers, and lengthy and variable time to reimbursement for patients across Europe. A consistent, single European relative clinical scientific benefit assessment of medicines could become a key element in ensuring patients get equitable and timely access across Europe. The European Network for Health Technology Assessment (EUnetHTA) is responsible under Joint Action 3 (JA3, 2016–2020) to pilot more than 30 Relative Effectiveness Assessments (REAs) of medicines. The first EUnetHTA JA3 REA pilots are now being completed and Roche, with its participation in the REA pilot for alectinib, has gathered relevant experience.Methods:The goal of this analysis is to summarize and reflect upon the experience with one of the first EUnetHTA REA assessments in JA3. The authors also propose potential process improvements.Results:The experience with the alectenib REA shows that EUnetHTA processes have improved compared to JA2. The timing of the assessment has been aligned with the EU regulatory marketing authorization process by shortening the duration of the scoping phase. More EUnetHTA members than in JA2 seem to be committed to use the reports in national HTA, pricing and reimbursement processes. At the same time, the REA pilots have identified other areas that could benefit from further refinement, for example the active engagement of patient group representatives and clinical experts, rules and principles related to the handling of confidential information.Conclusions:Based on the limited number of REA pilots for medicines it is too early to draw final conclusions on the state of EU-level collaboration. But first signals indicate a positive development compared to REA pilots conducted in JA2. Interim evaluations are recommended to assess progress, and capture learnings for future pilots.

Assessment of Minimum Important Difference and Substantial Clinical Benefit with the Vascular Quality of Life Questionnaire-6 when Evaluating Revascularisation Procedures in Peripheral Arterial Disease

Patient reported outcomes are increasingly used to assess outcomes after peripheral arterial disease (PAD) interventions. VascuQoL-6 (VQ-6) is a PAD specific health-related quality of life (HRQoL) instrument for routine clinical practice and clinical research. This study assessed the minimum important difference for the VQ-6 and determined thresholds for the minimum important difference and substantial clinical benefit following PAD revascularisation. This was a population-based observational cohort study. VQ-6 data from the Swedvasc Registry (January 2014 to September 2016) was analysed for revascularised PAD patients. The minimum important difference was determined using a combination of a distribution based and an anchor-based method, while receiver operating characteristic curve analysis (ROC) was used to determine optimal thresholds for a substantial clinical benefit following revascularisation. A total of 3194 revascularised PAD patients with complete VQ-6 baseline recordings (intermittent claudication (IC) n=1622 and critical limb ischaemia (CLI) n=1572) were studied, of which 2996 had complete VQ-6 recordings 30 days and 1092 a year after the vascular intervention. The minimum important difference 1 year after revascularisation for IC patients ranged from 1.7 to 2.2 scale steps, depending on the method of analysis. Among CLI patients, the minimum important difference after 1 year was 1.9 scale steps. ROC analyses demonstrated that the VQ-6 discriminative properties for a substantial clinical benefit was excellent for IC patients (area under curve (AUC) 0.87, sensitivity 0.81, specificity 0.76) and acceptable in CLI (AUC 0.736, sensitivity 0.63, specificity 0.72). An optimal VQ-6 threshold for a substantial clinical benefit was determined at 3.5 scale steps among IC patients and 4.5 in CLI patients. The suggested thresholds for minimum important difference and substantial clinical benefit could be used when evaluating VQ-6 outcomes following different interventions in PAD and in the design of clinical trials.

Using health technology assessment to assess the value of new medicines: results of a systematic review and expert consultation across eight European countries

