Current and Emerging Technologies to Address the Placebo Response Challenge in CNS Clinical Trials: Promise, Pitfalls, and Pathways Forward.

Excessive placebo response rates have long been a major challenge for central nervous system (CNS) drug discovery. As CNS trials progressively shift toward digitalization, decentralization, and novel remote assessment approaches, questions are emerging about whether innovative technologies can help mitigate the placebo response. This article begins with a conceptual framework for understanding placebo response. We then critically evaluate the potential of a range of innovative technologies and associated research designs that might help mitigate the placebo response and enhance detection of treatment signals. These include technologies developed to directly address placebo response; technology-based approaches focused on recruitment, retention, and data collection with potential relevance to placebo response; and novel remote digital phenotyping technologies. Finally, we describe key scientific and regulatory considerations when evaluating and selecting innovative strategies to mitigate placebo response. While a range of technological innovations shows potential for helping to address the placebo response in CNS trials, much work remains to carefully evaluate their risks and benefits.

Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future.

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.

Comparison of Good Clinical Practice Inspection Processes for Marketing Applications Between the United States Food and Drug Administration and the European Medicines Agency.

BACKGROUND: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) began collaboration on Good Clinical Practice (GCP) inspections for marketing applications since 2009. The main characteristics of the GCP inspection processes between FDA and EMA were never evaluated. This is the first analysis comparing the GCP inspection processes between the two agencies. METHODS: We examined and analyzed the key characteristics of the GCP inspection processes, including the geographical distribution, inspection types and timelines from application submission to final inspection reporting for marketing applications from September 2009 through December 2015. RESULTS: Fifty-five shared applications were included for analysis. For these applications, a total of 433 GCP inspections were conducted in 47 countries. Most clinical investigator (CI) inspections were conducted in regions outside of each agency's own regulatory jurisdiction, while most sponsor/contract research organization (CRO) inspections were conducted in the U.S. by both agencies. Twenty-eight shared applications included common sites inspected by both agencies. There were 15 joint inspections conducted for seven of these applications and the remaining applications had common sites inspected by both agencies at separate times. Of the joint inspections, 73% were conducted in the U.S and 20% in the E.U. The median time from submission of an application to generation of final inspection reports was 232 days for FDA and 204 days for EMA, with no significant differences noted among applications with and without common sites. CONCLUSION: The inspection processes and timelines between the two agencies were similar, providing support for continued FDA-EMA GCP collaboration.

Descriptive Analysis of Good Clinical Practice Inspection Findings from U.S. Food and Drug Administration and European Medicines Agency.

BACKGROUND: The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have collaborated in good clinical practice (GCP) inspections since September 2009. The two agencies operate under different regulatory frameworks for GCP oversight. No systematic assessments of GCP inspection findings have been reported. METHODS: We identified common inspections of clinical investigators, sponsors, and contract research organizations conducted by both agencies in support of marketing applications that had the same trial data submitted between 2009 and 2015. We grouped inspection findings into deficiency areas. We reviewed and compared these findings and calculated concordance rate for each deficiency area. RESULTS: Twenty-six clinical investigator sites and 23 sponsors/contract research organizations were inspected by both agencies in support of 31 marketing applications during this period. For FDA, the most common GCP findings were deficiencies related to Protocol Compliance for clinical investigator inspections and Trial Management issues for sponsor/contract research organization inspections. For EMA, deficiencies related to Documentation (including Trial Master File) were the most common findings for both clinical investigator and sponsor/contract research organization inspections. There was high concordance, of approximately 90%, for deficiencies related to Protocol Compliance for clinical investigator inspections and Trial Management for sponsor/contract research organization inspections between the two agencies. There was a concordance rate of about 70% for Documentation deficiencies for both clinical investigator and sponsor/contract research organization GCP inspections. CONCLUSION: GCP inspection findings from 49 common clinical investigator and sponsor/contract research organization inspections were comparable, providing support for continued FDA-EMA GCP collaboration.

Using Artificial Intelligence-based Methods to Address the Placebo Response in Clinical Trials.

The placebo response is a highly complex psychosocial-biological phenomenon that has challenged drug development for decades, particularly in neurological and psychiatric disease. While decades of research have aimed to understand clinical trial factors that contribute to the placebo response, a comprehensive solution to manage the placebo response in drug development has yet to emerge. Advanced data analytic techniques, such as artificial intelligence (AI), might be needed to take the next leap forward in mitigating the negative consequences of high placebo-response rates. The objective of this review was to explore the use of techniques such as AI and the sub-discipline of machine learning (ML) to address placebo response in practical ways that can positively impact drug development. This examination focused on the critical factors that should be considered in applying AI and ML to the placebo response issue, examples of how these techniques can be used, and the regulatory considerations for integrating these approaches into clinical trials.

