Opportunities and Pitfalls in Drug Safety Studies after Marketing Approval An Evaluation with a Focus on Older Patients

In the next decades, the number of older people will rise substantially in Germany. Likewise, drug treatment and polypharmacy will also augment due to the high prevalence of multimorbidity in this subpopulation. Since older people are often excluded from randomized controlled trials prior to drug approval, pharmacoepidemiological safety studies (PSS) based on spontaneous reporting systems and electronic healthcare databases often represent the only opportunity to investigate the safety of drugs in this population. However, these studies have specific methodological challenges related to the clinical characteristics of older patients and the nature of the data sources. Thus, the overall aim of this thesis is to (1) critically assess methodological challenges of PSS based on spontaneous reporting systems and electronic healthcare databases with a focus on older patients and (2) to define further areas of research to enhance their quality. In this context, disproportionality analyses based on spontaneous reports, cohort studies, nested case control studies, and case only designs are introduced as study designs for PSS. Confounding (e.g., by frailty), outcome and exposure misclassification as well as time related biases in PSS are illustrated as selected methodological challenges. These challenges are then discussed in the context of my research articles with a focus on older people, and opportunities to address these challenges are presented. More specifically, the role of spontaneous reporting systems in the detection of adverse drug reactions in older people is critically assessed. Afterwards, drug utilization studies as well as the application of high dimensional propensity score methods and case only designs are discussed as options to overcome the specific problem of confounding by indication and unmeasured confounding in PSS among older people. Further, a detailed review of the patienta s profile is recommended to increase the specificity of the outcome case algorithms in administrative claims databases. Moreover, it is highlighted that sensitivity analyses in drug utilization and safety studies are particularly important in the case of a as neededa treatment among older patients and if information on the prescribed daily dose is missing. Finally, it is highlighted how time related biases can be prevented in cohort and nested case control studies using a time dependent analysis and risk set sampling, respectively. In the conclusion, future research perspectives with regard to PSS in older patients are pointed out as, for instance, the use of semi automated drug safety monitoring based on electronic healthcare databases, the availability of additional medical information in the context of the German a e healtha legislation or the need for external validation studies to study the impact of outcome and drug exposure misclassification

Opportunities and Pitfalls in Drug Safety Studies after Marketing Approval An Evaluation with a Focus on Older Patients

In the next decades, the number of older people will rise substantially in Germany. Likewise, drug treatment and polypharmacy will also augment due to the high prevalence of multimorbidity in this subpopulation. Since older people are often excluded from randomized controlled trials prior to drug approval, pharmacoepidemiological safety studies (PSS) based on spontaneous reporting systems and electronic healthcare databases often represent the only opportunity to investigate the safety of drugs in this population. However, these studies have specific methodological challenges related to the clinical characteristics of older patients and the nature of the data sources. Thus, the overall aim of this thesis is to (1) critically assess methodological challenges of PSS based on spontaneous reporting systems and electronic healthcare databases with a focus on older patients and (2) to define further areas of research to enhance their quality. In this context, disproportionality analyses based on spontaneous reports, cohort studies, nested case control studies, and case only designs are introduced as study designs for PSS. Confounding (e.g., by frailty), outcome and exposure misclassification as well as time related biases in PSS are illustrated as selected methodological challenges. These challenges are then discussed in the context of my research articles with a focus on older people, and opportunities to address these challenges are presented. More specifically, the role of spontaneous reporting systems in the detection of adverse drug reactions in older people is critically assessed. Afterwards, drug utilization studies as well as the application of high dimensional propensity score methods and case only designs are discussed as options to overcome the specific problem of confounding by indication and unmeasured confounding in PSS among older people. Further, a detailed review of the patienta s profile is recommended to increase the specificity of the outcome case algorithms in administrative claims databases. Moreover, it is highlighted that sensitivity analyses in drug utilization and safety studies are particularly important in the case of a as neededa treatment among older patients and if information on the prescribed daily dose is missing. Finally, it is highlighted how time related biases can be prevented in cohort and nested case control studies using a time dependent analysis and risk set sampling, respectively. In the conclusion, future research perspectives with regard to PSS in older patients are pointed out as, for instance, the use of semi automated drug safety monitoring based on electronic healthcare databases, the availability of additional medical information in the context of the German a e healtha legislation or the need for external validation studies to study the impact of outcome and drug exposure misclassification

Characterising the burden of chronic kidney disease among people with type 2 diabetes in England: a cohort study using the Clinical Practice Research Datalink.