BackgroundAlthough health technology assessment (HTA) systems base their decision making process either on economic evaluations or comparative clinical benefit assessment, a central aim of recent approaches to value measurement, including value based assessment and pricing, points towards the incorporation of supplementary evidence and criteria that capture additional dimensions of value.ObjectiveTo study the practices, processes and policies of value-assessment for new medicines across eight European countries and the role of HTA beyond economic evaluation and clinical benefit assessment.MethodsA systematic (peer review and grey) literature review was conducted using an analytical framework examining: (1) ‘Responsibilities and structure of HTA agencies’; (2) ‘Evidence and evaluation criteria considered in HTAs’; (3) ‘Methods and techniques applied in HTAs’; and (4) ‘Outcomes and implementation of HTAs’. Study countries were France, Germany, England, Sweden, Italy, Netherlands, Poland and Spain. Evidence from the literature was validated and updated through two rounds of feedback involving primary data collection from national experts.ResultsAll countries assess similar types of evidence; however, the specific criteria/endpoints used, their level of provision and requirement, and the way they are incorporated (e.g. explicitly vs. implicitly) varies across countries, with their relative importance remaining generally unknown. Incorporation of additional ‘social value judgements’ (beyond clinical benefit assessment) and economic evaluation could help explain heterogeneity in coverage recommendations and decision-making.ConclusionMore comprehensive and systematic assessment procedures characterised by increased transparency, in terms of selection of evaluation criteria, their importance and intensity of use, could lead to more rational evidence-based decision-making, possibly improving efficiency in resource allocation, while also raising public confidence and fairness.

Retrospective evaluation of toceranib phosphate (Palladia) use in cats with mast cell neoplasia.

Objectives The purpose of this study was to solicit and compile data from practicing veterinary specialists regarding their use of toceranib in cats with mast cell neoplasia and to provide initial assessment of possible clinical benefit and adverse events. Methods The American College of Veterinary Internal Medicine and Oncology listservs were used to solicit data pertaining to cases in which toceranib was used in the treatment of feline mast cell neoplasia. Cases were included if the following data were received: signalment (age, sex, breed), diagnosis of mast cell neoplasia by either cytology or histopathology, anatomic classification of disease (cutaneous, splenic/hepatic, gastrointestinal, other), previous and concurrent treatment, toceranib dose (mg/kg) and schedule, duration of therapy, best response and documentation of adverse events. Results Case data from 50 cats with cutaneous (n = 22), splenic/hepatic (visceral) (n = 10), gastrointestinal (n = 17) or other (n = 1) mast cell neoplasia were received. Clinical benefit was seen in 80% (40/50), including 86% (19/22) with cutaneous, 80% (8/10) with visceral and 76% (13/17) with gastrointestinal involvement. A majority of cats (n = 35) received glucocorticoids during toceranib treatment. Median duration of treatment in cats experiencing clinical benefit was 36 weeks (range 4-106 weeks), 48 weeks (range 12-199 weeks) and 23 weeks (range 13-81 weeks) for cutaneous, visceral and gastrointestinal cases, respectively. Toceranib was administered at a median dose of 2.5 mg/kg (range 1.6-3.5 mg/kg); in 90% (45/50) the drug was given three times per week. Treatment was generally well tolerated with 60% (30/50) of cats experiencing adverse events. The majority of these events were low-grade (grade 1 or 2) gastrointestinal or hematologic events that resolved with treatment break and/or dose adjustment. Conclusions and relevance Toceranib appears to be well tolerated in feline patients with mast cell neoplasia. Biologic activity of this drug is evident in the studied cats; however, further prospective studies are needed to elucidate fully its role in treatment of this disease.

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes.

To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. A total of 72 people [46 men, mean±sd age 54 ± 12years, mean±sd HbA1c 65±12mmol/mol (8.1±1.1%), mean±sd duration of diabetes 30±14years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose≤3.9mmol/l). During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P<0.0001) with insulin analogue. Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.

Efficacy and Safety of Ruxolitinib in Regularly Transfused Patients with Thalassemia: Results from Single-Arm, Multicenter, Phase 2a Truth Study

