A decade of early benefit assessment of ophthalmic drugs in Germany: success story or not?

OBJECTIVE: To analyze how ophthalmic drugs fared in the early benefit assessment (EBA) after its introduction in Germany up to 2020 and to quantify its impact on their negotiated prices. METHODS: Relevant documents were screened and essential content on added benefit outcomes and the underlying evidence was extracted next to pricing information. In addition to descriptive statistics, cross-stakeholder analyses and agreement statistics were implemented. RESULTS: Thirteen completed EBA were identified involving eight drugs. Only four drugs (30.8%) received an added benefit. The OR for no added benefit of ophthalmic drugs versus all other drugs was 2.971 (0.902-9.781). The agreement between manufacturers' claims and decision-maker appraisals is fair (kappa 0.435). In all cases, evidence was derived for RCTs, but for different reasons, not all of them allowed direct comparisons with the comparator as defined by the decision-maker. The negotiated rebates on manufacturer's selling prices varied from 6.8% up to 47.4%. Nevertheless, the rebates for ophthalmic drugs (median 14.5%) were lower than those for all negotiated drugs (median 24%). CONCLUSION: Over the past decade, the EBA of ophthalmic drugs was not necessarily a success story, but in most of the cases, the drugs were successful in the market.

Failure due to formal reasons within German benefit assessment of medicinal products: the dilemma between marketing authorization and HTA.

Objective: Due to the impact of the Federal Joint Committee's (FJC) appraisal on following price negotiations, it is crucial to understand the underlying reasons of failure in early benefit assessment (EBA) of medicinal products in Germany. Methods: Medicinal products for which no added benefit was granted, the underlying reasons given by the FJC were extracted and grouped into respective categories according to predefined working definitions. Several reasons may hold for one subgroup. Furthermore, binomial proportion analysis was performed to gather proportions and their precision for each therapeutic area regarding possible failure. Results: 293/427 subgroups did not receive an added benefit. For 265/293 the following main formal reasons were stated: deviation of label to the pivotal studies (59%), wrong comparator (20.5%), and methodological deficiencies of indirect comparisons (12.3%). The proportion of failure in EBA is heterogeneous and therapeutic area depending (p = 0.0005). For most of the therapeutic areas, the confidence intervals of binomial proportions include 50%. Conclusion: Various different reasons led to the failure of EBAs in the past. Despite different objectives, a better alignment between the requirements and methods in the marketing authorization procedure and the EBA might facilitate the design of pivotal studies, which may be useful in both procedures.

Health Care Use and Costs in Individuals With Diabetes With and Without Comorbid Depression in Germany: Results of the Cross-sectional DiaDec Study.

OBJECTIVE: Increased health care use and costs have been reported in individuals with diabetes with comorbid depression. Knowledge regarding cost differences between individuals with diabetes alone and those with diabetes and diagnosed/undiagnosed depression is, however, scarce. We therefore compared use and costs for patients with diabetes and no depression and patients with diabetes and documented depression diagnosis or self-reported depression symptoms for several cost components, including mental health care costs. RESEARCH DESIGN AND METHODS: Data from a 2013 cross-sectional survey of randomly sampled members of a nationwide German statutory health insurance (SHI) provider with diabetes (n = 1,634) were linked individually with SHI data covering four quarters before and after the survey. Self-reported depression symptoms were assessed with the Patient Health Questionnaire-9, with depression diagnosis taken from SHI data. We analyzed health care use and costs, using regression analysis to calculate cost ratios (CRs) with adjustment for sociodemographic/socioeconomic factors and comorbidities for two groups: 1) those with no symptoms and no diagnosis and 2) those with symptoms or diagnosis. In our explorative subanalysis we analyzed subgroups with either symptoms or diagnosis separately. RESULTS: Annual mean total health care costs were higher for patients with comorbid depression (EUR 5,629 [95% CI 4,987-6,407]) than without (EUR 3,252 [2,976-3,675], the CR being 1.25 [1.14-1.36]). Regression analysis showed that excess costs were highly associated with comorbidities. Mental health care costs were very low for patients without depression (psychotherapy EUR 2; antidepressants EUR 4) and still relatively low for those with depression (psychotherapy EUR 111; antidepressants EUR 76). CONCLUSIONS: Costs were significantly higher when comorbid depression was present either as symptoms or diagnosed. Excess costs for mental health services were rather low.

