Clinical Trials Methodology Conference 2011

4-5 October 2011 - Bristol

The "Clinical Trials Methodology Conference" was the first of its kind in the UK and it attracted a large audience of 450 delegates. Three plenary sessions and eighteen contributed sessions focussed on a wide variety of methodological issues.

Conference Abstracts

Plenary Session Presentations

Scientific Session Presentations

Click on the sessions below to view the slide presentations.

Aims

  • Review and discuss designs that change the allocation ratios, endpoints, dropping/adding treatment arms and/or early stopping rules
  • illustrate application of novel designs either using Bayesian or classical approaches
  • estimate treatment effects and the use bias reduction methods
  • design multiple trials so that better decisions are made during the life-course of intervention development; this includes seamless trials

Oral Presentations

Clinical trials collect data on both efficacy and safety. Whereas efficacy data are collected, verified, analysed and reported to address specific trial hypotheses, the handling of safety data is sometimes not as robust. One particular aspect of current importance relates to meta-analyses of safety data based on published summary data. Unfortunately, meta-analyses of safety data are sometimes published without adequate consideration of the comprehensiveness and validity of the input data which might come from both RCTs and observational data, the use of fixed vs random effects modelling, inability to adjust for potentially important covariates, handling of missing data, use of different comparators, Simpson's paradox and, critically, multiple testing. Meta-analytic techniques have the potential to play an important role in the identification and quantification of important safety signals; however they must be robustly conducted in order to make appropriate conclusions.

Aims

  • highlight the potentially important role of meta-analyses for the identification and quantification of safety concerns with marketed medicines
  • review current standards of published meta-analyses on safety
  • discuss methodological issues to be considered when performing, describing and publishing a meta-analysis and the potentially misleading nature of meta-analyses conducted to poor methodological standards
  • present and discuss a case study

Oral Presentations

Clustering is commonly encountered in pragmatic trials, in both cluster and individually randomised controlled trials.

Aims

  • review and discuss how we can account for therapist and group effects within the context of individually randomised controlled trials
  • identify sources of clustering and how these should be accounted for in the design and analysis of both types of trials
  • consider advances in the sample size estimation of cluster randomised trials, including how to deal with variation in cluster size within the sample

Oral Presentations

Complex interventions are widely used in the health service, in public health practice, and in areas of social policy that have important health consequences, such as education, transport, and housing’. The ‘MRC Framework for the Development and Evaluation of Complex Interventions’, sought to improve the design and feasibility of such trials. Since then, the Framework has been updated, and it has been applied in a wide variety of different trial settings.

Aims

  • review and discuss the process of developing, designing and running trials of complex interventions.
  • address the methodological challenges in these trials
  • review new methodologies or offer empirical evidence on the value of different approaches
  • describe first hand experience of such trials

Oral Presentations

It is becoming increasingly clear that there is great heterogeneity in response of specific types of cancer to individual treatments. The integration of biomarkers that may predict sensitivity or resistance to individual treatments poses major methodological issues for the design and implementation of clinical trials.

Aims

  • discuss challenges of designing, implementing and analysing trials using biomarkers
  • review examples of trials in the oncology and cardiovascular fields that have successfully used biomarkers

Oral Presentations

This session will address current and perceived future challenges with equivalence trials and non-inferiority trials.

Aims

  • historical demonstration of efficacy and safety of reference treatment;
  • what information is necessary to assure a trial will have assay sensitivity (both before the trial begins and when it is completed);
  • choice of endpoint (i.e. Should it be the same as for earlier studies of the reference product, or different?)
  • should the endpoint be the most clinically important, or the most sensitive?

Oral Presentations

The last two decades have seen increasing use of the clinical trial as a vehicle for evaluating the cost-effectiveness of health care interventions. Over that time, the methods for trial-based economic evaluation have developed rapidly.

Aims

  • reflect on the rapid development of the methodology for economic evaluation alongside clinical trials
  • ask what is the future role of the clinical trial for informing economic evaluation.

Oral Presentations

In most trials outcomes are not obtained for some participants. The choice is to omit them from the analysis or impute the data.

Aims

  • discuss the impact of missing outcomes for some trial participants on trial results
  • review simple and more complex imputation strategies for accounting for missing data
  • consider recent advances in imputation methods and software

Oral Presentations

Accurate and consistent selection and reporting of clinical and patient reported outcomes in trials is critical to inform systematic reviews and meta-analyses, to allow cross study comparisons and to reduce reporting bias. Inclusion of patient reported outcomes (PROs) alongside clinical outcomes in trials has greatly increased, but PROs still seem to be under used once their relevance to clinical decision-making has been taken into account. Selection and reporting of valid and reliable clinical and patient reported outcomes in trials is needed. There is also a need to improve methods for reporting patient reported outcomes from trials to ensure that they are clinically meaningful, understood by clinicians, and used in clinical practice.

Aims

  • review strategies for the process of designing trials with PRO endpoints
  • address the challenges of PRO and clinical data analyses and presentation with examples of successes and problems
  • consider future research on strategies to optimize the use of PROs in trials
  • highlight methods for developing core outcomes sets to be reported as a minimum in trials
  • review methods for incorporating patient reported outcomes into core outcomes sets

Oral Presentations

It is now generally accepted that patients and the public have a right to be involved in decisions about the prioritisation, design, conduct and dissemination of research that can affect their lives. There are also many published accounts of how patient and public involvement (PPI) has made important contributions to clinical trials. Yet many questions remain about the most effective methods of PPI. This session will focus on the methodological issues, from the researcher’s perspective, in involving patients and the public where the goal is to improve the design and conduct of clinical trials.

Aims

  • different models for PPI in clinical trials and their advantages and disadvantages
  • pptimising PPI to the diverse needs of different trials
  • selecting, training and sustaining the engagement of PPI representatives
  • training and supporting the clinical trial community in implementing PPI
  • methods for assessing the impact of PPI on clinical trials, including what outcomes of PPI should be assessed
  • methods for assessing the effectiveness and cost-effectiveness of PPI in clinical trials

Oral Presentations

Pharmaceutical and biotechnology companies trying to limit the cost of drug development attempt to progress rapidly through late-phase exploratory development in order to start Phase III "confirmatory" trials as rapidly as possible. It is hypothesised that this results in decisions being made about which products to progress to large and expensive Phase III trials and decisions on how to design these trials that are ill-informed. In fact, there is a myriad of questions to try to address in Phase II "exploratory" trials, including the quantification of dose-response, dose selection, preliminary estimates of efficacy and safety to inform the "go / no-go" decision and the design of Phase III trials. The data generated to inform these decisions is frequently imprecise because of the size, scope and methodology of the prevailing exploratory development paradigm.

Aims

  • discuss the aims of late-phase exploratory trials
  • present different possible designs for this type of trial
  • introduce methodologies available to quantitatively compare different possible designs

Oral Presentations

Pragmatic trials estimate the effectiveness of a treatment, device or therapy in everyday healthcare practice. The characteristics of a pragmatic trial are that the variability in the sample is reflective of the entire patient population in which the treatment is indicated; comparison is usually best current practice; placebos are not usually used and hence patient and healthcare practitioners are not always blinded; the outcomes are of health policy and practice relevance and may include an economic appraisal. The trials are usually large, and run over many centres to maximise the generalisability of the findings.

Aims

  • provide an overview of the differences between exploratory and pragmatic trials
  • provide an update of new designs and methods being used in pragmatic trials
  • encourage a discussion of the methodological and practical challenges in running pragmatic trials

Oral Presentations

Failure to recruit adequate numbers of participants to randomised trials can lead to equivocal results or premature termination of the trial. This has implications for participants, funders and researchers. Recruitment to RCTs is complex. Reviews have highlighted delays in start-up for a significant number of trials, and poor recruitment (McDonald, 2006, Bower 2007). Factors from trial design, clinician and participant requirements, through to consent and follow-up procedures may influence recruitment.

Aims

  • review the methodological approaches that have been tested to improve recruitment to randomised trials
  • make recommendations on the future research directions on innovative new strategies for enhancing recruitment to randomised trials

Oral Presentations

In recent years there has been an increase in the regulatory and research governance burden for clinical trials in the UK. This has been driven by the translation of the EU Directive on clinical trials into UK law through the Clinical Trials Regulations which, although only relevant for trials of Investigational Medicinal Products (IMPs), has also had an impact on trials of other interventions. In parallel, the NHS Research Governance Framework which applies to all research within the NHS has increased the requirements for research governance for all types of clinical research. Whilst no one would question the need to ensure that all research is conducted to the highest standard to ensure the safety of participants and the reliability of the results, there are concerns that overly rigorous interpretation of the regulations has led to excessive and often inappropriate demands being made on those undertaking non-commercial trials who do not have a large regulatory affairs department to support them as in the pharmaceutical industry. There are many examples of the delays and increased costs of clinical trials as a result of the regulatory and governance demands.

Aims

  • discuss and give examples of the challenges faced
  • illustrate examples of efforts to minimise these demands and to ensure that management and oversight is proportionate to the risks to the participants and the results of the trials.
  • review the particular challenges of multicentre trials and those involving more than one EU country
  • discuss the Review undertaken by the Academy of Medical Sciences in 2010
  • Interim reports for data monitoring committee review vs final reports for regulatory filing A practical solution to ‘continuing care site’ issues in neonatal clinical trials

Oral Presentations

Difficulties with retaining participants in a trial and in dealing with lack of adherence to the trial intervention are common problems in trials. These issues are relevant for trials of long-term treatments (eg in TB and HIV) and of complex interventions. It may be an issue for the conduct and analysis of trials rather than design.

Aims

  • review and discuss trials of methods to improve retention and adherence
  • discuss the strengths and weaknesses of cluster and other designs to reduce contamination
  • discuss the design of feasibility studies to examine and improve adherence to trial interventions (rather than concentrating on recruitment)
  • discuss the implications of poor adherence – Is it a problem or is it a useful indicator of poor effectiveness of an intervention?
  • examine the interpretation of ITT analyses with contamination between arms

Oral Presentations

Time-to-event outcome measures are used in many trials. Some examples of such measures are time to disease recurrence, time to relief of symptoms and time to death. This session will consider newer methods for the design and analysis of such trials, with particular emphasis on the analysis. There are now some ‘standard’ tools to analyse such data which include the logrank test, hazard ratio, Kaplan-Meier curves and Cox Models. However, a number of these tools are used uncritically and make assumptions, such as proportional hazards. We also need alternatives or extensions of these methods for dealing with more complex situations, for example when there is unplanned crossover in the trial. A number of extensions of, and alternatives to, these methods have been proposed when assumptions cannot be assumed to hold, and when things are more complex.

Aims

  • present some of these methods looking at them critically both from a methodological and practical perspective, with the aim of proposing a broader range of practical methods for routine use in trials.

Oral Presentations

This session will address challenges in developing and testing therapies when there are a limited number of patients available to enter trials.

Aims

  • review real scenarios where solutions to the problem of small patient numbers have been successfully implemented
  • review cases of unsuccessful implementation but where important lessons can be learned
  • discuss issues arising post-trials, particularly collecting and assessing safety data as well as further efficacy data

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