Early benefit assessment of new drugs in Germany – Results from 2011 to 2012

Health Policy 116 (2014) 147–153

Contents lists available at ScienceDirect

Health Policy journal homepage: www.elsevier.com/locate/healthpol

Early benefit assessment of new drugs in Germany – Results from 2011 to 2012 Helmut Hörn ∗ , Katrin Nink, Natalie McGauran, Beate Wieseler Institute for Quality and Efficiency in Health Care, Im Mediapark 8, 50670 Cologne, Germany

a r t i c l e

i n f o

Article history: Received 13 August 2013 Received in revised form 11 December 2013 Accepted 19 December 2013

Keywords: (German) Act on the Reform of the Market for Medicinal Products (AMNOG) New drugs Early benefit assessment Dossier assessment Comparative effectiveness research

a b s t r a c t Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of “early benefit assessment”. The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non-quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Background The statutory health insurance (SHI) system covers about 90% of the population in Germany [1]. The main decision-making body of SHI is the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA), which is primarily responsible for reimbursement decisions [2]. The Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG), established in 2004, is Germany’s main health technology assessment (HTA) agency within SHI [3,4]. Its primary responsibility is the production of HTA reports on the

∗ Corresponding author. Tel.: +49 0221 35685 250; fax: +49 0221 35685 1. E-mail addresses: [email protected] (H. Hörn), [email protected] (K. Nink), [email protected] (N. McGauran), [email protected] (B. Wieseler). 0168-8510/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.healthpol.2013.12.008

patient-relevant benefit of drugs and non-drug interventions. These reports inform decision-making by the G-BA. Until 31 December 2010, the price of a new drug introduced into the German market was not regulated or negotiated by a health care or governmental body but solely set by the pharmaceutical industry. As a result, Germany generally pays higher drug prices than other European countries [5], and rising costs have led to the introduction of various cost-containment regulations. A major milestone, the Act on the Reform of the Market for Medicinal Products (Gesetz zur Neuordnung des Arzneimittelmarktes – AMNOG), came into effect on 1 January 2011 [6,7]. According to the German Federal Ministry of Health, AMNOG “aims to curb the spiralling expenditure for medicinal products by the statutory health insurance funds. It paves the way for fair competition and a stronger orientation to patients’ wellbeing” and “creates a new balance between innovation and the affordability of medicines” [6]. However, the introduction of AMNOG aroused substantial opposition, largely

148

H. Hörn et al. / Health Policy 116 (2014) 147–153

from the pharmaceutical industry, which queried the feasibility of early benefit assessments regardless of the fact that this type of procedure has been established in other countries for several years. For instance, it was doubted whether randomized controlled trials could be available at the time of market entry to demonstrate a “therapy relevant added benefit” of a new drug versus an established comparator treatment [8]. These concerns related particularly to oncology drugs [9]. The German Social Code Book V (Sozialgesetzbuch, SGB V) regulates the statutory health care services and has been amended in accordance with AMNOG. The new § 35a SGB V regulates the assessment of the benefit of new drugs (i.e. of drugs with new active ingredients): as soon as a new drug enters the German market, the pharmaceutical company is required to provide evidence of its added benefit for patients compared with an appropriate comparator therapy (ACT), i.e. the current standard treatment, specified by the G-BA [10]. For this purpose, the company must submit a dossier containing a systematic review of the results of all published and unpublished clinical trials on the new drug. This approach aims to prevent the well-known effects of publication and outcome reporting bias [11,12]. In addition, the company has to provide an estimate of the number of patients who could benefit from the new drug as well as an estimate of the corresponding drug costs. The G-BA is responsible for the early benefit assessment and generally commissions IQWiG to assess the dossier and evaluate the probability and extent of added benefit [13], which are determined as described in Box 1. The resulting assessment report by IQWiG is forwarded to the G-BA: this “dossier assessment” is published on the G-BA website together with the company’s dossier and informs the G-BA’s decision on added benefit. This decision, together with the estimated number of patients who may benefit from the new drug and the estimated drug costs, then form the basis for pricing negotiations between the SHI umbrella organization (GKV-Spitzenverband) and the pharmaceutical company. Exemptions from the above procedure apply to orphan drugs, which according to § 35a are classed as having an added benefit, provided their turnover is less than D 50 million per year [14]. However, the company responsible still has to submit a dossier, so that the extent of added benefit can be assessed by the G-BA and used as a basis for price negotiations. The results of benefit assessments of orphan drugs are not covered in this paper. The aim of our paper is to provide an overview of the first results of the early benefit assessment of new drugs in Germany. 2. The first year with AMNOG 2.1. Analysis of dossier assessments The first dossier assessment was published in October 2011. A German-language article by IQWiG published in October 2012 [15] presented results of dossier assessments published between October 2011 and June 2012. We extended the period to December 2012, and extracted the following information from the dossier assessments: number of dossiers assessed by IQWiG, number of dossiers

Box 1 Excursus – determination of the extent and probability of added benefit On the basis of the scientific data analysed, IQWiG draws conclusions on the (added) benefit or harm of a new drug for each patient-relevant outcome. Depending on the number of studies analysed, the certainty of their results, and the direction and statistical significance of treatment effects, conclusions on the probability of (added) benefit or harm are graded into 4 categories: (1) “proof”, (2) “indication”, (3) “hint”, or (4) “none of the first 3 categories applies” (i.e., no data available or conclusions 1–3 cannot be drawn from the available data), see [26]. The extent of added benefit or harm is graded into 6 categories: The categories of (1) major, (2) considerable, (3) minor or (4) non-quantifiable extent of added benefit are used if an added benefit is shown; in addition, (5) no added benefit, or (6) less benefit may apply), see Ref. [13]. The above categories for the extent of added benefit are defined verbally in the Regulation for Early Benefit Assessment of New Pharmaceuticals (ArzneimittelNutzenbewertungsverordnung) [27]. Based on the wording of the regulation, IQWiG has operationalized these categories by means of an algorithm that takes into account the relevance of the outcome (e.g. survival is weighted higher than a non-serious adverse event) and the magnitude of the treatment effect. Using this algorithm, in a first step IQWiG determines the extent and probability of added benefit of a new drug separately for each patient-relevant benefit and harm outcome. In a second step, these results are aggregated into an overall balancing of benefits and harms, resulting in a conclusion on the net added benefit in the IQWiG dossier assessments. The detailed approach is presented in the appendix to IQWiG’s first dossier assessment, Ticagrelor [13] and in the current version of IQWiG’s methods paper (Version 4.1: [26]).

containing sufficient data for assessment, types of drugs analysed, and results of the assessments of the extent of added benefit. IQWiG completed 27 dossier assessments by 31 December 2012. Two of these were on orphan drugs and are not considered further. Fourteen dossiers contained sufficient data for assessment (in all cases including evidence from active-controlled randomized trials); 11 contained insufficient data (Fig. 1). The trials included in the 14 dossiers represented direct comparisons of the new drug and the ACT in at least one relevant group of patients, i.e. patients for whom the drug had been approved. All of these trials investigated patient-relevant outcomes (or at least acceptable surrogate outcomes, see below). The therapeutic indications most commonly investigated were cancer (n = 6), and viral infections such as HIV (n = 2) and hepatitis C (n = 2) (Table 1). For 13 of the 14 new drugs, an added benefit was determined in at least one relevant patient group. No new drug was classified as showing a major added benefit; 13 showed either a hint, an indication or proof of a minor (n = 3), considerable (n = 8) or non-quantifiable (n = 2) added benefit. All 6 dossiers on cancer drugs contained data on overall survival. However, health-related quality of life was only

H. Hörn et al. / Health Policy 116 (2014) 147–153

149

Fig. 1. Flowchart of dossier assessment. (a) Second assessment (after provision of additional data by the pharmaceutical company).

analysed in 4 dossiers. Five cancer drugs were classified as showing either a hint, an indication or proof of a considerable benefit in at least one relevant patient group. One cancer drug was classified as showing no added benefit, as no statement on harms was possible due to inadequate analysis of harms data, thus preventing the overall weighing of benefits and harms. Several dossiers reported surrogate outcomes but provided insufficient evidence of their validity. Nevertheless, 2 of these outcomes were recognized by IQWiG as representing acceptable surrogates for patient-relevant outcomes in the 4 dossiers on HIV and hepatitis C drugs (“viral load” for “AIDS-defining diseases/death” and “sustained virological response” for “hepatocellular carcinoma”). 2.2. IQWiG’s conclusion on added benefit and the G-BA’s decision While IQWiG’s conclusion on added benefit is based on the scientific evidence available at the time of the dossier assessment, the G-BA’s decision on added benefit also considers further aspects: after publication of the dossier assessment on the Internet, specified parties, such as the manufacturer of the drug under assessment, may submit comments on the assessment. For instance, under certain

circumstances additional data may be submitted that may be considered in the G-BA’s decision. Moreover, the G-BA may weight certain aspects differently (e.g. relevance of harms). As a result, the G-BA’s decisions may deviate from IQWiG’s conclusions. As shown in Table 1, the decisions of the G-BA were more or less in line with IQWiG’s assessments: both IQWiG and the G-BA determined an added benefit in at least one relevant patient group in 13 of the 14 dossiers assessed. In addition, the G-BA derived an added benefit for 2 dossiers containing insufficient data and thus “no proof of added benefit” according to IQWiG. 2.3. Problems with data availability The amount of assessable data varied. For example, some dossiers only contained assessable data on small groups of relevant patients. This was often not actually due to the early benefit assessment itself, but to the preceding approval process, as the approval granted often did not precisely reflect the trials submitted for approval (e.g. concerning the patient populations investigated). For instance, in the case of fingolimod, a drug for multiple sclerosis (MS), the approval trials primarily investigated first-line therapy, whereas approval was primarily granted for second-line therapy.

150

H. Hörn et al. / Health Policy 116 (2014) 147–153

Table 1 Characteristics and results of dossier assessments by IQWiG.a Therapeutic indicationb

Conclusion on added benefit by IQWiGc

Decision on added benefit by G-BA

Locally advanced or metastatic breast cancer (third-line therapy)

No proof of added benefit (formulated with reservations due to missing data on harms)

PG 1 (re-treatment with taxanes/anthracyclines possible): hint of minor benefit PG 2 (different treatment): hint of minor added benefit

Cabazitaxel

Hormone-refractory metastatic prostate cancer

PG 1 (BSC population): indication of considerable added benefit PG 2 (docetaxel population): no proof of added benefit

PG 1: indication of minor added benefit PG 2: as IQWiG

Abiraterone

Castration-resistant metastatic prostate cancer

PG 1 (BSC population): indication of considerable added benefit PG 2 (docetaxel population): no proof of added benefit

As IQWiG

Axitinib

Advanced renal cell carcinoma

PG 1 (after failure of prior therapy with sunitinib): added benefit not proven PG 2 (after failure of prior therapy with a cytokine): hint of considerable added benefit

PG 1: as IQWiG

Drug Sufficient data Eribulin

PG 2: indication of minor added benefit

Vemurafenib

Advanced melanoma

Indication of considerable added benefit

As IQWiG; restriction of resolution to 1 year

Ipilimumab

Advanced melanoma

Indication of considerable added benefit

As IQWiG: restriction of resolution to 5 years

Rilpivirine

HIV

Considerable added benefit (proof for men, indication for women)

Proof of minor added benefit (for men and women)

Rilpivirine/emtricitabine/ tenofovir

HIV

Original conclusion: No proof of added benefit Addendum on the basis of subsequently presented data: considerable added benefit (proof for men, indication for women)

