Amgen (Australia)

Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use. We here report a case of pancytopenia associated with the development of neutralizing antibodies to TPO that occurred in a patient who had undergone multicycle chemotherapy with multiple cycles of subcutaneous administration of pegylated recombinant human megakaryocyte growth and development factor. Samples of the patient's bone marrow showed trilineage hypoplasia with absence of myeloid, erythroid, and megakaryocyte progenitor cells but with elevated endogenous levels of erythropoietin, granulocyte colony-stimulating factor, and stem-cell factor. To our knowledge, this is the first report of an aplastic anemia-like syndrome associated with neutralizing antibodies to TPO.

AIMS: To estimate the health and economic burden of new and established cardiovascular disease from 2020 to 2029 in Australia. METHODS AND RESULTS: A two-stage multistate dynamic model was developed to predict the burden of the incident and prevalent cardiovascular disease, for Australians 40-90 years old from 2020 to 2029. The model captured morbidity, mortality, years of life lived, quality-adjusted life years, healthcare costs, and productivity losses. Cardiovascular risk for the primary prevention population was derived using Australian demographic data and the Pooled Cohort Equation. Risk for the secondary prevention population was derived from the REACH registry. Input data for costs and utilities were extracted from published sources. All outcomes were annually discounted by 5%. A number of sensitivity analyses were undertaken to test the robustness of the study. Between 2020 and 2029, the model estimates 377 754 fatal and 991 375 non-fatal cardiovascular events. By 2029, 1 061 756 Australians will have prevalent cardiovascular disease (CVD). The population accrued 8 815 271 [95% uncertainty interval (UI) 8 805 083-8 841 432] years of life lived with CVD and 5 876 975 (5 551 484-6 226 045) QALYs. The total healthcare costs of CVD were projected to exceed Australian dollars (AUD) 61.89 (61.79-88.66) billion, and productivity losses will account for AUD 78.75 (49.40-295.25) billion, driving the total cost to surpass AUD 140.65 (123.13-370.23) billion. CONCLUSION: Cardiovascular disease in Australia has substantial impacts in terms of morbidity, mortality, and lost revenue to the healthcare system and the society. Our modelling provides important information for decision making in relation to the future burden of cardiovascular disease.

Denosumab, a bone-modifying agent, reduces the risk of skeletal-related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab-treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short-term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro-maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.

BACKGROUND: Multiple Myeloma (MM) is a cancer characterised by the proliferation of malignant plasma cells in the bone marrow. This study examined the treatment preferences of people living with MM compared to the treatment preferences of other groups involved in treatment decision making, including carers, as well as physicians and nurses who treat people living with MM in Australia. METHODS: Data were collected using discrete choice experiments (DCEs) through an online survey. The DCEs presented participants with a traditional treatment generic choice experiment (e.g., treatment A vs treatment B), focusing on the clinical benefits of treatments and the associated risks. The attributes and levels of the attributes were selected based on previous research, literature review, qualitative research and expert opinion. The DCE data were modelled using a Latent Class Model (LCM). RESULTS: The model revealed significant heterogeneity in preferences for treatment attributes. In particular, overall survival, remission period and annual out of pocket cost were the attributes with the most variation. In comparison to people living with MM, carers were less cost-sensitive and more concerned with quality of life (remission period). Physicians and nurses were generally more concerned with overall survival and more cost sensitive than people living with MM. CONCLUSIONS: This study demonstrated that not all people living with MM valued the same treatment attributes equally. Further, not all groups involved in MM treatment decision making had preference alignment on all treatment attributes. This has important implications for healthcare policy decisions and shared decision making. Results from this study could be used to guide decisions around the value of new MM medicines or the medical plan surrounding the needs of those living with MM, as well as those caring for them.

