Search

International sind in den letzten Jahren mehrere Initiativen entstanden, die sich mit der Weiterentwicklung der evidenzbasierten Bewertung von Arzneimitteln nach der Marktzulassung befassen, um Entscheidungssituationen in der gesundheitspolitischen oder klinischen Praxis zu unterstützen. Der Bericht analysiert Ziele, Arbeitsweise und Ergebnisse des von der Europäischen Kommission initiierten Arzneimittelforums mit seiner Arbeitsgruppe zu Relative Effectiveness, des europäischen Netzwerks für Health Technology Assessment EUnetHTA und des nationalen Programms für Comparative Effectiveness Research in den USA. Gemeinsamkeiten und Unterschiede der drei Initiativen und mögliche Implikationen für die Zulassung und HTA von Arzneimitteln in Deutschland und Europa werden abgeleitet. Abschließend werden Themen und Fragestellungen für weitere vertiefende Forschung identifiziert. Gedruckte Version im Universitätsverlag der TU Berlin (www.univerlag.tu-berlin.de) erschienen, ISBN 3-978-7983-2298-1 Over the past years several initiatives have developed internationally that address the further development of evidence-based assessments of pharmaceuticals after licensing in order to support decision making in policy and clinical practice. The report analyzes objectives, procedures, and results of the Pharmaceutical Forum initiated by the European Commission and its Working Group on Relative Effectiveness, of the European network for Health Technology Assessment EUnetHTA, and of the national US‐program for Comparative Effectiveness Research. Similarities and differences of the three initiatives are highlighted. Finally, issues and questions for further research areas are identified. Printed version published by Universitätsverlag der TU Berlin (www.univerlag.tu-berlin.de), ISBN 3-978-7983-2298-1

The different actors involved in health system decision-making and regulation have to deal with the question which are valid parameters to assess the health value of health technologies. So called surrogate endpoints represent in the best case preliminary steps in the casual chain leading to the relevant outcome (e. g. mortality, morbidity) and are not usually directly perceptible by patients. Surrogate endpoints are not only used in trials of pharmaceuticals but also in studies of other technologies. Their use in the assessment of the benefit of a health technology is however problematic. In this report we intend to answer the following research questions: Which criteria need to be fulfilled for a surrogate parameter to be considered a valid endpoint? Which methods have been described in the literature for the assessment of the validity of surrogate endpoints? Which methodological recommendations concerning the use of surrogate endpoints have been made by international HTA agencies? Which place has been given to surrogate endpoints in international and German HTA reports? For this purpose, we choose three different approaches. Firstly, we conduct a review of the methodological literature dealing with the issue of surrogate endpoints and their validation. Secondly, we analyse current methodological guidelines of HTA agencies members of the International network of agencies for Health Technology Assessment (INAHTA) as well as of agencies concerned with assessments for reimbursement purposes. Finally, we analyse the outcome parameter used in a sample of HTA reports available for the public. The analysis of methodological guidelines shows a very cautious position of HTA institutions regarding the use of surrogate endpoints in technology assessment. Surrogate endpoints have not been prominently used in HTA reports. None of the analysed reports based its conclusions solely on the results of surrogate endpoints. The analysis of German HTA reports shows a similar pattern. The validation of a surrogate endpoint requires extensive research, including randomized controlled trials (RCT) assessing clinical relevant endpoints. The validity of a surrogate parameter is rather technology-specific than disease-specific. Thus – even in the case of apparently similar technologies – it is necessary to validate the surrogate for every single technology (i. e. for every single active agent). The use of surrogate endpoints in the assessment of the benefit of health technologies is still to be seen very critically., GMS Health Technology Assessment; 5:Doc12; ISSN 1861-8863

Die Frage nach den Ergebnisparametern, die für eine valide Bewertung des Nutzens medizinischer Technologien verwendet werden können, beschäftigt alle an Entscheidungsfindungen und an der Regulierung im Gesundheitssystem beteiligten Akteure. Während die klinisch relevanten Endpunkte jene sind, die für den Patienten belangvoll sind (z. B. Morbidität, Mortalität), stellen Surrogatendpunkte im besten Fall Vorstufen der eigentlichen klinisch relevanten Endpunkte dar, die für den Patienten in der Regel nicht unmittelbar spürbar sind. Surrogatparameter werden nicht nur in Studien über die Wirksamkeit von Arzneimitteln eingesetzt, sondern auch in Studien zu anderen Technologien. Der Einsatz von Surrogatendpunkten in der Bewertung des Nutzens von Gesundheitstechnologien ist jedoch problematisch. In diesem Bericht wird folgenden Fragen nachgegangen: Welche Kriterien muss ein Surrogatparameter erfüllen, um als valider Endpunkt angesehen werden zu können? Welche Methoden werden zur Validierung von Surrogatendpunkten in der Literatur diskutiert? Welche methodischen Vorgaben machen internationale Agenturen aus dem Bereich Health Technology Assessment (HTA) oder Arzneimittelnutzenbewertung hinsichtlich des Einsatzes von Surrogatendpunkten? Welchen Stellenwert haben Surrogatendpunkte in HTA-Berichten internationaler HTA-Agenturen und in Berichten, die in Deutschland produziert werden? Entsprechend dieser Fragestellungen werden drei verschiedene methodische Herangehensweisen gewählt: Reviews der einschlägigen methodischen Literatur zu Surrogatendpunkten und ihre Validierung, Analyse der aktuellen Methodenpapiere von HTA-Institutionen, Analyse von abgeschlossenen sowie öffentlich zugänglichen internationalen und deutschen HTA-Berichten. Zusammenfassend zeigen die Empfehlungen der hier berücksichtigten Institutionen dahingehend eine kritische Einstellung zur Verwendung von Surrogatendpunkten in HTA. Es lässt sich zudem feststellen, dass Surrogatendpunkte einen geringen Stellenwert in HTA-Berichten haben. In keinem der untersuchten HTA-Berichte wird die Bewertung von nicht diagnostischen Technologien ausschließlich auf die Ergebnisse von Surrogatendpunkten gestützt. Die Ergebnisse der Analyse deutscher HTA-Berichte sind annährend identisch zu denen internationaler. Die Validierung eines Surrogatendpunkts erfordert ausführliche Forschung, einschließlich der Durchführung von randomisierten kontrollierten Studien (RCT) mit klinisch relevanten Endpunkten. Die Validität eines Surogatendpunkts ist eher technologie- als krankheitsspezifisch, so dass die Ergebnisse der Validierung eines Surrogatendpunkts nicht auf andere Technologien übertragen werden können (auch nicht bei einem angeblich ähnlichen Wirkmechanismus). Um ein Höchstmaß an Sicherheit zu erreichen, muss die Validität eines Surrogatendpunkts bei jeder Technologie bzw. jedem Wirkstoff einzeln geprüft werden. Nach wie vor ist der Einsatz von Surrogatendpunkten bei der Nutzenbewertung sehr kritisch zu betrachten., Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland; 91; ISSN 1864-9645

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which is accompanied by considerable disability and high costs. This report summarises the evidence on effectiveness and costs of beta-interferons and natalizumab in the treatment of multiple sclerosis.The review included systematic reviews and randomised controlled trials (with an observation time of at least one year) in patients with MS which assessed outcome parameters such as progression, exacerbations and adverse effects. An extensive literature search included databases such as MEDLINE, EMBASE, the Cochrane Library and various HTA-databases. Studies were selected according to predefined criteria, their quality was assessed according to criteria defined prospectively, and data were summarised systematically in tables. Cost-effectiveness evaluations were also included.Two systematic reviews and 24 randomised controlled trials of beta-interferon therapy were included, as well as three trials on the effectiveness of natalizumab. A total of 22 cost-effectiveness analyses for interferons were included, whereas no economic evaluations for natalizumab were identified.Use of interferon beta-1a or interferon beta-1b after a first demyelinating event led to a reduction of the conversion to definite MS during an observation time of two to three years. In relapsing remitting MS, interferon beta-1a reduced progression. The effects of interferon beta-1b on progression are unclear. Interferon beta-1a and interferon beta-1b reduced in some but not all studies outcomes relating to exacerbations. In direct comparison trials, interferon beta-1b (Betaferon(®) or Betaseron(®)) and interferon beta-1a (Rebif(®), higher dosage of 44 µg three subcutaneous injections per week) proved superior to interferon beta-1a (Avonex(®), 30 µg per week intramuscular) with respect to exacerbation outcomes. For secondary progressive MS, only one of five studies found a reduced progression with interferon beta-1a and only a part of the studies found an improvement with respect to outcomes relating to exacerbations. For primary progressive MS no advantage of therapy with beta-interferons was found with respect to patient-related outcomes. Beta-interferons showed characteristic and frequently occurring adverse effects, including reactions at the injection site and flu-like symptoms. A large proportion of patients stop interferon therapy because of adverse events. The other main reason for stopping therapy is the felt ineffectiveness of the treatment when patients experience a new exacerbation while on treatment. Many patients produce interferon-neutralising antibodies during therapy. The ultimate effect of neutralising antibodies on the efficacy of interferon treatment is unclear.In patients with relapsing remitting (and partially with secondary progressive) MS, treatment with natalizumab led to a reduction of progression and of exacerbation rates. However, a number of cases of progressive multifocal leucoencephalopathy have been reported after natalizumab therapy. These raise serious concerns about patient safety. Reliable data on the long term effectiveness of beta-interferons or natalizumab are not yet available.The absolute cost of interferon therapy is high and the available, international cost-effectiveness analyses indicate a high cost for achieving moderate benefits in quality of life. Further research is needed to provide specific cost-effectiveness estimates for Germany.

