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

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

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.

BACKGROUND: 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. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. METHODS: Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer's dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. RESULTS: A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. CONCLUSIONS: This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.

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

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

Comparison of post-authorisation measures from regulatory authorities with additional evidence requirements from the HTA body in Germany - are additional data requirements by the Federal Joint Committee justified?

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.

Analysis of endpoints used in marketing authorisations versus value assessments of oncology medicines 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.