***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Importance Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration ( FDA ) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit . Confirmatory trials are then required to determine whether these effects translate to clinical improvements . Objective To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval . Design and Setting Publicly available FDA documents were review ed to identify the preapproval trials leading to accelerated approval between 2009 and 2013 . Information on the status and findings of required confirmatory studies was extracted from the FDA ’s data base of postmarketing requirements and commitments , Clinical Trials.gov , and matched peer- review ed publications . Follow-up ended on April 7 , 2017 . Exposures Granting of accelerated approval . Main Outcomes and Measures Characteristics of preapproval and confirmatory studies were compared in terms of study design features ( r and omization , blinding , comparator , primary end point ) . Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized . Results The FDA granted accelerated approval to 22 drugs for 24 indications ( 19 for indications involving cancer treatment ) between 2009 and 2013 . A total of 30 preapproval studies supported the 24 indications . The  median number of participants enrolled in the preapproval studies was 132 ( interquartile range , 89 - 224 ) . Eight studies ( 27 % ) included fewer than 100 participants and 20 ( 67 % ) included fewer than 200 . At a minimum 3 years of follow-up , 19 of 38 ( 50 % ) required confirmatory studies were completed , including 18 published reports . Twenty-five of the 38 ( 66 % ) examined clinical efficacy , 7 ( 18 % ) evaluated longer follow-up , and 6 ( 16 % ) focused on safety The proportion of studies with r and omized design s did not differ before and after accelerated approval ( 12/30 [ 40 % ] vs 10/18 [ 56 % ] ; difference , 16 % ; 95 % CI , −15 % to 46 % ; P = .31 ) . Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications ( 42 % ) on the basis of trials that evaluated surrogate measures . Among the 14 of 24 indications ( 58 % ) that had not yet completed all requirements , at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 ( 8 % ) , were terminated in 2 ( 8 % ) , and were delayed by more than 1 year in 3 ( 13 % ) . Studies were progressing according to target timelines for the remaining 7 indications ( 29 % ) . Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior . Conclusions and Relevance Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009 - 2013 , efficacy was often confirmed in postapproval trials a minimum of 3 years after approval , although confirmatory trials and preapproval trials had similar design elements , including reliance on surrogate measures as outcomes Background In the primary analysis of the ERIVANCE BCC trial , vismodegib , the first US Food and Drug Administration – approved Hedgehog pathway inhibitor , showed objective response rates ( ORRs ) by independent review facility ( IRF ) of 30 % and 43 % in metastatic basal cell carcinoma ( mBCC ) and locally advanced BCC ( laBCC ) , respectively . ORRs by investigator review were 45 % ( mBCC ) and 60 % ( laBCC ) . Herein , we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC . Methods One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity . The primary end point was IRF-assessed ORR . Secondary end points included ORR , duration of response ( DOR ) , progression-free survival , overall survival ( OS ) , and safety . Results At data cutoff ( 39 months after completion of accrual ) , 8 patients were receiving the study drug ( 69 patients in survival follow-up ) . Investigator-assessed ORR was 48.5 % in the mBCC group ( all partial responses ) and 60.3 % in the laBCC group ( 20 patients had complete response and 18 patients had partial response ) . ORRs were comparable across patient subgroups , including aggressive histologic subtypes ( eg , infiltrative BCC ) . Median DOR was 14.8 months ( mBCC ) and 26.2 months ( laBCC ) . Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort . Adverse events remained consistent with clinical experience . Thirty-three deaths ( 31.7 % ) were reported ; none were related to vismodegib . Conclusions This long-term up date of the ERIVANCE BCC trial demonstrated durability of response , efficacy across patient subgroups , and manageable long-term safety of vismodegib in patients with advanced BCC.Trial registration This study was registered prospect ively with Clinical trials.gov , number NCT00833417 on January 30 , 2009 Background The European Society for Medical Oncology ( ESMO ) recently released a magnitude of clinical benefit scale ( ESMO-MCBS ) for systemic therapies for solid cancers . Here , we evaluate contemporary r and omized controlled trials ( RCTs ) against the proposed ESMO thresholds for meaningful clinical benefit . Methods RCTs evaluating  systemic therapy for breast cancer , nonsmall cell lung cancer ( NSCLC ) , colorectal cancer ( CRC ) , and pancreatic cancer published 2011 - 2015 were review ed . Data were abstract ed regarding trial characteristics and outcomes , and these were applied to the ESMO-MCBS . We also determined whether RCTs were design ed to detect an effect that would meet clinical benefit as defined by the ESMO-MCBS . Results About 277 eligible RCTs were included ( 40 % breast , 31 % NSCLC , 22 % CRC , 6 % pancreas ) . Median sample size was 532 and 83 % were funded by industry . Among all 277 RCTs , the experimental therapy was statistically superior to the control arm in 138 ( 50 % ) trials : results of only 31 % ( 43/138 ) of these trials met the ESMO-MCBS clinical benefit threshold . RCTs with curative intent were more likely to meet clinical ly meaningful thresholds than those with palliative intent [ 61 % ( 19/31 ) versus 22 % ( 24/107 ) , P < 0.001 ] . Among the 226 RCTs for which the ESMO-MCBS could be applied , 31 % ( 70/226 ) were design ed to detect an effect size that could meet ESMO-MCBS thresholds . Conclusion Less than one-third of contemporary RCTs with statistically significant results meet ESMO thresholds for meaningful clinical benefit , and this represents only 15 % of all published trials . Investigators , funding agencies , regulatory agencies , and industry should adopt more stringent thresholds for meaningful benefit in the design of future RCTs PURPOSE Systemic anaplastic large-cell lymphoma ( ALCL ) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30 . The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells . A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL . PATIENTS AND METHODS Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion . The primary end point of the study was overall objective response rate as assessed by independent central review . RESULTS Of 58 patients treated in the study , 50 patients ( 86 % ) achieved an objective response , 33 patients ( 57 % ) achieved a complete remission ( CR ) , and 17 patients ( 29 % ) achieved a partial remission . The median duration s of overall response and CR were 12.6 and 13.2 months , respectively . Grade 3 or 4 adverse events in ≥ 10 % of patients were neutropenia ( 21 % ) , thrombocytopenia ( 14 % ) , and peripheral sensory neuropathy ( 12 % ) . CONCLUSION Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL . Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy Introduction The efficacy of pharmaceuticals is most often demonstrated by r and omised controlled trials ( RCTs ) ; however , in some cases , regulatory applications lack RCT evidence . Objective To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency ( EMA ) and the US Food and Drug Administration ( FDA ) . Methods Drug approval data were downloaded from the EMA website and the ‘ Drugs@ FDA ’ data base for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014 . The details of eligible applications were extracted , including the therapeutic area , type of approval and review period . Results Over the period of the study , 76 unique indications were granted without RCT results ( 44 by the EMA and 60 by the FDA ) , demonstrating that a substantial number of treatments reach the market without undergoing an RCT . The majority was for haematological malignancies ( 34 ) , with the next most common areas being oncology ( 15 ) and metabolic conditions ( 15 ) . Of the applications made to both agencies with a comparable data package , the FDA granted more approvals ( 43/44 vs 35/44 ) and took less time to review products ( 8.7 vs 15.5 months ) . Products reached the market first in the USA in 30 of 34 cases ( mean 13.1 months ) due to companies making FDA su bmi ssion before EMA su bmi ssions and faster FDA review time . Discussion Despite the frequency with which approvals are granted without RCT results , there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate . We recommend a more open debate on the role of marketing authorisations granted without RCT results , and the development of guidelines on what constitutes an acceptable data package for regulators Bosutinib , a dual Src/Abl tyrosine kinase inhibitor ( TKI ) , has shown potent activity against  chronic myeloid leukemia ( CML ) . This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib . The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and /or nilotinib , with a median follow-up of 28.5 months . In this sub population , major cytogenetic response was attained by 32 % of patients ; complete cytogenetic response was attained by 24 % , including in one of 3 patients treated with 3 prior TKIs . Complete hematologic response was achieved/maintained in 73 % of patients . On-treatment transformation to accelerated/blast phase occurred in 5 patients . At 2 years , Kaplan-Meier-estimated progression-free survival was 73 % and estimated overall survival was 83 % . Responses were seen across Bcr-Abl mutations , including those associated with dasatinib and nilotinib resistance , except T315I . Bosutinib had an acceptable safety profile ; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash . Grade 3/4 nonhematologic adverse events ( > 2 % of patients ) included diarrhea ( 8 % ) and rash ( 4 % ) . Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs . This trial was registered at www . clinical trials.gov as NCT00261846 BACKGROUND Phosphatidylinositol-3-kinase delta ( PI3Kδ ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes . In a phase 1 study , idelalisib , an orally active selective PI3Kδ inhibitor , showed antitumor activity in patients with previously treated indolent non-Hodgkin 's lymphomas . METHODS In this single-group , open-label , phase 2 study , 125 patients with indolent non-Hodgkin 's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib , 150 mg twice daily , until the disease progressed or the patient withdrew from the study . The primary end point was the overall rate of response ; secondary end 
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Decision modifiers , contributing to granted reimbursement despite hugely uncertain cost-effectiveness ratios , were , for example , small population size , occasionally linked to budget impact , severity of disease , end of life and improved life expectancy .
CONCLUSION For drugs whose authorization is based on prospect i ve case series , most applications for reimbursement within public health care are granted .