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Publication Guidelines

Mitigating the Effects of Nonadherence in Clinical Trials (open access)

Thomas M. Shiovitz,MD , Earle E. Bain,MD, David J. McCann, PhD, Phil Skolnick, PhD, Thomas Laughren,MD, Adam Hanina,MBA, and Daniel Burch,MD
The Journal of Clinical Pharmacology 2016, 56(9) 1151–1164 C  2016, The American College of Clinical Pharmacology DOI: 10.1002/jcph.689
Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study.Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM)Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Emerson M. Wickwire , Scott G. Williams, Thomas Roth, Vincent F. Capaldi, Michael Jaffe, Margaret Moline, Gholam K. Motamedi, Gregory W. Morgan, Vincent Mysliwiec, Anne Germain, Renee M. Pazdan, Reuven Ferziger, Thomas J. Balkin, Margaret E. MacDonald, Thomas A. Macek, Michael R. Yochelson, Steven M. Scharf, Christopher J. Lettieri
Neurotherapeutics April 2016, Volume 13, Issue 2, pp 403-417
Disturbed sleep is one of the most common complaints following traumatic brain injury (TBI) and worsens morbidity and long-term sequelae. Further, sleep and TBI share neurophysiologic underpinnings with direct relevance to recovery from TBI. As such, disturbed sleep and clinical sleep disorders represent modifiable treatment targets to improve outcomes in TBI. This paper presents key findings from a national working group on sleep and TBI, with a specific focus on the testing and development of sleep-related therapeutic interventions for mild TBI (mTBI). First, mTBI and sleep physiology are briefly reviewed. Next, essential empirical and clinical questions and knowledge gaps are addressed. Finally, actionable recommendations are offered to guide active and efficient collaboration between academic, industry, and governmental stakeholders.

Biomarkers for drug development in early psychosis: Current issues and promising directions

Goff DC, , Romero K, Paul J, Perez-Rodriguez M, Crandall D, Potkin SG
European Neuropsychopharmacology 2016.01.009 (Public Access permission obtained)
A major goal of current research in schizophrenia is to understand the biology underlying onset and early progression and to develop interventions that modify these processes. Biomarkers can play a critical role in identifying disease state, factors contributing to underlying progression, as well as predicting and monitoring response to treatment. Once biomarker-based therapeutics are established, biomarkers can guide treatment selection. It is increasingly clear that a wide range of potential biomarkers should be examined in schizophrenia, given the large number of genetic and environmental factors that have been identified as risk factors. New models for analysis of biomarkers are needed that represent the central nervous system as a highly complex, dynamic, and interactive system. Many tools are available with which to study relevant brain chemistry, but most are indirect measures and represent only a small fraction of the potential etiologic factors contributing to the molecular, structural and functional components of schizophrenia. This review represents the work of the International Society for CNS Clinical Trials and Methodology (ISCTM) Biomarkers Working Group. It discusses advantages and disadvantages of different categories of biomarkers and provides a summary of evidence that biomarkers representing inflammation, oxidative stress, endocannabinoids, glucocorticoid, and biogenic amines systems are dysregulated and potentially interactive in early phase schizophrenia. As has been recently demonstrated in several neurodevelopmental and neurodegenerative disorders, a multi-modal, longitudinal strategy involving a diverse array of biomarkers and new approaches to statistical modeling are needed to improve early interventions based on the fuller understanding.

Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia

Keefe, R , Haig G, Marder S, Harvey P, Dunayevich E, Medalia A, Davidson M, Lombardo I, Bowie C, Buchanan R, Bugarski-Kirola D, Carpenter W, Csernansky J, Dago P, Durand D, Frese F, Goff D, Gold J, Hooker C, Kopelowicz A, Loebel A, McGurk S, Opler L, Pinkham A, Stern R
Schizophrenia Bulletin 10.1093/schbul/sbv111 Advance Access
If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

Prospective Assessment of Suicidal Ideation and Behavior: An Internet Survey of Pharmaceutical Sponsor Practices

ISCTM Suicidal Ideation and Behavior Working Group , Phillip B. Chappell, MD; Atul R. Mahableshwarkar, MD; Larry D. Alphs, MD, PhD; Mark E. Bangs, MD; Adam Butler, BA; Sarah J. Dubrava, MS; John H. Greist, MD; William R. Lenderking, PhD; James C. Mundt, PhD; and Michelle Stewart, PhD
Innovations in Clinical Neuroscience Vol11, 9-10
Objective: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. Design: An internet-based survey. Setting: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. Participants: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. Measurements: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. Results: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). Conclusion: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.