Tackling Challenging Data Integrity Topics in 2020: Update on Good Clinical Practice Perspectives from the US FDA and MHRA UK.

With the globalization of clinical trials, regulators have increased collaboration to evaluate the adequacy of clinical trial conduct and to optimize regulatory oversight. The 2020 joint Good Clinical Practice (GCP) symposium of the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency provided the agencies' perspectives on the challenges in ensuring data quality in novel clinical trial designs and the importance of the management and documentation of protocol deviations, sponsor oversight of clinical trials, and use of electronic source data, including electronic health records. This paper summarizes considerations of both agencies on these topics, along with case examples. This paper touches upon considerations when using real-world data to support regulatory decisions. It also discusses the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trial conduct and underscores the importance of well-designed, resilient, and adaptable systems for GCP compliance and data integrity.

Trial design issues and treatment effect modeling in multi-regional schizophrenia 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.

Data Integrity in Global Clinical Trials: Discussions From Joint US Food and Drug Administration and UK Medicines and Healthcare Products Regulatory Agency Good Clinical Practice Workshop.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials. Regulatory agencies conduct GCP inspections to verify the integrity of data generated in clinical trials and to assure the protection of human research subjects, in addition to ensuring that clinical trials are conducted according to the applicable regulations. The first joint GCP workshop of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA-UK) was held in October 2018 and provided the agencies' perspectives on the importance of data quality management practices on data integrity. Regulatory perspectives on data blinding to minimize introduction of bias, and the role of audit trails in assessing data integrity in global clinical trials were discussed. This paper summarizes considerations of both agencies on these topics, along with case examples.

Design considerations for handling dropouts in anti-depressant drug trials.

BACKGROUND: In clinical trials, statistical analysis often requires certain assumptions about missing data for a valid statistical inference. If the dropout rate is high, a wrong assumption about the missing data may compromise the validity of statistical inferences. PURPOSE: To mitigate the high dropout rates commonly observed in psychiatry clinical trials, we consider two design approaches for short-term controlled trials submitted in support of marketing applications for drug products for the major depressive disorder (MDD) indication: (1) shortening the trial duration and (2) treating time to treatment discontinuation as an alternative primary efficacy endpoint. METHODS: Subject-level efficacy data from 45 trials for drugs approved for an MDD indication between 1997 and 2014 were collected. We analyzed change from baseline in Hamilton Depression Rating Scale (HAMD-17) total score using the mixed model repeated measures approach. We compared the least squares means and the 95% confidence intervals of the treatment effect among three different trial durations, 4, 6, and 8weeks. We considered two definitions of discontinuation: (i) all-cause discontinuation, (ii) discontinuation due to lack of efficacy. We compared the two-sided log-rank p-values with the p-values from the protocol-specified primary analysis. CONCLUSIONS: Our findings suggest that MDD trials in the acute setting may be shortened to 6weeks provided that the treatment difference between drug and placebo on HAMD-17 total score reaches approximately 2units at Week 6. However, our exploratory analyses of available data do not support the use of time to treatment discontinuation as an alternative primary efficacy endpoint.

Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections.

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. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.

Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia.

INTRODUCTION: Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence. METHODS: The literature regarding SI/SB in older persons with cognitive impairment or dementia was reviewed by an Alzheimer's Association Taskforce with emphasis on epidemiology, classification, assessment, and regulatory requirements. RESULTS: Gaps in our knowledge were identified, challenges discussed and recommendations for future work provided. DISCUSSION: Currently available SI/SB data from geriatric persons with dementia do not provide adequate understanding of its epidemiology, identification, assessment, or management. The growing public health burden of this population requires greater attention from clinicians and researchers on tactics and assessment tools to meet these needs.

Summary of findings from the FDA regulatory science forum on measuring sexual dysfunction in depression trials.

