Prescribing of valproate and oral antiepileptics for women of childbearing age and during pregnancy in Germany between 2010 and 2020.

PURPOSE: To examine prescriptions of valproate and oral antiepileptic drugs (OAED) in Germany irrespective of the indication in women in general and particularly in women of childbearing age (13-49 years) and during pregnancy between 2010 and 2020, that is, before, during and after the implementation of the EU risk minimization measures (RMMs). METHODS: Analysis of claims data. STUDY POPULATION: all women continuously insured with the AOK health insurance fund in the respective observation year (2010-2020) and the previous year. OAED were identified by ATC code N03. Period of pregnancy was calculated based on birth information in claims data. MAIN OUTCOMES MEASURES: (i) prevalent use of valproate/OAED: number of women with at least one prescription of valproate/OAED per year divided by all women of the study population (rate per 1000 women); (ii) percentage of OAED recipients with at least one valproate prescription during pregnancy (13-49 years) in the respective observation year. RESULTS: Prevalence rate/1000 women for valproate use decreased by -31.33% across all age groups (2010-2014: -7.48%; 2014-2018: -16.47%; 2018-2020: -11,17%) with a strong reduction in women 13-49 years between 2014 and 2018 (-28.74%). The rate for OAED across all age groups rose from 33.43/1000 women in 2010 to 41.03/1000 (+22,73%). Valproate use during pregnancy of women with OAED declined from 1.29% in 2010 to 0.59% in 2020 (-54,26%) (2010-2014: -5.14%; 2014-2018: -42.31%; 2018-2020: -16.69%). CONCLUSION: Even if, due to the descriptive nature of the study, no causal relationship can be postulated between the RMMs and the strong decrease in valproate prescriptions, our results are compatible with the hypothesis that the measures have improved drug therapy safety.

Comparison of drug prescribing before and during the COVID-19 pandemic: A cross-national European study.

PURPOSE: The COVID-19 pandemic had an impact on health care, with disruption to routine clinical care. Our aim was to describe changes in prescription drugs dispensing in the primary and outpatient sectors during the first year of the pandemic across Europe. METHODS: We used routine administrative data on dispensed medicines in eight European countries (five whole countries, three represented by one region each) from January 2017 to March 2021 to compare the first year of the COVID-19 pandemic with the preceding 3 years. RESULTS: In the 10 therapeutic subgroups with the highest dispensed volumes across all countries/regions the relative changes between the COVID-19 period and the year before were mostly of a magnitude similar to changes between previous periods. However, for drugs for obstructive airway diseases the changes in the COVID-19 period were stronger in several countries/regions. In all countries/regions a decrease in dispensed DDDs of antibiotics for systemic use (from -39.4% in Romagna to -14.2% in Scotland) and nasal preparations (from -34.4% in Lithuania to -5.7% in Sweden) was observed. We observed a stockpiling effect in the total market in March 2020 in six countries/regions. In Czechia the observed increase was not significant and in Slovenia volumes increased only after the end of the first lockdown. We found an increase in average therapeutic quantity per pack dispensed, which, however, exceeded 5% only in Slovenia, Germany, and Czechia. CONCLUSIONS: The findings from this first European cross-national comparison show a substantial decrease in dispensed volumes of antibiotics for systemic use in all countries/regions. The results also indicate that the provision of medicines for common chronic conditions was mostly resilient to challenges faced during the pandemic. However, there were notable differences between the countries/regions for some therapeutic areas.

Trends and patterns in EU(7)-PIM prescribing to elderly patients in Germany.

PURPOSE: The aim of this study was to explore patterns and long-term development in prescribing potentially inappropriate medication (PIM) according to the EU(7)-PIM list to elderly patients in Germany. METHODS: We analysed anonymized German claims data. The study population comprised 6.0 million insured individuals at least 65 years old, including all their prescriptions reimbursed in 2019. For the analysis of long-term development, we used data for the years 2009-2019. Factors associated with PIM prescribing were considered from two perspectives: patient-oriented analysis was performed with logistic regression and prescriber-oriented analysis was performed with multiple linear regression. RESULTS: EU(7)-PIM prevalence was reduced from 56.9% in 2009 to 45.1% in 2019. Average annual volume (DDDs/insured) decreased from 145 in 2009 to 121 in 2019. These figures are substantially greater than those for the older PRISCUS list. The majority of investigated ATC level 2 groups with the highest EU(7)-PIM DDD volume exhibited substantial decreases; moderate increases were found for antihypertensive and urological drugs. Antithrombotics increased strongly with the introduction of direct oral anticoagulants. The most prevalent EU(7)-PIM medication was diclofenac; however, in the age group 85+ years, apixaban was twice as prevalent as diclofenac. Polypharmacy, female sex, age < 90 years, need for nursing care and living in Eastern regions were identified as risk factors. Prescriber specialty was the most marked factor in the prescriber-oriented analysis. CONCLUSION: Although the use of EU(7)-PIMs has been declining, regional differences indicate considerable room for improvement. The comparison with PRISCUS highlights the necessity of regular updates of PIM lists.