Nonadherence: A bitter pill for drug trials

Kelly Servick
Science 17 Oct 2014, Vol 346 #6207
Last week at a meeting on clinical trials for central nervous system treatments, researchers convened to grapple with what they see as a serious and underrecognized problem in drug development: the fact that many people in clinical trials stop taking their experimental medications or don't take them as prescribed. These nonadherent participants can diminish the apparent effects of a drug compared with placebo and can potentially mask a drug's side effects or safety risks. As researchers recognize the effect of the problem on their trial data, some are taking greater pains to measure adherence through blood tests or electronic monitoring, and some are considering ways to design more adherence-friendly trials.
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Methodological Approaches and Magnitude of the Clinical Unmet Need Associated with Amotivation and Mood Disorders

J Calabrese , M Fava, G Garibaldi, H Grunze, A Krystal, T Laughren, W Macfadden, R Marin, A Nierenberg, M Tohen
Journal of Affective Disorders (2014)

Adaptive Design Applied to Identification of the Minimum Effective Dose in Schizophrenia: Simulations of Scientific and Commercial Value

T Parke , V Dragalin, I Turkoz, O Marchenko and V Haynes
Therapeutic Innovation & Regulatory Science January 2014 48: 41-50

A New Proposal for Randomized Start Design to Investigate Disease-modifying Therapies for Alzheimer’s disease

R Zhang , AC Leon, C Chuang-Stein, S Romano
Clin Trials. 2011 Feb;8(1):5-14. doi: 10.1177/1740774510392255.
BACKGROUND: The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges.
PURPOSE: To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies.
METHODS: Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies.
RESULTS: The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial.
LIMITATIONS: A regulatory claim of disease modification for any compound will likely require additional verification of a drug's effect on a validated biomarker of Alzheimer's pathology.
CONCLUSIONS: Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Adaptive Design Clinical Trials and Trial Logistics Models in CNS Drug Development

S Wang , J Wang, R O'Neill
European Neuropsychopharmacology Volume 21, Issue 2, February 2011
In central nervous system therapeutic areas, there are general concerns with establishing efficacy thought to be sources of high attrition rate in drug development. For instance, efficacy endpoints are often subjective and highly variable. There is a lack of robust or operational biomarkers to substitute for soft endpoints. In addition, animal models are generally poor, unreliable or unpredictive. To increase the probability of success in central nervous system drug development program, adaptive design has been considered as an alternative designs that provides flexibility to the conventional fixed designs and has been viewed to have the potential to improve the efficiency in drug development processes. In addition, successful implementation of an adaptive design trial relies on establishment of a trustworthy logistics model that ensures integrity of the trial conduct.

In accordance with the spirit of the U.S. Food and Drug Administration adaptive design draft guidance document recently released, this paper enlists the critical considerations from both methodological aspects and regulatory aspects in reviewing an adaptive design proposal and discusses two general types of adaptations, sample size planning and re-estimation, and two-stage adaptive design. Literature examples of adaptive designs in central nervous system are used to highlight the principles laid out in the U.S. FDA draft guidance. Four logistics models seen in regulatory adaptive design applications are introduced. In general, complex adaptive designs require simulation studies to access the design performance. For an adequate and well-controlled clinical trial, if a Learn-and-Confirm adaptive selection approach is considered, the study-wise type I error rate should be adhered to. However, it is controversial to use the simulated type I error rate to address a strong control of the study-wise type I error rate.