Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study.

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.

Anticholinergic burden: First comprehensive analysis using claims data shows large variation by age and sex.

PURPOSE: The cumulative effect of medication inhibiting acetylcholine activity-also known as anticholinergic burden (AB)-can lead to functional and cognitive decline, falls, and death. Given that studies on the population prevalence of AB are rare, we aimed to describe it in a large and unselected population sample. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data from ~20% of the German population we analyzed outpatient drug dispensations in 2016. Based on the Anticholinergic Cognitive Burden (ACB) scale, we classified persons into four categories and determined the cumulative AB as continuous variable. RESULTS: Among 16,470,946 persons (54% female), the prevalence of clinically relevant AB (ACB≥3) was 10% (women) and 7% (men). Below age 40 it was highest in persons ≤18 years (6% both sexes). At older ages (50-59 vs. 90-99 years), prevalence of ACB≥3 increased from 7% to 26% (men) and from 10% to 32% (women). Medication classes contributing to the cumulative AB differed by age: antihistamines, antibiotics, glucocorticoids (≤19 years), antidepressants (20-49 years), antidepressants, cardiovascular medication, antidiabetics (50-64 years), and additionally medication for urinary incontinence/overactive bladder (≥65 years). Medication dispensed by general physicians contributed most to the cumulative AB. CONCLUSION: Although a clinically relevant AB is particularly common in older persons, prevalence in younger age groups was up to 7%. Given the risks associated with AB in older persons, targeted interventions at the prescriber level are needed. Furthermore, risks associated with AB in younger persons should be explored.

Potential of German claims data to characterize utilization of new cancer drugs: the example of crizotinib.

Aims: Premarketing clinical trials are typically conducted under controlled conditions and in selected study populations, so real-world information on the utilization of new cancer drugs is limited. We aimed to explore the potential of German claims data in this regard, exemplified by the ALK inhibitor crizotinib, used in non-small-cell lung cancer therapy. Materials & methods: We identified patients treated with crizotinib in the German Pharmacoepidemiological Research Database (2004-2017; 20% of the German population) and assessed patient characteristics, treatment and survival. Results: We identified 348 crizotinib-treated patients (56% female; 25% first-line users). After 2 years, overall survival was 48%, with higher survival in men than in women (58 vs 40%). Overall, 76% of patients discontinued crizotinib treatment. Of those, 41% received another ALK inhibitor afterward. Conclusion: The results underline the potential of German claims data for real-world monitoring of oncological drug utilization.

The cumulative false-positive rate in colorectal cancer screening: a Markov analysis.

BACKGROUND: Faecal occult blood testing is widely used in colorectal cancer screening. However, there is little empirical long-term evidence on the accumulation of false-positive test results over several screening rounds. We aimed to systematically explore and quantify the cumulative false-positive rate for various scenarios of colorectal cancer screening. METHODS: Using a Markov analysis, we estimated the lifetime cumulative number of false-positive test results (cumFP) per 100 000 50-year-old persons. We varied the screening interval and the specificity of a single screening test and the starting age of screening. RESULTS: For a test with a specificity of 98% used from 50 to 74 years, the cumFP at age 74 was 26 260 (1-year interval), 15 102 (2-year interval), and 10 819 (3-year interval), respectively. For a test with a specificity of, respectively, 95 and 92% used at a 2-year interval, the cumFP at age 74 was 2.2 times and 3.0 times higher as compared to a test with a specificity of 98%. The cumFP at age 74 was 18% lower for screening persons aged 54-74 years vs. 50-74 years. CONCLUSION: Our findings quantitatively illustrate the large variation of the cumFP in colorectal cancer screening between screening strategies, which is relevant to informed decision making and adequate resource planning.

Implementation of an algorithm for the identification of breast cancer deaths in German health insurance claims data: a validation study based on a record linkage with administrative mortality data.

OBJECTIVE: To adapt a Canadian algorithm for the identification of female cases of breast cancer (BC) deaths to German health insurance claims data and to test and validate the algorithm by comparing results with official cause of death (CoD) data on the individual and the population level. DESIGN: Validation study, secondary data, medical claims. SETTING: Claims data of two statutory health insurance providers (SHIs) for inpatient and outpatient care, CoD added via record linkage with epidemiological cancer registry (ECR).ParticipantsAll women insured with the two SHIs and who deceased in the period 2006-2013, were residents of North Rhine Westphalia (NRW) and were linked with ECR data: n=22 413. MAIN OUTCOME MEASURES: Based on inpatient and outpatient diagnoses in the year before death, six algorithms were derived and the accordance of the algorithm-based CoD with the official CoD was evaluated calculating specificity, sensitivity, negative and positive predictive values (NPV, PPV). Furthermore, algorithm-based age-specific BC mortality rates covering several calendar years were calculated for the entire insured female population and compared with official national rates. RESULTS: Our final algorithm, derived from the NRW subsample, comprised codes indicating the presence of BC, metastases, a terminal illness phase and the absence of codes for other tumours. Overall, specificity, sensitivity, NPV and PPV of this algorithm were 97.4%, 91.3%, 98.9% and 81.7%, respectively. In the age range 40-80 years, sensitivity and PPV slightly decreased with increasing age. Algorithm-based age-specific BC mortality rates agreed well with official rates except for the age group 85 years and older. CONCLUSIONS: The algorithm-based identification of BC deaths in German claims data is feasible and valid, except for higher ages. The algorithm to ascertain BC mortality rates in an epidemiological study seems applicable when information on the official CoD is not available in the original database.

A cohort study of mammography screening finds that comorbidity measures are insufficient for controlling selection bias.

OBJECTIVE: To examine the potential of claims-based comorbidity measures for controlling selection bias in observational studies of mammography screening. STUDY DESIGN AND SETTING: Based on claims data of a large German Statutory Health Insurance fund, the single comorbidities considered by the Charlson, Elixhauser, Multipurpose Australian Comorbidity Scoring System, and M3 comorbidity measures were identified for mammography screening participants and nonparticipants. Total death rates within 4 years after screening invitation were compared. Cox proportional hazards regressions were performed unadjusted and adjusted for age, federal state of residence, and comorbidity. RESULTS: Among 1,247,919 insured women aged 50-68 years (56.2% participants), 10,311 participants (death rate 375.8/100,000 person-years) and 18,113 nonparticipants (death rate 854.8/100,000 person-years) died from any cause during the follow-up. The unadjusted hazard ratio (HR) for death from any cause for participants vs. nonparticipants was 0.44 (99.9% confidence interval 0.42-0.46). Adjustments attenuated the HR to a maximum of 0.52 (0.50-0.54). CONCLUSION: The lower short-term all-cause mortality among participants cannot be explained by mammography screening effects and should be interpreted as selection bias. Adjusting for comorbidities only slightly attenuated this bias. Future studies should examine whether claims data include further information that is beneficial to adequately control selection bias in observational studies of mammography screening.

Development of new non-invasive tests for colorectal cancer screening: the relevance of information on adenoma detection.

Researchers are actively pursuing the development of a new non-invasive test (NIT) for colorectal cancer (CRC) screening as an alternative to fecal occult blood tests (FOBTs). The majority of pilot studies focus on the detection of invasive CRC rather than precursor lesions (i.e., adenomas). We aimed to explore the relevance of adenoma detection for the viability of an NIT for CRC screening by considering a hypothetical test that does not detect adenomas beyond chance. We used the Simulation Model of Colorectal Cancer (SimCRC) to estimate the effectiveness of CRC screening and the lifetime costs (payers' perspective) for a cohort of US 50-years-old persons to whom CRC screening is offered from age 50-75. We compared annual screening with guaiac and immunochemical FOBTs (with sensitivities up to 70 and 24% for CRC and adenomas, respectively) to annual screening with a hypothetical NIT (sensitivity of 90% for CRC, no detection of adenomas beyond chance, specificity and cost similar to FOBTs). Screening with the NIT was not more effective, but was 29-44% more costly than screening with FOBTs. The findings were robust to varying the screening interval, the NIT's sensitivity for CRC, adherence rates favoring the NIT, and the NIT's unit cost. A comparative modelling approach using a model that assumes a shorter adenoma dwell time (MISCAN-COLON) confirmed the superiority of the immunochemical FOBT over an NIT with no ability to detect adenomas. Information on adenoma detection is crucial to determine whether a new NIT is a viable alternative to FOBTs for CRC screening. Current evidence thus lacks an important piece of information to identify marker candidates that hold real promise and deserve further (large-scale) evaluation.

Association between socioeconomic and demographic characteristics and utilization of colonoscopy in the EPIC-Heidelberg cohort.

We aimed to describe the utilization of colonoscopy and its association with sociodemographic characteristics within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort study. We included 15 014 study participants (43% men) of the EPIC-Heidelberg cohort recruited between 1994 and 1998. At baseline recruitment, as well as in the 3-yearly follow-up surveys, study participants completed questionnaires on lifestyle, socioeconomic background variables, health status, and use of medications and medical services, including colonoscopy examinations. The present analyses focused on participants who completed the question on colonoscopy examination in all follow-up rounds. Our results show that by the end of the fourth follow-up round, more than half of all participants of the EPIC-Heidelberg cohort had had a colonoscopy. Colonoscopy was associated with some socioeconomic and demographic characteristics: a positive association with vocational training level as well as overall socioeconomic status level [International Standard Classification of Education (ISCED) classification]. A negative association was found for household size and employment status. Colonoscopy usage increased steeply within the subgroup of participants older than 55 years of age and decreased again within the subgroup of participants older than 75 years of age. Organized colorectal cancer screening should include a written invitation system, to overcome the problem of sociodemographic-related differential awareness of and attendance at colonoscopy examinations. Also, the high proportion of prescreened individuals should be taken into account to avoid unnecessary re-examinations.

