Clinical Trial Design Challenges in Mood Disorders

Mauricio Tohen, Charles Bowden, Andrew A. Nierenberg, John Geddes

• Publisher: Academic Press
• Year: 2015
• Print ISBN:
  9780124051706
• eBook ISBN:
  9780124051768
• Topic: Medicine
• Subtopic: Pharmacology

Poor clinical trial designs result in failed studies wasting research funds and limiting the advancement of cures for disorders. Clinical Trial Design Challenges in Mood Disorders outlines classic problems researchers face in designing clinical trials and discusses how best to address them for the most definitive and generalizable results. Traditional trial designs are included as well as novel analytic techniques. The book examines information on high placebo response, the generalizability of studies conducted in the developing world, the duration of maintenance studies, and the application of findings into clinical practice. With representation from contributors throughout the world and from academia, industry, regulatory agencies, and advocacy groups, this book will contribute toward improved clinical trial design and valid, precise, and reliable answers about what works better and faster for patients. - Summarizes common trial design problems and their solutions - Encompasses funding, subject selection, regulatory issues and more - Identifies best practices for definitive and generalizable results - Includes traditional trial designs and novel analytic techniques - Represents academia, industry, regulatory agencies, and advocacy groups

Chapter One

Clinical Trial Design of Maintenance Treatments in Bipolar Disorder

Mauricio Tohen, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

This chapter reviews traditional and novel designs in maintenance trials in bipolar disorder. Since 2000, there have been several new and novel designs. Factors that influence design include regulatory and cultural issues.

Keywords

bipolar disorder; clinical trial; design; maintenance treatment

Chapter Outline

Introduction 1

Design of Maintenance Treatment Trials in Bipolar Disorder 2

Need for a Uniform Nomenclature of Course and Outcome in Bipolar Disorders 2

Trial Duration 3

Definition of Outcome 5

Placebo-Controlled Maintenance Studies in Bipolar Disorder 5

Patient Recruitment 6

Course of Illness 6

Symptoms Ratings 7

Statistical Considerations 7

Regulatory Considerations 9

Conclusions 10

References 10

Introduction

The first well-controlled maintenance study in bipolar disorder was published in the early 1970s (Prien, Klett & Caffey, 1973). However, no controlled studies were published for the remainder of the century. It was not until 2000 that Bowden, Calabrese & McElroy (2000) published their results comparing valproate, lithium, and placebo. However, the design of maintenance studies in bipolar disorder gained major interest in recent years due to the availability of new molecules. During the early 2000s, several placebo-controlled studies were published, including the placebo-controlled comparison of lamotrigine versus lithium (Bowden et al., 2003; Calabrese et al., 2003). Soon after, maintenance studies with atypical antipsychotic agents were published starting with olanzapine (Tohen et al., 2005, 2006), followed by studies on aripiprazole (Keck et al., 2007), quetiapine (Suppes et al., 2009), ziprasidone (Bowden et al., 2010), and intramuscular long-lasting risperidone (Quiroz et al., 2010). In this chapter, we will review the major challenges surrounding the design of randomized controlled maintenance trials in bipolar disorder.

Compared with the design of acute studies, maintenance studies have additional inherent complexities, including trial duration, definitions of outcome, type of previous episode, definition of an episode, etc. A major challenge in the interpretation of results across trials is that there have not been consistent definitions of course and outcome, which makes comparison across studies difficult to interpret.

Design of Maintenance Treatment Trials in Bipolar Disorder

Need for a Uniform Nomenclature of Course and Outcome in Bipolar Disorders

Attempts have been made to develop a uniform definition of outcome.

Most recently, under the auspices of the International Society for Bipolar Disorders (ISBD), an international panel of experts proposed operational definitions in order to describe commonly used terms in clinical trials such as remission, recovery, relapse, and recurrence (Tohen, Frank & Bowden, 2009). The consensus panel also proposed definitions for other metrics commonly used in clinical trials and observational studies such as predominant polarity, switch, functional outcomes, and subsyndromal states. The use of consistent definitions is essential to improve patient care in order to make comparisons across studies. The task force acknowledged that the proposed definitions needed to be followed by further validation using existing databases and prospective use in observational studies and clinical trials. The task force suggested possible methodologies to validate the proposed operational definitions; for instance, the ability to predict duration of remission over a subsequent predetermined period could be used to validate response. Other validating techniques include the validation of symptoms severity scales such as the Montgomery and Äsberg Depression Rating Scale (MADRS) with cross-reference with an overall clinical global impression scale such as the Clinical Global Impressions (CGI) (Berk, Ng & Wang, 2008).

Clinical trials have been considered the gold standard for studying the efficacy and safety of pharmacologic treatments. By definition, a clinical trial is an experiment with patients as subjects of investigation (Rothman & Greenland, 1998). In general, the goal of a clinical trial is to evaluate the efficacy and safety of pharmacologic, device, or psychosocial treatments.