OBJECTIVE: To assess the safety and to analyse the cost-effectiveness of home treatment, including cytotoxic chemotherapy, for cancer patients. DESIGN: A restrospective overview of a home oncology nursing service over its first five years (1989-1994), and a detailed cost analysis over 12 months, firstly, by comparing direct costs of chemotherapy administration at home or in the hospital's day treatment ward and, secondly, by assessing the marginal cost of treating home care program patients in the hospital versus the total cost of the home care program. PATIENTS AND SETTING: Patients of the Haematology/Oncology Unit of a metropolitan teaching hospital treated either at home by an experienced oncology nurse, or in the hospital day care ward. INTERVENTION: Patients were offered treatments, including chemotherapy, at home rather than in hospital. MAIN OUTCOME MEASURES: Safety, assessed by the rate of major complications (i.e., requiring any patient to be admitted to hospital), and cost-effectiveness, assessed by comparing expenditure in the home and hospital settings. RESULTS: Over five years, there were 5444 home visits to 424 patients, including 1688 chemotherapy administrations to 179 patients. Only two of the 424 patients decided against continuing in the home program once it had begun. There were no major complications. The average cost of home chemotherapy administration (excluding drugs) was $49.91, compared with $116.00 in hospital. The cost of treating patients at home was $5.09 per patient more than the "marginal cost" of treating these patients in the hospital. CONCLUSIONS: Home anticancer chemotherapy is a safe and economically realistic alternative to traditional in-hospital treatment. Efforts should be made to overcome budgetary and administrative barriers to more widespread adoption of this model of care.

Infusions of ex vivo-expanded (EXE) mobilized blood cells have been explored to enhance haematopoietic recovery following high dose chemotherapy (HDT). However, prior studies have not consistently demonstrated improvements in trilineage haematopoietic recovery. Three cohorts of three patients with breast cancer received three cycles of repetitive HDT supported by either unmanipulated (UM) and/or EXE cells. Efficacy was assessed by an internal comparison of each patient's consecutive HDT cycles, and to 106 historical UM infusions. Twenty-one cycles were supported by EXE cells and six by UM cells alone. Infusions of EXE cells resulted in fewer days with an absolute neutrophil count (ANC) <0.1 x 10(9)/l (median 2 vs. 4 d, P = 0.002) and 3 d faster ANC recovery to >0.1 x 10(9)/l (median 5 vs. 8 d, P = 0.0002). This resulted in a major reduction in the incidence of febrile neutropenia compared with UM cycles (0% vs. 83%; P = 0.008) and in 66% of historical UM cycles (P = 0.01) and a marked reduction in hospital re-admission. There were also fewer platelet transfusions required (43% vs. 100%; P = 0.009). We conclude that EXE cells enhance both neutrophil and platelet recovery and reduce febrile neutropenia, platelet transfusion and hospital re-admission.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 β7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml(-1) . The PD effect on α4 β7 RO showed an EC50 of 0.01 μg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

BACKGROUND: It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. METHODS: Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. RESULTS: Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. CONCLUSIONS: Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term.

Abstract Background Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. Methods This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary &gt; 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. Discussion The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. Trial registration Prospectively registered on Australian New Zealand Clinical Trials Registry ( ACTRN12618001121257 ) on 06/07/2018.

BACKGROUND: There is good evidence of both community support for sharing public sector administrative health data in the public interest and concern about data security, misuse and loss of control over health information, particularly if private sector organizations are the data recipients. To date, there is little research describing the perspectives of informed community members on private sector use of public health data and, particularly, on the conditions under which that use might be justified. METHODS: Two citizens' juries were held in February 2020 in two locations close to Sydney, Australia. Jurors considered the charge: 'Under what circumstances is it permissible for governments to share health data with private industry for research and development?' RESULTS: All jurors, bar one, in principle supported sharing government administrative health data with private industry for research and development. The support was conditional and the juries' recommendations specifying these conditions related closely to the concerns they identified in deliberation. CONCLUSION: The outcomes of the deliberative processes suggest that informed Australian citizens are willing to accept sharing their administrative health data, including with private industry, providing the intended purpose is clearly of public benefit, sharing occurs responsibly in a framework of accountability, and the data are securely held. PATIENT AND PUBLIC CONTRIBUTION: The design of the jury was guided by an Advisory Group including representatives from a health consumer organization. The jurors themselves were selected to be descriptively representative of their communities and with independent facilitation wrote the recommendations.