OBJECTIVES: To describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in routine clinical care. DESIGN: Repeat cross-sectional study (6 monthly cross-sections) and cohort study from 1 January 2017 to 31 December 2019. SETTING: Primary care data from English practices contributing to the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. PARTICIPANTS: Patients with T2D aged >18 years, at least one year of registration data. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was prevalence of CKD defined as chronic kidney disease epidemiology collaboration (CKD-EPI) estimated glomerular filtration rate <60 mL/min/1.73 m2, and/or urinary albumin creatinine ratio ≥3 mg/mmol in the past 24 months. Secondary outcomes were prescriptions of medications of interest and clinical and demographic characteristics in the past 3 months.In the cohort study rates of renal and cardiovascular complications, all-cause mortality and hospitalisations over the study period were compared among those with and without CKD. RESULTS: There were 574 190 eligible patients with T2D as of 1 January 2017 and 664 296 as of 31 December 2019. Estimated prevalence of CKD across the study period was stable at approximately 30%. Medication use was stable over time in people with CKD and T2D, with low use of steroidal mineralocorticoid receptor antagonists (approximately 4.5% across all time points) and a low use but steady increase in use of sodium-glucose co-transporter-2 inhibitors (from 2.6% to 6.2%). Rates of all complications were higher in those with CKD at the start of the study period, with increasing rates, with increased severity of CKD, heart failure and albuminuria. CONCLUSIONS: The burden of CKD in patients with T2D is high and associated with substantially increased rates of complications particularly in those with comorbid heart failure

Moeglichkeiten und Schwierigkeiten in Arzneimittelrisikostudien nach Marktzulassung Eine Betrachtung mit Fokus auf aeltere Patientinnen und Patienten

In the next decades, the number of older people will rise substantially in Germany. Likewise, drug treatment and polypharmacy will also augment due to the high prevalence of multimorbidity in this subpopulation. Since older people are often excluded from randomized controlled trials prior to drug approval, pharmacoepidemiological safety studies (PSS) based on spontaneous reporting systems and electronic healthcare databases often represent the only opportunity to investigate the safety of drugs in this population. However, these studies have specific methodological challenges related to the clinical characteristics of older patients and the nature of the data sources. Thus, the overall aim of this thesis is to (1) critically assess methodological challenges of PSS based on spontaneous reporting systems and electronic healthcare databases with a focus on older patients and (2) to define further areas of research to enhance their quality. In this context, disproportionality analyses based on spontaneous reports, cohort studies, nested case control studies, and case only designs are introduced as study designs for PSS. Confounding (e.g., by frailty), outcome and exposure misclassification as well as time related biases in PSS are illustrated as selected methodological challenges. These challenges are then discussed in the context of my research articles with a focus on older people, and opportunities to address these challenges are presented. More specifically, the role of spontaneous reporting systems in the detection of adverse drug reactions in older people is critically assessed. Afterwards, drug utilization studies as well as the application of high dimensional propensity score methods and case only designs are discussed as options to overcome the specific problem of confounding by indication and unmeasured confounding in PSS among older people. Further, a detailed review of the patienta s profile is recommended to increase the specificity of the outcome case algorithms in administrative claims databases. Moreover, it is highlighted that sensitivity analyses in drug utilization and safety studies are particularly important in the case of a as neededa treatment among older patients and if information on the prescribed daily dose is missing. Finally, it is highlighted how time related biases can be prevented in cohort and nested case control studies using a time dependent analysis and risk set sampling, respectively. In the conclusion, future research perspectives with regard to PSS in older patients are pointed out as, for instance, the use of semi automated drug safety monitoring based on electronic healthcare databases, the availability of additional medical information in the context of the German a e healtha legislation or the need for external validation studies to study the impact of outcome and drug exposure misclassification

Frequency and trends of disease-modifying antirheumatic drug (DMARD) use in Germany

The aim of this study was to analyze the population-based frequency of classic (c-) and biologic (b-) disease-modifying antirheumatic drug (DMARD) use over time, selected underlying indications and the specialty of the prescribing physicians in Germany. Based on the claims data of the German Pharmacoepidemiological Research Database (GePaRD), yearly cross-sectional studies were conducted from 2004 to 2011. The prevalence of DMARD use was calculated as the number of persons with at least one dispensation per 1000 persons stratified by sex and age. In 2011, we also obtained the proportion of c- and b-DMARDs users with diagnoses of selected indications and the proportion of dispensations by specialty of the physician. Between 2004 and 2011, the annual prevalence of b-DMARD and c-DMARD use increased from 0.35‰ to 1.54‰ and from 6.53‰ to 8.93‰, respectively. In 2011, the study population comprised 12.8 million insurants with a mean age of 44.0 years. During this year, among c-DMARDs, methotrexate was prescribed most frequently (4.76‰), followed by azathioprine (1.72‰) and sulfasalazine (1.20‰). For b-DMARDs, adalimumab (0.57‰), etanercept (0.46‰), and rituximab (0.23‰) were most frequently used. Notably, b-DMARD users more often had a diagnosis of ankylosing spondylitis and psoriasis compared to c-DMARD-users (20.7% vs. 2.9% and 20.0% vs. 11.4%, respectively) and b-DMARDs were more frequently prescribed by rheumatologists and other specialists. Our population-based study highlights the increasing use of c- and b-DMARDs in Germany. Compared to c-DMARDs, b-DMARDs were commonly used for indications besides rheumatoid arthritis. Future research should therefore also focus on their prescription patterns and safety aspects in indications other than RA

