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 This analysis aims to compare recommendations in clinical guidelines and HTA appraisals of medicines that were withdrawn from the German market since the introduction of AMNOG in 2011. Methods: Medications withdrawn from the German market between January 2011 and June 2016 following benefit assessment were categorized as opt-outs (max. 2 weeks after start of price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 Twenty-one out of 22 withdrawn medicines (95%) received 'no additional benefit' appraisal by the G-BA (average 'no additional benefit' rating for all AMNOG products: 47%).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across clinical guidelines as well as between clinical guidelines and HTA appraisals of the medicines that were withdrawn from the German market.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.

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.

Objectives: The aim of this study was to compare post-authorisation measures (PAMs) from the European Medicines Agency (EMA) with data requests in fixed-termed conditional appraisals of early benefit assessments from the German Federal Joint Committee (G-BA).Methods: Medicinal products with completed benefit assessments during an assessment period of 3.5 years were considered. PAMs extracted from European Public Assessment Reports (EPARs) were compared with data requests issued by the G-BA in the context of conditional appraisals.Results: Twenty conditional appraisals (19 products) and 34 EPARs containing PAMs (33 products) were identified. Data categories (efficacy, safety, etc.), data types (type of study required to address the request) and clarity of requests were determined. Conditional appraisals disproportionately focused on oncology products (13/19 products with conditional appraisals vs. 14/33 products with PAMs). No clear rationale for the G-BA issuing conditional appraisals could be identified in public sources. Both EMA and G-BA requested mainly efficacy and safety data (44/54 and 23/35 categories requested, respectively); however, 28/35 G-BA data requirements went beyond requests made by the EMA. Almost half of the G-BA requests (9/20), but no PAMs, were unclear, and no methodological guidance for fulfilling the data requirements was provided by the G-BA.Conclusions: Better alignment between data requests from regulatory authorities and health technology assessment bodies is strongly recommended.

Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system.

Based on the pharmaceutical law (‘AMNOG’) that was introduced in Germany in 2011, the Federal Joint Committee (G-BA) is charged with the determination of the additional benefit of new medicines versus the available standard. This decision constitutes the basis for price negotiations between the statutory health insurance (GKV-SV) and the pharmaceutical companies. At any time the pharmaceutical companies may decide to withdraw their innovative drugs from the market. All withdrawals from the German market since 2011 were analysed with regards to the additional benefit granted by G-BA and recommendation status in clinical guidelines. Withdrawals from the German pharmaceutical market that completed a benefit assessment between January 2011 and June 2016 were identified and categorised into opt-out decisions (prior to completion of first price negotiation) and supply termination (during or after further price negotiations). Respective medicines were reviewed with regards to recommendation status in clinical guidelines and G-BA’s benefit decision. Of 139 medications, 10 opt-outs and 12 supply terminations were identified. Twenty-one (95%) thereof received a ‘no benefit’ rating. Of the 12 terminations, 9 (75%) underwent the arbitration procedure. Most frequently (9 of 22), withdrawals concerned metabolic disorders. At the time of the benefit assessment, 19% of the withdrawn medicines were recommended specifically and 62% by therapeutic class in ≥1 relevant therapeutic guideline per indication. A ‘no benefit rating’ suggests that, based on available data, the new medicine does not provide additional benefit to patients. Yet, some of those medications are recommended in clinical guidelines. Our analysis indicates that new medicines with a ‘no benefit’ rating might still provide additional value to patients and health care systems which are not captured within the early benefit assessment.

The introduction of AMNOG law in Germany in January 2011 stipulated an early benefit assessment (EBA) for new medicines. EBAs determine the extent of additional therapeutic benefit that a drug has on patient-relevant endpoints. We examined the acceptance of clinically acknowledged primary endpoints (PEs) from regulatory trials in EBAs conducted by the German Federal Joint Committee (G-BA). For drugs in five disease areas (oncology, diabetes, hepatitis C [HepC], multiple sclerosis [MS] and idiopathic pulmonary fibrosis [IPF]), EBAs and regulatory assessments were reviewed. The G-BA website was used to obtain manufacturers’ value dossiers and G-BA appraisals. Endpoints used in pivotal trials were obtained from the Summary of Product Characteristics available from the European Medicines Agency website. Acceptance of PEs by the G-BA was compared to acceptance by regulatory authorities. In 4 disease areas (diabetes, HepC, MS and IPF), PEs only addressed the dimension of morbidity; in oncology, they covered the dimensions of morbidity and of mortality. Acceptance of PEs by the G-BA differed between the evaluated disease areas. Both the G-BA and regulatory bodies accepted mortality PEs. The G-BA did not accept morbidity PEs in diabetes and IPF and only partially accepted them in oncology and MS, whereas they were fully accepted in HepC. More specifically, widely accepted morbidity PEs were not deemed patient-relevant by the G-BA in three of five evaluated disease areas (progression-free survival in oncology, haemoglobin A1c in diabetes and change in forced vital capacity in IPF). None of the reviewed pivotal trials included quality of life (QoL) endpoints as PEs. Whereas there was largely agreement on the acceptance of mortality PEs (where provided), considerable variability in the acceptance of morbidity PEs was observed between regulatory bodies and the G-BA. Established morbidity PEs were frequently not, or only partially, accepted by the latter.