OBJECTIVE: Sexual dysfunction is a significant treatment-emergent adverse reaction to the serotonergic antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]). However, the rate of sexual dysfunction is often underestimated in registration trials, which have relied on unsolicited reports. We conducted a literature search to examine the rates of sexual dysfunction with SSRIs/SNRIs when these rates were ascertained by structured questionnaires or standardized instruments. Additionally, we conducted exploratory analyses of major depressive disorder (MDD) registration trial data. DATA SOURCES: For the literature search, we used the PubMed and EMBASE databases, with a cutoff date of April 1, 2011. We included all the SSRIs and SNRIs that at the time had been approved for the treatment of MDD. For each of these drugs, a search was conducted with the following terms: sexual dysfunction, SD, sexual adverse effects, desire, arousal, excitement, and orgasm. For the exploratory analyses of US Food and Drug Administration in-house trial data, we searched our database for short-term (6-8 weeks), randomized, placebo-controlled MDD monotherapy trials of approved drugs included in New Drug Application submissions that used a standardized instrument to assess sexual function. STUDY SELECTION: For the literature search, we initially found a total of 123 nonduplicate articles, some of which included multiple studies. After screening based on our inclusion/exclusion criteria (and to remove duplicate trial-level data), we were left with 7 articles representing 11 unique studies in which sexual dysfunction was assessed with direct questioning or standardized instruments. The Changes in Sexual Functioning Questionnaire-Short-Form (CSFQ-14) and Arizona Sexual Experiences Scale (ASEX) were the only instruments represented. For the exploratory analyses of in-house MDD trial data, we found controlled studies using either the CSFQ-14 (6 trials) or ASEX (5 trials). DATA EXTRACTION: For the literature search, we were able to pool the results for the studies that included direct questioning. For the studies that used standardized instruments to assess sexual function, we simply describe our findings. For the exploratory analyses of in-house MDD trial data, we constructed a dataset containing all subject-level CSFQ-14 or ASEX item scores for each of the trials as well as demographic and other relevant variables. For each treatment or placebo group, analyses were performed on pooled data, including multiple studies, and on individual studies. RESULTS: For our literature search, regardless of which method was used to assess sexual function, the data from these articles were informative and showed the expected effects on sexual function with SSRIs/SNRIs. However, for our exploratory analyses, no trend was observed in CSFQ-14 or ASEX results for individual drugs or drug classes. CONCLUSIONS: These results raise the question as to why the CSFQ-14 and ASEX appeared to perform well in the published studies but not in our exploratory analyses of in-house MDD trial data. We discuss possible reasons and solutions.

Regulatory and scientific issues in studies to evaluate sexual dysfunction in antidepressant drug trials.

OBJECTIVE: Sexual dysfunction is an important side effect of serotonergic antidepressants, as it often leads to treatment nonadherence. However, sexual dysfunction is often underestimated in clinical trials submitted in support of drug approval. This is because such assessments are based mainly on unsolicited reporting. As a result, the characterization of sexual adverse events has become an important component of many of the development programs for new antidepressants. The purpose of this article is to discuss US Food and Drug Administration's (FDA's) current thinking on possible approaches to characterizing the effects of drugs on sexual function in depression drug trials. PARTICIPANTS: FDA's Division of Psychiatry Products, together with the Division of Biometrics I, in particular the authors of this article. EVIDENCE: The above-referenced FDA divisions conducted a regulatory science forum on measuring sexual dysfunction in depression trials. CONSENSUS PROCESS: Considering the evidence presented and discussed at the forum, we developed our preliminary regulatory views on the scientific issues with regard to study design, study population, use of available scales, testing strategy, and statistical analysis plans. CONCLUSIONS: Sexual dysfunction associated with antidepressants is an important entity that should be adequately assessed during clinical trials with the use of available instruments and described in product labels. It is important to appreciate the need for a positive control to establish assay sensitivity for any trial evaluating the impact of antidepressant medications on sexual function. Methodological improvement and additional data as well as experience with these approaches will be needed prior to further consideration of a formal regulatory guidance document by the FDA.

Review of maintenance trials for major depressive disorder: a 25-year perspective from the US Food and Drug Administration.

OBJECTIVE: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. DATA SOURCES: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. STUDY SELECTION: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. DATA EXTRACTION: Trial characteristics, relapse rates, and time to relapse in each study were examined. RESULTS: Relapse rates were significantly lower (P < .05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the double-blind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. CONCLUSIONS: 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.

Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration.