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 - 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 - 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cellsx106 L-1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support.

e19048 Background: AMG 655 is an investigational, fully human IgG1 monoclonal agonist antibody that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 15 mg/kg) of AMG 655 that can be safely administered with PC. Methods: Eligibility included: ≥ 18-years old, untreated, advanced NSCLC, and ECOG PS 0 or 1. Patients (pts) were enrolled in sequential dose cohorts of AMG 655 (5 or 15 mg/kg) + P (200 mg/m 2 ) and C (AUC = 6 mg/mL x min) IV every 3 weeks for up to 6 cycles. After completion/discontinuation of PC, pts may continue AMG 655 as monotherapy. Endpoints include: incidence of dose- limiting toxicities (DLT); adverse events (AE); pharmacokinetics (PK); levels of plasma genomic (g)DNA, serum caspase 3/7 activity, and M65 (cell death and apoptosis biomarkers); objective tumor response rate (by RECIST), and progression-free survival (PFS). Results: As of 09/08, 12 pts enrolled and received ≥ 1 dose of AMG 655 + PC. Ten were men; 11 had ECOG 1, and median (range) age = 68.5 (50–83) years. Median (range) time on AMG 655 = 5.2 (0.2–8.3) months; all pts have discontinued treatment. There was 1 DLT: grade 3 hyponatremia (15-mg/kg cohort). Five (42%) pts had grade 3 AE including neutropenia and dyspnea (2 pts each); 3 (25%) had grade 4 AE (2 with neutropenia, 1 with pulmonary embolism). After one 5- or 15-mg/kg dose of AMG 655 + PC, AMG 655 PK values (serum clearance, C max , AUC) were similar to the first-in-human study (LoRusso et al. JCO 2007; 25: abstr 3534) indicating no effect of PC on PK of AMG 655. Data also indicate no effect of AMG 655 on PK of PC. Plasma gDNA, serum caspse 3/7 activity, and serum M65 levels increased significantly from baseline 24 h after administration of AMG 655 + PC. Best overall tumor response: 1 complete response, 3 partial responses, 3 stable disease, and 3 progressive disease (2 pts had no on-treatment tumor assessments). Median (95% CI) PFS = 5.1 months (1.5, 7.0). Conclusions: AMG 655 administered with PC appears to be well tolerated with expected PK properties not altered by PC. A randomized phase 2 trial (AMG 655 ± PC) is ongoing. [Table: see text]

AIM: Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W). METHODS: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrollment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb >or= 100 g/L during the evaluation period (weeks 21-33). RESULTS: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb >or= 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 microg. Darbepoetin alfa was considered to be well-tolerated. CONCLUSION: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.

Although it is widely taught that all modern life descended via modification from a last universal common ancestor (LUCA), this dominant paradigm is yet to provide a generally accepted explanation for the chasm in design between prokaryotic and eukaryotic cells. Counter to this dominant paradigm, the viral eukaryogenesis (VE) hypothesis proposes that the eukaryotes originated as an emergent superorganism and thus did not evolve from LUCA via descent with incremental modification. According to the VE hypothesis, the eukaryotic nucleus descends from a viral factory, the mitochondrion descends from an enslaved alpha-proteobacteria and the cytoplasm and plasma membrane descend from an archaeal host. A virus initiated the eukaryogenesis process by colonising an archaeal host to create a virocell that had its metabolism reprogrammed to support the viral factory. Subsequently, viral processes facilitated the entry of a bacterium into the archaeal cytoplasm which was also eventually reprogrammed to support the viral factory. As the viral factory increased control of the consortium, the archaeal genome was lost, the bacterial genome was greatly reduced and the viral factory eventually evolved into the nucleus. It is proposed that the interaction between these three simple components generated a superorganism whose emergent properties allowed the evolution of eukaryotic complexity. If the radical tenets of the VE hypothesis are ultimately accepted, current biological paradigms regarding viruses, cell theory, LUCA and the universal Tree of Life (ToL) should be fundamentally altered or completely abandoned.

