Expanded Access as a source of real-world data: An overview of FDA and EMA approvals

Aims: To identify, characterize and compare all Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals that included real-world data on efficacy from expanded access (EA) programmes. Methods: Cross-sectional study of FDA (1955–2018) and EMA (1995–2018) regulatory approval documentation. We automated searching for terms related to EA in 22,506 documents using machine learning techniques. We included all approvals where EA terms appeared in the regulatory documentation. Our main outcome was the inclusion of EA data as evidence of clinical efficacy. Characterization was based on approval date, disease area, orphan designation and whether the evidence was supportive or pivotal. Results: EA terms appeared in 693 out of 22,506 (3.1%) documents, which referenced 187 approvals. For 39 approvals, data from EA programmes were used to inform on clinical efficacy. The yearly number of approvals with EA data increased from 1.25 for 1993–2013 to 4.6 from 2014–2018. In 13 cases, these programmes formed the main evidence for approval. Of these, patients in EA programmes formed over half (median 71%, interquartile range: 34–100) of the total patient population available for efficacy evaluation. Almost all (12/13) approvals were granted orphan designation. In 8/13, there were differences between regulators in approval status and valuation of evidence. Strikingly, 4 treatments were granted approval based solely on efficacy from EA. Conclusion: Sponsors and regulators increasingly include real-world data from EA programmes in the efficacy profile of a treatment. The indications of the approved treatments are characterized by orphan designation and high unmet medical need

Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands

Background: The purpose of this study was to determine generic, cancer-specific, and prostate cancer-specific health-related quality of life (HRQoL), pain and changes over time in patients with metastatic castration-resistant prostate cancer (mCRPC) in daily practice. Patients and Methods: PRO-CAPRI is an observational, prospective study in 10 hospitals in the Netherlands. Patients with mCRPC completed the EQ-5D, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Brief Pain Inventory-Short Form (BPI-SF) every 3 months and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer Module (EORTC QLQ-PR25) every 6 months for a maximum of 2 years. Subgroups were identified based on chemotherapy pretreatment. Outcomes were generic, cancer-specific, and prostate cancer-specific HRQoL and self-reported pain. Descriptive statistics were performed including changes over time and minimal important differences (MID) between subgroups. Results: In total, 151 included patients answered 873 questionnaires. The median follow-up from the start of the study was 19.5 months, and 84% were treated with at least 1 life-prolonging agent. Overall, patients were in good clinical condition (Eatern Cooperative Oncology Group performance status 0-1 in 78%) with normal baseline hemoglobin, lactate dehydrogenase, and alkaline phosphatase. At inclusion, generic HRQoL was high with a mean EQ visual analog score of 73.2 out of 100. The lowest scores were reported on role and physical functioning (mean scores of 69 and 76 of 100, respectively), and fatigue, pain, and insomnia were the most impaired domai

Het systeem van loonvorming aan de hand van de volgende vraag : aan welke vereisten dient de loonvorming niet te lande te voldoen uitr een oogpunt van economische groei, produktie-struktuur, inkomensverdeling en sociale verhoudingen.

Wittevaen (H.J

Traditional versus up-front [18F] fluorodeoxyglucose-positron emission tomography staging of non-small-cell lung cancer: A Dutch cooperative randomized study

Purpose: We investigated whether application of positron emission tomography (PET) immediately after first presentation might simplify staging while maintaining accuracy, as compared with traditional strategy in routine clinical setting. Methods: At first presentation, patients with a provisional diagnosis of lung cancer without overt dissemination were randomly assigned to traditional work-up (TWU) according to international guidelines or early PET followed by histologic/cytologic verification of lesions, or imaging and follow-up. Patients with [18F] fluorodeoxyglucose (18FDG) -avid, noncentral tumors without suspicion of mediastinal or distant metastases on PET proceeded directly to thoracotomy. Follow-up in presumed benign lesions was at least 12 months. In patients treated with surgery or neoadjuvant therapy, the quality of staging was measured by comparing the clinical stage to the final stage (combination of peroperative staging and 6 months of follow-up). To investigate test substitution, we analyzed the number of (non)invasive tests to achieve clinical TNM staging, and its associated costs. Results: Between 1999 and 2001, 465 patients (233 TWU, 232 PET) were enrolled at 22 hospitals. The mean (standard deviation) number of procedures to finalize staging was equal in the TWU arm and the PET arm: 7.9 (2.0) v 7.9 (1.9), P = .90, respectively. Mediastinoscopies occurred significantly less often in the PET arm. Agreement between clinical and final stage was good in both arms (K = .85 v .78; P = .07). Costs did not differ significantly. Conclusion: Up-front 18FDG-PET in patients with (suspected) lung cancer does not reduce the overall number of diagnostic test, but it maintains quality of TNM staging with the use of less invasive surgery

Evaluating adherence to the Dutch guideline for diagnosis, treatment and follow-up of laryngeal carcinomas

Contains fulltext : 47451.pdf (publisher's version ) (Closed access)BACKGROUND AND PURPOSE: An evidence-based clinical practice guideline for laryngeal carcinomas was introduced in the Netherlands late 1999. The objective of this guideline was to ensure uniformity in the diagnosis, treatment, and follow-up. We retrospectively evaluated whether clinical practice changed according to the recommendations of this guideline and whether it succeeded in its aim. MATERIAL AND METHODS: In five out of eight Dutch university hospitals, chart data of 459 patients treated before the guideline introduction were compared to data of 363 patients treated after the guideline introduction. RESULTS: Patient and tumour characteristics were comparable among both groups. In general, the guideline recommendations were properly complied with. The patients treated before the guideline introduction were actually also for a large part already treated according to the guideline's recommendations. After its introduction, several changes according to the guideline were observed: increased rates of reassessment of biopsy samples taken in local hospitals, psychological screening (although still only performed in 10.5% of patients), application of accelerated radiotherapy schedules, clinical trial treatments, function-preserving treatments, and decreased rates of total laryngectomy, and annual chest X-rays during follow-up. CONCLUSIONS: Although a causal relationship cannot be established in this kind of observational studies, several positive changes were observed after the introduction of the guideline, and therefore the guideline seems to have contributed to more uniformity. The largest changes were seen for the guideline recommendations based on the highest levels of evidence

Incidence and survival of castration-resistant prostate cancer patients with visceral metastases: results from the Dutch CAPRI-registry

Background: The objective of this real-world population study is to investigate incidence and treatment of visceral metastases (VMs) in castration resistant prostate cancer (CRPC) patients and their survival. Methods: CRPC-patients in the CAPRI-registry between 2010 and 2016 were included in the analyses and followed till 2017. Outcomes were proportion of patients radiologically screened for VMs and proportion of patients with VMs at CRPC-diagnosis and at the start of every treatment line. Groups have been created based on location of VMs (lung, liver, or both) at date of first VM diagnosis. The outcome for these groups was overall survival (OS). Statistics included descriptive analyses, Kaplan-Meier method, and Cox proportional hazard regression analysis for survival analyses. Results: Of 3602 patients from the CAPRI registry, 457 patients (12.7%) were diagnosed with VMs during follow-up: 230 patients with liver, 161 with lung, and 66 with both liver and lung metastases. The proportion of patients radiologically screened for VMs increased per treatment line as did the occurrence rate of VMs. However, 80% of patients at CRPC diagnosis to 40% in the 6th line were not screened for VMs at the start of a systemic treatment. Median OS was 8.6 months for patients with liver, 18.3 with lung and 10.9 with both liver and lung metastases (p < 0.001) from date of first VM diagnosis. After correction for prognostic factors patients with lung metastases had significantly better OS than patients with liver metastases (HR 0.650, p = 0.001). Conclusion: This real-world analysis showed that despite the increased rate of radiological staging during follow-up, still 80% to 40% of the patients (CRPC diagnosis to 6th treatment line respectively) were not screened for VMs at the start of a systemic treatment. VMs and location of VMs are key prognostic patient characteristics, impacts survival and have implications for treatment decisions, so routine staging of CRPC-patients is warranted. Clinical trial identification: The CAPRI study is registered in the Dutch Trial Registry as NL3440 (NTR3591)

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population

Background: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. Patients and methods: CRPC patients diagnosed in the years 2010–2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). Results: In both subgroups, the use of any LPD increased: from 57% (2010–2011) to 69% (2014–2015) in subgroup 1 and from 65% (2011–2012) to 79% (2015–2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46–29% and 20–9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014–2015 vs. 2010–2011 with HR 0.749, p < 0.001) and subgroup 2 (2015–2016 vs. 2011–2012 with HR 0.811, p = 0.037). Conclusion: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS

Cost-effectiveness of FDG-PET in staging non-small cell lung cancer: The PLUS study

Currently, up to 50% of the operations in early-stage non-small cell lung cancer (NSCLC) are futile owing to the presence of locally advanced tumour or distant metastases. More accurate pre-operative staging is required in order to reduce the number of futile operations. The cost-effectiveness of fluorine-18 fluorodeoxyglucose positron emission tomography (18FDG-PET) added to the conventional diagnostic work-up was studied in the PLUS study. Prior to invasive staging and/or thoracotomy, 188 patients with (suspected) NSCLC were randomly assigned to conventional work-up (CWU) and whole-body PET or to CWU alone. CWU was based on prevailing guidelines. Pre-operative staging was followed by 1 year of follow-up. Outcomes are expressed in the percentage of correctly staged patients and the associated costs. The cost price of PET varied between €736 and €1,588 depending on the (hospital) setting and the procurement of 18FDG commercially or from on-site production. In the CWU group, 41% of the patients underwent a futile thoracotomy, whereas in the PET group 21% of the thoracotomies were considered futile (P=0.003). The average costs per patient in the CWU group were €9,573 and in the PET group, €8,284. The major cost driver was the number of hospital days related to recovery from surgery. Sensitivity analysis on the cost and accuracy of PET showed that the results were robust, i.e. in favour of the PET group. The addition of PET to CWU prevented futile surgery in one out of five patients with suspected NSCLC. Despite the additional PET costs, the total costs were lower in the PET group, mainly due to a reduction in the number of futile operations. The additional use of PET in the staging of patients with NSCLC is feasible, safe and cost saving from a clinical and from an economic perspective