Background: Heart failure is a clinical syndrome of major epidemiological and economical importance. In Germany as in other industrialised countries it is one of the leading causes of mortality, morbidity and disability. For patients not responding to medical therapies ventricular assist devices are used as bridge to transplant, bridge to recovery or as destination therapy alternative to transplantation. Research questions: This report aims to present the actual evidence on clinical effectiveness, psychological and social aspects and economical aspects of left ventricular assist devices.MethodsWe conducted a systematic research of the literature in different databases (EMBASE, MEDLINE, Cochrane Library). The included studies were assessed by two reviewers and were presented in tables and in a narrative form. We also conducted a survey among hospitals using the technology. Results and discussion: We included 40 references, six of them were HTA-reports. LVAD patients as bridge to transplant had better survival rates and a better quality of life as compared to medical therapy. Mechanical assistance was associated with frequent and often serious adverse events which were often the cause of death. There were numerous psychological and psychiatric problems. Conclusions/Recommendations: LVAD showed to be clinically effective, however with high complications rate and seriousness of them. The use of technology is very costly. Cost-effective should be analysed for Germany. There is a need to further develop the technology before it can contribute seriously to a reduction of the need for heart transplantation.

Background: More than 200,000 persons died in 2002 in Germany as a consequence of cancer diseases. Cancer (ICD-9: 140-208, ICD-10: C00-C97) accounted for 28% of all male deaths and for 22% of all female deaths. Cancer treatment consists on surgery, radio- and chemotherapy. During chemotherapy patients may experience a wide variety of toxic effects (including life-threatening toxicity) which require treatment. The type and the intensity of chemotherapy toxicity are one of the limiting factors in cancer treatment. Toxic effects are also one of the factors affecting health related quality of life (HRQOL) during chemotherapy. Mistletoe extracts belong to the group of so called „unconventional methods“ and are used in Germany as complementary cancer treatments. It has been postulated that the addition of mistletoe to chemotherapeutical regimes could help reduce chemotherapy-induced toxicity and enhance treatment tolerability. The German social health insurance covers the prescription of ML I standardized mistletoe extracts when those are prescribed as palliative cancer treatments with the aim of improving HRQOL. Research questions: * Does the addition of mistletoe to chemotherapeutical regimes reduce their toxicity? * Does the addition of mistletoe to chemotherapeutical regimes contribute to improve quality of life? * Has the addition of mistletoe to chemotherapeutical regimes any effects on survival? * Has the addition of mistletoe to chemotherapeutical regimes any effects on tumor-remission? Methods: We conducted a systematic literature search in following databases: The Cochrane Library, DIMDI Superbase and Dissertation Abstracts. We included systematic reviews and randomized controlled trials (RCT). Appraisal of literature was done by two authors independently. Checklists were used to guide literature appraisal. The Jadad-Score was used to score quality of RCT. Evidence was summarized in tables and in narrative form. Results and discussion: The literature search yielded 437 potentially relevant papers. A total of 94 papers was retrieved. Of them, 48 were potentially relevant for answering the research questions and 46 for background information. In this report we summarize the results from three systematic reviews, five published RCT and two unpublished RCT. A protocol of an ongoing systematic review from the Cochrane Collaboration was also identified. The information gathered from the systematic reviews was insufficient to answer the research questions. The relevant studies identified and synthetised in these reviews were appraised and extracted again. In addition, a set of recently published RCT was identified and included in these report. None of the RCT defined frequency or severity of chemotherapy associated