OBJECTIVES: The Pharmaceutical Benefits Scheme (PBS) provides timely, reliable, and affordable access to necessary medicines for Australians. We reviewed the Pharmaceutical Benefits Advisory Committee (PBAC) submissions and their related outcomes and timelines since 2010. METHODS: We examined the PBS Website to identify submissions and their related PBAC outcomes for new medicines, new indications, and new combination products that had been considered by the PBAC since 2010. RESULTS: Thirty-five PBAC meetings were held during the study period, at which the Committee considered 781 submissions (1,074 medicine/patient population pairings). We saw an increase in the annual number of submissions (medicine/patient population parings). The recommendation rate for the study period was higher than the rejection rate. The annual mean value for the period from the date of initial PBAC recommendation to the date of PBS listing ranged from 357 to 644 days; the annual mean value for the period of the date of PBAC recommendation to the date of PBS listing ranged from 187 to 245 days. It took, on average, 1.70 submissions that included an economic evaluation to obtain a PBAC recommendation. It took more submissions to obtain a PBAC recommendation for a cost-effectiveness analysis submission than it did for a CMA submission. The PBAC was willing to recommend medicines for most acceptable base-case incremental cost-effectiveness ratio (ICER) bands, and the majority of the PBAC did not recommended any medicine in the study period that had a base-case ICER >AUD75,000. CONCLUSIONS: The results of our analyses reveal a minor reduction in the period from the date of PBAC recommendation to the date of PBS listing. Several analyses were hampered by a high proportion of missing data.

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group--VETOPEC I, Baby Brain 91, and VETOPEC II--have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.

This position paper is intended to provide recommendations that will help lay the foundation for best practices for medical science liaisons (MSLs) and their activities. Its objective is to outline the roles and responsibilities expected of an MSL and provide clarity on the juxtaposition of MSLs and Sales representatives (SRs) when it comes to scientific exchange versus promotional messaging. It is of utmost importance that industry integrity and ethical standards are assured during external stakeholder engagement as well as medical and scientific communications. This guidance, delivered through the lens of APPA, IFAPP, MAPS and the MSLS executive committees, has been prepared primarily as a supportive resource to assist the Medical Affairs teams in the industry to develop their own set of standard operating procedures (SOPs), codes of conduct and policies within the framework of relevant industry regulations. We acknowledge that whilst there are guidelines already available that provide excellent directive to the MSL function, this paper is a review and distillation of these existing recommendations combined with the perspectives of four peak professional bodies to offer a practically focused resource to help MSLs interact, collaborate and exchange scientific information appropriately with external experts when out in the field.

BACKGROUND: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data. METHODS AND RESULTS: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days). CONCLUSIONS: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

The 2022 Health Technology Assessment International (HTAi) Global Policy Forum (GPF) established the goal of developing a position statement and framework for lifecycle HTA (LC-HTA), through a Task Force leveraging multi-stakeholder monthly discussions and GPF member input. The Task Force developed a working definition: LC-HTA is a systematic process utilizing sequential HTA activities to inform decision making where the evidence base, the health technology itself, or the context in which it is applied, has a potential to meaningfully change at different points in its LC. Four key scenarios were identified where it was considered that an LC-HTA approach would add sufficient value to HTA bodies and their key stakeholders to justify the additional resource burden. Based on the four scenarios, a high-level LC-HTA framework was developed consisting of (i) defining the decision problem, (ii) sequencing of HTA activities, and (iii) developing optimization criteria. Subsequently, the Task Force developed operationalization guidance for LC-HTA in a companion paper.