Examining confidential wholesale margin estimates in European countries for the price negotiation of patented drugs in Germany: a statistical model.

BACKGROUND: Based on the legal framework laid down in section 130b (9) of Book V of the German Social Code, various criteria are relevant for the negotiated price for new patented drugs in Germany. European reference prices (ERPs) are one criterion. The ERP is based on the ex-factory prices (EFPs) of the countries included in the European country basket. However, in some of these countries, the EFP is not published due to confidential wholesale margins. Wholesale margins must therefore be estimated and deducted from purchase prices. In this context literature-based estimates to date do not assume regressive margins with higher pharmaceutical prices. This assumption is questionable and can lead to systematically underestimated country prices, especially for high-priced drugs. Percentage wholesale margins in the majority of European countries develop to a comparable extent regressively with increasing prices. It should therefore be examined (1) whether statistical models can predict the margins of individual countries, in principle and especially for countries where margins are unknown and regressive trends are likely, and (2) to what extent the estimation of margins improves when regressive statistical models are used to estimate margins instead of cross-price averages published in the literature. METHODS: Qualitative preliminary research explores the basic wholesale pricing mechanisms in countries with confidential wholesale margins. Wholesale margins for reimbursable drugs were then modeled for regulated European countries. Estimation quality and impact of the model was compared to estimations based on average margins. RESULTS: In both regulated countries and in countries with confidential wholesale margins, percentage margins of wholesalers develop regressively as drug prices rise. Regressive courses of margins can be resiliently modeled for the regulated countries using a power distribution with significantly lower mean squared errors in a linear mixed model in comparison to literature-based estimations with country-specific cross-price averages. CONCLUSION: If there is reason to believe that margins are regressive, confidential wholesale margins are expected to be better estimated by the power function based on margins of regulated countries than by the published country-specific average margins, reducing significantly inaccurate effects on margin estimations of high-price drugs.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Examining patient preferences in the treatment of rheumatoid arthritis using a discrete-choice approach.

BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) used in second-line treatment of rheumatoid arthritis (RA) are administered parenterally. However, so-called targeted synthetic DMARDs (tsDMARDs) - developed more recently - offer alternative (ie, oral) administration forms in second-line treatment. Since bDMARDs and tsDMARDs can be regarded as equal in terms of efficacy, the present study examines whether such characteristics as route of administration drive RA patients' treatment choice. This may ultimately suggest superiority of some second-line DMARDs over equally effective options, at least according to RA-patient preferences. OBJECTIVE: The current study assessed the importance of oral administration among other treatment characteristics differing between available second-line DMARDs for RA patients' preferences using a discrete-choice experiment (DCE). MATERIALS AND METHODS: The DCE involved scenarios of three hypothetical treatment options in a d-efficient design with varying levels of key attributes (route and frequency of administration, time till onset of drug effect, combination therapy, possible side effects), as defined by focus groups. Further patient characteristics were recorded by an accompanying questionnaire. In the DCE, patients were asked to choose best and worst options (best-worst scaling). Results were analyzed by count analysis and adjusted regression analysis. RESULTS: A total of 1,588 subjects completed the DCE and were eligible for final analyses. Across all characteristics included in the DCE, "oral administration" was most desired and "intravenous infusion" was most strongly rejected. This was followed by "no combination with methotrexate" being strongly preferred and "intake every 1-2 weeks" being strongly rejected. On average, levels of route of administration showed strongest influences on patients' decisions in post hoc bootstrapping analysis. CONCLUSION: According to the results, an oral DMARD that does not have to be combined with methotrexate and is not administered (only) every 1-2 weeks appears a highly favorable treatment option for patients with RA. DMARDs meeting these preferences may increase compliance and adherence in RA treatment.

Multiple sclerosis in Germany: data analysis of administrative prevalence and healthcare delivery in the statutory health system.

