Since the enactment of the AMNOG in Germany in 2011, pharmaceutical companies are required to prove the benefit of newly approved drugs within the therapeutic area(s) of interest. The potential benefit is evaluated by G-BA/IQWiG forming the basis for price negotiations with the statutory health insurance providers. Aim of this study was to investigate the distribution and the outcomes of the assessments from 2011 to May 2022. A database containing all evaluated AMNOG assessments was analysed. Information on G-BA assessments and decisions on added benefit were extracted. Prices at the time of launch including changes after G-BA decision were obtained from Lauer-Taxe®. Benefit assessments were qualitatively and quantitatively analysed for predictors of assessment outcome and impact on price negotiations. Overall, 741 concluded benefit assessments were published including 1,304 subpopulations predominantly in the indications of oncology (458), metabolic (271), infectious (183) and neurological diseases (52). The most frequent outcome of no added benefit ranged between 38-64% of assessed subpopulations. No definitive trend for quantifiable added benefit categories (major, considerable and minor) was found with major always being the rarest outcome (1-3%). Comparing the outcomes on benefit assessment level, no added benefit was granted in 41%. However, the G-BA determined no added benefit in 58% on subpopulation level. In the subsequent price negotiations, the mean rebate on the initial launch price was 24% and 32% for the categories added benefit and no added benefit, respectively. Since 2011, benefit assessments have become the key component in pricing of new drugs in Germany. To receive an added benefit that positively influences price negotiations, evidence must be generated in accordance with G-BA/IQWiG regulations. Our analysis shows that most subpopulations were not granted an added benefit, indicating that the provided evidence did not meet either sufficient efficacy, safety or methodological criteria.

The additional benefit of orphan drugs (OD) assessed by the G-BA is already acknowledged by approval. However, if the annual costs for the statutory health insurance exceed 50 million euros or the OD-status is lost, a standard assessment without OD privileges is mandatory. The aim of this study was to examine the change in the extent of the added benefit, time to reassessment and change of the price discount.

To investigate the G-BA's decisions regarding patient-relevance of non-OS endpoints across breast cancer (BC), chronic lymphocytic leukaemia, melanoma, non-small cell lung cancer, ovarian cancer, and prostate cancer (PC). All published G-BA appraisal reports (January 2011–October 2020) in the 6 selected indications were reviewed and relevant data were extracted for analysis. Reviewed G-BA appraisals (n=101) yielded 307 individual decisions regarding patient-relevance of non-OS endpoints, employing 56 different outcome measures. Although in 74% of decisions (n=226/307) non-OS endpoints were deemed patient-relevant in general, in 79% (179/226) of these cases, no additional medical benefit was granted either due to lack of compliance with G-BA's methodological requirements, inadequate/missing data, or statistically insignificant results. The G-BA did not accept progression-free survival, metastasis-free survival, complete remission, and objective response rate measured per imaging or laboratory tests. Patient-relevance decisions for health status (n=59), quality of life (n=103), and pain (n=10) related endpoints were positive across all indications. Decisions regarding the patient-relevance of other non-OS endpoints were indication-specific and variable, e.g. relapses as proxy for the failure of therapy with curative intent were judged patient-relevant in both BC (neoadjuvant and adjuvant settings) and melanoma (adjuvant setting), and symptomatic progression in the palliative setting in PC was judged patient-relevant. In comparison, time-to-first-subsequent-therapy and time-to-onset-of-cytotoxic-therapy were judged patient-relevant in principle, but not accepted due to methodological deficiencies, and/or lack of correlation with patient-relevant side-effects of subsequent treatment. Strict compliance with methodological requirements and specific relevance to disease context and treatment setting were key drivers of G-BA's acceptance of patient-relevance for non-OS endpoints. The impact of G-BA's stringent methodological requirements on establishing the holistic patient-relevance of non-OS endpoints requires further debate.