Predictors of negotiated prices for new drugs in Germany.

INTRODUCTION: In Germany, all new, innovative medicines are subject to an early benefit assessment by the German Federal Joint Committee with subsequent price negotiation and optional arbitration. The purpose of this study was to identify drivers of negotiated (including arbitrated) prices of new, non-orphan innovative medicines in Germany. METHODS: The analysis considered all non-orphan drugs that underwent a benefit appraisal between January 2011 and June 2016, and displayed a reimbursement price in the German Drug Directory (Lauer-Taxe®) in November 2017. Negotiated annual treatment costs were analyzed with respect to 11 explanatory variables in regression models. RESULTS: The total sample included 106 non-orphan drugs. The analysis showed a significant and positive association of log-transformed negotiated annual treatment cost of new medicines with log-transformed annual treatment cost of its comparator(s), extent of added benefit, and log-transformed size of the target population. Analyzing the effects of specific endpoints instead of the overall added benefit revealed that the single endpoint with the largest impact on price is adverse events (AEs). Surprisingly, an increase in AEs significantly increased the price. Various subgroup and sensitivity analyses demonstrated the robustness of the results. The adjusted R squared for all models was above 80%. CONCLUSIONS: The analysis was able to confirm that variables whose consideration is mandated by law are, in fact, the key drivers of negotiated prices. Somewhat puzzling, the analysis also found an increase in AEs to move prices significantly upward.

Determinants of Orphan Drug Prices in Germany.

BACKGROUND AND OBJECTIVE: Legislation introduced in 2011 in Germany has instituted an early benefit assessment of newly licensed pharmaceuticals with a subsequent price negotiation. For orphan drugs (ODs) a special legal framework applies, which accounts for the fact that ODs do not have to prove an added benefit over an appropriate comparative therapy previously determined by the decision maker. As, in addition, the content of negotiations between pharmaceutical companies and the payer is confidential, the aim of this study was to identify factors influencing the negotiated prices of ODs. METHODS: Twelve hypotheses on factors influencing the negotiated OD price were derived based on the existing literature and framework agreement between payers and pharmaceutical unions according to German social legislation. Univariate analyses were applied to detect statistically significant correlations between annual therapeutic costs of ODs and the hypothesized factors. Bivariate analyses were used to determine confounding factors. In addition, a multiple ordinary least squares (OLS) regression with backward selection was conducted. Finally, sensitivity analyses assessed the robustness of the results. RESULTS: Thirty-five ODs were included in the analysis. The univariate analyses and subsequent sensitivity analyses validated five of the 12 hypotheses formulated. Univariate analyses suggest a statistically significant association between the OD price and the (i) therapeutic area; (ii) approval for pediatric care; (iii) treatment population size; (iv) cost of comparative therapies; and (v) European prices. The OLS regression identified European prices as the variable with the strongest association with the negotiated prices. CONCLUSION: We show that German OD pricing is a multivariate phenomenon. However, due to interdependencies, these results must be treated with caution.

Methodological problems in the method used by IQWiG within early benefit assessment of new pharmaceuticals in Germany.