Proof of minor added benefit (as for rilpivirine monotherapy) based on data from addendum

Telaprevir

Chronic hepatitis C

For most PGs: indication of non-quantifiable added benefit

As IQWiG, but for all PGs

Boceprevir

Chronic hepatitis C

For most PGs: indication of non-quantifiable added benefit

As IQWiG, but for all PGs

Ticagrelor

Acute coronary syndrome

PG 1 (unstable angina or myocardial infarction without ECG changes) proof of considerable added benefit PG 2 (myocardial infarction with ECG changes): no proof of added benefit

PG 1: As IQWiG For parts of PG 2: hint of non-quantifiable added benefit

Apixaban

Prevention of thromboembolic events after hip or knee replacement

PG 1 (hip replacement): proof of minor added benefit PG 2 (knee replacement): no proof of added benefit

PG1: indication instead of proof PG2: As IQWiG

Fingolimod

Multiple sclerosis

Small PG (highly active RRMS): hint of minor added benefit; otherwise no proof of added benefit

As IQWiG

Belatacept

Immunosuppression after kidney transplant

PG 1 (standard criteria donor): indication of minor added benefit PG 2 (extended criteria donor): no proof of added benefit

For both PGs: indication of minor added benefit

Insufficient datad Belimumab

Systemic LE

No proof of added benefit

Indication of considerable added benefit

Cannabis extract

Spasticity due to MS

No proof of added benefit

Hint of minor added benefit

BSC: best supportive care; ECG: electrocardiogram; G-BA: Federal Joint Committee; HIV: human immunodeficiency virus; IQWiG: Institute for Quality and Efficiency in Health Care; LE: lupus erythematosus; MS: multiple sclerosis; PG: patient group; RRMS: relapsing/remitting multiple sclerosis a Only includes dossiers with sufficient relevant data (plus the cannabis and belimumab dossiers because of the G-BA’s decision). b In part shortened; exact therapeutic indications are specified in the corresponding Summaries of Product Characteristics. c Compared with appropriate comparator therapy (therapeutic standard specified by the G-BA). d But added benefit awarded by the G-BA.

H. Hörn et al. / Health Policy 116 (2014) 147–153

As stated, 11 dossiers provided insufficient data for assessment and IQWiG thus concluded that no added benefit had been proven (Fig. 1). In 2 cases the pharmaceutical company could probably have avoided such a conclusion: the dossier on vandetanib (a cancer drug) did not investigate those patients for whom the drug had been approved and the dossier on belimumab (a drug for autoimmune diseases) excluded a relevant study. Consequently, sufficient data would actually have been available for 16 of the 25 new drugs assessed. In the 9 remaining cases, the reasons why the company did not fulfil the requirements for a conclusion of added benefit were not fully clear; it is possible that real gaps in the evidence existed. In 3 cases, the company did not follow the ACT specified by the G-BA. In a further 4 cases, the companies (at least in part) followed the ACT, but did not submit direct comparative trials. The indirect comparisons submitted alternatively for 3 of these drugs, which were also compared with non-drug interventions, were insufficient due to the use of inappropriate statistical methods or comparisons. In the remaining 2 cases the submitted direct comparative trials were insufficient for benefit assessment.

151

problem should be a main focus in the future planning of trials of new drugs. Secondly, direct comparisons of drug and non-drug interventions were often lacking. More trials in this field would produce more evidence on the benefits and harms of different types of interventions and could provide a valuable decision aid when choosing, for example, between a drug and a surgical procedure. As for cancer drugs, the fact that all dossiers assessed contained data on overall survival seems to confirm the increasing inclusion of patient-relevant outcomes in cancer trials [17]. Although other patient-relevant outcomes such as health-related quality of life were only partly included, the experience so far has not confirmed fears voiced before the implementation of AMNOG, namely that new cancer drugs in particular would not be able to overcome the hurdle of early benefit assessment [9]. The availability of surrogate outcomes alone is not an insurmountable hurdle either; as long as they represent acceptable surrogates for patient-relevant outcomes, they can be considered in the early benefit assessment. 3.2. Decisions on added benefit versus regulatory decisions