toxic effects as its primary outcome. Some of the RCT reported, however, rates of toxic effects or parameters related to toxicity. The results are inconsistent among the RCT ranging from no effect on to positive effects (i. e. reduction) on chemotherapy toxicity. RCT with treatment toxicity as primary outcome are needed to answer the question of whether the addition of mistletoe extracts to chemotherapy regimes can help reducing treatment toxicity. HRQOL was the primary outcome in four RCT. The addition of mistletoe to chemotherapy showed to have a positive effect on HRQOL of women treated for breast cancer. Conclusions: The available evidence does not allow giving a conclusive answer to the question of whether the addition of mistletoe to chemotherapeutical regimes can reduce the toxicity of the latter. RCT are needed in which the primary outcome is treatment toxicity. The addition of standardised mistletoe extract to chemotherapeutical regimes in the treatment of women with breast cancer can lead to improvements in HRQOL. In the light of the results from RCT the coverage of mistletoe in cancer treatment should be restricted in Germany to the latter indication.

Introduction: Around 92 million urogenital infections are caused yearly by Chlamydia trachomatis worldwide [1]. The overall incidence of sexually transmitted diseases is increasing, as shown by the increases in the number of reported cases of syphilis and gonorrhea [2]. Chlamydia trachomatis infections are associated with various serious diseases in women, men and newborns, which could be, at least partially, avoided by means of early diagnosis and therapy. The Federal Joint Committee - responsible for decision-making concerning the benefit package of the German Social Health Insurance - has publicly announced the starting of deliberations on the issue of screening for Chlamydia trachomatis. Research Questions: The leading question to be answered is whether screening for Chlamydia trachomatis should be included in the German benefit basket. The aim of this report is to provide a summary of the available evidence concerning the issue of screening for Chlamydia trachomatis. Methods: The summary of published scientific evidence, including HTA reports, systematic reviews, guidelines and primary research is represented. The synthesis follows the structure given by the criteria of Wilson and Jungner [3] for the introduction of screening in a population: relevance of the condition, availability of an adequate test, effectiveness of screening, acceptance of the programme, and economical issues. A literature search was conducted for each aspect of the synthesis and the evidence has been summarised in evidence tables. Results: We identified five HTA reports from three European agencies [4], [5], [6], [7] and one from the USA [8]. In addition, we identified four guidelines from Northamerica [9], [10], [11], [12] and one from Europe [13]. A total of 56 primary research publications were included: relevance of the disease (n=26), availability of test (n=1), effectiveness of screening (n=11), acceptance of the programme (n=11), economical issues (n=7). Discussion: The main limitation of this report is that we relied only on published results. Most of research has been conducted in countries other than Germany. The fulfilment of the criteria for introduction of screening depends on contextual factors. More data from Germany are needed in order to answer the main questions concerning acceptance, use of selection criteria to identify subgroups and economical aspects of screening for Chlamydia trachomatis in Germany. Conclusions: The criteria for introduction of screening for Chlamydia trachomatis are partially fulfilled. The available evidence indicates that the success of a screening programme for Chlamydia trachomatis will depend on the implementation of strategies for uptake enhancement and probably on the participation of men as well. A pilot project should be conducted in order to assess cost-effectiveness, acceptance and feasibility of different screening strategies in Germany. On the light of the available evidence, the inclusion of screening for Chlamydia trachomatis in the benefit basket without embedding it in a multifaceted programme targeting primary prevention of sexually transmitted diseases and participation in screening cannot be recommende.