OBJECTIVE: There has been concern about a high rate of placebo response and a decline in treatment effect over time in schizophrenia trials as well as the implications of increasing conduct of such trials outside North America. This report explores differences in efficacy data over an 18-year period from randomized placebo-controlled trials submitted in support of new drug applications (NDAs) for the treatment of schizophrenia and differences in results between trials conducted in North America and elsewhere. DATA SOURCES: Clinical trial data that were submitted to the US Food and Drug Administration (FDA) as part of NDAs for the indication of schizophrenia between 1991 and 2009. STUDY SELECTION: Efficacy data were compiled from 32 clinical trials with 11,567 evaluable patients with schizophrenia. Data from completed, randomized, multicenter, double-blind, placebo-controlled, 4- to 8-week clinical trials in adult patients diagnosed with schizophrenia according to DSM-III or DSM-IV criteria were included. DATA EXTRACTION: Baseline demographic and disease characteristics, including mean Positive and Negative Syndrome Scale (PANSS) total scores, were summarized and compared between North American and multiregional trials. Mean change from baseline to endpoint in PANSS total scores was utilized as the primary outcome of interest. We explored differences in treatment effect and success rate of these trials based on when and where the studies were conducted, sample size, trial duration, and baseline patient characteristics. RESULTS: Twenty-one of the 32 trials were conducted solely in North America, and 11 were carried out in multiple regions. Of those 11 multiregional trials, 2 were conducted exclusively in foreign countries. Although the observed responses (change from baseline) in placebo and drug-treated groups in multiregional trials tended to be larger than in North American trials, the treatment effects (drug-placebo difference) were -9 and -8 PANSS units for North American and multiregional trials, respectively. When time of trial conduct was taken into account, an increasing placebo response and a diminishing treatment effect over time were observed in North American trials from -10.8 PANSS units for the first period (1991-1998) to -6.0 PANSS units for the later period (1999-2008). The overall trial success rate over the almost 2 decades was 78%, declining slightly in trials conducted after 1999, the time period during which multiregional trials were first conducted (74% for 1999-2008 vs 85% for 1991-1998), despite increasing sample sizes in the later period. The mean baseline PANSS total score was in the range of 87-100 for most of these trials. Trials in patients with higher mean baseline PANSS total scores tended to show larger treatment effects than those in patients with lower scores. The mean body weight and body mass index (BMI) were higher in patients in North American trials and North America-predominant multiregional trials compared to those in foreign-predominant multiregional trials (mean body weights of 85 kg and 81 kg vs 72 kg, and BMIs of 29 and 27 vs 25, respectively). Treatment effects decreased as body weights increased, especially in North American trials. In foreign-predominant multiregional trials, there were higher proportions of women than in North American trials and North America-predominant multiregional trials (40% vs 22% and 27%, respectively) and a relatively larger proportion of Asians (21% vs 1% and 8%, respectively). CONCLUSIONS: 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.

Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications.

OBJECTIVE: There has been concern about a high rate of placebo response and a substantial failure rate in recent clinical trials in major depressive disorder (MDD). This report explores differences in efficacy data from placebo-controlled MDD trials submitted in support of new drug applications (NDAs) over a 25-year period. METHOD: We compiled efficacy data from 81 randomized, double-blind clinical trials, with 21,611 evaluable patients, that were submitted to the US Food and Drug Administration as part of NDAs for an antidepressant claim between 1983 and 2008. Trial data were limited to completed, randomized, multicenter, double-blind, placebo-controlled clinical trials in adult patients diagnosed with MDD according to DSM-III or DSM-IV criteria. The database was further limited to patients who were involved in clinical trials for drugs widely viewed as effective antidepressants and for doses of these drugs also viewed as effective doses. Trials were rated as successful if they showed statistical superiority vs placebo for the investigational drug on change in Hamilton Depression Rating Scale (HDRS) score (last-observation-carried-forward data). (Trials with multiple investigational drug groups were successful if there was superiority in at least 1 drug group after adjustment for multiplicity.) In particular, we explored differences in effect size and success rate of these trials, based on when the studies were conducted, geographic location of the study sites (US vs non-US), trial duration, dosing regimen, study size, and baseline disease characteristics. RESULTS: Eighty-one percent of MDD patients were enrolled in US sites. Although the observed placebo and drug responses at non-US sites tended to be larger than at US sites, the treatment effect (drug-placebo difference) was similar (mean change from baseline of about -2.5 units in HDRS total score) in US and non-US trials. In both US and non-US trials, the placebo response showed a modest increase over the observation period (1983-2008). Treatment effect clearly diminished over this same period, at a similar rate for both US and non-US trials despite a marked increase in the sample size of the trials. Our analysis showed that 53% of all MDD trials in the last 25 years were successful. US trials had a higher success rate than non-US trials (58% vs 33%). Before 1995, the overall success rate was 55%, compared to 50% for trials in 1995 or later, and, in general, 6-week trials had a higher success rate than 8-week trials (55% vs 42%). It should be noted that the earlier trials were mostly 6 weeks, and the 6-week trials had higher mean baseline HDRS scores than the 8-week trials. Study size did not seem to influence trial success rates. Mean baseline HDRS total scores declined over the 25-year observation period for patients in both US and non-US trials, as did treatment effect in these trials, again, regardless of region. Fixed-dose trials had a numerically slightly greater success rate than flexible-dose trials (57% vs 51%), although on average treatment effect was numerically larger in the flexible-dose trials than in fixed-dose trials (mean of -2.9 vs -2.0 on HDRS units). CONCLUSIONS: 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.