Incidence of Multiple Sclerosis in Germany: A Cohort Study Applying Different Case Definitions Based on Claims Data

BACKGROUND: Data on the incidence of multiple sclerosis (MS) on the national level is scarce. We aimed to estimate the incidence of MS in Germany and to compare different MS case definitions based on claims data. METHODS: We conducted a cohort study with the German Pharmacoepidemiological Research Database in 2012 and calculated age- and gender-standardized incidence rates (sIRs) for 3 case definitions. In addition, the effect of stepwise reduction of the look-back period without MS diagnosis on the incidence rate was evaluated. RESULTS: Our cohort comprised 4,175,877 individuals. The first case definition based on ICD-10 diagnoses yielded an sIR of 21.8 (95% CI 20.2–23.5) per 100,000 person years, whereas the second and third case definitions with additional requirements for drug treatment and diagnostic tests resulted in lower sIRs of 10.1 (9.1–11.3) and 6.6 (5.8–7.6) respectively. We observed a higher incidence for shorter look-back periods. CONCLUSION: The incidence of MS in Germany might be substantially higher than suggested in earlier studies. In addition, our study highlights the importance of a look-back period of at least 36 months to identify incident MS cases based on claims data

Is there an unmet medical need for palliative care services in Germany? Incidence, prevalence, and 1-year all-cause mortality of palliative care sensitive conditions: real-world evidence based on German claims data

Aim: To characterize palliative care patients, to estimate the incidence, prevalence, and 1-year all-cause mortality in patients in Germany who received palliative care treatment. Subject and methods: The study analyzed the InGef Research Database, which covers 4 million people insured in German statutory health insurance companies. Specific outpatient and inpatient reimbursement codes were used to capture cases with palliative conditions. The prevalence was ascertained for the year 2015. The incidence was calculated for patients without documented palliative care services in the year before the observation period. The Kaplan–Meier method was used to analyze the 1-year all-cause mortality. Results: The incidence rate of palliative conditions was 41.3 and 34.9 per 10,000 persons in women and men, respectively. The prevalence per 10,000 persons was 61.3 in women and 51.1 in men. The 1-year all-cause mortality among patients receiving their first palliative care treatment was 67.5%. Mortality was lower in patients receiving general outpatient palliative care treatment (AAPV; 60.8%) compared to patients receiving specialized outpatient palliative care treatment (SAPV; 86.1%) or inpatient palliative care treatment (90.6%). Within the first 30 days, mortality was particularly high (~43.0%). Conclusions: In Germany, more than 400,000 patients per year receive palliative care treatment, which is lower compared to estimates of the number of persons with a potential need for palliative care. This gap was observed particularly in younger to middle-aged individuals. The findings indicate a demand for methodologically sound studies to investigate the public health burden and to quantify the unmet need for palliative care in Germany

Burden of community-acquired pneumonia, predisposing factors and health-care related costs in patients with cancer

Abstract Background Data on the burden of community-acquired pneumonia (CAP) and health-care related costs in patients with cancer is scarce. We aimed to estimate the CAP incidence rate, mortality, and healthcare-related costs of CAP patients with different cancer subtypes in Germany. Methods We used German health claims data of a representative sample of 4 million subjects to conduct cohort studies in patients with a new diagnosis of lung, hematological, breast, gastro-intestinal tract and renal/urinary-tract cancer and a comparator cohort without cancer between 2011 and 2015. CAP cases were identified in both the hospital and ambulatory care setting. Crude and age- and sex-standardized incidence rates (sIR) of CAP and mortality after CAP were calculated. To compare the health care-related costs of cancer patients with and without a diagnosis of CAP, a propensity-score (PS) matched control group was created. Results The study population comprised of 89,007 patients with cancer. In lung cancer patients, the sIR was increased 21-fold compared to the control cohort. For the other cancer subtypes, the sIR was increased 4.3-fold (hematological malignancies) to 1.7-fold (breast cancer) compared to the control cohort. The 30-day mortality in CAP cases was highest in lung cancer patients with 20.0% and ranged from 7.2 to 18.5% in CAP cases with other cancer subtypes. The highest costs were observed in CAP cases with hematological malignancies with 28,969 € (SD 37,142 €) and the lowest in patients with renal/urinary tract cancer with 17,432 € (SD 19,579 €). The absolute difference in the mean overall costs between CAP cases and controls without CAP ranged from 4,111€ to 9,826€, depending on the cancer type. CAP-related costs were predominantly triggered by substantially elevated hospital costs in CAP cases. Conclusions The incidence rate of CAP and related mortality is high in patients with cancer with strong variations by cancer subtype. Furthermore, CAP in cancer patients is associated with substantial direct excess costs