2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Independent data monitoring committees: preparing a path for the future.

Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021.

Importance: The US Food and Drug Administration (FDA) has 4 programs that can be used alone or in combination to expedite drug availability: Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review. Drugs using these programs can include novel drugs, which do not contain a previously FDA-approved active moiety, and orphan drugs, intended for diseases or conditions affecting fewer than 200 000 people; to date, no comprehensive evaluation of how these programs have been used in combination has been published. Objective: To assess how often and in what combinations expedited programs are used in the development and review of approved novel biologics and small-molecule drugs, stratified by orphan drug status and indication. Design, Setting, and Participants: This cross-sectional study evaluated all novel drugs that were FDA approved between January 1, 2008, and December 31, 2021. Main Outcomes and Measures: The main outcome was the frequency with which expedited programs were used and in what combinations, stratified by orphan drug status and drug type (small molecule vs therapeutic biologic). The unit of analysis was the novel drug-indication pair because a drug can be approved for multiple indications, each of which may use a different expedited program or differ in orphan drug status. Results: The study included 581 novel drug-indication pairs approved during the 14-year study period; 252 (43.4%) were orphan drugs, 139 (23.9%) were therapeutic biologics, and 442 (76.1%) were small-molecule drugs. Use of at least 1 expedited program increased from 11 of 26 drug-indication pairs (42.3%) in 2008 to 41 of 55 (74.5%) in 2021. Of the 363 approved drug-indication pairs using at least 1 expedited program, 225 (62.0%) were orphan drugs; at least 1 expedited program was used by 97 of the 139 approved biologic drugs (69.8%) and by 266 of the 442 approved small-molecule drugs (60.2%). Eighty-two of the 581 novel drug-indication pairs (14.1%) used the Accelerated Approval Program; of those, 65 (79.3%) were oncology drugs and 70 (85.4%) had an orphan designation. Conclusions and Relevance: The study showed that use of the FDA's expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue.

Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

The US Food and Drug Administration's Perspective on the New Antipsychotic Pimavanserin.

OBJECTIVE: To summarize the US Food and Drug Administration's (FDA's) review of the safety and effectiveness for pimavanserin, an atypical antipsychotic, for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. We describe the regulatory and clinical issues important to the FDA's approval of this New Drug Application, with special focus on the risk-benefit balance. We also describe a new labeling feature that presents additional efficacy data to clinicians. DATA SOURCES: Data sets for all relevant clinical trials of pimavanserin and the Applicant's and FDA's analyses of these data were considered in this review. Data were available from 616 patients with Parkinson's disease with hallucinations and delusions who received at least 1 dose of pimavanserin, with a total exposure of 825 patient-years in the Parkinson's disease psychosis population. RESULTS: Pimavanserin 34 mg/d was effective in treating hallucinations and delusions associated with Parkinson's disease. In the Applicant's single pivotal trial, 80.5% of pimavanserin patients experienced at least some improvement in symptoms compared to 58.1% of patients taking placebo. Pimavanserin did not worsen motor function, an adverse effect commonly observed with other antipsychotics, probably because of a lack of consequential dopamine binding. CONCLUSIONS: Pimavanserin is the only FDA-approved treatment for the hallucinations and delusions seen in patients with psychosis of Parkinson's disease. Although pimavanserin appears to have a pharmacologic mechanism that is different from other atypical antipsychotics, concern remained that the increased risk of death seen with antipsychotic use in elderly demented patients, and described in all approved antipsychotic labels, would also occur with pimavanserin. Pimavanserin bears the same boxed warning about the risk of death associated with antipsychotic use in elderly patients with dementia.

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.

The US Food and Drug Administration's perspective on the new antidepressant vortioxetine.

OBJECTIVE: This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. DATA SOURCES: The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. RESULTS: Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. CONCLUSIONS: Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs.

Vilazodone: clinical basis for the US Food and Drug Administration's approval of a new antidepressant.

OBJECTIVE: Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. DATA SOURCES: The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. STUDY SELECTION: Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. DATA EXTRACTION: The FDA had access to original raw data sets for these trials. RESULTS: Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. CONCLUSIONS: Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.