***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: Despite the accelerating pace of scientific discovery , the current clinical research enterprise does not sufficiently address pressing clinical questions . Given the constraints on clinical trials , for a majority of clinical questions , the only relevant data available to aid in decision making are based on observation and experience . Our purpose here is 3-fold . First , we describe the classic context of medical research guided by Poppers ’ scientific epistemology of “ falsificationism . ” Second , we discuss challenges and shortcomings of r and omized controlled trials and present the potential of observational studies based on big data . Third , we cover several obstacles related to the use of observational ( retrospective ) data in clinical studies . We conclude that r and omized controlled trials are not at risk for extinction , but innovations in statistics , machine learning , and big data analytics may generate a completely new ecosystem for exploration and validation Summary Background Long-term hormone therapy has been the st and ard of care for advanced prostate cancer since the 1940s . STAMPEDE is a r and omised controlled trial using a multiarm , multistage platform design . It recruits men with high-risk , locally advanced , metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy .  We report primary survival results for three research comparisons testing the addition of zoledronic acid , docetaxel , or their combination to st and ard of care versus st and ard of care alone . Methods St and ard of care was hormone therapy for at least 2 years ; radiotherapy was encouraged for men with N0M0 disease to November , 2011 , then m and ated ; radiotherapy was optional for men with node-positive non-metastatic ( N+M0 ) disease . Stratified r and omisation ( via minimisation ) allocated men 2:1:1:1 to st and ard of care only ( SOC-only ; control ) , st and ard of care plus zoledronic acid ( SOC + ZA ) , st and ard of care plus docetaxel ( SOC + Doc ) , or st and ard of care with both zoledronic acid and docetaxel ( SOC + ZA + Doc ) . Zoledronic acid ( 4 mg ) was given for six 3-weekly cycles , then 4-weekly until 2 years , and docetaxel ( 75 mg/m2 ) for six 3-weekly cycles with prednisolone 10 mg daily . There was no blinding to treatment allocation . The primary outcome measure was overall survival . Pairwise comparisons of research versus control had 90 % power at 2·5 % one-sided α for hazard ratio ( HR ) 0·75 , requiring roughly 400 control arm deaths . Statistical analyses were undertaken with st and ard log-rank-type methods for time-to-event data , with hazard ratios ( HRs ) and 95 % CIs derived from adjusted Cox models . This trial is registered at Clinical Trials.gov ( NCT00268476 ) and ControlledTrials.com ( IS RCT N78818544 ) . Findings 2962 men were r and omly assigned to four groups between Oct 5 , 2005 , and March 31 , 2013 . Median age was 65 years ( IQR 60–71 ) . 1817 ( 61 % ) men had M+ disease , 448 ( 15 % ) had N+/X M0 , and 697 ( 24 % ) had N0M0 . 165 ( 6 % ) men were previously treated with local therapy  , and median prostate-specific antigen was 65 ng/mL ( IQR 23–184 ) . Median follow-up was 43 months ( IQR 30–60 ) . There were 415 deaths in the control group ( 347 [ 84 % ] prostate cancer ) . Median overall survival was 71 months ( IQR 32 to not reached ) for SOC-only , not reached ( 32 to not reached ) for SOC + ZA ( HR 0·94 , 95 % CI 0·79–1·11 ; p=0·450 ) , 81 months ( 41 to not reached ) for SOC + Doc ( 0·78 , 0·66–0·93 ; p=0·006 ) , and 76 months ( 39 to not reached ) for SOC + ZA + Doc ( 0·82 , 0·69–0·97 ; p=0·022 ) . There was no evidence of heterogeneity in treatment effect ( for any of the treatments ) across prespecified subsets . Grade 3–5 adverse events were reported for 399 ( 32 % ) patients receiving SOC , 197 ( 32 % ) receiving SOC + ZA , 288 ( 52 % ) receiving SOC + Doc , and 269 ( 52 % ) receiving SOC + ZA + Doc . Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of st and ard of care for this population . Docetaxel chemotherapy , given at the time of long-term hormone therapy initiation , showed evidence of improved survival accompanied by an increase in adverse events . Docetaxel treatment should become part of st and ard of care for adequately fit men commencing  long-term hormone  therapy . Funding Cancer Research UK , Medical Research Council , Novartis , Sanofi-Aventis , Pfizer , Janssen , Astellas , NIHR Clinical Research Network , Swiss Group for Clinical Cancer Research BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily  and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone The benefits established in efficacy trials , usually r and omized , controlled trials conducted under highly controlled circumstances with maximized internal validity , can frequently not be demonstrated in clinical practice at the community level . Effectiveness trials are tools to evaluate the applicability of a treatment in a wider setting with maximized external validity , to observe uncommon adverse events , and to identify factors influencing the main outcomes and risks . Important areas in relation to lung cancer treatment that will benefit from effectiveness trials include gefitinib monotherapy and bevacizumab therapy combined with cytotoxic chemotherapy for advanced non-small cell lung cancer . These therapies were found to produce life-threatening nonhematologic toxicity at a high incidence of up to 5 % ; however , the risk factors for these toxicities have not yet been fully established . Effectiveness trials of adjuvant chemotherapy after surgery with long-term follow-up are also important to obtain reliable information as to secondary malignancy and noncancer-related deaths . Development of an infrastructure for effectiveness trials is crucial because of the necessity to deal with large numbers of patients , sometimes as many as 10,000 patients , from many hospitals . The extensive research time involved and the considerable cost of these trials may be reduced with the use of Internet re sources . Effectiveness trials are a fundamental step toward bridging the gap between clinical research and clinical practice and effectively implementing new therapies in clinical practice The new drug application data base su bmi tted to the US Food and Drug Administration for drug approval ( phases I-III or phases 1 - 3 ) is limited both in scope and size . Although r and omized controlled trials , the hallmark of phase III trials , are the gold st and ard for the drug-approval process , they invariably have a number of limitations , including relatively small sample sizes , selective population s , short follow-up , the use of intermediate ( surrogate ) endpoints ( almost always ) , and limited generalizability . The challenges of monitoring drugs once approved are also numerous . After approval by the Food and Drug Administration , marketed drugs undergo continued scrutiny , and this scrutiny is increasing because of problems that have surfaced with some drugs after their approval . Postmarketing research includes a variety of study design s and the use of registries and self-reporting of drug side effects . Along with this has come great confusion about what postmarketing research is and what a phase IV study is . Among the important strengths of phase IV research are the exposure of a broader range of patients to the drug under study , result ing in more " real-world " information about the drug 's safety and efficacy , and consideration of a broader range of clinical endpoints . As a result , phase IV , or postmarketing research , has become an integral part of the drug evaluation process for a wide range of agents . The authors discuss the different types of study design s that are common under the phase IV terminology and provide some examples . They also discuss the use of registries and self-reporting of adverse events using the MedWatch System PURPOSE Evolving treatments , disease phenotypes , and biology , together with a changing drug development environment , have created the need to revise  castration-resistant prostate cancer ( CRPC ) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups . METHODS An international expert committee of prostate cancer clinical investigators ( the Prostate Cancer Clinical Trials Working Group 3 [ PCWG3 ] ) was reconvened and exp and ed and met in 2012 - 2015 to formulate up date d criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations . RESULTS PCWG3 recommends that baseline patient assessment include tumor histology , detailed records of prior systemic treatments and responses , and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread . New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events , as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state . PCWG3 introduces the concept of no longer clinical ly benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment , and the importance of documenting progression in existing lesions as distinct from the development of new lesions . Serial biologic profiling using tumor sample s from biopsies , blood-based diagnostics , and /or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospect i ve trials . CONCLUSION PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC population s. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval BACKGROUND Treatment of metastatic castration-resistant prostate cancer ( mCRPC ) with chemotherapy improves disease control and survival in fit older men ( age 65 + ) but its impact on function is not clear . We hypothesized that chemotherapy would impair daily function in older men with mCRPC . METHODS Men aged 65 + with mCRPC starting chemotherapy or abiraterone  were enrolled in this prospect i ve observational pilot study . Daily function was evaluated with the OARS Instrumental Activities of Daily Living ( IADL ) scale . Three objective measures were used to assess physical function . Patients completed Functional Assessment of Cancer Therapy question naires measuring prostate-specific and general quality -of-life ( QOL ) . Vulnerability was evaluated using the Vulnerable Elders Survey ( VES-13 ) . Assessment s were completed before each cycle of chemotherapy or every 2 - 3 months for those receiving abiraterone . We compared outcomes pre- and post-treatment and with published minimal clinical ly important differences . RESULTS We evaluated 29 and 7 men on 1st-line and 2nd-line 
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Conclusions : Despite the high grade of heterogeneity among studies , treatment with AA seems to ensure good survival outcomes in the ‘ real-life ’ setting .