Estimating colorectal cancer treatment costs: a pragmatic approach exemplified by health insurance data from Germany.

BACKGROUND: The cost of colorectal cancer (CRC) treatment is a crucial parameter to inform cost-effectiveness analyses on CRC screening but it is not readily available and therefore often lacking. We aimed to elaborate and exemplify a pragmatic approach to estimate CRC treatment cost based on health insurance data from Germany. METHODS: We included two groups of persons who were continuously health-insured between 2005-2010: A) Cases: Persons with a hospital discharge diagnosis of CRC (ICD C18-C20) between 2007-2010 and no such a diagnosis between 2005-2006 (to focus on incident CRC cases); B) Controls: Persons without a diagnosis of CRC during the observation period, matched to CRC cases by age and sex (matching factor: 1∶5). We considered in-patient, out-patient and drug costs and calculated incremental costs as the difference in means between cases and controls. We divided costs into three phases of care (initial, intermediate and end-of-life phase). RESULTS: The initial, the intermediate and the end-of-life phase included 12,792, 5,280, and 3,779 CRC cases, respectively, and 63,960, 26,400, and 18,895 controls. The mean incremental costs--annualized for each phase--were €26,000, €2,300, and €51,700, respectively. The costs of the initial phase of care were higher for rectal than for colon cancer. Annualized stage-specific cost estimates ranged from €15,000 to €21,300 for early stages and from €29,800 to €35,000 for late stages. CONCLUSION: This pragmatic and feasible approach provided plausible estimates of CRC treatment costs in Germany; being transferable to other settings, it may thus facilitate to weigh up potential savings in treatment costs against the resources required for CRC control programs in various countries.

How should individuals with a false-positive fecal occult blood test for colorectal cancer be managed? A decision analysis.

Several industrialized nations recommend fecal occult blood testing (FOBT) to screen for colorectal cancer (CRC), but corresponding screening guidelines do not specify how individuals with a prior false-positive FOBT result (fpFOBT) should be managed in terms of subsequent CRC screening. Accordingly, we conducted a decision analysis to compare different strategies for managing such individuals. We used a previously developed CRC microsimulation model, SimCRC, to calculate life-years and the lifetime number of colonoscopies (as a measure of required resources) for a cohort of 50-year-olds to whom FOBT-based CRC screening is offered annually from 50 to 75 years. We compared three management strategies for individuals with a prior fpFOBT: (i) resume screening in 10 years with 10-yearly colonoscopy (SwitchCol_long); (ii) resume screening in 1 year with annual FOBT (ContinueFOBT_Short) and (iii) resume screening in 10 years (i.e., the recommended interval following a negative colonoscopy) with annual FOBT (ContinueFOBT_long). We performed sensitivity analyses on various parameters and assumptions. When using different management strategies for individuals with a prior fpFOBT, the variation in the number of life-years gained relative to no screening was <2%, whereas the variation in the lifetime number of colonoscopies was 23% (percentages are calculated as the maximum difference across strategies divided by the lowest number across strategies). The ContinueFOBT_long strategy showed the lowest lifetime number of colonoscopies per life-year gained even when key assumptions were varied. In conclusion, the ContinueFOBT_long strategy was advantageous regarding both clinical benefit and required resources. Specifying an appropriate management strategy for individuals with a prior fpFOBT may substantially reduce required resources within a FOBT-based CRC screening program without limiting its effectiveness.

A simulation model for colorectal cancer screening: potential of stool tests with various performance characteristics compared with screening colonoscopy.

OBJECTIVE: Many new stool tests intended to detect neoplastic cells or cell products are developed at present for colorectal cancer (CRC) screening. The aim of this study was to simulate a population-based screening setting to assess and compare the potential for early detection and prevention of CRC of screening based on stool tests with different sensitivity and specificity and of screening with colonoscopy as a primary screening tool. METHOD: A Markov model was developed aimed to estimate the proportion of CRC cases which are early detected or prevented due to screening as well as the number of equired stool tests and colonoscopies per early detected or prevented CRC case. Model outcomes were calculated for the offer of annual stool testing from age 55 to 74 in combination with colonoscopic follow-up of positive test results and for the offer of screening colonoscopy as a primary screening tool at ages 55 and 65. The long-lasting risk reduction of colonoscopy allowing the removal of precancerous lesions was taken into account quantitatively. RESULTS: For a variety of stool tests with different performance characteristics, the proportion of CRC cases early detected or prevented was estimated to be higher for stool testing in combination with colonoscopic follow-up of positive test results compared with screening colonoscopy assuming levels of compliance to be expected for the respective screening scheme. Optimizing performance characteristics of stool tests in terms of detecting precancerous lesions, in addition to those in terms of detecting CRC, seemed to be crucial for maximizing effectiveness of CRC screening with stool tests. CONCLUSION: Screening based on new stool tests with colonoscopic follow-up of positive test results might offer a high potential for early detection or prevention of CRC.