Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer’s first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer’s Association convened a Research Roundtable on the topic of NPS in AD. A major outcome of the Roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer’s Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome specific synthetic reviews and recommendations prepared by NPS-PIA Workgroups on depression, apathy, sleep, agitation, and psychosis.

Treatment effect has declined over time in MDD trials, and there has been a high failure rate for these trials during the entire period, but the reasons for these findings remain elusive. Baseline disease severity seems to be a more important factor in study outcome than study duration, dosing regimen, sample size, time when studies were conducted, and regions where data were generated. Close attention is needed to a variety of factors in the design and conduct of these studies, including patient population, diagnostic considerations, patient assessment, and clinical practice differences. These considerations become increasingly important as globalization of clinical trials continues to increase.

Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups.

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. .

A high and increasing placebo response and a declining treatment effect are of great concern in schizophrenia trials conducted in North America. In this era of global clinical trials, close attention is needed to the design and conduct of these trials.

Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.

In recent years, we have seen an increasing trend of foreign data as part of clinical trial data submitted in new drug applications (NDA) to US Food and Drug Administration (FDA). To understand the design and analysis characteristics, we studied schizophrenia multi-regional clinical trials (MRCTs). The schizophrenia data set consisted of a total of 12,585 patients collected from 33 clinical trials with 63.8% patients from North America, the largest region. The data set constituted 10 schizophrenia drug programs in support of NDAs submitted to FDA from December 1993 to December 2005. Two main objectives were pursued. First, we investigated some study design issues including potential heterogeneity of treatment effect via meta analysis and placebo response pattern over time. Second, we performed empirical modeling in two ways, supervised and unsupervised, to explain potential impact of baseline covariates on treatment effect in MRCTs. Based on our analysis results, placebo response appeared to increase over time and primarily attributed to US region. On average, the observed treatment effect in the US was generally smaller than non-US region. Both supervised and unsupervised empirical modeling selected baseline Positive and Negative Syndrome Scale total score as one of the most important covariates explaining a treatment effect. Region also played a role in explaining potential treatment effect heterogeneity. When baseline body weight was considered as a covariate in an empiric model, our results indicated that it alone did not seem to be an important factor in explaining regional difference.

Recently, regulatory bodies have published guidance related to this topic. 2-7 A common thread among these various documents is an emphasis on risk-based approach to data management, specifically targeting data and study procedures that are critical and have the greatest impact on maintaining subject safety and determining product efficacy. For example, the Medicines and Healthcare products Regulatory Agency (MHRA) Good Practices (GXP) Data Integrity Guidance and Definitions document discusses the data lifecycle, data governance, and other organizational culture features to be considered in a risk-based approach. 2 An open reporting culture in organizations should be encouraged as fundamental to data integrity promotion throughout the data lifecycle, including processes from generation or recording of data to destruction, if needed, and the intervening processes (Figure 1).