Integrative Review of Managed Entry Agreements: Chances and Limitations.

BACKGROUND AND OBJECTIVE: Managed entry agreements (MEAs) consist of a set of instruments to reduce the uncertainty and the budget impact of new high-priced medicines; however, there are concerns. There is a need to critically appraise MEAs with their planned introduction in Brazil. Accordingly, the objective of this article is to identify and appraise key attributes and concerns with MEAs among payers and their advisers, with the findings providing critical considerations for Brazil and other high- and middle-income countries. METHODS: An integrative review approach was adopted. This involved a review of MEAs across countries. The review question was 'What are the health technology MEAs that have been applied around the world?' This review was supplemented with studies not retrieved in the search known to the senior-level co-authors including key South American markets. It also involved senior-level decision makers and advisers providing guidance on the potential advantages and disadvantages of MEAs and ways forward. RESULTS: Twenty-five studies were included in the review. Most MEAs included medicines (96.8%), focused on financial arrangements (43%) and included mostly antineoplastic medicines. Most countries kept key information confidential including discounts or had not published such data. Few details were found in the literature regarding South America. Our findings and inputs resulted in both advantages including reimbursement and disadvantages including concerns with data collection for outcome-based schemes. CONCLUSIONS: We are likely to see a growth in MEAs with the continual launch of new high-priced and often complex treatments, coupled with increasing demands on resources. Whilst outcome-based MEAs could be an important tool to improve access to new innovative medicines, there are critical issues to address. Comparing knowledge, experiences, and practices across countries is crucial to guide high- and middle-income countries when designing their future MEAs.

The Expiry of Humira® Market Exclusivity and the Entry of Adalimumab Biosimilars in Europe: An Overview of Pricing and National Policy Measures.

Background: From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry. Objectives: The aim of this paper is to provide a European overview of (list) prices of originator adalimumab, before and after loss of exclusivity; to report changes in the reimbursement status of adalimumab products; and discuss relevant policy measures. Methods: Experts in European countries received a survey consisting of three parts: 1) general financing/co-payment of medicines, 2) reimbursement status and prices of originator adalimumab, and availability of biosimilars, and 3) policy measures related to the use of adalimumab. Results: In May 2019, adalimumab biosimilars were available in 24 of the 30 countries surveyed. Following introduction of adalimumab biosimilars, a number of countries have made changes in relation to the reimbursement status of adalimumab products. Originator adalimumab list prices varied between countries by a factor of 2.8 before and 4.1 after loss of exclusivity. Overall, list prices of originator adalimumab decreased after loss of exclusivity, although for 13 countries list prices were unchanged. When reported, discounts/rebates on originator adalimumab after loss of exclusivity ranged from 0% to approximately 26% (Romania), 60% (Poland), 80% (Denmark, Italy, Norway), and 80-90% (Netherlands), leading to actual prices per pen or syringe between €412 (Finland) and €50 - €99 (Netherlands). To leverage competition following entry of biosimilar adalimumab, only a few countries adopted measures specifically for adalimumab in addition to general policies regarding biosimilars. In some countries, a strategy was implemented even before loss of exclusivity (Denmark, Scotland), while others did not report specific measures. Conclusion: Even though originator adalimumab is the highest selling product in the world, few countries have implemented specific policies and practices for (biosimilar) adalimumab. Countries with biosimilars on the market seem to have competition lowering list or actual prices. Reported discounts varied widely between countries.

Impact of EU risk assessment process and administrative regulations for manufacturers of combined hormonal contraceptive prescribing. An analysis of developments in Germany and the implications.

