Neuroscience Trials of the Future Proceedings of a Workshop (2016) / Chapter Skim
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3 Clinical Trial Design
3 Clinical Trial Design
Pages 15-36
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From page 15... ...
. • Trial designs should be fit-for-purpose, and employ appropriate statistical expertise in the planning stage (Pencina)
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RDoC, described below, is one attempt to address these problems. In addition, several participants noted the need for better disease modeling -- using both existing and new tools -- and novel trial designs and statistical approaches.
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For example, diagnosing a major depressive episode requires a patient to exhibit five of nine symptoms. Many of these symptoms, such as sleep disruptions or hallucinations, occur across multiple diagnostic categories.
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NIMH encourages investigators to adopt RDoC principles in their clinical trials by focusing on functional domains or symptoms, thus increasing the probability that participants' disorders will share the same mechanism. Figure 3-1 illustrates NIMH's vision of this approach (Insel and Cuthbert, 2015)
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Enrollmeent criteriaa could be diiagnostically agnostic; an example is rrecruiting bassed on preesence of a syymptom such as psychosiss regardless oof the particullar diagnoosis (e.g., sch hizophrenia orr some other disorder) , orr perhaps in tthe future,, expression of a particu ular gene relaated to a psychopathologgic mechaanism.
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An analysis of associations between psychiatric disorders with other medical conditions culled from 1.5 million patient records showed an increased risk of nearly every psychiatric disorder with every other medical disorder, suggesting significant shared genetic variation (Rzhetsky et al., 2007)
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depression symp ptoms. Green liines represent positive assocciations, red lines negativ ve ones, and thhe thickness andd brightness off an edge indicaate the assoociation streng gth.
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For example, pharmacodynamic biomarkers may be used in early-stage drug development to demonstrate target engagement, while in later stages, prognostic or predictive biomarkers may be used to stratify participants in a clinical trial or demonstrate treatment response. Throughout the workshop, several participants expressed the need for more validated biomarkers in the field.
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Many different neuroimaging modalities may yield potential biomarkers, including structural magnetic resonance imaging (MRI) , diffusion tensor imaging (DTI)
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has also been applied to other clinical studies, including the aripiprazole and risperidone study mentioned at the beginning of this chapter, in which no difference in efficacy was seen. Among study participants who had undergone baseline restingstate fMRI scans, responders tended to have lower SCI than nonresponders, further supporting its potential as a predictive biomarker.
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ADNI was launched in 2004 with the initial goal of developing imaging and biochemical biomarkers for the early detection of AD, as well as for use in clinical trials. However, the impact of ADNI on the AD field and beyond has been far broader, said Alice Chen-Plotkin, assistant professor of neurology at the Perelman School of Medicine, University of Pennsylvania.
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. Identifying biomarkers to expedite clinical trials in Parkinson's disease (PD)
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In addition, Chen-Plotkin noted that biorepositories and sharing of biospecimens will enable the more efficient development of a wide range of biomarkers. CLINICALLY MEANINGFUL OUTCOMES In recent years, regulators and payers have increasingly required that clinical studies demonstrate not only statistical significance of an effect, but even more importantly, clinical significance (Ranganathan et al., 2015)
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, noted Adrian Felipe Hernandez, professor of medicine at the Duke University School of Medicine. NOVEL CLINICAL TRIAL DESIGNS Statistical Approaches and Considerations Many design and methodology approaches can increase trial efficiency, said Michael Pencina, director of biostatistics at the Duke Clinical Research Institute and professor of biostatistics and bioinformatics at Duke University.
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Following interim analysis those arms showing greater effect sizes could be enriched. • Sequential parallel comparison designs are used to reduce the impact of the placebo response.
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Clinical trials that allocate participants equally to the treatment and placebo arms are typically suboptimally powered, said Snowberg, in part because of the high rate of dropouts. More power can be achieved by randomizing more participants to the treatment arm.
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In the United Statees, the most ccommonly ussed treatm drug iss fosphenytoiin; however, a newer drugg, levetiracetaam, is easier to use annd has fewer side s y evidence ffrom uncontrrolled studies in effects, yet Europee, India, and other o places suggest s that vvalproic acid iis superior, saaid J Kappur.
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If a patient continues to seize and meets the inclusion criteria, the physician administers the study drug, which has been provided in prerandomized, blinded study boxes. The outcome is absence of seizures and regaining of consciousness at 60 minutes.
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This led to the creation of the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (Hernandez et al., 2009) , a large pragmatic trial focused on understanding clinically meaningful outcomes in the context of real-world use.
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. DEVELOPING MORE EFFECTIVE THERAPEUTICS THROUGH PRECISION MEDICINE: IMPLICATIONS FOR CLINICAL TRIALS Opportunities may also emerge from examination of success in other fields, said Shitij Kapur, executive dean and head of school at the Institute of Psychiatry, Psychology & Neuroscience, King's College London.
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Specifically, he noted that developing biomarkers that predict disease progression and treatment response longitudinally is needed for nervous system disorders. Several participants added that using multimodal approaches rather than a single approach may help to show which drugs or other intervention approaches work best for which patients.
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