The Prevention and Treatment of Missing Data in Clinical Trials (2010) / Chapter Skim
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Appendix A: Clinical Trials: Overview and Terminology
Appendix A: Clinical Trials: Overview and Terminology
Pages 123-138
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From page 123... ...
It is also useful to differentiate among the concepts of a simple treatment, which would usually consist of a prescribed dose of given frequency and duration; a treatment regimen, which would usually involve rules for dose escalation or reduction in order to obtain greater effect while avoiding intolerable adverse experiences; and a treatment strategy, which would
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From page 124... ...
Phase III studies should be much closer to an effectiveness study than would be the phase II studies that might use surrogate biomarkers as a primary outcome in a subpopulation of the patients that might ultimately receive an approved treatment. Whether the primary goal of a clinical trial is effectiveness or efficacy, the scientific validity of the comparison of the new treatment to some standard depends on the comparability of the groups that receive the experimental and control treatments.
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From page 125... ...
In such a case, an indication for a new treatment might indicate the treatment's use only in patients for whom the standard therapy is a priori judged inadvisable due to concurrent medical conditions (e.g., pediatrics, pregnancy, poor renal function in a drug cleared by the kidneys) or who cannot take the standard therapy (e.g., due to lack of tolerance with respect to side effects or lack of efficacy)
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From page 126... ...
Initially, some targeted disease is characterized from observational studies (including epidemiologic studies of risk factors for the disease) , clinical observation of typical disease progression and predictors of outcomes, and laboratory studies of biochemical and histologic changes in the diseased
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From page 127... ...
When sufficient preclinical studies have been performed to conclude that the treatment is basically safe, work moves to experiments in human volunteers. In order to sequentially investigate safety and then efficacy and effectiveness issues in a manner that protects human subjects from harm, the process of investigating new treatments typically goes through a phased series of clinical trials.
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From page 128... ...
Such a screening process is more efficient than other approaches in finding effective treatments from a large population of ideas. Even when the phase II clinical trials demonstrate a desired effect on the biologic outcome, it is common for investigators to use the results of the clinical trial to identify more specific factors: • a more precise definition of the disease characteristics that would indicate the types of patients likely to benefit most from the treatment, • a more refined definition of the population to be treated in order to eliminate subjects who might experience greater toxicity, • a single treatment regimen (dose or dosing strategy, frequency, duration, auxiliary prophylactic, or rescue therapies)
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From page 129... ...
Depending on the disease and patient population, anecdotal occurrence of unexpected extremely serious adverse events will often dictate further study of a proposed treatment. Evidence from phase III studies that strongly support the proposed indication will generally lead to adoption of the therapy.
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From page 130... ...
The other is that if the observed difference in treatment benefit/risk is spurious, the commercial sponsor will have lost income from sales to B as well as having the added expense of further studies in that subgroup. Phase IV clinical trials are postmarketing trials that are meant to evaluate rare but serious effects that cannot be assessed in the smaller Phase III studies.
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From page 131... ...
In addition, the care that the comparison groups receive might not be the standard of care the patient would have received in the absence of the randomized controlled trial. Moreover, the primary outcome may not be the clinical outcome of greatest public health relevance because it may be measured using techniques or
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From page 132... ...
Third, the comparison group in the efficacy trial does not encompass the true standard of care that patients would receive in the absence of the experimental treatment, and the experimental treatment does not provide added benefit over that standard of care. Fourth, the primary outcome used in the efficacy trial is not predictive of the true clinical outcome, because (a)
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From page 133... ...
, and duration. • Treatment regimen includes nominal experimental treatment as above, prescribed prophylactic treatments to prevent adverse events, dose modifications in the presence of adverse events or demonstrated efficacy, and prescribed auxiliary treatments for known adverse events.
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From page 134... ...
The other is surrogate outcomes, which include modification of risk factors for clinical outcomes (e.g., blood pressure, HbA1c) , intermediate subclinical outcomes (e.g., tumor progression)
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From page 135... ...
6. Reduced follow-up after study treatment discontinuation: a subject has stopped nominal treatment or treatment regimen, as well as most invasive or inconvenient monitoring schedule, and but is still followed for passively observable major clinical outcomes (e.g., survival)
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From page 136... ...
• Safety population: covers the patients included for the experimental treatment population, but any patient receiving the experimental intervention is analyzed with the experimental group. Types of Clinical Trial Data The types of data collected in a clinical trial can be characterized by their ultimate use:
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From page 137... ...
and on realized treatment, which includes duration of treatment, cumulative dosing, and dose intensity. • Postrandomization concomitant or auxiliary treatments: data include safety and efficacy outcomes, including intermediate measures and surrogate measures, as well as measures of secondary outcomes.
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From page 138... ...
Here is an outline of the steps leading to a comprehensive sensitivity analysis for such models: (1) Presumed mechanisms of missing data: steps would include identification of data likely to be missing, speculation on mechanisms leading to that missing data, and specification of analyses of missing data patterns.
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