3. Discussion 3.1. Summary of experience with AMNOG As stated above, before the implementation of AMNOG concerns were raised as to its feasibility. But as already shown in other countries, the findings above show that in principle the early benefit assessment of drugs at market entry is also feasible in Germany. The fact that about 60% of the dossiers analysed contained direct comparisons with the ACT for at least some relevant patient groups, although the ACT was specified by the G-BA after the trials included in the dossiers had been completed, indicates that these concerns were largely unwarranted. It is reasonable to expect that the proportion of dossiers containing direct comparisons with the ACT will increase in the future as the G-BA offers consultation on the ACT, which can take place at an early stage, i.e. before the start of Phase III trials [16]. Pharmaceutical companies can thus considerably increase their chances of achieving an added benefit for their new drug by consulting the G-BA about the ACT (and patientrelevant outcomes) at an early stage and conducting direct comparisons with the ACT specified. However, it should be acknowledged that the choice of an active comparator in trials that reflect the appropriate comparator in all countries is difficult. Nevertheless, even if different active comparators are required in different countries, consultation with the G-BA on the ACT is still meaningful to inform the planning of trials to be used in indirect comparisons. Consultation with the G-BA is also meaningful when the clinical development programme of a new drug has already been completed, as this can inform the selection of available indirect comparisons as well as support preparation of the specific dossier. The first year with AMNOG also revealed considerable gaps in the evidence. Firstly, the coverage of patient-relevant outcomes was incomplete, and surrogates submitted alternatively lacked validity. Solving this

It has been queried whether the regulatory decision is contradicted by the fact that, in some cases, IQWiG and the G-BA agreed on “no added benefit” of a new drug, even though it is approved. However, this is not the case: regulatory approval and benefit assessment for pricing purposes pose different questions. Regulatory approval requires a sufficiently positive benefit-risk ratio according to the criteria of drug legislation. In most cases, the underlying trials, which may or may not consider patient-relevant outcomes, investigate superiority over placebo or noninferiority to an active comparator. In contrast, IQWiG’s conclusions and the G-BA’s decisions are based on assessment of the added benefit of a new drug compared with the ACT according to the criteria of SGB V. The underlying trials consider patient-relevant outcomes and investigate superiority over an active comparator representing the current therapeutic standard. 3.3. Financial impact of AMNOG The early benefit assessment of new drugs forms the basis for price negotiations between the SHI umbrella organization and the pharmaceutical companies. In 2012, reimbursement prices were set for 17 new drugs. A report by the Research Institute of Germany’s largest SHI fund (AOK Research Institute, WIdO) presented initial calculations for AMNOG and showed savings of D 25 million for these 17 drugs, which achieved gross sales of D 670 million [18]. At first glance this hardly seems impressive, as savings of about D 2 billion were predicted by the German Ministry of Health when AMNOG was introduced [19]. However, according to the above report, future savings will be substantially higher, as new drugs usually achieve their maximum annual revenue 10–12 years after market entry. For instance, savings of about D 81 million have been estimated for 2014 for the 17 drugs above. But the authors of the report also state that noteworthy savings can only be

152

H. Hörn et al. / Health Policy 116 (2014) 147–153

achieved if the range of drugs under assessment is extended [18] (see below).

to institutions such as the Agency for Health Research and Quality (AHRQ) and the newly established PatientCentered Outcomes Research Institute (PCORI) [23,25].

