The Prevention and Treatment of Missing Data in Clinical Trials (2010) / Chapter Skim
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2 Trial Designs to Reduce the Frequency of Missing Data
2 Trial Designs to Reduce the Frequency of Missing Data
Pages 21-38
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From page 21... ...
786) The primary benefit from randomizing clinical trial participants into treatment and control groups comes from balancing the distributions of known and unknown characteristics among these groups prior to study treatments.
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From page 22... ...
There is clearly a need for more research on the specific reasons underlying missing data, a topic addressed in Chapter 3. TRIAL OUTCOMES AND ESTIMANDS A clinical trial typically measures outcomes that quantify the impact of the interventions under study for a defined period of time.
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From page 23... ...
The estimand should be decided before the protocol for a clinical trial is final, since alternative choices of estimand may have important implications for trial design and implementation, the inferences that are made, and the amount of missing data that might be expected. For instance, an important consideration is whether to collect outcome data after a subject discontinues assigned treatment or there are other deviations from the protocol.
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From page 24... ...
A trial design that supports the use of this estimand is a parallel-group randomized trial in which outcome data are collected on all subjects, regardless of whether the study treatment is received. A trial design that does not support the use of this estimand is a parallel-group randomized trial in which outcome data are not collected on participants after they drop out or switch from the assigned treatment.
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Given that in many settings some amount of intolerability or nonadherence is unavoidable, this estimand reflects the effects of an infeasible treatment policy. This estimand provides insight into the magnitude of improvement in efficacy that might be achieved if one could develop therapeutic strategies that produced very high levels of adherence in real-world settings; ultimately, such therapeutic strategies would then need to be evaluated in randomized clinical trials conducted to assess their effect on the estimand "outcome improvement for all randomized participants." A trial design that supports the use of this estimand is a parallel-group randomized design in which all subjects are provided adjunctive or supportive therapies, assuming that such therapies are available and ensure tolerance and adherence.
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. The choice of causal estimand and trial design needs to take into consideration the fact that clinical trials are often part of a larger strategy of exploring various features of an intervention prior to approval.
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Such a design may result in a more efficient study with less missing data, but it likely will not adequately estimate the rate of adverse events in the broader population. Some clinical trials have also used a run-in period to identify participants who are likely to respond positively to the study treatment.
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Allow Rescue Medication in the Event of Poor Response Dropout can be reduced by allowing alternative treatments for participants who are not responding to the study treatment. If this design option is adopted, the estimand and associated outcome measurements need to be carefully defined in the protocol.
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From page 29... ...
However, it is not always useful to use composite outcomes to avoid the occurrence of missing data, since composite outcomes can be difficult to interpret if individual components of the composite provide contrasting evidence about the intervention or if a weaker component dominates. In addition, primary outcome measures that require substantial invasive procedures (e.g., liver biopsies)
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For example, if the primary estimand does not require the collection of the outcome after participants discontinue assigned treatment, such as with the estimand (4) above (area under the outcome curve during tolerated treatment)
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From page 31... ...
This is rarely done and is an area for research.5 It should be added that the most worrisome effect of missing values on the inference for clinical trials is not the reduction of power, though that can be problematic, but biased estimation of the treatment effect. The bias from an unaccounted association between the indicator of missing values and the outcome of interest is not addressed by simply inflating the sample size.
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Trials for Chronic Pain Clinical trials for assessing interventions to relieve chronic pain are often subject to high rates of missing data because of inadequate efficacy and participants' inability to tolerate treatment. Participants who discontinue study treatment usually switch to a proven (approved)
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From page 33... ...
(pain relief in tolerators) , two study designs that limit missing data are a randomized withdrawal design, in which patients are treated with the test treatment open-label for 12 weeks, and subjects who tolerate and have adequate response to the treatment are randomized to continue or to withdraw (e.g., are switched to placebo)
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From page 34... ...
loss to follow-up, and (4) HIV RNA level of greater than or equal to 50 copies/mL at or prior to 48 weeks on study drug.6 Suggested Estimands and Study Designs Again, we emphasize the need to start by determining the causal estimand.
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From page 35... ...
treatment success rate (e.g., the proportion of all randomized participants who stay on assigned treatment, remain in the study, and achieve an HIV RNA level of less than 50 copies/mL at 48 weeks) , which is often the estimand in current practice.
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Trials for Mechanical Circulatory Devices for Severe Symptomatic Heart Failure Device trials in patients with severe symptomatic heart failure have high rates of missing data for measures of functional status and healthrelated quality of life. The missing data arises because of deaths, some of which may be associated with the implantation procedure, failure to attend study follow-up examinations, and inability or unwillingness to perform functional tests or complete self-administered questionnaires.
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From page 37... ...
Also, plans should be developed for visiting patients to obtain the health status assessments if they cannot attend clinic examinations.
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