Charalabos-Markos Dintsios

Reflections on the changing face of German pharmaceutical policy: how far is Germany from value-based pricing?

Statutory health insurance (SHI) in Germany serves 90% of the population. Predicted SHI deficits for 2010 and 2011, of h7 billion and h10–12 billion, respectively, resulted in a law freezing the prices of drugs already in the market (which came into effect on 1 August 2010). The subsequent ‘Act to Reorganize the Pharmaceuticals’ Market in the SHI System’ (Gesetz zur Neuordnung des Arzneimittelmarktes in der gesetzlichen Krankenversicherung [AMNOG]) passed through Federal Parliament on 11 November 2010 and came into effect on 1 January 2011. What implications does this have for the health economic evaluation of new drugs in Germany? We delineate where and how health economic evaluation will be tied in with decision making on drug prices, and also explore how close the new law will come to value-based pricing, a question verymuch in discussion in other healthcare systems.

Patient relevant endpoints in oncology: current issues in the context of early benefit assessment in Germany

The German AMNOG healthcare reform includes a mandatory early-benefit-assessment (EBA) at launch. As per German social code, EBA is based on registration trials and includes evaluation of the patient-relevant effect of the new medicines compared to an appropriate comparator as defined by the Federal Joint Committee (G-BA). Current EBA decisions released have unveiled issues regarding the acceptance of some patient-relevant endpoints as G-BA and IQWiG are grading the endpoints, focusing on overall survival as the preferred endpoint in oncology.A taskforce of experienced German outcomes research, medical, health-technology assessment and biostatistics researchers in industry was appointed. After agreement on core assumptions, a draft position was prepared. Input on iterative versions was solicited from a panel of reviewers from industry and external stakeholders.Distinctive features of registration trials in oncology need to be considered when these studies form basis for EBA, especially in cancer-indications with long post-progression survival; and with several consecutive therapeutic options available post-progression. Ethical committees, caregivers and patients often demand cross-over-designs diluting the treatment-effect on overall survival. Regulatory authorities require evaluation of morbidity-related study endpoints including survival of patients without their disease getting worse (i.e., progression-free survival). Also, progression requires treatment-changes, another strong indicator for its relevance to patients.Based on specific guidelines and clinical trial programs that were developed to be consistent with regulatory guidance, endpoints in oncology are thoroughly evaluated in terms of their patient-relevance. This extensive knowledge and experience should be fully acknowledged during EBA when assessing the patient-relevant benefit of innovative medicines in oncology.JEL codesD61; H51; I18.

Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach

Questioning Patient Subgroups for Benefit Assessment: Challenging the German Gemeinsamer Bundesausschuss Approach Jorg Ruof, MD, MPH, MBA*, Charalabos-Markos Dintsios, PhD, MPH, Friedrich Wilhelm Schwartz, MD Roche Pharma AG, Grenzach-Wyhlen, Germany; Hannover Medical School, Hannover, Germany; German Association of Researchbased Pharmaceutical Companies (vfa), Berlin, Germany; Department of Public Health, Heinrich Heine University, Dusseldorf, Germany

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 Cohens 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.

Re: “Early benefit assessment of new drugs in Germany – Results from 2011 to 2012” [Health Policy 116 (2–3) (2014) 147–153]

The overview given by Horn et al. of positive and negtive AMNOG assessments (2011–2012), independently, f IQWiG assessment result or subsequent final decision aken by G-BA is considered, is misleading. This is mainly ased on two reasons. Considering the overall number of AMNOG processes 2011–2012), the majority seemed to be successful and dded benefit was granted. However, looking at the level f assessed subgroups of a new drug or at the patient poplation level the extent of added benefit shows a quite ifferent picture. Of 100% success on the product level, nly 63% are successful on subgroup level and only 68% on atient level (prevalence approach). This issue has already een addressed by Ruof et al. [1] and underlines a defiitely less positive picture than drawn by IQWiG. Not to ention the fact that clinical evidence delivered for subroups defined by IQWiG was mostly not assessed based on upposed formal reasons (e.g. clinical study design, patient opulations of interest). Furthermore, the subsequent price negotiation – which s still far away to reflect value based pricing [2,3] – is only artly based on the outcome of the benefit assessment and ocuses on price and potential volume of the new drug. This

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

BackgroundThe 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.ObjectiveTo investigate if criticism is justified and to propose methodological adaptations.MethodsAnalysis of the available dossiers up to the end of 2016 using statistical tests and multinomial logistic regression and simulations.ResultsIt 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.ConclusionBy 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.

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

BackgroundType 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.MethodsWe 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.DiscussionThe 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 registrationPROSPERO CRD42017069983.