BACKGROUND: The decision matrix applied by the Institute for Quality and Efficiency in Health Care (IQWiG) for the quantification of added benefit within the early benefit assessment of new pharmaceuticals in Germany with its nine fields is quite complex and could be simplified. Furthermore, the method used by IQWiG is subject to manifold criticism: (1) it is implicitly weighting endpoints differently in its assessments favoring overall survival and, thereby, drug interventions in fatal diseases, (2) it is assuming that two pivotal trials are available when assessing the dossiers submitted by the pharmaceutical manufacturers, leading to far-reaching implications with respect to the quantification of added benefit, and, (3) it is basing the evaluation primarily on dichotomous endpoints and consequently leading to an information loss of usable evidence. OBJECTIVE: To investigate if criticism is justified and to propose methodological adaptations. METHODS: Analysis of the available dossiers up to the end of 2016 using statistical tests and multinomial logistic regression and simulations. RESULTS: It was shown that due to power losses, the method does not ensure that results are statistically valid and outcomes of the early benefit assessment may be compromised, though evidence on favoring overall survival remains unclear. Modifications, however, of the IQWiG method are possible to address the identified problems. CONCLUSION: By converging with the approach of approval authorities for confirmatory endpoints, the decision matrix could be simplified and the analysis method could be improved, to put the results on a more valid statistical basis.

Quantified patient preferences for lifestyle intervention programs for diabetes prevention-a protocol for a systematic review.

BACKGROUND: The 20-70% participation of diabetes patients in lifestyle interventions (LSI) worldwide seems to be rather sub-optimal, in spite of all intents of such interventions to delay further progress of the disease. Positive effects through LSI are expected in particular for patients who suffer less from diabetes-related limitations or other chronic diseases. Seeing that diabetes prevalence and with it mortality are increasing, LSI have become an inherent part of diabetes treatment standards. Various qualitative studies have been carried out to identify participation barriers for LSI. However, these have not resulted in more detailed knowledge about the relative importance of factors with an inhibiting impact on participation. Since it cannot be assumed that all of the influencing factors have equivalent values, it is necessary to investigate their individual importance with regard to a positive or negative decision about participating. There are no systematic reviews on patient preferences for LSI programs in diabetes prevention. As a result, the main objectives of this systematic review are to (i) identify existing patient preference elicitation studies related to LSI for diabetic patients, (ii) summarize the methods applied and findings, and (iii) appraise the reporting and methodological quality of such studies. METHODS: We will perform systematic literature searches to identify suitable studies from 14 electronic databases. Retrieved study records will be included based on predefined eligibility criteria as defined in this protocol. We will run abstract and full-text screenings and then extract data from all selected studies by filling in a predefined data extraction spreadsheet. We will undertake a descriptive, narrative synthesis of findings to address the study objectives, since no pooling for quantified preferences is for methodological reasons implementable. We will pay special attention to aspects of methodological quality of preference elicitation by applying established evaluation criteria of the ISPOR and some own developed criteria for different elicitation techniques. All critical stages within the screening, data extraction, and synthesis processes will be conducted by two pairs of authors. This protocol adheres to PRISMA and PRISMA-P standards. DISCUSSION: The proposed systematic review will provide an overview of the methods used and current practice in the elicitation and quantification of patients' preferences for diabetes prevention lifestyle interventions. Furthermore, the methodological quality of the identified studies will be appraised as well. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018086988.

"Market withdrawals" of medicines in Germany after AMNOG: a comparison of HTA ratings and clinical guideline recommendations.

BACKGROUND: According to the AMNOG act, the German Federal Joint Committee (G-BA) determines the additional benefit of new medicines as a basis for subsequent price negotiations. Pharmaceutical companies may withdraw their medications from the market at any time during the process. This analysis aims to compare recommendations in clinical guidelines and HTA appraisals of medicines that were withdrawn from the German market since the introduction of AMNOG in 2011. METHODS: Medications withdrawn from the German market between January 2011 and June 2016 following benefit assessment were categorized as opt-outs (max. 2 weeks after start of price negotiations) or supply terminations (during or after further price negotiations). Related guidelines were systematically analyzed. For all withdrawals, therapeutic area, additional benefit rating and recommendation status in relevant clinical guidelines were assessed. RESULTS: Among 139 medications, 10 opt-outs and 12 supply terminations were identified. Twenty-one out of 22 withdrawn medicines (95%) received 'no additional benefit' appraisal by the G-BA (average 'no additional benefit' rating for all AMNOG products: 47%). Of the 22 medicines, 15 (68%) were recommended by at least one guideline at the time of benefit assessment and 18 (82%) on 1 June 2016. Heterogeneity among guidelines was high. Acceptance of clinical trial endpoints was different between G-BA appraisals and clinical guidelines. CONCLUSION: Our analysis revealed considerable differences across clinical guidelines as well as between clinical guidelines and HTA appraisals of the medicines that were withdrawn from the German market. Better alignment of the clinical perspective and close collaboration between all involved parties is required to achieve and maintain optimization of patient care.

Effect of Crossover in Oncology Clinical Trials on Evidence Levels in Early Benefit Assessment in Germany.

BACKGROUND: In oncology clinical trials, crossover is used frequently but may lead to uncertainties regarding treatment effects. OBJECTIVE: To investigate the handling of evidence from crossover trials by the European Medicines Agency (EMA) and the German Federal Joint Committee (G-BA). METHODS: For oncology medicines with early benefit assessments before January 2015, presence of crossover, clinical data, EMA requests for additional data, and G-BA benefit ratings/evidence levels were analyzed from manufacturers' dossiers, G-BA appraisals, European Public Assessment Reports, and original publications. RESULTS: Eleven of 21 benefit assessments included crossover trials. Significant intergroup differences (P < 0.05) in overall survival (OS) were noted in 7 of 11 trials with and 7 of 10 without crossover. For 6 of 11 medicines with crossover, these were demonstrated before crossover. Treatment effects generally worsened with increasing proportions of crossover. The EMA requested additional data more frequently if crossover was performed, particularly if no OS data were available before crossover. The G-BA granted a considerable benefit to 73% of medicines with crossover and 40% of those without. Evidence levels were intermediate for 50% and 75%, respectively. None of the medicines received the highest evidence level. CONCLUSIONS: In G-BA appraisals, oncology medicines with crossover received better additional benefit ratings, but were assigned lower evidence levels, than those without. The five medicines with crossover after progression were assigned lower evidence levels than the six medicines with crossover after demonstration of superior OS, indicating that the way in which crossover is implemented may be one factor influencing the assignment of evidence levels by the G-BA.

Budgetary Impact and Cost Drivers of Drugs for Rare and Ultrarare Diseases.

OBJECTIVES: To review recent studies reporting health care expenditures (budgetary impact) for orphan medicinal products (OMPs) in Europe and to contribute to our understanding of the cost drivers of nononcological OMPs by means of an empirical analysis in Germany. METHODS: A systematic search for relevant studies on rare diseases was conducted in PubMed and Embase (until December 2016). In addition, annual treatment costs of nononcological OMPs in Germany were analyzed with respect to five explanatory variables: total prevalence of disease, prevalence with added benefit, availability of alternative treatments for the same indication, extent/probability of treatment benefit, and evidence for a treatment effect on mortality. RESULTS: A total of nine studies with specific estimates of the budget impact of OMPs for a total of 11 countries were identified; one study addressed specifically ultrarare diseases. Annual per-capita spending for OMPs ranges from €1.32 in Latvia to €16 in France. Per-patient annual treatment costs vary between €27,811 and €1,647,627 in Germany. On the basis of the German data set, the regression analysis shows that log prevalence has a significant inverse relationship with log annual treatment cost. In this model, doubling the prevalence leads to a 43% decrease in annual treatment cost. CONCLUSIONS: Despite per-patient annual treatment costs ranging up to several hundreds of thousands of euros for some OMPs, per-capita spending for OMPs is relatively small. In this study an inverse relationship between prevalence and annual treatment costs was found.

Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs.

The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable.

Longterm persistence and nonrecurrence of depression treatment in Germany: a four-year retrospective follow-up using linked claims data.

