Clinical Evidence Informing Treatment Guidelines on Repurposed Drugs for Hospitalized Patients During the Early COVID-19 Pandemic: Corticosteroids, Anticoagulants, (Hydroxy)chloroquine.

INTRODUCTION: In early 2020, the coronavirus disease 2019 (COVID-19) pandemic spread worldwide, overwhelming hospitals with severely ill patients and posing the urgent need for clinical evidence to guide patient care. First treatment options available were repurposed drugs to fight inflammation, coagulopathy, and viral replication. A vast number of clinical studies were launched globally to test their efficacy and safety. Our analysis describes the development of global evidence on repurposed drugs, in particular corticosteroids, anticoagulants, and (hydroxy)chloroquine in hospitalized COVID-19 patients based on different study types. We track the incorporation of clinical data in international and national treatment guidelines and identify factors that characterize studies and analyses with the greatest impact on treatment recommendations. METHODS: A literature search in MEDLINE was conducted to assess the clinical evidence on treatment with corticosteroids, anticoagulants, and (hydroxy)chloroquine in hospitalized COVID-19 patients during the first year of the pandemic. Adoption of the evidence from this clinical data in treatment guidelines of the World Health Organization (WHO), Germany, and United States (US) was evaluated over time. RESULTS: We identified 106 studies on corticosteroids, 141 studies on anticoagulants, and 115 studies on (hydroxy)chloroquine. Most studies were retrospective cohort studies; some were randomized clinical trials (RCTs), and a few were platform trials. These studies were compared to studies directly and indirectly referred to in WHO (7 versions), German (5 versions), and US (21 versions) guidelines. We found that initially large, well-adjusted, mainly retrospective cohort studies and ultimately large platform trials or coordinated meta-analyses of RCTs provided best available clinical evidence supporting treatment recommendations. DISCUSSION: Particularly early in the pandemic, evidence for the efficacy and safety of repurposed drugs was of low quality, since time and scientific rigor seemed to be competing factors. Pandemic preparedness, coordinated efforts, and combined analyses were crucial to generating timely and robust clinical evidence that informed national and international treatment guidelines on corticosteroids, anticoagulants, and (hydroxy)chloroquine. Multi-arm platform trials with master protocols and coordinated meta-analyses proved particularly successful, with researchers joining forces to answer the most pressing questions as quickly as possible.

Assessment of Metastatic Colorectal Cancer Patients' Preferences for Biologic Treatments in Germany Using a Discrete Choice Experiment.

BACKGROUND: Current treatment regimens for metastatic colorectal cancer (mCRC) include biologics such as epidermal growth factor receptor and vascular endothelial growth factor inhibitors, which have specific side-effect profiles. There is a lack of information on mCRC patient preference in Germany regarding biologics in combination with chemotherapy. This study aims to identify German mCRC patients' preference for these treatments PATIENTS AND METHODS: This was a multicenter cross-sectional discrete choice experiment (DCE). Data were collected using electronic case report forms and structured phone interviews. DCE attributes were related to efficacy, side effects, frequency of administration, and distance to treating physicians' practice. Patients' characteristics and choices were analyzed descriptively. Choice data was modeled using a random utility maximization framework. RESULTS: All attributes, except distance to treating physicians' practice, had a significant impact on patients' decision. The most important driver of patients' treatment decision was overall survival, followed by safety-related attributes and frequency of administration. Overall survival was the main driver in all subgroups analyzed. Risk of severe skin toxicities was more important to women, than men. In patients with prior experience of side effects, the risk of side effects accounted for 45% of a patient's decision, compared to 35% in those without prior experience. CONCLUSION: Overall survival remains the most important driver in mCRC patients' preferences for biologic treatment in combination with chemotherapy. Attributes related to safety were less important to patients when considering their treatment decision. These results indicate that understanding patient preferences may lead to increased treatment compliance.

Management of Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Novel Combination Therapies in Routine Clinical Practice in Germany.

INTRODUCTION: Multiple myeloma remains an incurable plasma cell malignancy which, despite improvements in overall survival over the last decade, is characterized by recurrent relapse and is associated with a poor prognosis. This study investigates the use of novel agents in current real-world clinical practice in the management of relapsed and/or refractory multiple myeloma (RRMM) in Germany over different lines of therapy. METHODS: A retrospective chart review was conducted for patients with RRMM treated at multiple centers across Germany between May 2017 and June 2018. Variables included patient demographics and clinical characteristics, current and prior treatment regimens, treatment response, cytogenetic abnormalities, testing methodology, and resource utilization. RESULTS: Data were analyzed from 484 patients from 47 centers across Germany (60% male; average age over 70 years; majority at International Staging System stage 2 or 3). Bone pain and anemia were the most common symptoms at diagnosis, with 63% of patients receiving osteoprotective drugs. Approximately one-third (32%) of patients had received autologous stem cell transplantation and approximately 70% underwent cytogenetic testing. After failure to respond to first-line treatment, most patients received regimens containing second-generation proteasome inhibitors and monoclonal antibodies, with overall response rates greater than 90% in second line (95% and 90% for daratumumab-based and carfilzomib-based therapies, respectively). The incidence of unplanned hospitalization ranged from 11% to 16% across all treatment lines, with longer hospital stays required for treatment administration than for treatment-related toxicity. CONCLUSION: Although treatment patterns for RRMM in Germany differ by line of therapy and are adapted as disease progresses, patients mostly receive combination regimens with carfilzomib or daratumumab in second and third lines, with high overall response rates achieved in all lines.

Treatment patterns in adults with immune thrombocytopenia before, during and after use of thrombopoietin receptor agonists: a longitudinal prescription database study from Germany.

OBJECTIVE: To assess real-world treatment patterns in patients with immune thrombocytopenia (ITP) who received thrombopoietin receptor agonists (TPO-RAs) in Germany. METHODS: This was a longitudinal, retrospective study using anonymized patient-level data (IQVIA healthcare prescription database, covering 82% of German statutory prescriptions). Eligible patients (aged ≥18 years) had received ≥1 TPO-RA prescription (romiplostim/eltrombopag) from July 2016 to June 2019 (treatment duration ≥30 days). ITP medication use was assessed for 18 months prior to, during and for ≥6 months after TPO-RA treatment. RESULTS: A total of 3553 patients (median age 64 years) were included. Median persistence on TPO-RAs was 12 months (range 1-34). In the periods before, during and after TPO-RA treatment, oral corticosteroids were the most commonly used therapy (64.4%, 43.4% and 36.1% of patients, respectively); median cumulative doses across each period were 2521.9, 2000.0 and 2277.8 mg. The median total duration of corticosteroid use before, during and after TPO-RA therapy was 15, 18 and 32 weeks, respectively. The total median cumulative corticosteroid dose was 6799.7 mg. CONCLUSION: We identified a potential overuse of corticosteroids in patients with ITP in Germany. Earlier use of TPO-RA therapy after a short course of corticosteroids could avoid side effects associated with long-term use.

Healthcare resource utilization and costs among patients with relapsed and/or refractory multiple myeloma treated with proteasome inhibitors in real-world clinical practice in Germany.

AIMS: To assess the real-world healthcare resource utilization (HRU) and costs associated with different proteasome inhibitors (PIs) for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM) in Germany. METHODS: We conducted a retrospective medical chart review of treatment patterns, outcomes, and HRU for patients with RRMM treated with bortezomib, carfilzomib, or ixazomib in second- or third-line (2L or 3L) therapy in Germany. Data were collected between 1 January 2017 and 30 June 2017. Costs were calculated based on drug prices and unit costs in Germany. RESULTS: Physicians provided data on 302 patients. Mean monthly total direct costs per patient receiving PI-based therapy were €7,925 and €10,693 for 2L and 3L, respectively, of which approximately 90% was anti-myeloma drug costs. Overall, the highest costs were associated with patients receiving 3L therapy. Regardless of treatment line, costs were higher for patients who had received a stem cell transplant (SCT) in a previous treatment line than for those who had not; the data suggest that this reflects the use of triplet regimens following a SCT. Patients with a complete response (CR) experienced no unplanned hospitalizations during the study period, whereas patients with progressive disease experienced the highest number of unplanned and planned hospitalizations. In 2L therapy, the highest proportion of patients with a CR was observed in those receiving carfilzomib (12% carfilzomib; 4% bortezomib; 0% ixazomib). LIMITATIONS: Patients with missing or incomplete follow-up data were included in the study and were accounted for using monthly cost estimates. CONCLUSIONS: Anti-myeloma drugs were the main contributor to total HRU costs associated with RRMM in Germany. Improved treatment response was associated with lower costs and reduced hospitalizations.

Real-World Evaluation of Health-Related Quality of Life in Patients With Multiple Myeloma From Germany.

INTRODUCTION: Real-world health-related quality of life (HRQoL) data in patients with multiple myeloma (MM) are scarce. Here, we report HRQoL by line of therapy in adults with MM in clinical practice in Germany. PATIENTS AND METHODS: This descriptive, multicenter, observational study included patients receiving all lines of MM therapy or best supportive care (BSC). The primary endpoint was HRQoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 global health status [GHS]) by line of therapy; secondary endpoints included patient/disease characteristics and treatments by line of therapy. RESULTS: Overall, 490 patients were included from 40 centers (mean age 71.0 years, 62% male); 59% had an Eastern Cooperative Oncology Group performance status of 0 or 1% and 35% had undergone stem cell transplantation. First-line therapy included proteasome inhibitors in 81% of patients; subsequent treatments varied. The mean overall GHS/QoL score was 49.5; HRQoL decreased by therapy line (P < .001) and was lowest in those receiving BSC. Functional and symptoms scores worsened with increasing treatment line. The largest HRQoL reduction occurred when patients switched from active treatment to BSC. Compared with those on active treatment, patients in a treatment-free interval generally had better GHS/QoL, functioning, and fewer symptoms (P < .05). GHS/QoL also generally improved and symptoms lessened in those with ≥1 versus <1 year of ongoing treatment (P < .05). Worse GHS/QoL was observed in patients with ≥1 grade 3/4 toxicity versus those with none (P = .012). Eastern Cooperative Oncology Group performance status was the strongest determinant of HRQoL. CONCLUSIONS: This real-world study shows that patients with MM have impaired HRQoL and that HRQoL deteriorates with increasing lines of therapy.

Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany.

INTRODUCTION: Real-world data reflects treatments and outcomes in clinical practice in contrast with controlled clinical trials. This study evaluates real-life multiple myeloma (MM) patients receiving proteasome inhibitor (PI)-based treatments in the second or third therapy line in 2017 in Germany. METHODS: This is a retrospective chart review on adult relapsed/refractory MM patients treated with ≥1 dose of a PI-based regimen in either the second or the third line of therapy. Participating physicians had ≥3 years of clinical experience in treating symptomatic MM patients and used PI according to the label. RESULTS: Distinct patient profiles for each PI-based regimen emerged. Younger, fitter, transplant-eligible patients received novel PI triplets such as carfilzomib in combination with lenalidomide and dexamethasone (KRd) or IRd. Patients receiving lenalidomide in first-line therapy mostly received lenalidomide-free regimens in second-line therapy. In high-risk patients, no clear treatment patterns could be ascertained. The complete response rates were highest with KRd (13.0%), followed by carfilzomib in combination with dexamethasone (Kd) (5.7%) and bortezomib (4.8%). The very good partial response rates were highest with IRd (76.9%), followed by KRd (53.7%), Kd (25.7%), and bortezomib (20.5%). None of the KRd- or IRd-treated patients responded below a partial response. DISCUSSION/CONCLUSION: Clear patient profiles for each PI type were observed. In second-line therapy, younger, fitter, transplant-eligible patients received novel-PI-based triplets, e.g., KRd or IRd. Patients treated with lenalidomide in first-line therapy mostly received lenalidomide-sparing regimens in second-line therapy. In high-risk patients no clear treatment patterns could be ascertained due to the limited sample size.

Health-related quality of life of carfilzomib- and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma, based on German benefit assessment data.

BACKGROUND: Carfilzomib and daratumumab are licensed in relapsed/refractory multiple myeloma (RRMM), but no head-to-head trials have been conducted. METHODS: We used data from dossiers prepared for the German Federal Joint Committee based on two phase III randomized trials of carfilzomib-based therapies (ASPIRE, ENDEAVOR) and two of daratumumab-based therapies (POLLUX, CASTOR) to conduct a descriptive assessment of health-related quality of life (HRQoL). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer 30-item HRQoL Questionnaire, with hazard ratios calculated for carfilzomib- and daratumumab-based therapy versus comparators for time to HRQoL deterioration of ≥ 10 points. Analyses were also conducted on data from the EORTC 20-item myeloma-specific questionnaire, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, and the visual analog scale of the EuroQoL 5-dimension, 5-level questionnaire, where results for these instruments were available. As the designs and patient population of the four trials were similar but not identical, the analysis included only indirect, descriptive comparisons. RESULTS: Compared with lenalidomide/dexamethasone, median time to deterioration in global health status/QoL was longer for carfilzomib-based therapy versus control, but similar for daratumumab-based therapy and control. Compared with bortezomib/dexamethasone, time to deterioration was significantly longer for carfilzomib-based therapy versus control for global health status/QoL and numerous functional and symptom subscales. HRQoL measurement is feasible in large RRMM populations. CONCLUSION: Descriptive assessment of HRQoL data suggests potential benefits for carfilzomib-based over daratumumab-based therapy.

Relevance of indirect comparisons in the German early benefit assessment and in comparison to HTA processes in England, France and Scotland.

Early benefit assessment in Germany under the legislative framework of AMNOG (Arzneimittelmarktneuordnungsgesetz) requires direct comparisons of the new drug with appropriate comparators determined by the Federal Joint Committee (G-BA). In case no head-to-head studies are available for direct comparisons, the submission of indirect comparisons is permitted to assess the additional benefit of the new drug. However, the Institute for Quality and Efficiency in Health Care (IQWiG) states a clear preference for head-to-head trials and defines strict requirements for indirect comparisons to be considered in the benefit assessment. Similar requirements also exist in other countries with mandatory health technology assessments (HTA), like France, England and Scotland. Our evaluation shows that a comparison of the different HTA regarding indirect comparisons is difficult. Overall, external preconditions and methodological requirements are demanding and hardly to fulfill by pharmaceutical companies for implementation of indirect comparisons in early benefit assessment. The determination of the appropriate comparators, outcomes, patient subgroups and study choice are the main target within indirect comparisons for the future. To compare and assess submitted indirect comparisons it would be desirable that a transparent process was established, including the mandatory publication of HTA-reports within Europe and international guidelines, accepted by a large number of HTA-agencies.