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1.  Experiences and challenges in data monitoring for clinical trials within an international tropical disease research network 
Background
Models for the structure and procedures of data and safety monitoring boards (DSMBs) continue to evolve in response to issues of new and of old concern. Some authors have called for an open dialogue on these questions through publication of the experiences of DSMBs in addressing them.
Purpose
The goal of this paper is to add to the current discussion about acceptable models for establishing, serving on, and reporting to monitoring committees, particularly those that oversee multiple studies in less developed countries. The paper seeks to do so by describing the establishment and subsequent operation of one such multi-trial DSMB over a five-year period. This DSMB was formed to monitor trials conducted by members of the International Centers for Tropical Disease Research (ICTDR) network of the National Institute of Allergy and Infectious Diseases (NIAID). Methods The operational model and experiences are summarized by the authors, who had immediate responsibilities for directing the DSMB's activities.
Results
The board played an active, traditional role in assuring that patient safety was maintained and that current standards for clinical research were met. In addition, both NIAID and the board members viewed education of investigators to be an important role for the board to play in this particular setting. This affected the threshold for identifying which trials would be monitored, and it impacted several procedures adopted by the board.
Limitations
This report reflects the observations of those involved in managing the DSMB, including comments offered by the DSMB and by investigators, but not data gathered in a systematic way.
Conclusions
The operational model described here has allowed the DSMB to fulfill its role in the oversight of the trials. We hope that the ideas we present may help others facing similar situations and may stimulate further critical thinking about DSMB structure and function.
doi:10.1177/1740774506070710
PMCID: PMC4058498  PMID: 17060220
2.  The role of the Data and Safety Monitoring Board in a clinical trial: The CRISIS Study 
Objective
Randomized clinical trials are commonly overseen by a data and safety monitoring board (DSMB) comprised of experts in medicine, ethics, and biostatistics. DSMB responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. DSMB decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate DSMB oversight into the design, monitoring, and reporting of randomized trials.
Design
Case study, narrative review.
Methods
The DSMB’s role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.
Findings
The NIH-appointed CRISIS DSMB was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested DSMB interim review before opening CRISIS to children below one year of age. The first interim analysis found higher 28-day mortality in one treatment arm. The DSMB maintained trial closure to younger children, and requested a second interim data review six months later. At this second meeting, mortality was no longer of concern, while a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the DSMB elected to examine conditional power, and unmask treatment arm identities. Upon finding somewhat greater efficacy in the placebo arm, the DSMB recommended stopping CRISIS due to futility.
Conclusions
The design and operating procedures of a multicenter randomized trial must consider a pivotal DSMB role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The DSMB must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.
doi:10.1097/PCC.0b013e318274568c
PMCID: PMC3648617  PMID: 23392377
clinical trials; randomized; interim analysis; safety; nosocomial infection; sepsis
3.  25th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 10–14 December 2002 Update on clinical research 
Breast Cancer Research  2003;5(2):113-116.
The Annual San Antonio Breast Cancer Symposium has become a key forum for the presentation and discussion of both translational scientific aspects as well as clinical aspects of breast cancer care. In this report of the 25th Annual Meeting, an update of the salient clinical data is presented. The findings of the CALGB 9741 trial, an updated analysis of the Arimidex, Tamoxifen, Alone or in Combination study, and other significant paper and poster presentations are discussed. Summaries are also given of the clinical plenary lectures and minisymposia on adjuvant therapy and aromatase inhibitors.
PMCID: PMC154154  PMID: 12631392
adjuvant chemotherapy; anastrozole; aromatase inhibitor; tamoxifen; trastuzumab
4.  Data and safety monitoring in social behavioral intervention trials: the REACH II experience 
Background
Psychosocial and behavioral interventions trials targeting a broad range of complex social and behavioral problems such as smoking, obesity and family caregiving have proliferated in the past 30 years. At the same time the use of Data and Safety Monitoring Boards (DSMBs) to monitor the progress and quality of intervention trials and the safety of study participants has increased substantially. Most of the existing literature and guidelines for safety monitoring and reporting of adverse events focuses on medical interventions. Consequently, there is little guidance for investigators conducting social and behavior trials.
Purpose
This paper summarizes how issues associated with safety monitoring and adverse event reporting were handled in the Resources for Enhancing Alzheimer’s Caregiver Health (REACH II) program, a multisite randomized clinical trial, funded by the National Institutes on Aging (NIA) and the National Institutes of Nursing Research (NINR), that tested the efficacy of a multicomponent social/behavioral intervention for caregivers of persons with Alzheimer’s disease.
Methods
A task force was formed to define adverse events for the trial and protocols for reporting and resolving events that occurred. The task force conducted a review of existing polices and protocols for data and safety monitoring and adverse event reporting and identified potential risks particular to the study population. An informal survey regarding data and safety monitoring procedures with investigators on psychosocial intervention trials was also conducted.
Results
Two categories of events were defined for both caregivers and patients; adverse events and safety alerts. A distinction was also made between events detected at baseline assessment and those detected post-randomization. Standardized protocols were also developed for the reporting and resolution of events that occurred and training of study personnel. Results from the informal survey indicated wide variability in practices for data safety and monitoring across psychosocial intervention trials.
Conclusions
Overall, the REACH II experience demonstrates that existing guidelines regarding safety monitoring and adverse event reporting pose unique challenges for social/behavioral intervention trials. Challenges encountered in the REACH II program included defining and classifying adverse events, defining “resolution” of adverse events and attributing causes for events that occurred. These challenges are highlighted and recommendations for addressing them in future studies are discussed.
doi:10.1191/1740774506cn136oa
PMCID: PMC1484572  PMID: 16773953
5.  Sports and exercise-related tendinopathies: a review of selected topical issues by participants of the second International Scientific Tendinopathy Symposium (ISTS) Vancouver 2012 
In September 2010, the first International Scientific Tendinopathy Symposium (ISTS) was held in Umeå, Sweden, to establish a forum for original scientific and clinical insights in this growing field of clinical research and practice. The second ISTS was organised by the same group and held in Vancouver, Canada, in September 2012. This symposium was preceded by a round-table meeting in which the participants engaged in focused discussions, resulting in the following overview of tendinopathy clinical and research issues. This paper is a narrative review and summary developed during and after the second ISTS. The document is designed to highlight some key issues raised at ISTS 2012, and to integrate them into a shared conceptual framework. It should be considered an update and a signposting document rather than a comprehensive review. The document is developed for use by physiotherapists, physicians, athletic trainers, massage therapists and other health professionals as well as team coaches and strength/conditioning managers involved in care of sportspeople or workers with tendinopathy.
doi:10.1136/bjsports-2013-092329
PMCID: PMC3664390  PMID: 23584762
Tendons
6.  Experience collecting interim data on mortality: an example from the RALES study 
Introduction
The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status.
Methods
We used computer simulation to evaluate the effect of the sweeps.
Results
The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis.
Discussion
Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory.
Conclusion
We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.
doi:10.1186/cvm-2-1-059
PMCID: PMC56203  PMID: 11806773
data safety monitoring boards; data sweeps; interim analysis; randomized clinical trials
7.  The 21st International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, 20-23 March 2001 
Critical Care  2001;5(3):138-141.
The 21st International Symposium on Intensive Care and Emergency Medicine was dominated by the results of recent clinical trials in sepsis and acute respiratory distress syndrome (ARDS). The promise of extracorporeal liver replacement therapy and noninvasive ventilation were other areas of interest. Ethical issues also received attention. Overall, the 'state of the art' lectures, pro/con debates, seminars and tutorials were of a high standard. The meeting was marked by a sense of renewed enthusiasm that positive progress is occurring in intensive care medicine.
doi:10.1186/cc1013
PMCID: PMC137274  PMID: 11353930
ARDS; ethics; hepatic failure; non-invasive ventilation; sepsis
8.  Stopping the Control Arm in Response to the DSMB: Mother’s Choice of HIV Prophylaxis during Breastfeeding in the BAN Study 
Contemporary Clinical Trials  2011;33(1):55-59.
The Data and Safety Monitoring Board (DSMB) for the Breastfeeding, Antiretrovirals, and Nutrition study, a clinical trial aimed to prevent postnatal HIV transmission, recommended halting randomization to the enhanced standard-of-care (control) arm. The 67 mother-infant pairs on the control arm and less than 21 weeks postpartum at the time of the DSMB recommendation were read a script informing them of the DSMB decision and offering them the the maternal or infant antiretroviral interventions for the remainder of the 28-week breastfeeding period. This paper describes the BAN study response to the DSMB decision and what the women on the control arm chose, when given a choice to start the maternal or infant antiretroviral interventions.
doi:10.1016/j.cct.2011.10.006
PMCID: PMC3253884  PMID: 22041453
Postnatal HIV transmission; breastfeeding; antiretorival prophylaxis
9.  Teaching medical ethics symposium. A student-led approach to teaching. 
Journal of Medical Ethics  1987;13(3):139-143.
It is increasingly agreed that ethics has a place in undergraduate medical education. There is, however, debate about how it should be taught, and by whom. We present our experience of teaching ethics in a general practice module over six years. During this period there has been a shift from a teacher-centred to a student-centred approach in which students choose ethical issues to explore within a framework provided. The issues raised are discussed with examples, and the future directions of our ethics teaching outlined.
PMCID: PMC1375665  PMID: 3669043
10.  Sharing Individual Participant Data from Clinical Trials: An Opinion Survey Regarding the Establishment of a Central Repository 
PLoS ONE  2014;9(5):e97886.
Background
Calls have been made for increased access to individual participant data (IPD) from clinical trials, to ensure that complete evidence is available. However, despite the obvious benefits, progress towards this is frustratingly slow. In the meantime, many systematic reviews have already collected IPD from clinical trials. We propose that a central repository for these IPD should be established to ensure that these datasets are safeguarded and made available for use by others, building on the strengths and advantages of the collaborative groups that have been brought together in developing the datasets.
Objective
Evaluate the level of support, and identify major issues, for establishing a central repository of IPD.
Design
On-line survey with email reminders.
Participants
71 reviewers affiliated with the Cochrane Collaboration's IPD Meta-analysis Methods Group were invited to participate.
Results
30 (42%) invitees responded: 28 (93%) had been involved in an IPD review and 24 (80%) had been involved in a randomised trial. 25 (83%) agreed that a central repository was a good idea and 25 (83%) agreed that they would provide their IPD for central storage. Several benefits of a central repository were noted: safeguarding and standardisation of data, increased efficiency of IPD meta-analyses, knowledge advancement, and facilitating future clinical, and methodological research. The main concerns were gaining permission from trial data owners, uncertainty about the purpose of the repository, potential resource implications, and increased workload for IPD reviewers. Restricted access requiring approval, data security, anonymisation of data, and oversight committees were highlighted as issues under governance of the repository.
Conclusion
There is support in this community of IPD reviewers, many of whom are also involved in clinical trials, for storing IPD in a central repository. Results from this survey are informing further work on developing a repository of IPD which is currently underway by our group.
doi:10.1371/journal.pone.0097886
PMCID: PMC4038514  PMID: 24874700
11.  Systematic review of safety in paediatric drug trials published in 2007 
Background
There is now greater involvement of children in drug trials to ensure that paediatric medicines are supported by sound scientific evidence. The safety of the participating children is of paramount importance. Previous research shows that these children can suffer moderate and severe adverse drug reactions (ADRs) in clinical trials, yet very few of the trials designated a data safety monitoring board (DSMB) to oversee the trial.
Methods
Safety data from a systematic review of paediatric drug randomised controlled trials (RCTs) published in 2007 were analysed. All reported adverse events (AEs) were classified and assessed to determine whether an ADR had been experienced. ADRs were then categorised according to severity. Each trial report was examined as to whether an independent DSMB was in place.
Results
Of the 582 paediatric drug RCTs analysed, 210 (36%) reported that a serious AE had occurred, and in 15% mortality was reported. ADRs were detected in more than half of the RCTs (305); 66 (11%) were severe, and 79 (14%) were moderate. Severe ADRs involved a wide range of organ systems and were frequently associated with cytotoxic drugs, antiparasitics, anticonvulsants and psychotropic drugs. Two RCTs reported significantly higher mortality rates in the treatment group. Only 69 (12%) of the RCTs stated there was a DSMB. DSMBs terminated five RCTs and changed the protocol in one.
Conclusions
Children participating in drug RCTs experience a significant amount and a wide range of ADRs. DSMBs are needed to ensure the safety of paediatric participants in clinical drug trials.
doi:10.1007/s00228-011-1112-6
PMCID: PMC3256313  PMID: 21858432
Paediatric clinical trials; Adverse drug reactions (ADRs); Drug safety; Data safety monitoring boards (DSMBs); Systematic review
12.  Teaching medical ethics symposium. Reflections from New Zealand. 
Journal of Medical Ethics  1987;13(3):137-138.
The Medical Faculty of the University of Otago, New Zealand is experimenting with a new approach to the teaching of medical ethics, making it an integral part of several courses in all years of the medical curriculum. During the author's twelve-month period as a visiting professor in the faculty, trial runs in ethics have been introduced in the preclinical sciences, in behavioural science and medical-decision analysis and in every clinical attachment. Proposals for permanent course requirements will be considered by the faculty after a full evaluation of these experiments by both students and teaching staff. If such courses are to be implemented and maintained, medical facilities will need to appoint specialists in ethics, at least on a part-time basis.
PMCID: PMC1375664  PMID: 3669042
13.  Predicting clinical trial results based on announcements of interim analyses 
Trials  2014;15:73.
Background
Announcements of interim analyses of a clinical trial convey information about the results beyond the trial’s Data Safety Monitoring Board (DSMB). The amount of information conveyed may be minimal, but the fact that none of the trial’s stopping boundaries has been crossed implies that the experimental therapy is neither extremely effective nor hopeless. Predicting success of the ongoing trial is of interest to the trial’s sponsor, the medical community, pharmaceutical companies, and investors. We determine the probability of trial success by quantifying only the publicly available information from interim analyses of an ongoing trial. We illustrate our method in the context of the National Surgical Adjuvant Breast and Bowel (NSABP) trial, C-08.
Methods
We simulated trials based on the specifics of the NSABP C-08 protocol that were publicly available. We quantified the uncertainty around the treatment effect using prior weights for the various possibilities in light of other colon cancer studies and other studies of the investigational agent, bevacizumab. We considered alternative prior distributions.
Results
Subsequent to the trial’s third interim analysis, our predictive probabilities were: that the trial would eventually be successful, 48.0%; would stop for futility, 7.4%; and would continue to completion without statistical significance, 44.5%. The actual trial continued to completion without statistical significance.
Conclusions
Announcements of interim analyses provide information outside the DSMB’s sphere of confidentiality. This information is potentially helpful to clinical trial prognosticators. ‘Information leakage’ from standard interim analyses such as in NSABP C-08 is conventionally viewed as acceptable even though it may be quite revealing. Whether leakage from more aggressive types of adaptations is acceptable should be assessed at the design stage.
doi:10.1186/1745-6215-15-73
PMCID: PMC3973959  PMID: 24607270
Predictive probabilities; DSMB; Interim analyses; Operational bias; Prior distribution; Bevacizumab; Colon cancer
14.  Human biomonitoring data interpretation and ethics; obstacles or surmountable challenges? 
Environmental Health  2008;7(Suppl 1):S13.
The use of human samples to assess environmental exposure and uptake of chemicals is more than an analytical exercise and requires consideration of the utility and interpretation of data as well as due consideration of ethical issues. These aspects are inextricably linked.
In 2004 the EC expressed its commitment to the development of a harmonised approach to human biomonitoring (HBM) by including an action in the EU Environment and Health Strategy to develop a Human Biomonitoring Pilot Study. This further underlined the need for interpretation strategies as well as guidance on ethical issues. A workshop held in December 2006 brought together stakeholders from academia, policy makers as well as non-governmental organisations and chemical industry associations to a two day workshop built a mutual understanding of the issues in an open and frank discussion forum. This paper describes the discussion and recommendations from the workshop.
The workshop developed key recommendations for a Pan-European HBM Study:
1. A strategy for the interpretation of human biomonitoring data should be developed.
2. The pilot study should include the development of a strategy to integrate health data and environmental monitoring with human biomonitoring data at national and international levels.
3. Communication strategies should be developed when designing the study and evolve as the study continues.
4. Early communication with stakeholders is essential to achieve maximum efficacy of policy developments and facilitate subsequent monitoring.
5. Member states will have to apply individually for project approval from their National Research Ethics Committees.
6. The study population needs to have sufficient information on the way data will be gathered, interpreted and disseminated and how samples will be stored and used in the future (if biobanking) before they can give informed consent.
7. The participants must be given the option of anonymity. This has an impact on follow-up.
8. The pilot study should develop guidelines and best practice for Ethics for pan European studies.
In conclusion all participants felt there that there has to be stakeholder involvement in any planned pan-European Human Biomonitoring Study and the format of the workshop was appropriate for such dialogue.
doi:10.1186/1476-069X-7-S1-S13
PMCID: PMC2423450  PMID: 18541067
15.  Approaches to interim analysis of cancer randomised clinical trials with time to event endpoints: A survey from the Italian National Monitoring Centre for Clinical Trials 
Trials  2008;9:46.
Background
Although interim analysis approaches in clinical trials are widely known, information on current practice of planned monitoring is still scarce. Reports of studies rarely include details on the strategies for both data monitoring and interim analysis. The aim of this project is to investigate the forms of monitoring used in cancer clinical trials and in particular to gather information on the role of interim analyses in the data monitoring process of a clinical trial. This study focused on the prevalence of different types of interim analyses and data monitoring in cancer clinical trials.
Methods
Source of investigation were the protocols of cancer clinical trials included in the Italian registry of clinical trials from 2000 to 2005. Evaluation was restricted to protocols of randomised studies with a time to event endpoint, such as overall survival (OS) or progression free survival (PFS). A template data extraction form was developed and tested in a pilot phase. Selection of relevant protocols and data extraction were performed independently by two evaluators, with differences in the data assessment resolved by consensus with a third reviewer, referring back to the original protocol. Information was obtained on a) general characteristics of the protocol b) disease localization and patient setting; c) study design d) interim analyses; e) DSMC.
Results
The analysis of the collected protocols reveals that 70.7% of the protocols incorporate statistical interim analysis plans, but only 56% have also a DSMC and be considered adequately planned. The most concerning cases are related to lack of any form of monitoring (20.0% of the protocols), and the planning of interim analysis, without DSMC (14.7%).
Conclusion
The results indicate that there is still insufficient attention paid to the implementation of interim analysis.
doi:10.1186/1745-6215-9-46
PMCID: PMC2533282  PMID: 18657271
16.  The definition of dietary fiber – discussions at the Ninth Vahouny Fiber Symposium: building scientific agreement 
Food & Nutrition Research  2010;54:10.3402/fnr.v54i0.5750.
A definition for dietary fiber was adopted in June 2009 by the Codex Alimentarius Commission based on the recommendation for endorsement of the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) in November 2008. The definition listed three categories of carbohydrate polymers that are not hydrolyzed by the endogenous enzymes in the small intestine of humans. However, the definition left the inclusion of carbohydrates with degrees of polymerization (DP) in the range of 3 and 9 to the discretion of national authorities and left the ‘physiological effect(s) of benefit to health’ as undefined. The ILSI Europe and ILSI North America's committees on dietary carbohydrates organized a forum at the Ninth Vahouny Fiber Symposium in 2010 to discuss these implementation issues with the objective of building scientific consensus on how to resolve them. The results of this session are encouraging and indicated that the scientific community agrees on maintaining a worldwide consensus regarding the inclusion of non-digestible carbohydrates with ≥DP3 as dietary fiber and on a core, non-exhaustive list of beneficial physiological effects that dietary fibers have. These results are consistent with previous worldwide agreements.
doi:10.3402/fnr.v54i0.5750
PMCID: PMC2972185  PMID: 21052531
dietary fiber; degree of polymerization; physiological effects; Vahouny Symposium; Codex Alimentarius
17.  Report of the Second International Symposium on Molecular Epidemiology in Childhood Leukaemia and Embryonal Tumours, Rio de Janeiro, Brazil 
The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4–6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms’ tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below.
doi:10.3332/eCMS.2008.86
PMCID: PMC3234066  PMID: 22275972
18.  2010 Keystone Symposium Meeting Report: Alzheimer’s disease beyond Aβ 
Many of the Alzheimer’s disease (AD) clinical trials have made it far enough down the pipeline to allow conclusions about targeting the amyloid-β peptide (Aβ) as a therapeutic approach. Based on these results, it is becoming clear that a multifocal approach to AD treatment is probably necessary. However, critical discussion beyond Aβ is necessary to enable the next wave of AD therapeutic targets. For this reason, the 2010 Keystone Symposium, ‘Alzheimer’s Disease Beyond Aβ’, was organized by JoAnne McLaurin and Tony Wyss-Coray to spark topical discussion and debate. While researchers struggled to get beyond that ever-present pathognomonic feature of AD, new and exciting evidence was presented that raised our awareness of what is around the corner for next-generation AD therapeutics beyond Aβ. This report will describe some of the highlights from Copper Mountain Resort throughout the meeting period of 10–15 January 2010 in Colorado (USA). Despite illuminating scientific presentations and intense discussions, a number of important questions remain concerning the best biomarkers and targets to focus on, and when and how to therapeutically intervene.
PMCID: PMC2872183  PMID: 20429127
19.  Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study 
The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up.
The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues.
The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power.
Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.
doi:10.1177/1740774511432726
PMCID: PMC3790961  PMID: 22334468
20.  The Second Annual Symposium on Nanomedicine and Drug Delivery: exploring recent developments and assessing major advances. 19-20 August, 2004, Polytechnic University, Brooklyn, NY, USA 
Expert opinion on drug delivery  2004;1(1):181-184.
The meeting was dedicated to novel aspects of nanomedicine including polymer drug delivery systems (DDS) and biomaterials. Self-assembled micellar DDS have been evaluated in term of morphology, biological properties, and results of clinical trials. Important advances in design of nanoparticles as DDS have been highlighted in various presentations. Unexpected issues of polymer-related biological effects, including gene expression, were stressed in relation to polymer DDS. Great potential of nanofabrication of biomaterials, and preliminary data on design of polymer scaffolds were demonstrated in a number of reports. This symposium demonstrated how timely is the development of nanosized DDS with advances in understanding the disease-related mechanisms, and outlined major area of application of nanomedicine technology.
doi:10.1517/17425247.1.1.181
PMCID: PMC1351158  PMID: 16296729
biomaterials; nanofibers; nanogels; nanomedicine; polymer micelles; polymer scaffolds
21.  Issues and Challenges in the Development of Pneumococcal Protein Vaccines: A Two Day International Symposium 
Expert review of vaccines  2012;11(3):279-285.
In view of the increasing licensure and use of pneumococcal conjugate vaccines (PCVs), their relatively high cost, and growing issues with serotype emergence, there is a need to re-evaluate the role of pneumococcal protein vaccines (PPVs) and pathways to their licensure. This paper summarizes the discussion and viewpoints from an expert meeting regarding the development of PPVs. A wide spectrum of pneumococcal vaccine researchers, developers, and regulators met to review the state of PPVs, identify research and development needs, and provide consensus opinions to support the introduction of new PPVs where possible. They also discussed clinical and regulatory aspects pertinent to these vaccines and generated a series of recommendations for moving the field forward.
doi:10.1586/erv.12.5
PMCID: PMC3777823  PMID: 22380821
Streptococcus pneumoniae; pneumococcal vaccine; protein; animal models
22.  26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3–6 December 2003: update on preclinical and translational research 
Breast Cancer Research  2004;6(2):E10.
The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side. Each year sees the continued evolution of our understanding of the basic mechanisms of breast cancer initiation and progression, and the clinical application of this knowledge. Major topics of discussion at the symposium this year were the cell cycle, new evolving concepts of estrogen receptor action, breast cancer stem cells, new predictive and prognostic markers (including microarray studies), and continued exploration of the mechanisms of drug resistance. This report will summarize preclinical and translational highlights from the meeting.
PMCID: PMC400657  PMID: 14979916
BRCA1; cell cycle; drug resistance; estrogen receptor; growth factor receptors; microarray; prognostic and predictive markers
23.  Registration of Clinical Trials: Is it Really Needed? 
Background and Aims:
Withholding findings of clinical trials for publication or presentation to the regulatory authorities is a major concern. We aimed to address the importance of clinical trial registration and whether it is needed or not.
Discussion:
For ethical conduct of clinical trial, registration is an important but debatable issue due to proprietary interest of the pharmaceutical industry. Over the years, investigating agencies uncovered several instances of misconduct during the clinical trial. The International committee of medical journal editors requires registration of trial methodology, but does not require registration of trial results; however, the U.S. Food and Drug Administration Amendments does require researchers to register results.
Conclusion:
Prospective registration of clinical trial is mandatory for more transparent research and sustaining the validity of evidence based practice and availability of reliable data. Clinical trials registration has the potential to contribute substantially to improve clinical trial transparency and reducing publication bias and selective reporting.
doi:10.4103/1947-2714.123266
PMCID: PMC3877534  PMID: 24404555
Clinical trials; Ethics; Healthcare; Registration; Research
24.  Cardiac sympathetic neuroimaging: summary of the First International Symposium 
The First International Symposium on Cardiac Sympathetic Neuroimaging brought together for the first time clinical and preclinical researchers evaluating autonomic and neurocardiologic disorders by this modality. The invited lectures and posters presented some uses of cardiac sympathetic neuroimaging for diagnosis, prognosis, and monitoring treatments. The Symposium also included a discussion about whether and how to expand the availability of cardiac sympathetic neuroimaging at medical centers in the United States. Here, we review the background for the Symposium, provide an annotated summary of the lectures and posters, discuss some of the take-home points from the roundtable discussion, and propose a plan of action for the future.
doi:10.1007/s10286-009-0002-9
PMCID: PMC2963152  PMID: 19266158
Sympathetic nervous system; Fluorodopamine; MIBG; Positron-emission tomography
25.  Keystone symposium: The role of microenvironment in tumor induction and progression, Banff, Canada, 5–10 February 2005 
Breast Cancer Research  2005;7(3):113-118.
The first Keystone symposium on the role of microenvironment in tumor induction and progression attracted 274 delegates from 13 countries to Banff in the heart of the Canadian Rockies. The meeting was organized by Mina Bissell, Ronald DePinho and Luis Parada, and was held concurrently with the Keystone symposium on cancer and development, chaired by Matthew Scott and Roeland Nusse. The 30 oral presentations and over 130 posters provided an excellent forum for discussing emerging data in this rapidly advancing field.
doi:10.1186/bcr1030
PMCID: PMC1143569  PMID: 15987441

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