BACKGROUND: Ruxolitinib (RUX) is approved in adult patients (pts) with myelofibrosis (MF), and in pts with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea. Splenomegaly, a key clinical feature in advanced MF/PV, is also common in pts with transfusion-dependent thalassemia (TDT). In pts with TDT, splenomegaly worsens anemia, leading to increased transfusion requirement (TR). Similar to murine models of MF (Ostojic A, 2012), JAK2 inhibition led to a decrease in spleen size in murine models of thalassemia (Musallam KM, 2013). Additionally, thalassemia-related ineffective erythropoiesis was associated with hyperactivation of JAK-STAT pathway in preclinical studies. These findings indicate that RUX treatment (Tx) might benefit pts with TDT and splenomegaly. Present exploratory study aims to evaluate the effect of RUX Tx on TR, spleen volume (SV), and pre-transfusion hemoglobin (Hgb) levels. METHODS: TRUTH is a single-arm, multicenter, phase 2a study exploring the efficacy and safety of RUX in regularly transfused adult pts (N = 30) with thalassemia and splenomegaly, for 30 weeks (core study). Starting dose of RUX was 10 mg twice daily (maximum dose of 25 mg in 5 mg/10 mg increments). Pts were required to receive iron chelation (deferoxamine/deferasirox) for at least 4 week prior to screening and throughout the study. Primary end point was the percent change of red blood cells (RBCs) transfused between week 6 to 30 vs baseline period (BL; defined as period between 24 weeks prior to start of Tx and week 0). Change of SV from BL (by MRI/CT) at week 12 and week 30 was a secondary end point. Other secondary end points included safety (N = 30, safety set) and change of pre-transfusion Hgb level from BL. RESULTS: Of the 30 pts enrolled (median age, 24 years; 60% male), 26 completed the core phase at week 30 and 4 discontinued before week 30 (adverse event [AE], N = 2; withdrew consent, N = 1; subject/guardian decision, N = 1). Of those 26 who completed core Tx, 20 pts continue to receive RUX beyond the core study via other mechanisms. The median duration of exposure during the core phase was 30.2 weeks and median actual dose intensity of RUX was 27.2 mg/day (range, 13.3-39.0 mg/day). Mean hematocrit (HCT) adjusted volume of transfused RBC per 4 weeks was 605 mL for the BL period and 560 mL for the on-Tx period (between week 6-30; N = 27, per protocol set; 3 pts received 50 × 109/L, while no pt had PLT counts CONCLUSION: RUX Tx showed a trend for improvement in transfused red cells and a slight improvement in pre-transfusion Hgb; while, there was a noticeable reduction in SV over time. As per investigator assessment of clinical benefit, a majority of pts continued Tx beyond the core study. RUX was well tolerated in the study population with modest incidences of G 3 or 4 and serious AEs, with no new safety findings. Given the sustained decrease in SV, further studies could be valuable to determine if RUX Tx may be an alternative to splenectomy in pts with TDT. Disclosures Aydinok:Shire: Research Funding; Cerus: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Karakas:Novartis: Research Funding. Siritanaratkul:Jansen-Cilag: Research Funding; Novartis: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Hollaender:Novartis: Employment. Mahuzier:Novartis: Employment. Gadbaw:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding; Celgene: Research Funding.

Global Health and Graduate Medical Education: A Systematic Review of the Literature.

Global health (GH) interest is increasing in graduate medical education (GME). The popularity of the GH topic has created growth in the GME literature. The authors aim to provide a systematic review of published approaches to GH in GME. We searched PubMed using variable keywords to identify articles with abstracts published between January 1975 and January 2015 focusing on GME approaches to GH. Articles meeting inclusion criteria were evaluated for content by authors to ensure relevance. Methodological quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI), which has demonstrated reliability and validity evidence. Overall, 69 articles met initial inclusion criteria. Articles represented research and curricula from a number of specialties and a range of institutions. Many studies reported data from a single institution, lacked randomization and/or evidence of clinical benefit, and had poor reliability and validity evidence. The mean MERSQI score among 42 quantitative articles was 8.87 (2.79). There is significant heterogeneity in GH curricula in GME, with no single strategy for teaching GH to graduate medical learners. The quality of literature is marginal, and the body of work overall does not facilitate assessment of educational or clinical benefit of GH experiences. Improved methods of curriculum evaluation and enhanced publication guidelines would have a positive impact on the quality of research in this area.

Validation of prognostic scoring and assessment of clinical benefit for patients with bone sarcomas enrolled in phase I clinical trials.

BackgroundWe sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival.Patients and MethodsWe retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC's Phase I Clinical Trials Program.ResultsNinety-two patients with Ewing sarcoma (N = 47), osteosarcoma (N = 22), chondrosarcoma (N = 16), and other tumors (N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials. The median overall survival (OS) was 8.8 months (95% confidence interval [CI] = 6.8–13.7 months). Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level <10.5 g/dL, platelet count >200 x103/L, creatinine level ≥1.3 mg/dL, and lactate dehydrogenase level >ULN. Patients with good RMH scores (0-1) had longer OS than patients with poor RMH scores (2-3) (HR = 5.8, 95% CI = 2.9–11.0; P < 0.0001), as did patients with low MDACC scores (0-1) as compared to patients with higher MDACC scores (2–4) (HR = 3.2, 95% CI = 1.9–5.6; P < 0.0001).ConclusionThe RMH prognostic score can be used to predict the OS of bone cancer patients referred for phase I trials. The MDACC score added no value to the RMH score and therefore does not have a role in assessment of patients with bone tumors. Patients with advanced bone sarcomas should be considered for phase I trials.

Progression-free survival, overall survival and quality of life: What is their medicoeconomic importance in oncology?

Medico-economic evaluations estimate, for a given health technology, the added cost and the clinical benefit compared to a reference strategy. The objective here is to analyze the criteria used to measure clinical benefit as the basis for market access and reimbursement decisions for drugs in oncology both in France and in Europe. Prolonged overall survival is the criterion of choice to demonstrate the benefit of an anticancer drug; a survival gain of 2 to 3 months or more would be considered as relevant for a new product versus the comparator. In the absence of survival benefit or mature data on survival, progression-free survival or symptom-free survival and the availability of alternative curative treatments, decrease in drug toxicity and quality of life improvement may be considered. Differences in clinical benefit assessment between regulatory agencies and payers are not specific to France. Case studies show that it is difficult to find a consistency in reimbursement and pricing decisions and to identify factors that may fully explain reimbursement decisions when survival benefit is not demonstrated.

Genomic mutation profiling (GMP) and clinical outcome in patients (pts) treated with ribociclib (CDK4/6 inhibitor) in the Signature program.

2528Background: The Signature program comprises a series of 8 tissue-agnostic, mutation-specific, signal-seeking protocols without predetermined study sites, thereby bringing the protocol to the pt. Pts included in the ribociclib (LEE011) protocol had CDK4/6 pathway aberrations, identified via standard-of-care physician-directed profiling. Separate ribociclib phase 3 studies in breast cancer are ongoing. Methods: Pts with measurable advanced malignancies and no established standard therapy options were eligible. The primary objective was assessment of clinical benefit (CB; CR + PR + SD) at wk 16 by local investigator. Ribociclib was given orally (600 mg QD; 3 wk on, 1 wk off). Statistical design adaptively clustered pts into cohorts for independent analysis of early futility or efficacy. GMP of pt tumors was performed centrally for post hoc eligibility confirmation. Results: As of 28 Aug 2015, 106 pts were enrolled across 31 tumor types. Median age was 63 years (range, 19-86 years), 53% were women, and me...

Phase 3, Placebo-Controlled, ASPIRE Study (TRC114968) of Eltrombopag (EPAG) Treatment of Thrombocytopenia (TCP) in Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Assessment of Clinical Benefit, Safety, and Tolerability