OBJECTIVE: Combined hormonal contraceptives (CHC) exhibit differing risks for cardiovascular and thrombotic events (VTE). A European referral process confirmed higher VTE risks for 3rd generation gestagens and drospirenone. CHC are now grouped in risk classes (RC) I, II, and III, with RC III having a higher risk than RC I and X (risk not yet known). Marketing authorization holders were obliged to implement pharmacovigilance measures and risk minimization measures including changes of prescribing information. The study assessed whether these activities induced changes in prescription patterns. METHODS: German prescription data for 1.1 million women below 20 years of age were used to analyze the effects of interventions and potential influence factors using logistic regression. Descriptive statistics were calculated for prescriptions for 3.3 million women from January 2011 to March 2016. RESULTS: Shares of RC I and RC X recipients rose substantially over the observation period, while RC III recipient share showed a steady decrease. The referral induced a slightly faster decrease in RC III and increase in RC X. The implementation of pharmacovigilance measures manifested no additional effect. CONCLUSION: The decrease in RC III share already observed before the referral process can be explained with pre-existing discussions around CHC. The effect attributable to the referral was statistically significant, although very small. While evidence for a connection between interventions and prescription change is only indirect, the study shows that routine data are suitable for impact analyses, and monitoring prescribing patterns can be recommended as feedback after regulatory or political interventions. This is being followed up.

Policies for biosimilar uptake in Europe: An overview.

BACKGROUND: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. OBJECTIVES: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. METHODS: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. RESULTS: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. CONCLUSIONS: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market.

[Prescription differences of dementia drugs in urban and rural areas in Germany]. / Antidementivaverordnungen in Stadt und Land--Ein Vergleich zwischen Ballungszentren und Flächenstaaten in Deutschland.

OBJECTIVE: The objective of this study was to detect regional variability in anti-dementia drug prescriptions in metropolitan and rural regions of Germany in order to assess the widespread assumption that dementia treatment coverage is lower in rural areas because of the lower physician density in ambulatory care, especially for neuropsychiatrists. METHODS: We compared the 2007 prescription rates for Donepezil, Rivastigmine, Galantamine and Memantine in defined daily doses per capita in the population aged 65 and older insured in the German Statutory Health Insurance. The prescription data for the States of Berlin and Hamburg were compared with those in the adjacent rural-type States of Brandenburg and Lower Saxony. RESULTS: We found a greater proportion of both general practitioners and neuropsychiatrists prescribing dementia drugs and a higher population coverage with dementia drugs in the rural states compared to the urban states. CONCLUSIONS: The data suggest that the drug coverage in case of dementia is better in rural than in urban states in spite of a lower physician density. This unexpected result can be explained by the fact that a smaller proportion of physicians participate in the prescription of dementia drugs in urban areas, a phenomenon probably related to differences in task description and clientele selection between physicians in urban and rural areas.

[Assessment of the number of cardio- and cerebrovascular events due to rofecoxib (Vioxx) in Germany between 2001 and 2004]. / Schätzung der unter Rofecoxib (Vioxx) in Deutschland in den Jahren 2001-2004 aufgetretenen kardio- und zerebrovaskulären Ereignisse.

BACKGROUND AND PURPOSE: After the recall of rofecoxib (Vioxx), there was repeated national and international discussion on the potential number of patients harmed by causally related cardio- and cerebrovascular events. In individual cases, it cannot be determined whether a myocardial infarction or stroke that occurred during rofecoxib therapy was actually directly caused by this drug. On the basis of the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial and German prescription data provided by the Scientific Institute of the Local Health Care Fund, the authors therefore conservatively estimated the number of patients harmed by rofecoxib in Germany between 2001 and 2004. METHODS: Under simplifying assumptions that, as in the VIGOR study, the risk of rofecoxib or naproxen therapy can be described by a Cox model with exponentially distributed event times, it is possible to calculate the daily risk of cardio- and cerebrovascular events in patients treated with these drugs. The estimated number of patients experiencing cardio- and cerebrovascular events under rofecoxib or naproxen therapy can be calculated by multiplying the daily risks by the defined daily doses prescribed in Germany. The difference between these numbers produces the estimated number of patients harmed by rofecoxib. RESULTS: On the basis of the data pool, a total of 7,092 additional diseased or deceased patients due to rofecoxib therapy were estimated (95% confidence interval: 2,004-15,416). The simplifying assumptions made together with the underreporting of events in the VIGOR trial are more likely to lead to an underestimation than an overestimation of affected patients. When assessing the benefit-harm ratio of rofecoxib, it needs to be considered that its protective gastrointestinal effects were not assessed compared with the optimum long-term therapy. It can be assumed that a comparison of rofecoxib with a combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric mucosal barrier protectors (e. g., misoprostol) would not have shown an advantage in favor of rofecoxib therapy. CONCLUSION: The example of rofecoxib and the relatively high number of patients harmed by it in Germany indicate that, before widely prescribing a new drug, a more thorough assessment of the benefit-harm ratio of the drug is required as well as a stronger consideration of therapeutic alternatives and a timely conduct of meaningful clinical studies. The results of these studies should be promptly communicated in full to physicians and patients.