OBJECTIVES: To measure persistence and nonrecurrence of depression treatment and investigate potential risk factors. METHODS: We retrospectively observed a closed cohort of insurees with new-onset depression treatment in 2007 and without most psychiatric comorbidity for 16 quarters (plus one to ascertain discontinuation). We linked inpatient/outpatient/drug-data per person and quarter. Person-quarters containing specified depression services were classified as depression-treatment-person-quarters (DTPQ). We defined longterm-DTPQ-persistence as 16 + 1 continuous DTPQ and longterm-DTPQ-nonrecurrence as 12 continuous quarters without DTPQ and used multivariate logistic regression to explore associations with these outcomes. RESULTS: Within first 16 quarters, 28,348 patients' first period (total time) persisted for a mean/median 5.4/3 (8.7/8) quarters. Fourteen percent had longterm-DTPQ-persistence, associated (p < .05) with baseline hospital (odds ratio, OR = 1.80), psychotherapy/specialist-interview and antidepressants (OR = 1.81), age (years, OR = 1.03), unemployment (OR = 1.21), retirement (OR = 1.31), and insured as a dependent (OR = 1.32). Thirty-four percent had longterm-DTPQ-nonrecurrence, associated with psychotherapy/specialist-interview (OR = 1.40), antidepressants (OR = 0.54), female sex (OR = 0.84), age (years, OR = 0.99), retirement (OR = 1.18), and insured as a dependent (OR = 0.88). Women differed for episodic and not chronic treatment. CONCLUSION: Treatment measures compared to survey's symptoms measures. We suggest further research on "treatment-free-time." Antidepressants(-) and psychotherapy/specialist-interview(+) were significantly associated with longterm-DTPQ-nonrecurrence. This was presumably moderated by possible short-time/low-dosage antidepressants use(-) and selective therapy assignment(+). Sample selectivity limited data misclassification.

INDUSTRY'S EXPERIENCES WITH THE SCIENTIFIC ADVICE OFFERED BY THE FEDERAL JOINT COMMITTEE WITHIN THE EARLY BENEFIT ASSESSMENT OF PHARMACEUTICALS IN GERMANY.

OBJECTIVES: Optional scientific advice (SA) for the early benefit assessment of pharmaceuticals is offered by the German decision maker, the Federal Joint Committee (FJC). The aim of this study was to elicit manufacturers' experiences with the SA procedures offered by the FJC to date. METHODS: A preliminary survey on a small sample size was conducted. Subsequently, a questionnaire comprising eight items, which was developed on the basis of that survey, was used. Data were analyzed using qualitative and quantitative approaches. RESULTS: The elicitation, including a sample of 25 percent of the completed advice, highlighted the following, regarding the process as well as to the content shortcomings of the SA procedures from an industrial perspective: inconsistencies, FJC's lack of expertise in conducting clinical trials, partially incomplete answers. and a low willingness of the FJC to engage in dialogue with industry were criticized. On the other hand, the majority of respondents expressed a positive attitude concerning unambiguousness, completeness, traceability, discussion atmosphere, and the protocol of the advice. Early SA, before pivotal trials start, showed a significantly higher completeness compared with late SA with respect to endpoints and study duration. Within 4 years the quality of FJC's propositions on some topics improved significantly. CONCLUSIONS: Only a few statistically significant differences were detectable between early versus late SA. A positive trend in industry's perception of the SA can be observed over time. A more active involvement of additional stakeholders and the incorporation of procedural elements from other healthcare systems could improve the quality of the SA offered by the FJC.

[Checklist for the Development and Assessment of Cost-of-Illness Studies]. / Checkliste zur Erstellung und Bewertung von Krankheitskostenstudien.