▪Introduction: Thrombocytopenia (TCP) is a serious and life-threatening complication of advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is approved for treatment of chronic immune thrombocytopenic purpura and severe aplastic anemia. Preclinical studies showed that EPAG has potential antileukemic effects. A phase 1 study in advanced MDS/AML demonstrated an acceptable safety profile at doses up to 300 mg, with no worsening of leukemia, and it also showed a trend towards efficacy. Eltrombopag as monotherapy in MDS/AML has not been studied in a randomized fashion.Methods: In Study TRC114968 (ASPIRE), after 8 weeks of open-label, dose-defining EPAG treatment (Study Part 1), patients with highly advanced MDS or AML were randomized 2:1 to EPAG 100-300 mg or placebo (PBO) once daily for 12 weeks (Part 2), then entered a 6-month, open-label extension (Part 3). Patients were stratified by baseline platelet count (<10 Gi/L vs ≥10 Gi/L), and by MDS vs AML. Eligibility included 10-50% baseline bone marrow blasts and a baseline platelet count of <25 Gi/L. The primary endpoint was improvement in the clinically relevant thrombocytopenic event (CRTE) rate during the 12-week double-blind period. CRTE was a composite of a platelet transfusion requirement, significant bleeding event, or platelet count <10 Gi/L. Part 1 results have been presented previously. Blinded results for patients randomized in Part 2 of the study are presented below. Analyses of results by treatment arm, including those for the primary endpoint of CRTE, are ongoing and will be presented at the meeting.Results: A total of 145 patients were enrolled and randomized. According to WHO criteria, 72 (50%) had MDS and 73 (50%) had AML. See Table 1 for baseline characteristics. The majority of patients (n=91, 63%) were escalated to 300 mg (150 mg for East Asians) once daily. 70 patients (48%) completed the randomized portion of the study, and 58 (40%) entered the open-label extension. Patient disposition is described in Table 2. Out of the 144 treated patients, 97 patients (67%) have died (67 patients in Part 2 and 30 patients in Part 3). The main reasons for withdrawal from the study were adverse events (49 patients, 34%) and progressive disease (39 patients, 27%). The most common adverse events in Part 2 were petechiae, epistaxis, fatigue, pyrexia, and diarrhea. The main serious adverse events in Part 2 were pneumonia, sepsis, and febrile neutropenia. Liver test abnormality occurred in 1 (<1%). The median number of platelet transfusions for both groups was 10.Conclusions: This is the first study to evaluate EPAG as monotherapy in a randomized fashion in patients with advanced MDS or AML and severe thrombocytopenia. Overall safety was as expected for this patient population with no unexpected adverse events. This study provides evidence for the safety of EPAG in this mostly heavily pretreated patient population. An Independent Response Committee (IRC) is currently assessing responses and disease progression centrally by arm, and final data will be presented at the meeting.Funding: This study was sponsored by GlaxoSmithKline; eltrombopag is an asset of Novartis AG as of March 2, 2015. [Display omitted] [Display omitted] DisclosuresMittelman:Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Novartis Pharmaceuticals Corporation: Research Funding; Roche: Research Funding; Amgen: Research Funding. Off Label Use: Eltrombopag is a once daily oral thrombopoietin receptor agonist approved for treatment of chronic ITP, hepatitis C associated thrombocytopenia, severe aplastic anemia, and pediatric cITP. Data will be presented on use in myeloid malignancies for which eltrombopag is not approved.. Platzbecker:Novartis: Honoraria; Celgene: Honoraria; Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Wong:Johnson & Johnson: Research Funding; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Anagnostopoulos:GlaxoSmithKline: Research Funding. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Mannino:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Stone:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Chan:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Mostafa Kamel:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau.

Trastuzumab Rechallenge After Lapatinib- and Trastuzumab-Resistant Disease Progression in HER2-Positive Breast Cancer

BackgroundMultiple anti-HER2 therapies have improved the outcome for patients with HER2-positive breast cancer. However, optimal management has yet to be established for lapatinib (LAP)- and trastuzumab (Tmab)-resistant disease progression. Data from our institution were reviewed to contribute to the search for best practices. Patients and MethodsBetween June 2009 and March 2013, 74 HER2-positive advanced breast cancer (ABC) patients were treated with LAP with capecitabine (LAPCAP). Patients re-treated with Tmab-based chemotherapies were identified, with a focus on baseline characteristics, chemotherapies, and efficacy. The study focused on the clinical outcomes of 50 patients re-treated with Tmab after LAPCAP-resistant disease progression (LAPCAP-PD), with an assessment of tumor response and clinical benefit (CB). Progression-free survival (PFS) was used as a predictive surrogate marker for the efficacy of Tmab rechallenge. ResultsAll patients were pretreated with Tmab- and LAP-based chemotherapies. At a median follow-up of 7.9 months, PFS was 4.6 months, and overall survival was 33.7 months after LAPCAP-PD. Rechallenges with Tmab-based chemotherapies included gemcitabine (GEM) in 23 patients, vinorelbine in 14, taxanes in 5, endocrine treatments in 2, and others. The CB rate was 32%, including complete response for 1, partial response for 3, and > 6 months of stable disease for 12. Although the median PFS was longer for patients treated with microtubule inhibitors (MTIs) than with GEM, various chemotherapies had different efficacy regardless of whether or not previous LAPCAP had CBs. ConclusionTmab rechallenge combined with not only MTIs but also an antimetabolite agent is effective against some LAPCAP-PD HER2-positive ABC.