3.4. Assessment of established drugs Assessment of drugs already established in the German market, that is, already approved before the implementation of AMNOG and still protected by data exclusivity, has been introduced as a further component of drug assessment in Germany in SGB V § 35a. According to this law, these drugs should primarily be assessed if they are important in health care and/or compete with drugs that already have undergone early benefit assessment. The first group of drugs assessed were gliptins for type 2 diabetes in June 2013, meaning that for the first time an assessment covered a whole group of drugs (i.e. both established and newly approved ones) [20,21], a further milestone in comparative effectiveness research (CER) in Germany. The G-BA has also specified binding criteria for the assessment of drugs already established in the German market and determined 6 further drug classes for assessment [22]. Together with the gliptins, these drugs are expected to achieve gross sales of D 1.5 billion in 2014 [18]. However, the future of the assessment of established drugs is currently under discussion. 3.5. Approaches in other countries With the implementation of the benefit assessment of both new and established drugs, Germany is catching up with other countries in the field of CER. Many countries have long adopted such an approach to inform reimbursement decisions. Differences exist, for instance, regarding the time of assessment in relation to market entry or the inclusion of unpublished data [23]. However, the approaches generally share a common ground, that is, the comparative assessment of the effectiveness or efficacy of a drug versus a drug or non-drug treatment alternative (often using definitions similar to “usual care”), as well as preferential inclusion of patient-relevant outcomes [23]. France applies a similar approach to Germany: the Haute Autorité de Santé (HAS) assesses the “clinical added value” of a new drug. The result of the assessment is used in price negotiations with industry [23]. In contrast, most other European countries focus more on cost-effectiveness approaches [23]. For instance, the British National Institute for Health and Care Excellence (NICE), besides evaluating the “clinical effectiveness” of a new technology, also performs cost-effectiveness assessments and expresses health effects in terms of Quality Adjusted Life Years (QALYs) [24]. Cost-effectiveness approaches are also well established in several other European countries such as Sweden, the Netherlands, Austria, and Poland [23]. There is no organization in the United States that performs drug assessments similar to those in Europe to inform reimbursement decisions on a national level, as reimbursement decisions are the responsibility of the various health plans and insurances, which primarily belong to the private sector [23]. However, the relevance of CER has increased dramatically with the introduction of the American Recovery and Reinvestment Act of 2009, which allocated over $1 billion

4. Conclusions The introduction of AMNOG means that, despite considerable doubts raised beforehand and some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry. The procedure not only supports price negotiations, but also provides early and independent information on a new drug, and thus supports informed decisionmaking for patients, clinicians and policy makers. It would also be desirable for the same assessment standards, i.e. performance of a full benefit assessment to apply to orphan drugs, independent of their turnover, so as to ensure that the most complete evidence base possible is available. Conflicts of interest All authors are employed by IQWiG. Funding source This work was supported by IQWiG. References [1] Bundesministerium für Gesundheit. Mitgliederstatistik KM6: Statistik über Versicherte gegliedert nach Status, Alter, Wohnort und Kassenart zum 01.07.2010 [Federal Ministry of Health: statistics of insured members classed according to status, age, place of residence and type of insurance fund] [updated 7 September 2010; cited 12 August 2013]. Available from: http://www.bmg.bund.de/fileadmin/ dateien/Downloads/Statistiken/GKV/Mitglieder Versicherte/ Mitgliederstatistik KM6.xls [2] Gemeinsamer Bundesausschuss [Federal Joint Committee]. The Federal Joint Committee [cited 12 August 2013]. Available from: http://www.english.g-ba.de/ [3] Institute for Quality and Efficiency in Health Care. Responsibilities and objectives of IQWiG [cited 12 August 2013]; 2014. Available from https://www.iqwig.de/en/about us/responsibilities and objectives of iqwig.2946.html [4] Sawicki PT, Bastian H. German health care: a bit of Bismarck plus more science. BMJ 2008;337:a1997. [5] Kanavos P, Vandoros S, Irwin R, Nicod E, Casson M. Differences in costs and access to pharmaceutical products in the EU [updated 2011; cited 12 August 2013]; 2014. Available from http:// www.europarl.europa.eu/document/activities/cont/201201/ 20120130ATT36575/20120130ATT36575EN.pdf [6] Federal Ministry of Health. The Act on the Reform of the Market for Medicinal Products (Gesetz zur Neuordnung des Arzneimittelmarktes – AMNOG) [updated 3 September 2013; cited 5 November 2013]; 2014. Available from http://www.bmg.bund.de/ministerium/ english-version/health/amnog.html [7] Henschke C, Sundmacher L, Busse R. Structural changes in the German pharmaceutical market: price setting mechanisms based on the early benefit evaluation. Health Policy 2013;109(3):263–9. [8] Verband Forschender Arzneimittelhersteller [German Association of Research-Based Pharmaceutical Companies]. Stellungnahme zum Gesetzentwurf der Fraktionen von CDU/CSU und FDP: Entwurf eines Gesetzes zur Neuordnung des Arzneimittelmarktes in der gesetzlichen Krankenversicherung (AMNOG); Bundestagsdrucksache 17/2413 [Comment on the draft of an act prepared by the CDU/CSU and FDP parliamentary groups: draft of the Act on the Reform of the Market for Medicinal Products in Statutory Health Insurance, AMNOG] [updated 22 September 2010; cited 12 August 2013]; 2014. Available from http://www.bundestag.de/