Since the enactment of the AMNOG in Germany in 2011, pharmaceutical companies are required to prove the benefit of newly approved drugs over the standard of care within the therapeutic area(s) of interest. This benefit is evaluated by G-BA/IQWiG and forms the basis for price negotiations with the statutory health insurance providers. The aim of this study was to investigate the distribution of the awarded added benefit from 2011 to 2019 and to examine the development of outcomes in this timeframe. A database containing all evaluated AMNOG dossiers from 2011 to 2020 was analysed. Information on G-BA assessments and decisions on added benefit were extracted. Results were grouped by completed calendar year and added benefit category. Trends in development of the benefit categories for regular as well as orphan drugs (OD) were evaluated. In total, 455 concluded benefit assessments were published including 889 subpopulations. The most frequent outcome was no added benefit for 43% to 64% of assessed subpopulations from 2011 to 2019. There is no definitive trend for either of the three quantifiable added benefit categories (major, considerable, minor) with major added benefit always being the rarest outcome. However, the number of subpopulations granted a non-quantifiable additional benefit increased in recent years which correlates with increased numbers of OD assessments. OD are by law granted at least a non-quantifiable additional benefit. In 8 years, only 4 subgroup assessments resulted in less benefit than the comparative therapy. Since 2011, benefit assessments have become a key component in pricing of new drugs in Germany. To receive an additional benefit positively influencing price negotiations, the evidence must be generated in accordance with G-BA/IQWiG regulations. Our analysis shows that most subpopulations are not granted an additional benefit, indicating that the provided evidence did not meet the required criteria.

The treatment landscape in ES/LA-NSCLC is rapidly evolving with new treatment options for patients including immunotherapy (IO) and targeted therapies. Since any new treatment preparing for reimbursement may need to demonstrate relative treatment efficacy and safety against new-to-market comparator(s), we conducted a forward-looking NMA feasibility study to gain insight into considerations when developing future indirect treatment comparisons for ongoing trials with results currently unavailable in ES/LA-NSCLC. Using systematic literature review (SLR) methodology, we reviewed SLRs/NMAs in ES/LA-NSCLC (stage IB−III) to identify currently-available curative treatment options. We supplemented this with a search via clinicaltrials.gov for ongoing trials. We extracted key information across relevant studies and conducted an NMA feasibility study, with separate networks in resectable and unresectable ES/LA-NSCLC. New IO and targeted therapies are currently under investigation in both resectable and unresectable disease. There are however limited options available to comparatively analyze those treatments targeting actionable alterations due to differences in patient populations and/or choice of comparator(s). For outcome selection in NMAs, the most commonly-reported endpoints in resectable ES/LA-NSCLC include major pathological response rate, disease-free survival and overall survival. A future NMA in ES/LA-NSCLC should also consider an analysis by drug-class to maximize the number of trials available for evaluation, and by specific type of treatment to guide reimbursement decision-making, although the latter approach causes some trials to disconnect from the network. Based on the primary trial completion dates reported on clinicaltrials.gov, in resectable NSCLC there will be a gradual release of data from 2020—2023, steadily increasing options for analysis over time. The treatment landscape for ES/LA-NSCLC is complex with limited NMAs available. Careful consideration is needed on how to maximize the connections of newer treatments within an NMA, while maintaining the validity of the analysis to guide decision-making.

Advanced therapy medicinal products (ATMPs) are based on viable cells or tissues and show a complex mode of action. European approval relies on specific regulations and involves the European Medicines Agency’s Committee for Advanced Therapies. Here, the evaluation of German HTA authorities (Federal Joint Committee, G-BA) regarding the quality of evidence and possible options to improve the data basis for ATMPs (e.g. via evaluation of registry data) will be discussed. A list of all centrally or regionally approved ATMPs was retrieved from the Paul-Ehrlich-Institute and the EMA. Information regarding the assessment of the added medical benefit according to AMNOG, the evidence basis and the outcome of the assessment was collected from the website of G-BA. To date 21 ATMPs have been approved in Germany (eight gene therapeutics, two somatic cell therapeutics, one tumor vaccine, ten tissue engineered products). Five gene therapeutics and both somatic cell therapeutics were obliged to AMNOG assessments so far. None of the assessments revealed a quantifiable added benefit. ATMPs approved for Orphan Diseases reached a nonquantifiable added benefit due to specific regulations for Orphan Drugs in Germany. Three benefit assessments presented data of randomized controlled trials whereas four assessments are based on single arm studies. In three cases data from post authorization studies (e.g. registry data) were demanded for follow up assessment by G-BA. Approval studies in ATMPs often show limited evidence due to the small number of patients. RCTs have been conducted for some ATMPs but feasibility strongly depends on the size of patient population. For single arm studies, G-BA requested to submit additional evidence (RCT or registry data) to a later date. German authorities are currently preparing a draft law to make additional data acquisition (e.g. registries) legally binding if the approval data are insufficient for the benefit assessment according to AMNOG.

