Subgroup analyses and pre-specification.

Large clinical trials provide the opportunity to assess treatment effects in subgroups of patients, based on baseline demographic and disease-related factors, and there is always great interest in these analyses. Generally, the term "pre-specification" has major ramifications for clinical trials, particularly for adequate and well-controlled trials that are designed for formal hypothesis testing. Pre-specification is the "holy grail" of modern trials, as choosing analytical approaches with data in-hand will inflate the type I error rate. But "pre-specification" often has a different meaning with respect to subgroup analyses.

Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.

Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel From the Heart Failure Collaboratory and Academic Research Consortium.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Standardized definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Endpoints in Heart Failure Drug Development: History and Future.

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.

Design of a "Lean" Case Report Form for Heart Failure Therapeutic Development.

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

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.

Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory.

The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory.

Personalized Cardiovascular Medicine Today: A Food and Drug Administration/Center for Drug Evaluation and Research Perspective.

Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective.

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.

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.

A call for transparent reporting to optimize the predictive value of preclinical research.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

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.