An ideal experiment would be designed by creating circumstances where all parameters on two contrasting populations remain stable with the exception of one factor affecting the outcome of interest. In the case of a maintenance treatment clinical trial comparing the difference of two maintenance treatments with the outcome time to a new episode in patients with bipolar disorder, the only variable that is different is the treatment to which patients are assigned through a randomization process (Rothman & Greenland, 1998; Tohen, 1992). Clinical trials represent the most valid tool to establish contrasts between two treatments. Their validity rest in three principles (Miettinen, 1985):

1. use of placebo or sham treatment to assure comparability of effects;

2. use of randomization to assure comparability of populations; and

3. use of blinding to assure comparability of information.

However, clinical trials may have limitations. First, inclusion and exclusion criteria need to be followed. The inclusion of some participants into clinical trials may not be ethical, for instance those with presence of suicidal thoughts or plans, thus limiting the generalizability of the findings. In addition, clinical trial findings may not be generalized if the protocol excluded participants whose condition was at a low risk of a particular outcome during a specified period of time. An example in bipolar disorder could be first-episode patients who had a low risk of relapsing in a short period of time or patients who were at a high risk of relapsing such as patients with a rapid cycling course. Other limitations include the lack of statistical power due to the combination of a small sample size and the selection of a rare outcome, such as relapse to a mixed episode, which would limit the possibility of finding a statistically significant treatment effect difference between treatments even when one does exist.

Trial Duration

In the design of clinical trials for maintenance treatment of bipolar disorder, one of the first questions faced by investigators is how long shall the duration of the trial be. A reasonable approach to the duration question is to take into account the clinical epidemiology of the condition, specifically what is the expected rate of relapses over a specified period of time. In order to differentiate prevention of relapses between two treatments, the duration of the observation time should be long enough to allow events (relapses) to take place. As mentioned above, epidemiologic data obtained from observational studies could be the basis of determining the length of a trial. For instance, Figure 1.1 shows a relapse survival curve of an observational study conducted at McLean Hospital, Belmont, MA (Tohen, Waternaux & Tsuang, 1990). As the curve depicts, 51% of patients had a relapse during the first year of follow-up. From year 1 to year 4, only an additional 23% of patients relapsed.

Figure 1.1 Cumulative probability of not relapsing. Source: Tohen et al. (1990).

These findings can serve as the basis of making the decision of having a double-blind observation period of either 18 months (Tohen, Chengappa & Suppes, 2004) or 12 months (Bowden et al., 2000, 2003; Calabrese et al., 2003; Quiroz et al., 2010; Tohen et al., 2004, 2005, 2006). Other studies in maintenance treatments in bipolar disorder have utilized observation periods as short as 6 months (Bowden et al., 2010; Keck et al., 2007), which may limit the observation of events of interest. Of course, for other psychiatric or medical conditions, the observation period for a maintenance study should be determined by the clinical course of each condition.

An important consideration is that the expected time to relapse not only varies by individual but also within the same individual as the duration of time to new episodes will vary depending on the number of previous episodes in the same individual, which tends to be shorter as the number of episodes progresses but tends to plateau after the occurrence of three or more relapses (Goodwin & Jamison, 2007). It has also been suggested that the definition of relapse/recurrence should depend in the type of the index episode (Ghaemi, Pardo & Hsu, 2004; Goodwin & Jamison, 2007). The rationale is that if the natural course of manic episodes is expected to last 2–4 months and 3–6 months for depressive episodes then a differentiation should be specified in terms of the new episode being relapse to the same period episode or into a new episode (recurrence). In this case, the definition of relapse and recurrence would vary depending on the index episode. In other words, the duration of the remission period to consider recovery would vary depending on the type of the index episode where for index mania recovery would be defined as 8 weeks in remission while for depression recovery would require a longer duration. Therefore, if the goal is to prevent recurrence, then the duration definition would depend on the type of index episode. The ISBD task force based on the available empirical evidence did not support taking the type of index episode into account when differentiating re-emergence of the previous episode from emergence of a new episode. The key point to remember is that if these definitions help us in better understanding the natural course of the condition or the selective use of specific treatments, then its use is r...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Chapter One. Clinical Trial Design of Maintenance Treatments in Bipolar Disorder
• Chapter Two. Meta-Analysis of Clinical Trials in Bipolar Disorder
• Chapter Three. Effectiveness Trials in Bipolar Disorders
• Chapter Four. Long-Term Treatment of Mood Disorders: Follow-Up of Acute Treatment Phase Studies Versus Continuation and Maintenance Phase Studies, and Enriched Versus Non-Enriched Designs
• Chapter Five. The Role of Noninferiority Designs in Bipolar Disorder Clinical Trials
• Chapter Six. The Use of Mixed Methods in Drug Discovery: Integrating Qualitative Methods into Clinical Trials
• Chapter Seven. Sequential Multiple Assignment Randomized Treatment (SMART): Designs in Bipolar Disorder Clinical Trials
• Chapter Eight. Novel Study Designs for Clinical Trials in Mood Disorders
• Chapter Nine. Rating Scales in Bipolar Disorder
• Chapter Ten. Clinical Applicability of Results from Drug Trials in Bipolar Disorder – An Attempt to Shed Light on a Complex Issue
• Chapter Eleven. Clinical Trials in Developing Countries: Challenges in Design, Execution, and Regulation
• Index