H. Hörn et al. / Health Policy 116 (2014) 147–153

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

bundestag/ausschuesse17/a14/anhoerungen/Archiv/c AMNOG/ Stellungnahmen/17 14 0065 23 1 .pdf Klein L. IMS Health Studies: AMNOG verzögert Einführung neuer Arzneien [IMS Health Study: AMNOG delays introduction of new drugs] [updated 29 November 2010; cited 12 August 2013]; 2014. Available from http://www.deutsche-apotheker-zeitung.de/politik/ news/2010/11/29/amnog-verzoegert-einfuehrung-neuer-arzneien. html SGB V Sozialgesetzbuch: Gesetzliche Krankenversicherung; § 35a SGB V Bewertung des Nutzens von Arzneimitteln mit neuen Wirkstoffen [SGB V Social Code Book: Statutory Health Insurance; § 35a SGB V assessment of the benefit of pharmaceuticals with new active ingredients] [cited 12 August 2013]; 2014. Available from http://www.sozialgesetzbuch-sgb.de/sgbv/35a.html Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technology Assessment 2010;14(8):1–220. McGauran N, Wieseler B, Kreis J, Schüler YB, Kölsch H, Kaiser T. Reporting bias in medical research: a narrative review. Trials 2010;11:37. Institute for Quality and Efficiency in Health Care. Ticagrelor: benefit assessment according to § 35a Social Code Book V; extract; appendix A; explanation of the operationalization of the extent of added benefit on the outcome level in accordance with the Regulation for Early Benefit Assessment of New Pharmaceuticals [updated 29 November 2011; cited 12 August 2013]; 2014. Available from https://www.iqwig.de/download/A11-02 Extract of dossier assessment Ticagrelor.pdf Gemeinsamer Bundesausschuss [Federal Joint Committee]. Questions and answers about the procedure: are orphan drugs exempt from early assessment? [cited 12 August 2013]; 2014. Available from http://www.english.g-ba.de/benefitassessment/information/faq/#3 Nink K, Hörn H, Pieper K, Böhler YB. Ein Jahr frühe Nutzenbewertung: das IQWiG zieht Bilanz [One year of early benefit assessment - IQWIG takes stock]. GGW 2012;12(4):18–24. Federal Joint Committee. The benefit assessment of pharmaceuticals in accordance with the German Social Code, Book Five (SGB V), section 35a [cited 5 November 2013]; 2014. Available from http://www.english.g-ba.de/benefitassessment/information/ Schott G, Gökbuget N, Pachl H, Ludwig WD. Klinische Studien in der Onkologie: Defizite und Lösungsvorschläge [Clinical trials in oncology: deficits and proposals for solutions]. Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen 2011;105(9):657–66. Schaufler J, Schröder H, Telschow C, Weiss J. Ökonomische Aspekte des deutschen Arzneimittelmarktes 2012 [Economic aspects of the German drug market 2012]. In: Schwabe U, Paffrath D, editors. Arzneiverordnungs-Report 2013. Berlin: Springer; 2013. p. 157–214. Bundesministerium für Gesundheit. Das Gesetz zur Neuordnung des Arzneimittelmarktes (AMNOG) [Act on the Reform of the Market for Medicinal Products] [updated 16 April

[20]

[21]

[22]

[23]

[24]

[25] [26]

[27]

153

2013; cited 20 July 2013]; 2014. Available from http://www. bmg.bund.de/krankenversicherung/arzneimittelversorgung/ arzneimittelmarktneuordnungsgesetz-amnog/das-gesetz-zuneuordnung-des-arzneimittelmarktes-amnog.html Gemeinsamer Bundesausschuss [Federal Joint Committee]. GBA veranlasst Nutzenbewertung von Arzneimitteln aus dem Bestandsmarkt [G-BA initiates benefit assessment of pharmaceuticals from the established market] [updated 7 June 2012; cited 12 August 2013]; 2014. Available from http://www. g-ba.de/institution/presse/pressemitteilungen/439/#footer Gemeinsamer Bundesausschuss [Federal Joint Committee]. Erste Bestandsmarktbewertungen abgeschlossen: zwei Gliptine mit geringem Zusatznutzen; Beschlüsse befristet [First assessments of established market completed: two gliptins with minor added benefit; resolutions temporary] [updated 1 October 2013; cited 2 November 2013]; 2014. Available from: http://www.g-ba.de/ institution/presse/pressemitteilungen/507/ Gemeinsamer Bundesausschuss [Federal Joint Committee]. G-BA legt Kriterien für Bestandsmarktaufruf fest und bestimmt erste Wirkstoffgruppen für die Nutzenbewertung [G-BA specifies criteria for call up of drugs from established market and specifies first drug classes for benefit assessment]. [updated 10 April 2013; cited 2 November 2013]; 2014. Available from: http://www.g-ba.de/ institution/presse/pressemitteilungen/485/ Kleijnen S, Goettsch W, D’Andon A, Vitre P, George E, Goulden S, et al. EUnetHTA JA WP5: relative effectiveness assessment (REA) of pharmaceuticals; background review [updated July 2011; cited 12 August 2013]; 2014. Available from http://www.eunethta. eu/sites/5026.fedimbo.belgium.be/files/Final%20version%20of%20 Background%20Review%20on%20Relative%20Effectiveness%20 Assessment+appendix.pdf National Institute for Health and Clinical Excellence. Guide to the methods of technology appraisal 2013 [updated 4 April 2013; cited 02 November 2013]; 2014. Available from http://www. nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal 2013.pdf Sox HC. Comparative effectiveness research: a progress report. Annals of Internal Medicine 2010;153(7):469–72. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [Institute for Quality and Efficiency in Health Care]. Allgemeine Methoden: Version 4.1 [General Methods: Version 4.1] [updated 28 November 2013; cited 11 December 2013]; 2014. Available from https://www.iqwig.de/download/IQWiG Methoden Version 4-1.pdf Bundesminister für Gesundheit. Verordnung über die Nutzenbewertung von Arzneimitteln nach § 35a Absatz 1 SGB V für Erstattungsvereinbarungen nach § 130b SGB V (ArzneimittelNutzenbewertungsverordnung–AM-NutzenV) [Regulation for Early Benefit Assessment of New Pharmaceuticals acc. to § 35a (1) Social Code Book V for reimbursement agreements acc. to § 130b Social Code Book V]. Bundesgesetzblatt Teil 2010;1(68): 2324–8.