In Germany, an early benefit assessment (EBA) by the Federal Joint Committee (G-BA) is compulsory for all new drugs. Pre-defined treatment switching, often called ‘cross-over’, is often seen in oncology clinical trials. Cross-over is usually implemented for ethical reasons, i.e. to ensure access to a beneficial treatment for all patients, but may confound data analysis by improving efficacy in the control arms. We aimed to analyse the impact of cross-over on evidence levels granted by the G-BA. Oncology medicines with completed EBAs by 01 Jan 2015 were analysed for i) presence of cross-over in pivotal trials; ii) efficacy results before and after cross-over and iii) evidence levels granted by the G-BA (proof, indication or hint). Cross-over was frequent in oncology, concerning 14 of 28 EBAs (50%). For 6 of the 14 medicines, cross-over could be considered ethically required as significant differences in overall survival (OS) were demonstrated prior to cross-over. For most medicines, data on OS and progression-free survival were reported after cross-over (10/14 and 8/14, respectively). Significant differences in OS post-cross-over could only be shown for 2 out of the 8 medicines for which no such differences were demonstrated before cross-over. An evidence level of proof was granted by the G-BA for 3 out of the 14 medicines, all of which were orphan drugs, but none were granted for medicines with ethically required cross-over. The G-BA regards evidence standards as only partially fulfilled in cases of ethically required cross-over in oncology. Highly efficacious drugs with ethically mandated cross-over are therefore systematically disadvantaged with regards to the achievable evidence category, indicating a bias against innovation. Medicines with a demonstration of superior efficacy and subsequent ethically justified cross-over deserve an evidence level of proof.

Ethics committees often require cross-over design for highly sensitive circumstances where it may be unethical to withhold active therapy. This can be the case particularly in oncology. Cross over can, however, dilute the treatment effect seen in trial analyses. The German Institute for Quality and Efficiency in Health Care (IQWiG) follows distinct thresholds for comparative treatment effect, which it requires for a positive early benefit assessment (EBA) rating. The upper 95% confidence interval must be at least 0.85 to receive the highest rating. We evaluated if cross-over designs may negatively affect benefit assessment in Germany. Oncology medicines that finished EBA procedures in Germany until June 2014 were evaluated for cross over in the manufacturer’s dossier. The extent of cross over on the observed treatment effects was investigated, as well as how the designs may affect the EBA ratings. Ten out of 24 EBAs in oncology included assessment of trials with cross-over design. Cross over may have affected the observed treatment effects as demonstrated by a number of examples. Firstly, the proportion of patient cross over was as high as 62% for crizotinib. For vandetanib, 12 out of 13 remissions in the control group could be attributed to a switch to active therapy. The hazard ratio for overall survival (OS) with vemurafenib versus dacarbazine was 0.37 without cross over at first data-cut in comparison to 0.62 with 24% cross over at a later timepoint. These examples suggest that cross-over designs are both present in EBAs in oncology, and may affect the extent of comparative treatment effect. The affect of cross-over design was not systematically considered by IQWiG. Cross-over design is an ethical necessity. However, it is known that these designs dilute treatment effect signals. German HTA EBAs need to improve in systematically accounting for such cross-over affects.

Regulatory authorities such as the European Medicines Agency (EMA) can make marketing authorisation contingent upon post-authorisation measures (PAMs) so as to fill in information gaps in efficacy and safety. PAMs are generally formulated in agreement with manufacturers, and evaluate clinical hypotheses in an ethical and practical way. In Germany, novel medicines must also undergo an early benefit assessment (EBA) by the Federal Joint Committee (G-BA) following marketing authorisation. G-BA may demand additional evidence in order to formulate an opinion on added therapeutic value, which then leads to determination of reimbursement. We compared selected PAMs with the corresponding G-BA demands to see if they were similar. Medicines that received a restricted EBA from G-BA before 15 June 2014 were evaluated and compared with their marketing authorisations by EMA. PAMs from EMA, and EBA restrictions from G-BA, were assessed in terms of their required additional evidence. Twenty-eight percent of all 79 medicines assessed by G-BA received a restricted EBA. Only nine of those had obligations for PAMs. Four of these were conditional approvals or approval under exceptional circumstances, while five received unconditional marketing authorisation. G-BA justified restricted EBAs for the four conditional approvals based upon agreement with the EMA opinion. For the five unconditional approvals, G-BA required considerably more information than EMA. The additional evidence requested by the two bodies rarely corresponded to one another. EBA restrictions were more influenced by transferability to the German health care context, choice of subgroups and appropriate comparator, than were the corresponding EMA PAMs. G-BA often demands more evidence than specified in EMA PAMs from medicines granted unconditional approval. Although PAMs are discussed and agreed between EMA and manufacturers, G-BA demands and restrictions are not. The possibility for such discussions with G-BA would be an improvement for the future.

Since 2011 Germany follows a formal process of evaluating new pharmaceuticals for their incremental benefit vs. an appropriate comparator to inform price negotiations with Insurers. This study summarizes the rationale underlying the German authorities’ (G-BA) final assessment of manufacturers’ submissions following successful approval by regulators. G-BA decisions (1/2011 to 2/2014) were evaluated for their alignment (full, partial or none) between manufacturer’s development programs and expectations concerning: (1) target population; (2) comparator; (3) clinical endpoints, including indirect comparisons. Also addressed was the role of safety and how the G-BA addressed the potential for bias. Of 69 completed submissions, 3 were resubmissions and 7 lacked a dossier. 59 completed submissions were subjected to a detailed review. Ten (17%) were for orphan disease indications. Major disagreement existed for 37 (63%), of which 17 (46%) were considered fully inadequate, and 20 (54%) inadequate for significant subgroups. Main reasons for inadequacy were: wrong comparator (27 of 37 [73%], wrong endpoint 6 [16%] and use of historical controls (3 [11%] ). For 34 (92%) the major disagreement also led to a lower benefit judgment. All 19 indirect treatment comparisons were considered flawed. Safety was a differentiator for 24 of the 59 submissions, either primary (2) or in addition to efficacy (22). G-BA disagreed with the manufacturer on safety for 12 (50%) of the 24 submissions. This analysis of the first 3 years of G-BA’s early benefit appraisal illustrates that a majority of the submissions fail to convince the German authorities despite having obtained licensing approval. A wrong comparator was the main reason for full or partial rejection. Indirect treatment comparisons were never accepted. Decisions taken early in the development program have important repercussions on reimbursement negotiations with authorities in Germany.

Background and aims: In Germany, a mandatory early benefit assessment (EBA) by the Federal Joint Committee (G-BA) is required for reimbursement of new marketing-authorised medicines. Additional benefit is based on patient-relevant endpoints in mortality, morbidity and health-related quality of life (HRQoL). We aimed to compare endpoints and related benefit categories used in marketing authorisation to those considered by G-BA in the field of oncology.Methods: We evaluated EBAs in oncology commencing prior to 31 December 2013. Endpoints for the appropriate medicines, derived from European Medicines Agency's (EMA) Summary of Product Characteristics (SPC), manufacturers' value dossiers and G-BA decisions, were grouped into the three benefit categories.Results: Of 23 oncology medicines evaluated, primary clinical trial endpoints were included in only 12 G-BA value decisions. Mortality endpoints were generally accepted by EMA and G-BA. However, G-BA excluded 80% of (co-)primary morbidity endpoints. Only 5 SPCs reported HRQoL instruments. G-BA accepted applied instruments in 15 medicines, but the manufacturers' analyses only in 5 medicines, of which 2 indicated an additional benefit.Conclusions: Mortality endpoints are accepted by EMA and G-BA. EMA accepted well established and clinically relevant morbidity endpoints (e.g. progression-free survival and response rate), which were mostly excluded by G-BA from their value decisions. The applicability of methods used for benefit assessments to HRQoL differs from the mortality and morbidity categories, and requires further clarification. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.