Defining and managing expectations for early immunotherapy cancer trials.

This review discusses the concept of expectations in assessing direct benefit to participants in phase I immunotherapy studies. With the push toward a faster assessment of clinical benefit or efficacy, limiting phase I studies to safety determination only is now viewed as obsolete and has been replaced by designs that draw attention to therapeutic benefit or efficacy. While this approach is touted as being more flexible in trial conduct, these designs are particularly problematic for immunotherapy studies. Defining and managing expectations is paramount on understanding the key axioms that emerge that include i) understanding bias in models and mechanistic results, ii) that no test is perfect, iii) it is difficult to select a good predictive biomarker in the absence of clinical data, even for targeted therapies, iv) markers predictive for monotherapy may not be predictive for combination therapy, and v) all about improved patient selection. Considering the heterogeneity of cancers and the immune response of the host, we think that immunotherapy should be developed in parallel with the identification of different clinico-pathological models of immune response to cancer. This approach would accomplish two important goals: 1) provide a biological understanding of the complete in vivo environment, thereby giving investigators the opportunity to optimize and maximize the effect of a specific immunotherapy agent and 2) addressing host environment issues simultaneously so that safety data and perceived benefit can be achieved more quickly.

Validation study of the Japanese version of M.D. Anderson Symptom Inventory Brain Tumor Module.

e17658 Background: It has been recognized that patient reported outcomes measures be incorporated into the assessment of clinical benefit of novel therapies for brain tumor patients, with growing e...

PCN143 - Pcodr – the pointless canadian oncology drug review?

The pan-Canadian Oncology Drug Review (pCODR) was established in 2010 to appraise oncology drugs in order to help guide provincial reimbursement decision-making. pCODR is currently being transferred to Canadian Agency for Drugs and Technologies in Health (CADTH) offering the opportunity for reform. This research aims to measure the impact of this process on access to oncology drugs in Canada and compare this with Quebec, which does not refer to pCODR. All published pCODR and Institut national d’excellence en santé et en services sociaux (INESSS, the Quebec Health Technology Assessment body) reports were identified alongside pCODR provincial funding summaries up to 30 September 2014 and the dates, decision, and key rationale were extracted. All statistical comparisons were made using ANOVA and t-tests. Most (62% [21/34]) pCODR recommendations were conditional on cost-effectiveness being demonstrated (20% recommended, 18% not recommended). Following pCODR recommendations, an average of 6.7 months from submission, there is an additional average 8.9 month delay for provincial funding decision-making. The time required for provincial decision making was no faster for drugs recommended by pCODR versus those conditional on acceptable cost-effectiveness (9.3 vs. 9.3 months, p=0.49). INESSS issued recommendations for these corresponding oncology drugs an average of only 2.1 months after pCODR, 6.8 months before the other provinces, a difference which is statistically significant (p=0.0013). Given that the key issue for most candidate oncologics facing reimbursement is cost-effectiveness, pCODR issuing large numbers of recommendations conditional on cost-effectiveness being demonstrated adds a time-consuming step that does not speed provincial decision making. INESSS, operating independently to pCODR, issue recommendations significantly sooner than other provinces. Based on this, we recommend that acceptable pCODR cost-effectiveness be a mandatory requirement prior to provincial consideration or that the pCODR process be curtailed into just providing a clinical benefit assessment.

Dual platelet inhibitors in intensive care units

The introduction of clopidogrel was a milestone in the development of modern antiplatelet therapy. However, the shortcomings in the pharmacokinetics of clopidogrel have led to the development of alternative substances. The two new drugs prasugrel and ticagrelor were included in the current guidelines for the treatment of patients with acute coronary syndrome. These potent platelet inhibitors, however, are associated with an increased rate of bleeding events, which is of particular importance in critically ill patients. However, the new platelet inhibitors are less effective in patients with cardiogenic shock or patients treated with therapeutic hypothermia. Recent studies underscore the assessment of the net clinical benefit in patient management. Since there is only a thin line between efficacy and safety in critically ill patients, future studies for risk stratification of antiplatelet therapy in terms of personalized medicine are mandatory.

Natural History of Acute Stroke due to Occlusion of the Middle Cerebral Artery and Intracranial Internal Carotid Artery

The natural history of acute ischemic stroke (AIS) due to anterior circulation large artery occlusion is not well established. This information is essential for assessment of clinical benefit derived from recanalization therapies. Patients with AIS due to anterior circulation large artery occlusion not treated with reperfusion therapies admitted from January 2005 to September 2010 were consecutively selected. Site of occlusion was assessed with transcranial duplex according to Thrombolysis in Brain Infarction (TIBI) grades. Poor outcome was considered as a modified Rankin Scale>2 at 90 days. A total of 120 patients were studied. Site of occlusion was terminal internal carotid artery (TICA) in 13 (10.8%), proximal middle cerebral artery (MCA) in 69 (57.5%), and distal MCA in 38 (31.7%) patients. Overall, 74.2% of patients had poor outcome. There were significant differences in poor outcome between patients with TICA, proximal MCA, and distal MCA occlusion (92%, 87%, 47%, P < .001) and mortality at 90 days (23%, 12%, 3%, P = .001). Outcome of AIS patients with anterior circulation large artery occlusion not treated with reperfusion therapies is extremely poor in TICA and proximal MCA occlusions with better outcomes noted in distal MCA occlusions. These findings are relevant for estimation of treatment effect of reperfusion therapies according to occlusion location.

PHP184 - Acceptance of Surrogate Endpoints by HTA Agencies in Europe

To compare how different European HTA agencies assess surrogate endpoints to demonstrate efficacy. We identified 8 therapies with surrogate endpoints that were evaluated in the last 6 years by NICE and/or SMC (UK), HAS (France) and G-BA (Germany). The acceptability of the use of surrogate endpoints and any specific comments made by these agencies were analysed. Commonly used surrogate endpoints such as glycated haemoglobin (HbA1c) in diabetes, progression free survival (PFS) in oncology and forced expiratory volume (FEV1) for respiratory diseases have been generally accepted as sufficient evidence to gain reimbursement by HTA agencies. Especially when a surrogate endpoint has been accepted by EMA, it is usually considered a valid outcome measure. Less well-accepted were several surrogate cardiovascular endpoints such as 6 minute walk test, blood pressure and LDL cholesterol. For G-BA it is important that surrogate endpoints have been properly validated and are patient relevant but they did accept endpoints such as sustained virological response (SVR) for hepatitis treatments, FEV1 and body mass index (BMI) based on minor evidence. NICE and SMC also strongly value evidence to demonstrate the correlation between surrogate endpoints and clinical outcomes. Interestingly SMC has recently become more cautious in accepting widely established endpoints such as HbA1c. With regards to the HAS, they often did not comment on the use of surrogate endpoints at all in their published reports. The use of surrogate endpoints in the assessment of clinical benefit is still controversial; however, attempts are made to establish clearer regulations such as the recently published EUnetHTA guidelines regarding surrogate endpoints. In the absence of evidence on final patient-relevant clinical endpoints, several commonly used biomarkers and intermediate endpoints will be considered as valid surrogate endpoints by HTA agencies. Newer, less established surrogate endpoints will be more subject to strict validation requirements.

A randomized open-label phase II study evaluating antitumor activity of the survivin antisense oligonucleotide LY2181308 (LY) in combination with docetaxel (DO) for second-line treatment of patients with non-small cell lung cancer (NSCLC) using change in tumor size (CTS).

8051^ Background: Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO+LY compared with DO alone. Methods: Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N=180) 2:1 to receive DO+LY (LY 750 mg IV loading ×3, Q1W maintenance) or DO alone (75 mg/m2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. Results: 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY+DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84–3.65) with LY+DO and 3.35 mo (95% CI, 2.69–4.57) with DO (log-rank p=0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30–0.68, p=0.0001). Median OS was 7.9 mo (90% CI, 6.6–9.7) with LY+DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p=0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY+DO as was the PK profile. Conclusions: Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.