BACKGROUND: Cost-of-illness (CoI) studies are important instruments for estimating the socioeconomic burden of specified diseases. CoI studies provide important information about the cost structure of a disease, the resulting research need, approaches to improve aspects of care and, monetary consequences from different perspectives. This information can be useful for healthcare research and health policy. Due to heterogeneity of available Cost-of-Illness studies, the working group 'Health Economics' of the German Network for Healthcare Research (DNVF) in accordance with the German Society for Health Economics (DGGÖ) developed an instrument for the planning, conduct and assessment of CoI studies. METHODS: The checklist was developed based on a systematic literature search of published national and international checklists as well as guidelines and recommendations for development and assessment of CoI studies and health economic evaluations. Structure and subject matter of the generic checklist was designed, approved and, finally, examined in a pretest by the working group. RESULTS: Based on the results of the literature search (n=2 454), 58 articles were used for the identification of relevant criteria for the checklist. With respect to the results of the pretest, 6 dimensions were included in the checklist: (i) general aspects, (ii) identification of resources, (iii) description and quantification of resource consumption, (iv) valuation of resources (v) analysis and presentation of results and (vi) discussion and conclusion. In total, the 6 dimensions were operationalized through 37 items. CONCLUSION: This checklist is an initial approach to improve transparency and understanding of CoI studies in terms of the extent, structure and development of the socioeconomic burden of diseases. The checklist supports the comparability of different studies and facilitates study conception.

External validation of type 2 diabetes computer simulation models: definitions, approaches, implications and room for improvement-a protocol for a systematic review.

BACKGROUND: Type 2 diabetes mellitus (T2DM), a highly prevalent chronic disease, puts a large burden on individual health and health care systems. Computer simulation models, used to evaluate the clinical and economic effectiveness of various interventions to handle T2DM, have become a well-established tool in diabetes research. Despite the broad consensus about the general importance of validation, especially external validation, as a crucial instrument of assessing and controlling for the quality of these models, there are no systematic reviews comparing such validation of diabetes models. As a result, the main objectives of this systematic review are to identify and appraise the different approaches used for the external validation of existing models covering the development and progression of T2DM. METHODS: We will perform adapted searches by applying respective search strategies to identify suitable studies from 14 electronic databases. Retrieved study records will be included or excluded based on predefined eligibility criteria as defined in this protocol. Among others, a publication filter will exclude studies published before 1995. We will run abstract and full text screenings and then extract data from all selected studies by filling in a predefined data extraction spreadsheet. We will undertake a descriptive, narrative synthesis of findings to address the study objectives. We will pay special attention to aspects of quality of these models in regard to the external validation based upon ISPOR and ADA recommendations as well as Mount Hood Challenge reports. All critical stages within the screening, data extraction and synthesis processes will be conducted by at least two authors. This protocol adheres to PRISMA and PRISMA-P standards. DISCUSSION: The proposed systematic review will provide a broad overview of the current practice in the external validation of models with respect to T2DM incidence and progression in humans built on simulation techniques. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069983 .

Arbitration Board Setting Reimbursement Amounts for Pharmaceutical Innovations in Germany When Price Negations between Payers and Manufacturers Fail: An Empirical Analysis of 5 Years' Experience.

BACKGROUND: In Germany, an arbitration board is setting reimbursement amounts for drug innovations when price negations between payers and manufacturers fail. OBJECTIVE: To empirically analyze all arbitrations since the reform of Germany's Act to Reorganize the Pharmaceuticals' Market in the Statutory Health Insurance System came into effect. METHODS: All available relevant documents up to January 2016 were screened and the identified contentious issues between the negotiation parties extracted. Reimbursement requests of both the negotiating parties and the arbitrations were transformed into a comparable format on the basis of defined daily doses and then contrasted among each other. RESULTS: In the given period, 16 arbitrations took place. The arbitration board is implementing the same criteria used in the negotiations between manufacturers and payers. Almost all arbitrations dealt with generic appropriate comparative therapies. Reimbursement amounts set by arbitration were on average 38.4% less than the mean of negotiation parties' requests (69.2% less than the manufacturers' requests). The corresponding prescription volumes were arranged rather centrally. All but one arbitration refer to a 1-year contract period. The arbitration board rarely decided on further technical contentious points. Hence, no heuristics referring to them were derivable. CONCLUSIONS: There is some evidence for a quasi-algorithmic approach of the arbitration board, even though it is legally determined that it has to decide while taking the peculiar conditions of each case into due consideration, including the characteristics of the respective therapeutic area. The balance of interests proved to be within a very narrow space albeit it concerns in principle discretionary decisions. Thus, the purpose of arbitration seems not to be achieved sufficiently.