In clinical trials surrogate endpoints are oftentimes used as substitute for patient-relevant endpoints. However, in the early benefit assessment of pharmaceuticals in Germany and in order be able to provide patient-relevant evidence a validation of surrogate endpoints is critical. The aim of this study was to assess the utilization, methodology and acceptance of surrogate validations in AMNOG benefit dossiers. Dossiers for benefit assessment were retrieved from the homepage of the Federal Joint Committee (G-BA). It was assessed whether the pharmaceutical companies performed a surrogate validation and if a surrogate parameter was considered for benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) and later accepted by the G-BA. In total 397 AMNOG dossiers were analyzed. In 105 (26.4%) dossiers a surrogate validation was presented. Of all attempted surrogate validations, 36 (34.3%) were rejected and 51 (48.6%) were not further commented (e. g. due to limitations in study design). In total, 18 validations (17.1% of all attempted validations) were accepted as valid. Validations were only accepted in infectious indications (94.4%) and oncological diseases (5.6%). Accepted endpoints were (sustained) virologic response for reduced risk for hepatocellular carcinoma as well as AIDS-defining diseases/death, CD4 cell count for AIDS-defining diseases/death and disease-free survival (DFS) for overall survival. In most cases the pharmaceutical companies referred to prior benefit assessments. Only for DFS a comprehensive surrogate validation including systematic literature search and statistical calculations was performed. Even though the methodological demands by IQWiG are high, in one quarter of submitted dossiers pharmaceutical companies attempted to validate a surrogate parameter as a patient-relevant endpoint. Overall, the acceptance of validations is possible; however, the success rate is small (17%). Most accepted surrogate validations were within infectious diseases and their validation referred to prior benefit assessments.

For benefit assessment of new pharmaceuticals in Germany, the Federal Joint Committee (FJC) defines appropriate comparators of four categories: one specific drug, a list of drugs, patient individualized therapy, and best supportive care (BSC). The aim of the study was to evaluate factors influencing the outcome of the assessments in oncological indications with a negative benefit rating in addition to complying with the assigned appropriate comparator. Information on appropriate comparators and benefit assessment were retrieved from a databank containing information on all AMNOG dossiers in the field of oncology. Dossiers were analyzed for data on indication, target population, line of therapy, appropriate comparator, and added Benefit. 109 dossiers including 215 separate (sub) labels were identified in the field of oncology between 2011 and 2018. The appropriate comparators assigned by FJC were distributed as follows: 51 (24%) specific drug, 88 (40%) list of drugs, 35 (17%) patient individualized therapy, and 41 (20%) BSC. More than half of these benefit assessments resulted in no added benefit despite compliance with the FJC-assigned comparator in the dossier. Factors leading to a negative benefit rating in these assessments were identified by analyzing the reasons for the FJC decision. Four major reasons for negative benefit ratings can be determined: low quality of evidence, lack of patient relevant study endpoints, discrepancy between label and study population and insufficient study design. The appropriate comparator assigned by FJC significantly influences the outcome of AMNOG benefit assessment. Even if a comparison against the appropriate comparator is performed in the AMNOG dossier, further factors play an important role for a positive outcome of the assessment, comprising the quality of evidence, the patient relevance of study endpoints, the alignment between study and label population as well as and the quality and validity of the study.

In recent years HrQoL has become an important component of benefit assessments within the AMNOG process. The aim of the study was to analyse the spectrum of instruments and statistical methods of HrQoL within submitted AMNOG dossiers as well as to identify key factors for the acceptance by G-BA/IQWiG. A database containing all AMNOG dossiers conclusively assessed by G-BA until the end of April 2019 was searched for multiple myeloma, melanoma and breast cancer drugs. Relevant dossiers were screened regarding the operationalization of HrQoL, methodological comments and the granted added benefit. 42 dossiers (multiple myeloma n=13, melanoma n=24, breast cancer n=12) with 49 subpopulations were identified. For 45 subpopulations HrQoL was reported, applying nine different instruments. The validated cancer-specific questionnaire EORTC QLQ-C30 was most prevalent, supported by indication-specific questionnaires (e. g. EORTC QLQ-My20, FACT-M, EORTC QLQ-BR23). Predominantly, time-to-event responder analyses (33%) were performed and the mean difference between treatment arms (32%; e. g. MMRM analyses) was calculated. HrQoL data were methodologically accepted by G-BA in 28 subpopulations. An additional benefit based on HrQoL was granted in 11 cases. Major reasons for non-acceptance were formal issues (e. g. inappropriate comparator), limitations of the instrument (e. g. missing validation) or shortcomings regarding the analyses (e. g. statistical methodology). Crucial for the acceptance of HrQoL data in AMNOG benefit assessments is that generic and indication-specific instruments are validated. Another key factor is the choice of an adequate statistical approach, such as time-to-event responder analyses. In case a validated minimal important difference is not available, G-BA/IQWiG refers to MMRM analyses (combined with Hedges'g) to assess the clinical benefit. However, if the formal criteria postulated by G-BA (e. g. appropriate comparator, adequate indirect comparison) are not met, even methodologically adequate HrQoL data are not considered for benefit assessment.