BACKGROUND: Healthcare-utilization data for multiple sclerosis (MS) are scarce in Germany. The Purpose of the study was to analyse administrative prevalence of MS, medication use and type of specialists involved in MS treatment in the outpatient setting in Bavaria. METHODS: Pseudonymized claims data from Bavarian Statutory Health Insurance (SHI)-accredited physicians were used. Administrative prevalence of MS was defined as having ≥1 MS diagnosis (International Classification of Diseases, 10th edition, code G35) documented by a neurologist or psychiatrist, or ≥1 prescription for disease-modifying drugs (DMDs)). The administrative prevalence calculated for Bavaria was projected to Germany. DMD prescription and involvement of different specialities in health care service for MS patients was analysed. RESULTS: Administrative prevalence of MS in Bavaria increased from 0.123% to 0.175% of insured persons between 2005 and 2009; when projected, this yielded ~102,000-143,000 patients with MS in the German population. The percentage of patients receiving ≥1 DMD prescription increased from 45.5% to 50.5%. Patients with MS were mainly treated by neurologists in the ambulatory care setting. CONCLUSIONS: These results provide important information on the administrative prevalence of MS in Bavaria and on healthcare provision for patients, which is relevant for resource planning in the healthcare sector.

Predictors of response to early basal insulin treatment in patients with type 2 diabetes--the EARLY experience.

BACKGROUND: It was the aim of this study to assess baseline predictors for glycosylated hemoglobin (HbA1c) reduction, treatment-to-target, and insulin glargine dose in patients with an HbA1c level of ≥ 7.5% (58 mmol/mol) at baseline despite 3 months of maximum tolerated dose of metformin under daily conditions. SUBJECTS AND METHODS: This was an open, multicenter, prospective observational study with a 6-month follow-up including 1,438 patients with type 2 diabetes. Baseline variables independently associated with HbA1c (overall reduction and achievement of target values) and insulin glargine dose used were determined using a stepwise multivariate linear regression analysis. RESULTS: In a multivariate linear regression analysis (R(2)=0.545) baseline HbA1c (ß=-0.722; P<0.001) and retinopathy (ß=-0.064; P=0.007) were associated with a greater HbA1c reduction at 6 months, whereas duration of diabetes was associated with a lesser HbA1c reduction (ß=0.084; P<0.001). In another multivariate linear regression analysis, weight (odds ratio [OR] 0.99; 95% confidence interval [CI] 0.98 to <1.00), duration of diabetes (OR 0.96; 95% CI 0.93-0.99), and baseline HbA1c (OR 0.65; 95% CI 0.56-0.76) were associated with a reduced likelihood of achieving an HbA1c level of <7% (53 mmol/mol); baseline HbA1c (OR 0.66; 95% CI 0.51-0.85) was the only variable associated with a reduced likelihood of achieving an HbA1c level of <6.5% (48 mmol/mol). In a further analysis (R(2)=0.135) the insulin dose needed was increased in those with a higher body weight (ß=0.230; P<0.001), a longer duration of diabetes (ß=0.134; P<0.001), a higher baseline HbA1c level (ß=0.205; P<0.001), and the presence of microalbuminuria (ß=0.096; P=0.003). CONCLUSIONS: Identified predictors of greater HbA1c reduction, target goal achievement, and insulin dose needed may help to optimize the balance of benefits and risks with the use of insulin glargine.

Influence on persistence and adherence with oral bisphosphonates on fracture rates in osteoporosis.

BACKGROUND AND AIM: Oral bisphosphonates have been shown to reduce the risk of fractures in patients with osteoporosis. It can be assumed that the clinical effectiveness of oral bisphosphonates depends on persistence with therapy. METHODS: The influence of persistence with and adherence to oral bisphosphonates on fracture risk in a real-life setting was investigated. Data from 4451 patients with a defined index prescription of bisphosphonates were included. Fracture rates within 180, 360, and 720 days after index prescription were compared between persistent and non-persistent patients. In an extended Cox regression model applying multiple event analysis, the influence of adherence was analyzed. Persistence was defined as the duration of continuous therapy; adherence was measured in terms of the medication possession ratio (MPR). RESULTS: In patients with a fracture before index prescription, fracture rates were reduced by 29% (p = 0.025) comparing persistent and non-persistent patients within 180 days after the index prescription and by 45% (p < 0.001) within 360 days. The extended Cox regression model showed that good adherence (MPR >/= 0.8) reduced fracture risk by about 39% (HR 0.61, 95% CI 0.47-0.78; p < 0.01). CONCLUSIONS: In patients with osteoporosis-related fractures, good persistence and adherence to oral bisphosphonates reduced fracture risk significantly.