Political background: As a German novelty, the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; IGWiG) was established in 2004 to, among other tasks, evaluate the benefit of pharmaceuticals. In this context it is of importance that patented pharmaceuticals are only excluded from the reference pricing system if they offer a therapeutic improvement. The institute is commissioned by the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) or by the Ministry of Health and Social Security. The German policy objective expressed by the latest health care reform (Gesetz zur Modernisierung der Gesetzlichen Krankenversicherung, GMG) is to base decisions on a scientific assessment of pharmaceuticals in comparison to already available treatments. However, procedures and methods are still to be established. Research questions and methods: This health technology assessment (HTA) report was commissioned by the German Agency for HTA at the Institute for Medical Documentation and Information (DAHTA@DIMDI). It analysed criteria, procedures, and methods of comparative drug assessment in other EU-/OECD-countries. The research question was the following: How do national public institutions compare medicines in connection with pharmaceutical regulation, i.e. licensing, reimbursement and pricing of drugs? Institutions as well as documents concerning comparative drug evaluation (e.g. regulations, guidelines) were identified through internet, systematic literature, and hand searches. Publications were selected according to pre-defined inclusion and exclusion criteria. Documents were analysed in a qualitative matter following an analytic framework that had been developed in advance. Results were summarised narratively and presented in evidence tables. Results and discussion: Currently licensing agencies do not systematically assess a new drug's added value for patients and society. This is why many countries made post-licensing evaluation of pharmaceuticals a requirement for reimbursement or pricing decisions. Typically an explicitly designated drug review body is involved. In all eleven countries included (Austria, Australia, Canada, Switzerland, Finland, France, the Netherlands, Norway, New Zealand, Sweden, and the United Kingdom) a drug's therapeutic benefit in comparison to treatment alternatives is leading the evaluation. A medicine is classified as a therapeutic improvement if it demonstrates an improved benefit-/risk-profile compared to treatment alternatives. However, evidence of superiority to a relevant degree is requested. Health related quality of life is considered as the most appropriate criterion for a drug's added value from patients' perspective. Review bodies in Australia, New Zealand, and the United Kingdom have committed themselves to include this outcome measure whenever possible. Pharmacological or innovative characteristics (e.g. administration route, dosage regime, new acting principle) and other advantages (e.g. taste, appearance) are considered in about half of the countries. However, in most cases these aspects rank as second line criteria for a drug's added value. All countries except France and Switzerland perform a comparative pharmacoeconomic evaluation to analyse costs caused by a drug intervention in relation to its benefit (preferably by cost utility analysis). However, the question if a medicine is cost effective in relation to treatment alternatives is answered in a political and social context. A range of remarkably varying criteria are considered. Countries agree that randomised controlled head-to-head trials (head-to-head RCT) with a high degree of internal and external validity provide the most reliable and least biased evidence of a drug's relative treatment effects (as do systematic reviews and meta-analyses of these RCT). Final outcome parameters reflecting long-term treatment objectives (mortality, morbidity, quality of life) are preferred to surrogate parameters. Following the concept of community effectiveness, drug review institutions also explicitly favour RCT in a "natural" design, i.e. in daily routine and country specific care settings. The countries' requirements for pharmacoeconomic studies are similar despite some methodological inconsistencies, e.g. concerning cost calculation. Outcomes of clinical and pharmacoeconomic analyses are largely determined by the choice of comparator. Selecting an appropriate comparative treatment is therefore crucial. In theory, the best or most cost effective therapy is regarded as appropriate comparator for clinical and economic studies. Pragmatically however, institutions accept that the drug is compared to the treatment of daily routine or to the least expensive therapy. If a pharmaceutical offers several approved indications, in some countries all of them are assessed. Others only evaluate a drug's main indication. Canada is the only country which also considers a medicine's off-label use. It is well known that clinical trials and pharmacoeconomic studies directly comparing a drug with adequate competitors are lacking - in quantitative as well as in qualitative terms. This is specifically the case before or shortly after marketing authorisation. Yet there is the need to support reimbursement or pricing decisions by scientific evidence. In this situation review bodies are often forced to rely on observational studies or on other internally less valid data (including expert and consensus opinions). As a second option they use statistical approaches like indirect adjusted comparisons (in Australia and the United Kingdom) and, commonly, economic modelling. However, there is consensus that results provided by these techniques need to be verified by valid head-to-head comparisons as soon as possible.ConclusionsIn the majority of countries reimbursement and pricing decisions are based on systematic and evidence-based evaluation comparing a drug's clinical and economic characteristics to daily treatment routine. However, further evaluation criteria, requirements and specific methodological issues still lack internationally consented standards.