Since the enactment of the AMNOG in 2011, pharmaceutical companies are required to prove the benefit of newly approved drugs including new area of application compared to the standard of care in Germany. This benefit is evaluated by G-BA/IQWiG. The aim of this study was to investigate the effect of the benefit assessment on the negotiated reimbursement price with the GKV-SV. A database containing all evaluated AMNOG dossiers from 2011 until the end of April 2019 was analysed. Information on G-BA assessments and decisions on added benefit were extracted. Prices at the time of launch including alterations were obtained from Lauer-Taxe®. Benefit assessments were qualitatively and quantitatively analysed for predictors of assessment outcome, major pitfalls and impact on price negotiations. In total, 391 concluded benefit assessments were published including 763 subpopulations, mostly in the field of oncology (247), metabolic (167) and infectious diseases (134). Approximately 37% of the assessed subpopulations received an added benefit whereas 59% received no added benefit. Other outcomes were a lesser benefit or discontinued procedures. In the subsequent price negotiations, a proven added benefit allowed the manufacturer to negotiate higher reimbursement prices. In contrast, for drugs with no added benefit the appropriate comparator determines the upper limit for the negotiated price. Since 2011 benefit assessments have become a key component in pricing of new drugs in Germany. It is important to be in line with G-BA/IQWiG regulations as well as to provide sufficient evidence to receive an added benefit, which in turn positively influences price negations. No added benefit leads to a lower price and in worst case, results in market withdrawal.

Within the German Act on the Reform of the Market for Medical Products (AMNOG) process the medical benefit is evaluated against an appropriate comparator, determined by the G-BA. Study aim was to assess the change in appropriate comparators for Multiple Myeloma (MM) over time. A database containing all AMNOG dossiers published until end of April 2019 was screened for MM dossiers; information on appropriate comparators and added benefit was extracted for relevant dossiers. Twelve relevant assessments were identified including 15 subpopulations. Of these, seven were orphan drugs, where the added benefit is set by law and no appropriate comparator is defined. For the remaining assessments, G-BA assigned appropriate comparators depending on treatment line and suitability for targeted therapy treatment. For newly diagnosed patients, Daratumumab was the only assessed drug. G-BA initially assigned the appropriate comparators Bortezomib+Melphalan+Prednisone and Thalidomide+Melphalan+Prednisone. During the assessment process G-BA subsequently updated the list of appropriate comparators repeatedly, resulting in combination therapy at the discretion of the physician taking recommendations of clinical guidelines into account. For patients with at least one prior therapy G-BA assigned the appropriate comparators Bortezomib, Bortezomib+pegylated liposomal Doxorubicin, Bortezomib+Dexamethasone and Lenalidomide+Dexamethasone for Elotuzumab. G-BA assigned a minor added benefit against Lenalidomide+Dexamethasone. As a result, G-BA replaced Bortezomib monotherapy by Elotuzumab+Lenalidomide+Dexamethasone in the list of appropriate comparators for Carfilzomib and Daratumumab in 2017. Although Carfilzomib, Daratumumab and Ixazomib were previously granted an added benefit as orphan drug, they weren’t considered as appropriate comparators. For patients with at least two prior therapies, patient individual therapy at the discretion of the physician was defined as appropriate comparator for Pomalidomide in 2015. Contemporaneously, G-BA aligned the initially defined appropriate comparator for Daratumumab. For MM, assigned appropriate comparators by G-BA change quickly as G-BA takes recently published resolutions, current developments and clinical guidelines into consideration.