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  1. Home
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  3. Clinical Trials in Neurology
  • Cited by 8
Publisher:
Cambridge University Press
Online publication date:
May 2012
Print publication year:
2012
Online ISBN:
9781139032445
DOI:
https://doi.org/10.1017/CBO9781139032445
Subjects:
Statistics for Life Sciences, Medicine and Health, Neurology and Clinical Neuroscience, Medicine, Statistics and Probability
Information

Book description

Translating laboratory discoveries into successful therapeutics can be difficult. Clinical Trials in Neurology aims to improve the efficiency of clinical trials and the development of interventions in order to enhance the development of new treatments for neurologic diseases. It introduces the reader to the key concepts underpinning trials in the neurosciences. This volume tackles the challenges of developing therapies for neurologic disorders from measurement of agents in the nervous system to the progression of clinical signs and symptoms through illustrating specific study designs and their applications to different therapeutic areas. Clinical Trials in Neurology covers key issues in Phase I, II and III clinical trials, as well as post-marketing safety surveillance. Topics addressed include regulatory and implementation issues, outcome measures and common problems in drug development. Written by a multidisciplinary team, this comprehensive guide is essential reading for neurologists, psychiatrists, neurosurgeons, neuroscientists, statisticians and clinical researchers in the pharmaceutical industry.

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Contents

Page 2 of 2

Contents
  • 19 - Premarket Review of Neurological Devices
    pp 206-214
  • View abstract

    Summary

    Selection designs and futility designs offer investigators a way to screen potential therapies in early phase clinical research with fewer patients than would be required for a traditional phase 3 trial for each candidate. There are some avoidable-pitfalls when planning a futility study. The first is that if the sample size is too small, a rather awkward situation can arise. The last pitfall relates to the use of historical control data in the single-arm design. Selection procedures offer an attractive approach to the problem of screening potentially good treatments. There are many different procedures for general ranking and selection goals such as selection from among more than two treatments, selection of best subsets of treatments, and ranking treatments in order of efficacy. Although selection procedures efficiently achieve their goal of selecting best treatments, the desire to 'test something' with an accompanying statement of statistical significance seems irresistible.
  • 21 - Alzheimer’s Disease
    pp 227-241
  • View abstract

    Summary

    The rapid proliferation of interest in adaptive designs, and inconsistent use of terminology, has created confusion about similarities and differences among the various techniques. This chapter focuses on some specific adaptive designs that have received the most attention to date. Although many adaptive designs employ the use of Bayesian statistical techniques, it is important to consider both Bayesian and Frequentist approaches to adaptive designs. Adaptive designs are generally well accepted and encouraged for early phases of drug development. For confirmatory trials, regulatory agencies will accept some adaptive designs but are cautious about others. A number of adaptive designs have been classified as 'generally well understood adaptive designs with valid approaches to implementation' in the FDA guidance document on adaptive designs. The major barriers to the implementation of adaptive designs in future clinical trial protocols are primarily logistical, rather than statistical.
  • 22 - Acute Ischemic Stroke
    pp 242-256
  • View abstract

    Summary

    This chapter describes crossover trials and their applications in neurology. Crossover trials could be used to study aspects of many common neurological disorders and psychiatric disorders. To illustrate the efficiency of crossover designs, the chapter presents sample size estimates for two placebo-controlled parallel and one crossover design for a trial examining the efficiency of donepezil in treating dementia in patients with Parkinson's disease. It also describes approaches to mitigate carryover effects. Alternatives to the 2 x 2 design are used to increase efficiency, provide unbiased estimates in the presence of carryover effects, and to compare more than two treatments. This chapter reviews response adaptive designs, matching and N of 1 trial along with several recent innovations in design. Simple carryover depends only on the treatment in the period prior to when carryover occurs. Crossover trials have logistical challenges beyond the careful planning and implementation that accompanies any successful clinical trial.
  • 23 - Multiple Sclerosis
    pp 257-272
  • View abstract

    Summary

    Special trial designs have been developed to distinguish the symptomatic and disease modifying effects of treatment using clinical outcome measures. These designs, termed 'two-period' designs, include the so-called withdrawal and delayed-start (or 'staggered-start') designs and their variations. This chapter describes these study designs in terms of their rationale, assumptions, design features, implementation, statistical analysis, and sample size considerations. It also discusses the important limitations of the designs. Simulation studies using disease progression modeling suggest that the withdrawal design may provide more power than the delayed start design to detect disease-modifying effects of a treatment. A statistical model for data from a complete two-period design assumes that a normally-distributed outcome termed µ 2. There are alternative approaches to evaluating the disease-modifying effects of an intervention that require only a single treatment period.
  • 24 - Amyotrophic Lateral Sclerosis
    pp 273-283
  • View abstract

    Summary

    Enrichment designs are being increasingly used in fields such as chronic pain research because they may better reflect routine clinical practice than other study designs. Researchers use a variety of methods to perform the first stage of an enrichment design trial. This chapter examines the varied strategies involved in developing a trial using an enrichment design, the advantages and disadvantages of this method and considers the issues when planning a study using enrichment strategies. Issues related to washout periods were considered in the trial using the enrichment design to examine the use of gabapentin for treatment of postherpetic neuralgia (PHN). The distinction between enrichment by response and enrichment by expected mechanism of action is significant. An enrichment design is well suited to examine treatments with small effect sizes in a general population with increased efficiency, particularly those treatments with a greater expected effect in a particular subpopulation of subjects.
  • 25 - Epilepsy
    pp 284-294
  • View abstract

    Summary

    This chapter mentions multi-arm randomized trials in multiple hypothesis testing and non-inferiority trials with more than two treatments. Randomization is as central to the conduct of noninferiority as it is to superiority trials. Well-defined endpoints, clearly prioritized and stated in advance, are important components of powerful trials yielding useful results. As with most aspects of the analysis of a randomized clinical trial, the standard to which the worst performance of the treatment vs. the control is to be compared should be specified in advance. Non-inferiority trials can make useful scientific contributions when ethical considerations disallow a placebo or other inactive control. However, unlike the scenario of a superiority trial with a placebo, their assay sensitivity is not directly ensured by randomized comparison and so there are numerous cautions in their use. The measures of study quality mentioned in key comparisons between superiority and noninferiority trials are examined.
  • 26 - Insomnia
    pp 295-308
  • View abstract

    Summary

    Accumulating data may be reviewed regularly in all phases of clinical development for decision-making based on safety or clinical benefit. This chapter discusses the process of reviewing accumulating clinical trial data in a formal manner. It provides an overview of the structure and the operations of a data monitoring committee (DMC), and elucidates the statistical issues and challenges of interim monitoring. The chapter describes several commonly used approaches for interim monitoring. Multi-center trials must be coordinated and administered efficiently. A DMC's objectivity is in part due to independence of the members. A formal statistical framework can enhance the objectivity by providing a universal language to communicate the accumulating evidence. Group sequential methods for determining the critical values to be used during interim analyses represent a key advancement in the theory and application of sequential analyses. EAST is highly regarded as an excellent tool for interim monitoring of clinical trials.
  • Section 7 - Part
    pp 309-361
  • View abstract

    Summary

    This chapter discusses the broad categories of clinical investigations used in post-market drug safety assessment. It presents the three main methods of clinical post-marketing safety assessment: case reports and case series; observational epidemiological studies; and clinical trials. Active surveillance systems are also being explored to identify and examine drug safety issues. Drug safety active surveillance systems, which take advantage of large repositories of automated healthcare data, are now being developed and tested by multiple organizations. The two most common observational epidemiological study designs are the case-control design and the cohort design. The majority of clinical trials are performed primarily to assess the efficacy of a product. The design of a post-marketing clinical trial testing a safety hypothesis is often an active-controlled trial that uses a non-inferiority study design. Relative to observational epidemiological studies, clinical trials designed to answer drug safety questions are usually more costly and more time-consuming.
  • 28 - Clinical Trial Implementation, Analysis, and Reporting:
    pp 338-351
  • An Academic and Industry Perspective
  • View abstract

    Summary

    This chapter discusses the basic ethical principles and practices for human experimentation. It touches on the related subject of regulatory and legal issues in neurological research. Disorders of the central nervous system (CNS) present a number of challenges for specifying core principles and practices of research ethics. In CNS research, the tensions between regulation and ethics are greatest around the use of placebo controls. Phase 1 trials of new CNS interventions, as with all interventions, generally present a high degree of risk and uncertainty. Many trials involving neurological disorders show evidence of placebo responses. Many CNS drug trials involve brain imaging, in one report, brain abnormalities, like malignancies or vascular malformations, were detected in as many as 18% of healthy volunteers. Issues of justice arise with particular frequency whenever CNS trials involve placebos. Researchers should also attend to various non-verbal or affective elements of communication that shape public expectations.

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