Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Earlier Use of Long-Acting Injectable Paliperidone Palmitate Versus Oral Antipsychotics in Patients With Schizophrenia: An Integrated Patient-Level Post Hoc Analysis.

Objective: To assess the efficacy and safety of paliperidone palmitate (PP) long-acting injectable antipsychotic (LAI) versus oral antipsychotic (OAP) treatment in adult patients diagnosed with schizophrenia (per DSM-IV or DSM-5 criteria) and varying duration of illness (0-3 years and > 3 years).Methods: Patient-level data from the PRIDE, PROSIPAL, and DREaM studies were included in a post hoc analysis. Efficacy and safety outcomes, including relapse assessments, Personal and Social Performance scale scores, Medication Satisfaction Questionnaire total scores, and treatment-emergent adverse events (TEAEs), were measured systematically. Treatment failure (TF) included relapses due to psychiatric hospitalizations, arrest or incarceration, suicidal or homicidal ideation or behavior, discontinuation due to inadequate efficacy and/or safety or tolerability, treatment supplementation due to inadequate efficacy, and significant worsening of symptoms.Results: Fewer TFs were observed with PP versus OAP in both the 0-3 years group (17.7% and 25.3%, respectively) and the > 3 years group (32.3% and 42.4%, respectively). Time to first TF was significantly longer with PP versus OAP treatment in both duration of illness groups. TEAE rates were similar between the PP and OAP groups, with no new safety signals identified.Conclusions: This post hoc analysis suggests that PP provides significant benefit in reducing TF or relapse compared with OAPs regardless of duration of illness and highlights the potential benefit of implementing PP earlier in the course of schizophrenia.Trial Registration: ClinicalTrials.gov identifiers NCT01157351 (PRIDE), NCT01081769 (PROSIPAL), and NCT02431702 (DREaM).

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.

ASPECT-R-A Tool to Rate the Pragmatic and Explanatory Characteristics of a Clinical Trial Design.

OBJECTIVE: Clinical and observational trials can be broadly categorized into having explanatory or pragmatic approaches with specific trial designs located somewhere along this spectrum. Two 10-domain instruments, the PRECIS and Pragmascope, have been developed to facilitate clinical trial design within a framework that is either more explanatory or pragmatic. DESIGN: We have adapted the PRECIS and Pragmascope instruments to permit both design support and post-hoc evaluation of clinical trials and to improve consistency of use and interpretation across raters. This adapted instrument, A Study Pragmatic-Explanatory Characterization Tool-Rating-or ASPECT-R-is described. RESULTS: Adaption of the PRECIS and Pragmascope instruments included reducing the 10 original domains to six. Each of the six ASPECT-R domains has a definition of domain terminology and detailed descriptive anchors. The domains are rated from 0 to 6, where 0 is considered extremely explanatory and 6 extremely pragmatic. Using an Excel®-based file with cover page cells for entry of the study objective(s) and study population of interest, the ASPECT-R instrument has individual domain-related worksheets where the user rates each of the six domains. Each of the six domain worksheets has a section provided for the user to summarize and record the rationale for their domain scoring. Each domain worksheet page also contains a radar graph that auto-populates each of the domain ratings as the user completes these ratings. CONCLUSION: This new tool, ASPECT-R, should provide a reliable, objective way to rate studies along the explanatory-pragmatic spectrum that will better support trial design and facilitate interpretation of completed trials. The complete ASPECT-R tool and guide materials can be accessed online by clicking or visiting this link: http://innovationscns.com/aspect-r-tool-and-training-materials/.

Inter-rater Reliability Assessment of ASPECT-R: (A Study Pragmatic-Explanatory Characterization Tool-Rating).

OBJECTIVE: The increasing importance of real-world data for clinical and policy decision making is driving a need for close attention to the pragmatic versus explanatory features of trial designs. ASPECT-R (A Study Pragmatic-Explanatory Characterization Tool-Rating) is an instrument informed by the PRECIS tool, which was developed to assist researchers in designing trials that are more pragmatic or explanatory. ASPECT-R refined the PRECIS domains and includes a detailed anchored rating system. This analysis established the inter-rater reliability of ASPECT-R. DESIGN: Nine raters (identified from a convenience sample of persons knowledgeable about psychiatry clinical research/study design) received ASPECT-R training materials and 12 study publications. Selected studies assessed antipsychotic treatment in schizophrenia, were published in peer-reviewed journals, and represented a range of studies across a pragmatic-explanatory continuum as determined by authors (CB/LA). After completing training, raters reviewed the 12 studies and rated the study domains using ASPECT-R. Intraclass correlation coefficients were estimated for total and domain scores. Qualitative ratings then were assigned to describe the inter-rater reliability. RESULTS: ASPECT-R scores for the 12 studies were completed by seven raters. The ASPECT-R total score intraclass correlation coefficient was 0.87, corresponding to an excellent inter-rater reliability. Domain intraclass correlation coefficients ranged from 0.85 to 0.31, corresponding to excellent to poor inter-rater reliability. CONCLUSION: The inter-rater reliability of the ASPECT-R total score was excellent, with excellent to good inter-rater reliability for most domains. The fair to poor inter-rater reliability for two domains may reflect a need for improved domain definition, anchoring, or training materials. ASPECT-R can be used to help understand the pragmaticexplanatory nature of completed or planned trials.

Long-acting injectable versus daily oral antipsychotic treatment trials in schizophrenia: pragmatic versus explanatory study designs.

Trial design characteristics related to the explanatory : pragmatic spectrum may contribute toward the inconsistent results reported in studies comparing long-acting injectable (LAI) versus daily oral antipsychotic (AP) treatments in schizophrenia. A novel approach examined the hypothesis that a more pragmatic design is important to show the advantages of LAI versus oral APs. A literature search identified comparative studies assessing the clinical efficacy/effectiveness of LAI versus oral APs in more than 100 schizophrenia patients, with 6-month or more duration/follow-up, and published between January 1993 and December 2013 (n=11). Each study's design was rated using the six-domain ASPECT-R (A Study Pragmatic : Explanatory Characterization Tool-Rating). Nonparametric Wilcoxon rank-sum tests compared ratings of studies supporting (n=7) and not supporting (n=4) a LAI advantage. ASPECT-R total and domain scores were significantly higher (more pragmatic) in studies finding a LAI versus oral AP treatment advantage than those that did not. The rank order of this significance among domains was as follows: 'participant compliance assessment' (P=0.005), 'medical practice setting/practitioner expertise' (P=0.006), 'intervention flexibility' (P=0.007), 'follow-up intensity/duration' (P=0.009), 'primary trial outcomes' (P=0.012), and 'participant eligibility' (P=0.015). Findings support that more pragmatic, less explanatory design features are important to show advantages for LAI treatment. Explanatory studies may introduce features that obscure advantages related to adherence.

Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices.

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.

Comparative Validation of the S-STS, the ISST-Plus, and the C-SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories.

OBJECTIVE: This exploratory study examines the concurrent validity for mapping symptoms of suicidal ideation, self-harm, and suicidal behavior as recorded on the InterSePT Scale for Suicidal Thinking-Plus, the Sheehan-Suicidality Tracking Scale (clinician- and patient-rated and reconciled patient/clinician versions), and the Columbia-Suicide Severity Rating Scale to the 11 United States Food and Drug Administration-Classification Algorithm of Suicide Assessment (September 2012) categories. METHOD: Forty subjects with varying degrees of suicidal ideation and behavior severity (from not present to extremely severe) were recruited from inpatient, outpatient, and emergency room settings. Each patient was interviewed using all three scales (InterSePT Scale for Suicidal Thinking-Plus, the Sheehan-Suicidality Tracking Scale, and the Columbia-Suicide Severity Rating Scale) on the same day. The scales were administered in a random sequence by three independent raters who were blind to the ratings on the other scales. RESULTS: The Sheehan-Suicidality Tracking Scale and the InterSePT Scale for Suicidal Thinking-Plus show acceptable agreement with the Columbia-Suicide Severity Rating Scale in detecting the presence or absence of the 2012 Food and Drug Administration-Classification Algorithm of Suicide Assessment categories 1, 5, 6, 10, and 11 (passive ideation; active ideation with method, intent, and plan; completed suicide; preparatory actions; and self-injurious behavior) but not of categories 2, 3, and 4 (3 other active suicidal ideation combination categories) or to 8 and 9 (aborted and interrupted attempt). Despite the significant disagreement between the Columbia-Suicide Severity Rating Scale on the one side and the InterSePT Scale for Suicidal Thinking-Plus and the Sheehan-Suicidality Tracking Scale on the other in the ability to accurately map to the 2012 Food and Drug Administration-Classification Algorithm of Suicide Assessment categories on some items, there was close agreement between the InterSePT Scale for Suicidal Thinking-Plus and the Sheehan-Suicidality Tracking Scale on these categories. CONCLUSION: The results of this exploratory study invite discussion and debate about the validity of the Columbia-Suicide Severity Rating Scale and its ability to accurately assess key active suicidal ideation categories, since it disagrees so much with the other two standardized scales that agree so closely with each other.

Simple Measures of Hopelessness and Impulsivity are Associated with Acute Suicidal Ideation and Attempts in Patients in Psychiatric Crisis.

OBJECTIVE: To explore the authors' predictions 1) that hopelessness would positively correlate with suicidal ideation and that impulsivity (either transient urges to self-harm or impulsive acting out) would positively correlate with suicidal behavior, and 2) that the recent or long-standing nature of the traits will have corresponding effects on reported histories of suicidal ideation and behavior. DESIGN: Questionnaire validation trial in which each subject received every measure in counterbalanced fashion. SETTING: Inpatient and outpatient psychiatric settings associated with a medium-sized medical school in the southeastern United States. PARTICIPANTS: Forty-five subjects presenting with varying levels of suicidal ideation and behavior completed measures providing information about their histories of suicidal ideation and behavior, recent feelings of hopelessness, feelings of general hopelessness, recent feelings of difficulty controlling urges to self-harm, and feeling about general levels of impulsivity. MEASUREMENTS: The InterSePT Scale for Suicidal Thinking-Plus, the Sheehan-Suicidality Tracking Scale, the Columbia-Suicide Severity Rating Scale, and six additional questions to assess hopelessness and impulsivity. RESULTS: Recent and trait hopelessness correlated positively with suicidal ideation. Patients who reported any suicide attempt endorsed higher levels of general impulsivity than those who did not report a history of at least one suicide attempt. Those enrolled in the study secondary to a very recent suicide attempt reported more difficulties with recent suicidal impulses. CONCLUSION: Simple measures of hopelessness and impulsivity are associated with suicidal ideation and attempts and may add to determination of suicide risk.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a consensus statement.

OBJECTIVE: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. PARTICIPANTS: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies of major depression, bipolar disorder, schizophrenia, substance abuse/dependence, and other psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. EVIDENCE: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. CONSENSUS PROCESS: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this scholarly article, which has been developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement have been noted. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a C-CASA-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a brief report.

OBJECTIVE: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. PARTICIPANTS: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies in studies of psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. EVIDENCE: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. CONSENSUS PROCESS: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this brief report and the accompanying full article from which it is distilled. The full article was developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement at the conference have been noted in the text. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed.