Can we effectively assess a new treatment arm within an ongoing trial?
If the statistical concepts identified within this review are considered and addressed during the design of a trial amendment, it is possible to effectively assess a new treatment arm within an ongoing trial without compromising the original trial outcomes. Confirmatory clinical trials can take many years to run, requiring considerable resources.
What is a multiple arm clinical trial?
Trials involving several arms, or randomized trials, treat randomly-selected groups of patients with different therapies in order to compare their medical outcomes.
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How can optimal allocation of treatment arms increase power?
An increase in overall power can be achieved when optimal allocation is used once a treatment arm has been added to the trial, rather than continuing with equal allocation to all treatment arms. Keywords: Adaptive design; Adding a treatment arm; Family-wise error rate control; Multiple testing; Optimal allocation.
What is a treatment arm?
Treatment Arm: A group or subgroup of participants in a clinical trial. Each group receives a specific intervention, study drug dose, or sometimes no intervention, according to the study protocol. Randomization: The process in which study participants are randomly assigned to different treatment groups.
What is on treatment population?
In an ITT population, none of the patients are excluded and the patients are analyzed according to the randomization scheme. In other words, for the purposes of ITT analysis, everyone who is randomized in the trial is considered to be part of the trial regardless of whether he or she is dosed or completes the trial.
What is arm in RCT?
The RCT design most familiar to most people is probably the standard two-armed, parallel-design, individually randomised trial. The two arms in this case generally include the treatment arm and the control arm (alternative treatment/placebo arm).
What does single arm mean in clinical trials?
The simplest trial design is a single-arm trial. In this design, a sample of individuals with the targeted medical condition is given the experimental therapy and then followed over time to observe their response.
What is ITT and mITT?
Trials were categorized based on the "type" of intention-to-treat reporting as follows: ITT, trials reporting the use of standard ITT approach; mITT, trials reporting the use of a "modified intention-to-treat" approach; and "no ITT", trials not reporting the use of any intention-to-treat approach.
What is on treatment?
In many randomized clinical trials, assessment of safety relies on so-called on-treatment analysis, where data on adverse events are collected only while the participant is taking study medication and perhaps for a few (7, 14, or 30) days after stopping.
What is a 3 arm study?
A 3-arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment.
What does Arm mean in research?
Arm refers to each group or subgroup of participants in a clinical trial that receives specfic interventions (or no intervention) according to the study protocol.
What is a 2 arm study?
For a two-arm study, with two short-term outcomes, study participants are randomised to either the control or active intervention arms.
What is the difference between cohort and arm?
Multiple arms allow the effects of different interventions to be compared. Participants in a control arm may receive no intervention, placebo, or an intervention with a known effect. In observational studies, a pre-defined population may be observed over time and is termed, a cohort.
What are the 4 phases of clinical trials?
Each stage of a clinical trial has its own purpose in ensuring that a treatment is safe and effective for use by the public....Phases of Clinical TrialsPhase 1 Clinical Trial. ... Phase 2 Clinical Trial. ... Phase 3 Clinical Trial. ... Monitoring Post-FDA Approval.
Can a single arm study be randomized?
While Phase 3 trials are frequently randomized in order to provide more precise data on safety and effectiveness outcomes, a Phase 3 trial might use a single arm if a small target population makes conducting a randomized trial impractical.
Abstract
Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time.
1 INTRODUCTION
In recent years, a multiarm multistage design is becoming an attractive alternative to the classical randomised treatment‐control design, especially in phase II and phase III trial settings.
3 A CASE STUDY
We first describe a completed study and illustrate how one might make the optimal decision after observing stage one of the trial. Then, we show the role of the prior distribution on the decision made.
4 RELATIONSHIP BETWEEN STAGE ONE RESPONSES AND OPTIMAL DECISION
We now explore how the optimal decision depends on the stage one data. Having chosen the utility and the values of { m10, m20, v10, v20 }, we can identify the optimal decisions for a range of stage one mean response of treatments.
5 DISCUSSION
The development of treatments for diseases is a long process. It is often the case that potential treatments are not available at the same time for conducting phase II/III studies. This work highlights the benefits of adding a new treatment arm to an existing study at an interim analysis.
ACKNOWLEDGEMENTS
This research has been funded by the Medical Research Council (grant codes MR/N028171/1 and MC_UP_1302/4). We acknowledge Dr. Siew Wan Hee for comments on this work. Data sharing is not applicable to this article as no new data were created or analyzed in this study.
1 THE DERIVATION OF EXPECTED GAIN OF ADDING AN ARM
This section illustrates the intermediate steps of obtaining the expected utilities in Section 3.2, ie,
What is statistical treatment?
‘Statistical treatment’ is when you apply a statistical method to a data set to draw meaning from it . Statistical treatment can be either descriptive statistics, which describes the relationship between variables in a population, or inferential statistics, which tests a hypothesis by making inferences from the collected data.
Why do you need to know statistical treatment?
This is because designing experiments and collecting data are only a small part of conducting research.
Why is guidance needed for adding new arms to existing trials?
Guidance is needed to allow amendments that add new arms to existing trials to be made only with robust statistical integrity. The benefits in cost, time and patient resource savings from such amendments are clearly very substantial; and therefore further methodological work in this area is the subject of current research, so that the addition of new arms to existing trials can, in the future, be recommended and encouraged.
How can clinical trials speed up research?
Recent initiatives in clinical trials are aimed at speeding up research by making better use of scarce resources. For example, the FDA’s Critical Path Initiative ‘to drive innovation in the scientific processes through which medical products are developed, evaluated, and manufactured’ included the production of guidance on adaptive designs to increase the efficiency of studies. In the UK, the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme recently released a call for ‘Efficient Study Designs’ with a focus on research that ‘will demonstrate particular design features to allow either more rapid conduct, or lower costs’. It is clear that there is the demand to improve the efficiency of clinical trials in order to speed up the overall process of getting the best therapies to patients. If a suitable treatment emerges whilst a trial in a similar population is ongoing, there would be many advantages to modifying the existing trial by adding the new arm, as long as the statistical considerations are addressed appropriately.
What happens if an amendment compromises the statistical validity of a trial?
If the amendment compromises the statistical validity of the trial such that a primary hypothesis cannot be answered, it may render the trial unethical and waste resources.
Is adding an arm advantageous?
Only a very small number of trials were identified to have added arms in practice, indicating that although this type of amendment may be advantageous , it is very rarely implemented. Of the trials that had added an arm, some failed to adequately address the statistical issues and suffered from lack of power and difficulties of interpretability. However, it is clear that this type of amendment is desirable and advantageous, with the statistical and logistical issues seeming by no means insurmountable.