Phase I/II Clinical Trial-Based Early Economic Evaluation of Acalabrutinib for Relapsed Chronic Lymphocytic Leukaemia

Objectives: The objective of this study was to construct an early economic evaluation for acalabrutinib for relapsed chronic lymphocytic leukaemia (CLL) to assist early reimbursement decision making. Scenarios were assessed to find the relative impact of critical parameters on incremental costs and quality-adjusted life-years (QALYs). Methods: A partitioned survival model was constructed comparing acalabrutinib and ibrutinib from a UK national health service perspective. This model included states for progression-free survival (PFS), post-progression survival (PPS) and death. PFS and overall survival (OS) were parametrically extrapolated from ibrutinib publications and a preliminary hazard ratio based on phase I/II data was applied for acalabrutinib. Deterministic and probabilistic sensitivity analyses were performed, and 1296 scenarios were assessed. Results: The base-case inc

Reporting of quality attributes in scientific publications presenting biosimilarity assessments of (intended) biosimilars: a systematic literature review

Last years, more than 46 unique biosimilars were approved by EMA and/or US-FDA following patent expiration of reference products. Biosimilars are not identical like generics, but highly similar versions where demonstrating biosimilarity of quality attributes (QAs) to a reference product is the basis of development and regulatory approval. Information on QAs assessed to establish biosimilarity may not always be publicly available, although this information is imperative to understand better the science behind biosimilars approval. This study aims to identify QA types reported in publications presenting biosimilarity assessments of (intended) biosimilars over time. English full-text publications presenting biosimilarity assessments of QAs for (intended) biosimilars between 2000 and 2019 identified from PubMed and EMBASE. Publication characteristics and QAs classified into: structural (physicochemical properties, primary structure, higher-order structures (HOSs), post-translational modifications (PTMs), and purity and impurities) and functional (biological and immunochemical activities) were extracted from publications. Seventy-nine publications were identified (79% open-access, 75% industry-sponsored, 62% including unapproved biosimilars, and 66% involving antibodies). Reporting frequencies varied for QA types: biological activity (94%), physicochemical properties (81%), PTMs (79%), primary structure (77%) purity and impurities (73%), HOSs (58%), and immunochemical activity (41%). The number of publications increased from 6 (7%) during 2009–2011 to 62 (79%) during 2015–2019. Eighteen (28%) publications reported all QA types relevant to an active-biological-substance. Reporting of most QA types increased over time that most evidenced by immunochemical activity (from 0% to 47%) which occured after EMA monoclona

Risk factors and diagnostic strategies in colorectal cancer

Colorectal cancer (CRC) is a major public health problem. The goal of this thesis was to investigate factors that influence the risk of developing CRC and to examine the clinical value of various diagnostic procedures to investigate the large bowel. Screening for adenomas is an effective way to reduce mortality from CRC. A significant number of polyps is missed during routine colonoscopy. The Third Eye Retroscope, abbreviated as Third Eye, provides an additional, retrograde view that is able to detect polyps behind folds and curves in the colon. In this thesis, we report that the risk of missing a lesion during colonoscopy without the Third Eye compared to colonoscopy with the Third Eye was more than 2.5 times higher for polyps (

CHALLENGES IN ACHIEVING MARKET ACCESS SUCCESS FOR ADVANCED THERAPIES IN EUROPE: A CASE STUDY

Objectives: Advanced Therapy Medicinal Product (ATMPs) hold great promise as treatments for previously incurable diseases. While expectations are high and full pipelines are observed, few ATMPs are currently on the EU market. This study aimed to identify root-causes of challenges experienced in achieving successful market access (MA) for commercially developed ATMPs in Europe. Methods: We completed a qualitative case study by conducting 10 semi-structured interviews amongst ATMP company representatives. MA success was defined as receiving reimbursement for an authorized product in at least one Member State. Company MA actions, strategies, experiences and know-how were questioned, as well as how was dealt with encountered challenges. Developers in the study sample differed in: ATMP type (cell and gene therapies), development stage, (Phase I-II, Phase III, regulatory application, Phase IV, discontinued) and company size (Small-Medium-sized Enterprises (SMEs) and large companies). Interviews were recorded, transcribed and coded. Recurring themes were classified via thematic content analysis. Results: Large companies had more experience developing non-ATMP products, giving them an advantage over SMEs in creating value dossiers and HTA authority contact. Large companies also experienced more financial stability. Therefore, they were able to look ahead, while SMEs were also occupied funding their current development stage. Developers who early on involved MA expertise (in-house or external) and had a detailed business plan from the start, seemed more successful. Respondents mentioned a business plan should at least include: short- and long-term goals, market access strategy and return on investment predictions. Some SMEs partnered with large companies to solve funding issues and utilize expertise. No differences between cell and gene therapies were found. Conclusions: Obtaining market access for ATMP development requires more planning and specialised skills compared to more traditional pharmaceutical development. A MA strategy and business plan should be drafted as soon as possible in ATMP development

Plasma and dietary carotenoids and vitamines A,C and E and the risk of colon and rectal cancer in the European prospective investigation into cancer and nutrition

Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (alpha- and beta-carotene, canthaxanthin, beta-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (alpha-, beta- and gamma-and delta-tocopherol) and dietary consumption of beta-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary beta-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties

Challenges in Advanced Therapy Medicinal Products Development: A survey amongst companies in Europe

Advanced Therapy Medicinal Products (ATMPs) hold a promise as treatments for previously untreatable and high burden diseases. Expectations are high and active company pipelines are observed, yet only ten market authorizations were approved in Europe. Our aim was to identify challenges experienced in European ATMP clinical development by companies. A survey-based cohort study was conducted among commercial ATMP developers. Respondents shared challenges experienced during various development phases as well as developer and product characteristics. Descriptions of challenges were grouped in domains (clinical, financial, human-resource-management, regulatory, scientific, technical, other) and further categorized using thematic content analysis. A descriptive analysis was performed. We invited 271 commercial ATMP developers of which 68 responded providing 243 challenges. Of products in development, 72% were in early clinical development and 40% were gene therapies. Most developers were small or medium-sized enterprises (65%). The most often mentioned challenges wererelated to country specific requirements (16%), manufacturing (15%) and clinical trial design (8%). The European ATMP field is still in early stages and developers experience challenges on many levels. Challenges are multifactorial and a mix of ATMP-specific and generic development aspects, such as new and orphan indications, novel technologies and inexperience adding complexity to development efforts

Does meal ingestion enhance sensitivity of visceroperception assessment in irritable bowel syndrome?

Background Visceral hypersensitivity is frequently observed in irritable bowel syndrome (IBS). Previous studies have shown that administration of a meal can aggravate symptoms or increase visceroperception in IBS patients. We investigated whether meal ingestion could increase the sensitivity of the barostat procedure for the detection of visceral hypersensitivity in IBS patients. Methods Seventy-one IBS patients and 30 healthy controls (HC) were included in the study. All subjects underwent a barostat procedure under fasted and postprandial conditions to measure visceroperception. Urge, discomfort, and pain were scored on a visual analog scale. Furthermore, percentages of hypersensitive IBS patients and HC were calculated and dynamic rectal compliance was assessed. Key Results In IBS patients, urge, discomfort, and pain scores were significantly increased postprandially vs the fasted state. The HC showed increased scores for urge and pain only. Rectal dynamic compliance remained unaltered in both groups. Postprandial hypersensitivity percentages did not significantly differ vs the fasted state in IBS patients, nor in HC. Conclusions & Inferences Postprandial barostat measurement enhances visceroperception in IBS but has no added value to detect visceral hypersensitivity in individual IBS patients

Representations of temporal sleep dynamics: Review and synthesis of the literature

Sleep is characterized by an intricate variation of brain activity over time. Measuring these temporal sleep dynamics is relevant for elucidating healthy and pathological sleep mechanisms. The rapidly increasing possibilities for obtaining and processing sleep registrations have led to an abundance of data, which can be challenging to analyze and interpret. This review provides a structured overview of approaches to represent temporal sleep dynamics, categorized based on the way the source data is compressed. For each category of representations, we describe advantages and disadvantages. Standard human-defined 30-s sleep stages have the advantages of standardization and interpretability. Alternative human-defined representations are less standardized but offer a higher temporal resolution (in case of microstructural events such as sleep spindles), or reflect non-categorical information (for example spectral power analysis). Machine-learned representations offer additional possibilities: automated sleep stages are useful for handling large quantities of data, while alternative sleep stages obtained from clustering data-driven features could aid finding new patterns and new possible clinical interpretations. While newly developed sleep representations may offer relevant insights, they can be difficult to interpret in for example a clinical context. Therefore, there should always be a balance between developing these sophisticated sleep analysis techniques and maintaining clinical explainability

Krankengymnastik und physikalische Therapiemassnahmen zur konservativen Therapie der Arthrose

Glucagon-like Peptide-1 receptor agonists (GLP1-ra) are a relatively new class of anti-hyperglycemic drugs which may positively affect bone metabolism and thereby decrease (osteoporotic) bone fracture risk. Data on the effect of GLP1-ra on fracture risk are scarce and limited to clinical trial data only. The aim of this study was to investigate, in a population-based cohort, the association between the use of GLP1-ra and bone fracture risk. We conducted a population-based cohort study, with the use of data from the Clinical Practice Research Datalink (CPRD) database (2007-2012). The study population (N = 216,816) consisted of all individuals with type 2 diabetes patients with at least one prescription for a non-insulin anti-diabetic drug and were over 18 years of age. Cox proportional hazards models were used to estimate the hazard ratio of fracture in GLP1-ra users versus never-GLP1-ra users. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and the use of other drugs. There was no decreased risk of fracture with current use of GLP1-ra compared to never-GLP1-ra use (adjusted HR 0.99, 95 % CI 0.82-1.19). Osteoporotic fracture risk was also not decreased by current GLP1-ra use (adjusted HR 0.97; 95 % CI 0.72-1.32). In addition, stratification according to cumulative dose did not show a decreased bone fracture risk with increasing cumulative GLP1-ra dose. We showed in a population-based cohort study that GLP1-ra use is not associated with a decreased bone fracture risk compared to users of other anti-hyperglycemic drugs. Future research is needed to elucidate the potential working mechanisms of GLP1-ra on bone