The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.

INTRODUCTION: Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles. Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL). Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA. METHOD: A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence. CONCLUSIONS: Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of efficacy, safety and QoL when compared with available ASMs.

EMA Review of Daratumumab for the Treatment of Adult Patients with Multiple Myeloma.

On May 20, 2016, a conditional marketing authorization valid through the European Union (EU) was issued for daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who had demonstrated disease progression on the last therapy. The review of daratumumab was conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, especially from the point of view of therapeutic innovation.Daratumumab monotherapy achieved an overall response rate of 29.2% (95% confidence interval [CI] 20.8 to 38.9) in patients with multiple myeloma who had received at least three prior lines of therapy (including a PI and IMiD) or were double refractory to a PI and an IMiD (Study MMY2002). In patients with multiple myeloma relapsed from or refractory to two or more different prior therapies, including IMiDs (e.g., thalidomide, lenalidomide) and PI, an overall response was observed in 15 patients (35.7%, 95% CI: 21.6 to 52.0) (Study GEN501).On April 28, 2017, the therapeutic indication was extended to include the use of daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. This was based on two subsequent phase III studies of daratumumab in combination with lenalidomide/low-dose dexamethasone (MMY3003) and bortezomib/low dose dexamethasone (MMY3004).The most common side effects (grade 3-4) associated with daratumumab included neutropenia (37%), thrombocytopenia (23%), anemia (16%), pneumonia (10%), lymphopenia (8%), infusion-related reactions (6%), upper respiratory tract infection (5%), and fatigue (5%).The objective of this study was to summarize the scientific review done by the CHMP of the application leading to regulatory approval in the EU. The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: A conditional Marketing authorization was issued in the European Union for daratumamb as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, based on the response rate data from two single-agent studies. Darzalex, a novel monoclonal antibody targeted against CD38, demonstrated a durable response rate in a heavily pre-treated population with limited treatment options based on the response rate data from two single-agent studies. The addition of daratumumab to lenalidomide and dexamethasone (study MMY3003), or bortezomib and dexamethasone (MMY3004), demonstrated a positive effect on progression-free survival in patients with multiple myeloma who had received at least one prior therapy. Following submission of the controlled data of the MMY3003 and MMY3004 studies, the efficacy and safety of daratumumab was confirmed and the approval of daratumumab was converted to standard approval.

The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy.

On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression-free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0.69; 95% confidence interval, 0.57-0.83; one-sided log-rank p value < .0001). The most frequently observed toxicity (grade ≥3, treatment arm vs. control arm) in the phase III trial included neutropenia (29.6% vs. 26.5%), anemia (17.9% vs. 17.7%), thrombocytopenia (16.8% vs. 12.3%), pneumonia (12.5% vs. 10.5%), fatigue (7.7% vs. 6.4%), hypertension (4.6% vs. 2.1%), diarrhea (3.8% vs. 4.1%), and respiratory tract infection (4.1% vs. 2.1%).The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the European Union. The scientific review concluded that the gain in PFS of 8.7 months observed with the combination of CRd was considered clinically meaningful and was supported by a clear trend in overall survival benefit, although the data were not mature. The delay in disease progression appeared superior to available alternatives in the setting of relapsed MM at the time of the marketing authorization of carfilzomib. Therefore, given the overall accepted safety profile, which was considered manageable in the current context, the benefit risk for CRd was considered positive. IMPLICATIONS FOR PRACTICE: Carfilzomib (Kyprolis) was approved in the European Union in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The addition of carfilzomib to lenalidomide and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression-free survival compared with lenalidomide and dexamethasone, which was supported by a clear trend in overall survival benefit, although the data were not mature. At the time of the marketing authorization of carfilzomib, the delay in disease progression appeared superior to available alternatives in the setting of relapsed multiple myeloma. In terms of safety, the overall accepted safety profile was considered manageable.

The European medicines agency review of pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use.

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1-21 of repeated 28-day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open-label study (CC-4047-MM-003) in which pomalidomide plus low-dose dexamethasone therapy (POM+LoDEX) was compared with high-dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent-to-treat population, median progression-free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0-20.1) in the POM+LoDEX group versus 8.0 weeks (95% CI: 7.0-9.0) in the HiDEX group (log-rank p value <.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI: 0.37-0.74]). The most commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use.

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph⁺) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph⁺ leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study).

BACKGROUND: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. OBJECTIVE: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. METHODS: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. RESULTS: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade ≤ 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. CONCLUSIONS: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk.

Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis.

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.