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data monitoring in Adaptive Dose-Ranging Trials

STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2010年第4期2卷 513-521页

作者： Gallo, Paul Fardipour, Parvin Dragalin, Vladimir Krams, Michael Littman, Gary S. Bretz, Frank Novartis Pharmaceut E Hanover NJ 07936 USA Pfizer BioTherapeut Res Unit Collegeville PA 19426 USA Quintiles Innovat Ctr Stat Drug Dev Morrisville NC 27560 USA Janssen Pharmaceut CNS Neurol Franchise Titusville NJ 08560 USA Appl Clin Intelligence Bala Cynwyd PA 19004 USA Novartis Pharma AG Stat Methodol CH-4002 Basel Switzerland

In clinical studies that address dose-finding objectives, the use of trial designs that allow adaptations based upon accruing unblinded data have much potential to introduce added efficiency and to improve the decision making process, compared to traditional designs. In this paper we consider the processes by which such adaptations may be made. Conventions for interim data monitoring and decision making, particularly with regard to restricting access to data, have largely evolved based upon the needs in Phase III nonadaptive studies;as such, they may not be an ideal fit for adaptive dose-ranging studies, because of the different natures of the trials, their placement in the drug development process, and the objectives of the monitoring. In this paper, we specifically discuss what processes for interim monitoring, analysis, decision making and implementation, might be advantageous and appropriate for adaptive dose-ranging studies, and then illustrate how processes were implemented and carried out in a particular case study.

关键词： Adaptive trial data monitoring committee Dose finding Interim analysis

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Experiences in the design and implementation of phase II trials in CLL

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Trials 2011年第1期12卷 1-1页

作者： Dena R Cohen Julia M Brown Walter M Gregory Peter Hillmen Clinical Trials Research Unit University of Leeds Leeds UK Leeds Teaching Hospitals NHS Trust St James's University Hospital Leeds UK

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The importance of planning for a seamless transition in an adaptive phase II randomised trial

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Trials 2011年第1期12卷 1-1页

作者： Andrea Marshall Janet A Dunn Julie Fletcher Helen B Higgins Christopher J Poole Warwick Clinical Trials Unit University of Warwick Coventry West Midlands CV4 7AL UK

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Function after spinal treatment, exercise and rehabilitation (FASTER): improving the functional outcome of spinal surgery

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BMC MUSCULOSKELETAL DISORDERS 2010年第1期11卷 17-17页

作者： McGregor, A. H. Dore, C. J. Morris, T. P. Morris, S. Jamrozik, K. Univ London Imperial Coll Sci Technol & Med Fac Med London W6 8RP England MRC Clin Trials Unit London NW1 2DA England UCL Dept Epidemiol & Publ Hlth London WC1E 6BT England Univ Adelaide Sch Populat Hlth Adelaide SA 5005 Australia Univ Adelaide Clin Practice Off Adelaide SA 5005 Australia

Background: The life-time incidence of low back pain is high and diagnoses of spinal stenosis and disc prolapse are increasing. Consequently, there is a steady rise in surgical interventions for these conditions. Current evidence suggests that while the success of surgery is incomplete, it is superior to conservative interventions. A recent survey indicates that there are large differences in the type and intensity of rehabilitation, if any, provided after spinal surgery as well as in the restrictions and advice given to patients in the post-operative period. This trial will test the hypothesis that functional outcome following two common spinal operations can be improved by a programme of post-operative rehabilitation that combines professional support and advice with graded active exercise and/or an educational booklet based on evidence-based messages and advice. Methods/Design: The study design is a multi-centre, factorial, randomised controlled trial with patients stratified by surgeon and operative procedure. The trial will compare the effectiveness and cost-effectiveness of a rehabilitation programme and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression, each compared with "usual care" using a 2 x 2 factorial design. The trial will create 4 sub-groups;rehabilitation-only, booklet-only, rehabilitation-plus-booklet, and usual care only. The trial aims to recruit 344 patients, which equates to 86 patients in each of the four sub-groups. All patients will be assessed for functional ability (through the Oswestry Disability Index - a disease specific functional questionnaire), pain (using visual analogue scales), and satisfaction pre-operatively and then at 6 weeks, 3, 6 and 9 months and 1 year post-operatively. This will be complemented by a formal analysis of cost-effectiveness. Discussion: This trial will determine whether the outcome of spinal surgery can be enhanced by either a postoperat

关键词： Usual Care Oswestry Disability Index Spinal Stenosis data monitoring committee Disc Prolapse

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Interim Analysis: What Regulatory Affairs Professionals Need to Know

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DRUG INFORMATION JOURNAL 2010年第6期44卷 703-712页

作者： Coutant, David Eli Lilly & Co Lilly Corp Ctr Indianapolis IN 46285 USA

A data monitoring committee (DMC) is often responsible for monitoring a clinical trial via interim analyses. Those responsible for regulatory strategy and implementation need to be fully engaged with this oversight process to ensure that the trial will achieve its goals with regulators. In the United States, both 21 CFR 312.50 and 21 CFR 312.56 describe sponsor responsibilities related to ongoing clinical trials conducted under an Investigational New Drug Application. Herein, I review the types of trials that may benefit from DMC involvement and provide an example of a DMC clinical trial model. I highlight important features of the roles of the sponsor, DMC, statistician, and the regulatory professional in interim analysis. I review the importance of early planning, knowing when to release interim data, and avoiding type I error rate inflation. Finally, I examine key points that lead to early stopping or study alteration.

关键词： Interim analysis data monitoring committee DMC data and safety monitoring board DSMB

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The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial

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TRIALS 2010年第1期11卷 40-40页

作者： Shakur, Haleema Elbourne, Diana Guelmezoglu, Metin Alfirevic, Zarko Ronsmans, Carine Allen, Elizabeth Roberts, Ian London Sch Hyg & Trop Med Clin Trials Unit London WC1E 7HT England WHO Dept Reprod Hlth & Res CH-1211 Geneva 27 Switzerland Univ Liverpool Liverpool Womens Hosp Div Perinatal & Reprod Med Liverpool L8 7SS Merseyside England London Sch Hyg & Trop Med Med Stat Unit London WC1E 7HT England London Sch Hyg & Trop Med Infect Dis Epidemiol Unit London WC1E 7HT England

Background: Each year, worldwide about 530,000 women die from causes related to pregnancy and childbirth. Of the deaths 99% are in low and middle income countries. Obstetric haemorrhage is the leading cause of maternal mortality, most occurring in the postpartum period. Systemic antifibrinolytic agents are widely used in surgery to prevent clot breakdown (fibrinolysis) in order to reduce surgical blood loss. At present there is little reliable evidence from randomised trials on the effectiveness of tranexamic acid in the treatment of postpartum haemorrhage. Methods: The Trial aims to determine the effect of early administration of tranexamic acid on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events) in women with clinically diagnosed postpartum haemorrhage. The use of health services and safety, especially thromboembolic effect, on breastfed babies will also be assessed. The trial will be a large, pragmatic, randomised, double blind, placebo controlled trial among 15,000 women with a clinical diagnosis of postpartum haemorrhage. All legally adult women with clinically diagnosed postpartum haemorrhage following vaginal delivery of a baby or caesarean section will potentially be eligible. The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage. Treatment will entail a dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation. A second dose may be given if after 30 minutes bleeding continues, or if it stops and restarts within 24 hours after the first dose. The main analyses will be on an 'intention to treat' basis, irrespective of whether the allocated treatment was received or not. Subgroup analyses for the primary outcome will be based on type of delivery;administration or not o

关键词： Thromboembolic Event Tranexamic Acid Postpartum Haemorrhage data monitoring committee Trial Steering committee

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Neonatal ECMO Study of Temperature (NEST) - a randomised controlled trial

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BMC PEDIATRICS 2010年第1期10卷 24-24页

作者： Field, David J. Firmin, Richard Azzopardi, Denis V. Cowan, Frances Juszczak, Edmund Brocklehurst, Peter Univ Leicester Dept Hlth Sci Leicester Leics England Glenfield Gen Hosp ECMO Dept Leicester LE3 9QP Leics England Univ London Imperial Coll Sci Technol & Med Fac Med Div Clin Sci London England Hammersmith Hosp London England Univ Oxford Natl Perinatal Epidemiol Unit Oxford England

Background: Existing evidence indicates that once mature neonates with severe cardio-respiratory failure become eligible for Extra Corporeal Membrane Oxygenation (ECMO) their chances of intact survival are doubled if they actually receive ECMO. However, significant numbers survive with disability. NEST is a multi-centre randomised controlled trial designed to test whether, in neonates requiring ECMO, cooling to 34 degrees C for the first 48 to 72 hours of their ECMO course leads to improved later health status. Infants allocated to the control group will receive ECMO at 37 degrees C throughout their course, which is currently standard practice around the world. Health status of both groups will be assessed formally at 2 years corrected age. Methods/Design: All infants recruited to the study will be cared for in one of the four United Kingdom (UK) ECMO centres. Babies who are thought to be eligible will be assessed by the treating clinician who will confirm eligibility, ensure that consent has been obtained and then randomise the baby using a web based system, based at the National Perinatal Epidemiology Unit (NPEU) Clinical Trials Unit. Trial registration. Babies allocated ECMO without cooling will receive ECMO at 37 degrees C +/- 0.2 degrees C. Babies allocated ECMO with cooling will be managed at 34 degrees C +/- 0.2 degrees C for up to 72 hours from the start of their ECMO run. The minimum duration of cooling will be 48 hours. Rewarming (to 37 degrees C) will occur at a rate of no more than 0.5 degrees C per hour. All other aspects of ECMO management will be identical. Primary outcome: Cognitive score from the Bayley Scales of Infant and Toddler Development, 3(rd) edition (Bayley-III) at age of 2 years (24-27 months). Discussion: For the primary analysis, children will be analysed in the groups to which they are assigned, comparing the outcome of all babies allocated to "ECMO with cooling" with all those allocated to "ECMO" alone, regardless of deviation from the

关键词： Mild Hypothermia data monitoring committee Chief Investigator Trial Steering committee Extra Corporeal Membrane Oxygenation

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Brain Research to Ameliorate Impaired Neurodevelopment - Home-based Intervention Trial (BRAIN-HIT)

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BMC PEDIATRICS 2010年第1期10卷 27-27页

作者： Wallander, Jan L. McClure, Elizabeth Biasini, Fred Goudar, Shivaprasad S. Pasha, Omrana Chomba, Elwyn Shearer, Darlene Wright, Linda Thorsten, Vanessa Chakraborty, Hrishikesh Dhaded, Sangappa M. Mahantshetti, Niranjana S. Bellad, Roopa M. Abbasi, Zahid Carlo, Waldemar Univ Calif Merced Psychol Sci & Hlth Sci Res Inst Merced CA 95343 USA RTI Int Dept Stat & Epidemiol Res Triangle Pk NC 27709 USA Univ Alabama Birmingham Dept Psychol Birmingham AL 35294 USA JN Med Coll Dept Physiol Belgaum 590010 Karnataka India JN Med Coll Dept Med Educ Belgaum 590010 Karnataka India Aga Khan Univ Dept Community Hlth Sci Karachi 74800 Pakistan Aga Khan Univ Dept Family Med Karachi 74800 Pakistan Univ Teaching Hosp Lusaka Zambia Western Kentucky Univ Dept Publ Hlth Bowling Green KY 42101 USA Eunice Kennedy Shriver Natl Inst Child Hlth & Hum Ctr Res Mothers & Children Rockville MD 20852 USA JN Med Coll Dept Pediat Belgaum 590010 Karnataka India Univ Alabama Birmingham Dept Pediat Div Neonatol Birmingham AL 35233 USA

Background: This randomized controlled trial aims to evaluate the effects of an early developmental intervention program on the development of young children in low-and low-middle-income countries who are at risk for neurodevelopmental disability because of birth asphyxia. A group of children without perinatal complications are evaluated in the same protocol to compare the effects of early developmental intervention in healthy infants in the same communities. Birth asphyxia is the leading specific cause of neonatal mortality in low-and low-middle-income countries and is also the main cause of neonatal and long-term morbidity including mental retardation, cerebral palsy, and other neurodevelopmental disorders. Mortality and morbidity from birth asphyxia disproportionately affect more infants in low-and low-middle-income countries, particularly those from the lowest socioeconomic groups. There is evidence that relatively inexpensive programs of early developmental intervention, delivered during home visit by parent trainers, are capable of improving neurodevelopment in infants following brain insult due to birth asphyxia. Methods/Design: This trial is a block-randomized controlled trial that has enrolled 174 children with birth asphyxia and 257 without perinatal complications, comparing early developmental intervention plus health and safety counseling to the control intervention receiving health and safety counseling only, in sites in India, Pakistan, and Zambia. The interventions are delivered in home visits every two weeks by parent trainers from 2 weeks after birth until age 36 months. The primary outcome of the trial is cognitive development, and secondary outcomes include social-emotional and motor development. Child, parent, and family characteristics and number of home visits completed are evaluated as moderating factors. Discussion: The trial is supervised by a trial steering committee, and an independent data monitoring committee monitors the trial. Findings

关键词： Home Visit Birth Asphyxia Conventional Care Early Child Development data monitoring committee

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A prospective randomised trial comparing nasogastric with intravenous hydration in children with bronchiolitis (protocol) The comparative rehydration in bronchiolitis study (CRIB)

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BMC PEDIATRICS 2010年第1期10卷 37-37页

作者： Oakley, Ed Babl, Franz E. Acworth, Jason Borland, Meredith Kreiser, David Neutze, Jocelyn Theophilos, Theane Donath, Susan South, Mike Davidson, Andrew Monash Med Ctr Dept Emergency Med Clayton Vic 3168 Australia Murdoch Childrens Res Inst Parkville Vic 3052 Australia Monash Univ Fac Med Nursing & Hlth Sci So Clin Sch Clayton Vic 3800 Australia Royal Childrens Hosp Dept Emergency Med Parkville Vic 3052 Australia Univ Melbourne Fac Med Dent & Hlth Sci Dept Paediat Melbourne Vic 3010 Australia Royal Childrens Hosp Brisbane Dept Emergency Med Herston Qld 4006 Australia Princess Margaret Hosp Dept Emergency Med Perth WA 6008 Australia Sunshine Hosp Dept Emergency Med St Albans Vic 3021 Australia Kidz First Hosp Dept Emergency Med Auckland 2025 New Zealand Royal Childrens Hosp Dept Med Parkville Vic 3052 Australia Royal Childrens Hosp Dept Anaesthesia Parkville Vic 3052 Australia

Background: Bronchiolitis is the most common reason for admission of infants to hospital in developed countries. Fluid replacement therapy is required in about 30% of children admitted with bronchiolitis. There are currently two techniques of fluid replacement therapy that are used with the same frequency-intravenous (IV) or nasogastric (NG). The evidence to determine the optimum route of hydration therapy for infants with bronchiolitis is inadequate. This randomised trial will be the first to provide good quality evidence of whether nasogastric rehydration (NGR) offers benefits over intravenous rehydration (IVR) using the clinically relevant continuous outcome measure of duration of hospital admission. Methods/Design: A prospective randomised multi-centre trial in Australia and New Zealand where children between 2 and 12 months of age with bronchiolitis, needing non oral fluid replacement, are randomised to receive either intravenous (IV) or nasogastric (NG) rehydration. 750 patients admitted to participating hospitals will be recruited, and will be followed daily during the admission and by telephone 1 week after discharge. Patients with chronic respiratory, cardiac, or neurological disease;choanal atresia;needing IV fluid resuscitation;needing an IV for other reasons, and those requiring CPAP or ventilation are excluded. The primary endpoint is duration of hospital admission. Secondary outcomes are complications, need for ICU admission, parental satisfaction, and an economic evaluation. Results will be analysed using t-test for continuous data, and chi squared for categorical data. Non parametric data will be log transformed. Discussion: This trial will define the role of NGR and IVR in bronchiolitis

关键词： Bronchiolitis Fluid Replacement Parental Satisfaction data monitoring committee Trial Steering committee

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A systematic review of the reporting of data monitoring committees' roles, interim analysis and early termination in pediatric clinical trials

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BMC PEDIATRICS 2009年第1期9卷 77-77页

作者： Fernandes, Ricardo M. van der Lee, Johanna H. Offringa, Martin Univ Lisbon Hosp Santa Maria Ctr Hosp Lisboa Norte EPE Dept Crianca & FamiliaInst Mol MedFac Med Lisbon Portugal Univ Lisbon Fac Med Inst Mol Med Lab Farmacol Clin & Terapeut Lisbon Portugal Univ Amsterdam Acad Med Ctr Emma Childrens Hosp Dept Pediat Clin Epidemiol NL-1105 AZ Amsterdam Netherlands

Background: Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of data monitoring committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials. Methods: We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination. Results: 110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included;68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%);62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods. Conclusions: Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.

关键词： Early Termination Interim Analysis Consort Statement data monitoring committee Pediatric Trial

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