The impact of pharmaceuticals on the decline of cardiovascular mortality in Germany.

PURPOSE: The effect of innovative medicines and surgical interventions on the decline of (cardiovascular) mortality is often called into question. The increase in general economic prosperity is often seen as the main reason for the continuous increase in life expectancy. The purpose of this study is to investigate the extent to which mortality from cardiovascular diseases has been affected by pharmaceuticals and other medical interventions over the last 30 years in Germany. METHODS: Main outcome measures were the time series of direct method death rates (DMDR) of cardiovascular and non-cardiovascular mortalities. To control for socioeconomic and secular trends the difference between both time series was calculated. The impact of interventions on mortality was analysed by developing two linear regression models: The onset model analyses whether the introduction of interventions influences mortality or not. The consumption model estimates the quantitative impact of interventions in two phases. RESULTS: Cardiovascular mortality as a percentage of total mortality fell from 40 to 38% over the study period. All investigated interventions had statistically significant effects on the decline of cardiovascular diseases, which is expressed by the standardised regression coefficient: onset model: preventive behaviour index (PBI) -8.3, angioplasty/CABG -0.6, antithrombotic agents -1.5, diuretics -0.9, beta-blockers -1.0, calcium channel blockers -0.8 and ACE inhibitors -1.1 (all interventions p < 0.01); consumption model: innovative drugs phase I -7.5 (p = 0.017), innovative drugs phase II -6.9 (p < 0.01), PBI -13.1 (p < 0.01) and angioplasty/CABG -9.9 (p < 0.01). CONCLUSIONS: All innovative drug classes and surgical interventions had a positive effect on the decline of cardiovascular mortality.

Comparison of the effects of diclofenac or other non-steroidal anti-inflammatory drugs (NSAIDs) and diclofenac or other NSAIDs in combination with proton pump inhibitors (PPI) on hospitalisation due to peptic ulcer disease.

PURPOSE: Up to 25% of patients taking non-steroidal anti-inflammatory drugs (NSAIDs) chronically experience gastrointestinal side effects. This report aims to determine the gastroprotective effects of proton pump inhibitors (PPI) in patients taking NSAIDs, especially diclofenac. METHODS: From the claims database of a German sickness fund with 1.4 million beneficiaries, we used data from patients enrolled in the health plan continuously from 2000 until 2004 with an inpatient diagnosis of peptic ulcer disease in 2003 and 2004. For our nested case-control study, we matched these cases for calendar time with up to 10 controls per case. Our main outcome measure were the adjusted odds ratios (ORs) for peptic ulcer disease associated with diclofenac and other NSAIDs. RESULTS: In the study population of 752 613 beneficiaries, 979 cases and 10 319 controls were identified. A stratified analysis according to the prescription of diclofenac alone or in combination with PPI showed that diclofenac prescriptions increased the risk for hospitalisation due to peptic ulcer significantly (adjusted OR 2.4 [95%CI 1.94, 3.05]). If PPI were prescribed concomitantly with diclofenac, we observed a risk reduction (OR 1.3 [95%CI 0.7, 2.3]). The significance of the PPI effect was shown using an interaction term in a regression model without stratification, where a risk reduction of 60% (OR 0.4 [95%CI 0.2, 0.7], p < 0.05) was found. CONCLUSIONS: The concomitant prescription of PPI and diclofenac decreases the hospitalisation risk due to peptic ulcer significantly. The results support the use of PPI as gastroprotective agents in patients who receive NSAIDs.