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.
adjuvant chemotherapy; anastrozole; aromatase inhibitor; tamoxifen; trastuzumab
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.
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.
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.
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.
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.
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.
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.
We used computer simulation to evaluate the effect of the sweeps.
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.
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.
We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.
data safety monitoring boards; data sweeps; interim analysis; randomized clinical trials
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.
ARDS; ethics; hepatic failure; non-invasive ventilation; sepsis
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.
Postnatal HIV transmission; breastfeeding; antiretorival prophylaxis
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.
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.
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.
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.
Paediatric clinical trials; Adverse drug reactions (ADRs); Drug safety; Data safety monitoring boards (DSMBs); Systematic review
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.
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.
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.
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%).
The results indicate that there is still insufficient attention paid to the implementation of interim analysis.
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.
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.
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.
dietary fiber; degree of polymerization; physiological effects; Vahouny Symposium; Codex Alimentarius
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.
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.
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.
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.
biomaterials; nanofibers; nanogels; nanomedicine; polymer micelles; polymer scaffolds
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.
Streptococcus pneumoniae; pneumococcal vaccine; protein; animal models
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.
BRCA1; cell cycle; drug resistance; estrogen receptor; growth factor receptors; microarray; prognostic and predictive markers
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.
Sympathetic nervous system; Fluorodopamine; MIBG; Positron-emission tomography
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.
Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI.
Methods and analysis
LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI.
Ethics and dissemination
Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy.
acute lung injury; acute respiratory ditress syndrome; aspirin; critical illness; prevention; clinical trial
Gait and balance measures have particular potential as outcome measures in Multiple Sclerosis (MS) because, of the many hallmarks of MS disability, gait and balance dysfunction are present throughout the course of the disease, impact many aspects of a person's life, and progress over time. To highlight the importance and relevance of gait and balance measures in MS, explore novel measurements of gait and balance in MS, and discuss how gait, balance, and fall measures can best be used and developed in clinical and research settings, the 1st International Symposium on Gait and Balance in Multiple Sclerosis was held in Portland, Oregon, USA on October 1, 2011. This meeting brought together nearly 100 neurologists, physiatrists, physical therapists, occupational therapists, nurses, engineers, and others to discuss the current status and recent advances in the measurement of gait and balance in MS. Presentations focused on clinician-administered, self-administered, and instrumented measures of gait, balance, and falls in MS.
Unlike research ethics committees, which were created in 1988, the number of functioning hospital based ethical organisations in France, such as clinical ethics committees, is unknown. The objectives of such structures are diverse. A recent law created regional ethical forums, the objectives of which are education, debate, and research in relation to healthcare ethics. This paper discusses the current situation in France and the possible evolution and conflicts induced by this law. The creation of official healthcare ethics structures raises several issues.
hospital ethics committees; clinical ethics; France
The Second Annual Symposium of the Global Cancer Genomics Consortium (GCGC) was held at the Tata Memorial Center in Mumbai, India, from November 19 to 20, 2012. Founded in late 2010, the GCGC aims to provide a platform for highly productive, collaborative efforts on next-generation cancer research through bridging the latest scientific and technology developments with clinical oncology challenges. This year’s presenters brought together highly innovative interdisciplinary views and strategies to meet major challenges in cancer research. The symposium featured 3 major themes: OMICS approaches toward the identification of cancer molecular drivers, single-cell analysis in cancer, and clinical and translational genomics. Each theme was represented in presentations of new findings, with an obvious implication in cross-disciplinary components of OMICs and an overwhelming participation by students. In summary, the GCGC symposium provided a discussion and congregation of the latest advances in basic and translational cancer research and offered the participants with a highly cooperative network environment for future collaboration.
genomics medicine; anticancer target; cancer therapy
The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials.