Trials Of New Drugs Research Articles

The clinical trials of China innovative new anti-cancer drugs

With the support of the national policies, the improvement of research ability and the development of economy and society, China clinical trials have developed rapidly. Many achievements are made in the clinical trials of new anti-cancer drugs during last several decades. Many innovative new drugs have come into the market and gained influence at home and abroad. Those drugs provide more treatment options for Chinese patients. This article reviews the results of new anti-tumor drug clinical trials, with special focus on the challenge and chance for the new anti-cancer drug clinical trials in China.

Amyotrophic lateral sclerosis: pathogenetic mechanisms and new approaches to pharmacotherapy (literature review)

Amyotrophic lateral sclerosis is a neurodegenerative disease, resulting in the loss of self-service and death of the middle-aged and elderly people. In the last 2 decades, significant progress has been made in the study of the pathogenesis of this disease. Two known drugs (riluzole and edaravone) have been approved by the Food and Drug Administration for treatment of amyotrophic lateral sclerosis. The efficacy of these drugs is extremely low, so clinical trials of new drugs are ongoing all over the world. This review discusses the current achievements and future directions of therapy of this disease.

GCP Inspection of Clinical Trials of New Drugs Approved in Japan from FY2013 to FY2017 and FDA GCP Inspection in Japan

GCP Inspection of Clinical Trials of New Drugs Approved in Japan from FY2013 to FY2017 and FDA GCP Inspection in Japan

First Person: Paul Bunn, Jr, MD, FASCO

First Person: Paul Bunn, Jr, MD, FASCO

Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1c levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min-1·1.73 m-2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1c on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

Antibody-mediated rejection: challenge of the treatment in kidney transplantated patients

Antibody-mediated rejection (ABMR) is one of the factors affecting the long-term graft survival after kidney transplantation (KT). Two kidney transplant centres (University of Debrecen and University of Pécs) followed up their data of cadaveric KTs that had been performed between 2013 and 2017, and reviewed the literature. There were 454 KTs in the mentioned period, 18 cases (4%) were recognised as ABMRs. Biopsy has been performed in all cases. 22% were primary, and 78% retransplanted patients. The average age was 51.2 ± 6 years. ABMR occurred 15.4 ± 22.1 months after KT. Histology showed C4d positivity in 39% of the cases. The treatment was steroid bolus + intravenous immunoglobulin (IVIG) + plasma exchange (PE) in 16 cases, rituximab was additionally given in 5 cases. 47.4% of the patients are alive with a functioning graft, four (21%) died, and 31% of the patients had a graft loss due to ABMR. ABMR is a dangerous complication after KT. Diagnostic criteria has been unclear for years. Gold standard is the histology, however, accelerated ABMR may occur even in C4d negative cases. The exposed group includes young, retransplanted patients, having a preformed donor-specific antibody (DSA), and receiving a graft from an EC donor. The occurrence of de novo DSA and the kinetics of mean fluorescence intensity (MFI) of existing ones can be a signal for the risk of an ABMR. The effectiveness of rituximab is not proven, there is a lack of long-term controlled trials for new drugs. Our results of over 40% recovery is an extensively good result. Orv Hetil. 2018; 159(46): 1913-1929.

Eligibility for clinical trials is limited for youth with type 2 diabetes: Insights from the Pediatric Diabetes Consortium T2D Clinic Registry.

Restrictive eligibility criteria have hampered enrollment into trials for new drugs for youth with type 2 diabetes (T2D). We utilized Pediatric Diabetes Consortium (PDC) T2D Registry enrollment data to estimate the percentage of patients who would be excluded from current T2D trials based on out-of-range HbA1c levels. We also examined whether well-controlled patients could be included because baseline HbA1c would rise during a 6 to 12-month study if assigned to control group. Clinical characteristics and HbA1c levels were collected from 956 T2D patients aged 10 to <18 years upon Registry enrollment. HbA1c levels were also analyzed in 6-month intervals during the first 30 months of T2D duration. There was an approximately 2:1 ratio of females to males; the majority were obese and from economically disadvantaged minority families. On enrollment in the Registry, 53% of patients would be excluded from current trials because HbA1c levels were either <6.5% (<48 mmol/mol) (37%) or >10.5% (>91 mmol/mol) (16%). Furthermore, in patients with HbA1c levels <6.5% (<48 mmol/mol) and T2D duration between 6 and 30 months, mean HbA1c levels increased by 0.6% (6 mmol/mol) and 0.9% (10 mmol/mol) over the subsequent 6 and 12 months, respectively. Eligibility criteria for current clinical trials still exclude a large proportion of pediatric T2D patients because of HbA1c levels. Including patients with HbA1c <6.5% (<48 mmol/mol) would enhance recruitment and allow comparisons of the investigational treatment with placebo-assigned subjects in whom HbA1c levels would on average increase during the 6 to 12 months of the trial.

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center.

PurposePompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center.MethodsThe medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT.ResultsCommon initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT.ConclusionAs ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

Clinical Overview of Innovative New Drug Approvals in 2017

The FDA has approved 46 new drugs in 2017, another record approval in two decades on a similar pace to the gangbuster year of 2015. Many of these new medicines address significant and meaningful needs, or offer additional therapeutic choices for patients worldwide. These new drugs also cover a broad range of indications including immuno-oncology (Imfinzi and Bavencio), Parkinson’s disease (Xadago), eczema (Dupixent), psoriasis (Siliq and Tremfya), multiple sclerosis (Ocrevus), and different types of cancer (Idhifa, Aliqopa, Calquence, and Besponsa). A few important orphan drugs were approved, including in mucopoly-saccharidosis type VII (Mepsevil) and Batten’s Disease (Brineuria). Many of these new drugs are for rare diseases and sub-types of cancer, which often target very small populations, although they can cost hundreds of thousands of dollars. Yet the pharma companies saw average returns on their research and development spending fall, reflecting more competitive pressures and the growing share of new products now coming from biotech companies. Recently, the US has introduced the Right-to-Try Act, wherein patients can access experimental treatments if they are unable to participate in any clinical trial of new drugs and if they have no other options. Such policies are expected to increase the database for new experimental drugs and help accelerate drug approvals.

Changing role of histopathology in the diagnosis and management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and fatal cancer in the world. HCC frequently presents with advanced disease, has a high recurrence rate and limited treatment options, which leads to very poor prognosis. This warrants urgent improvement in the diagnosis and treatment. Liver biopsy plays very important role in the diagnosis and prognosis of HCC, but with technical advancements and progression in the field of imaging, clinical guidelines have restricted the role of biopsy to very limited situations. Biopsy also has its own problems of needle tract seeding of tumor, small risk of complications, technical and sampling errors along with interpretative errors. Despite this, tissue analysis is often required because imaging is not always specific, limited expertise and lack of advanced imaging in many centers and limitations of imaging in the diagnosis of small, mixed and other variant forms of HCC. In addition, biopsy confirmation is often required for clinical trials of new drugs and targeted therapies. Tissue biomarkers along with certain morphological features, phenotypes and immune-phenotypes that serve as important prognostic and outcome predictors and as decisive factors for therapy decisions, add to the continuing role of histopathology. Advancements in cancer biology and development of molecular classification of HCC with clinic pathological correlation, lead to discovery of HCC phenotypic surrogates of prognostic and therapeutically significant molecular signatures. Thus tissue characteristics and morphology based correlates of molecular subtypes provide invaluable information for management and prognosis. This review thus focuses on the importance of histopathology and resurgence of role of biopsy in the diagnosis, management and prognostication of HCC.

Comparison of New Glucose-Lowering Drugs on Risk of Heart Failure in Type 2 Diabetes: A Network Meta-Analysis

ObjectivesThe authors conducted a systematic review and network meta-analysis of placebo-controlled, randomized clinical trials in the post–Food and Drug Administration (FDA) guidance era to formally compare the effects of 3 new classes of glucose-lowering drugs on hospitalization for heart failure (HF) in type 2 diabetes mellitus. BackgroundThe 2008 FDA Guidance for Industry launched an era of cardiovascular outcome trials for new glucose-lowering drugs in T2DM, including glucagon-like peptide (GLP)-1 agonists, dipeptidyl peptidase (DPP)-4 inhibitors, and sodium glucose co-transporter (SGLT)-2 inhibitors. MethodsWe searched Embase, PubMed, Cochrane Library, and clinicaltrials.gov between December 1, 2008, and November 24, 2017, for randomized placebo-controlled trials, and performed network meta-analyses by Bayesian approach using Markov-chain Monte Carlo simulation method to compare the effects of glucose-lowering drugs on risk of HF hospitalization and estimate the probability that each treatment is the most effective. ResultsNine studies were identified, yielding data on 87,162 participants. In the network meta-analysis, SGLT-2 inhibitors yielded the greatest risk reduction for HF hospitalization compared with placebo (relative risk [RR]: 0.56; 95% CrI [credibility interval]: 0.43 to 0.72). Moreover, SGLT-2 inhibitors were associated with significant risk reduction in pairwise comparisons with both GLP-1 agonists (RR: 0.59; 95% CrI: 0.43 to 0.79) and DPP-4 inhibitors (RR: 0.50; 95% CrI: 0.36 to 0.70). Ranking of the classes revealed 99.6% probability of SGLT-2 inhibitors being the optimal treatment for reducing the risk of this outcome, followed by GLP-1 agonists (0.27%) and DPP-4 inhibitors (0.1%). ConclusionsCurrent evidence suggests that SGLT-2 inhibitors are more effective than either GLP-1 agonists or DPP-4 inhibitors for reducing the risk of hospitalization for HF in type 2 diabetes mellitus.

Optimal Patient Enrollment in Sequential Adaptive Clinical Trials with Binary Response

Adaptive clinical trials for new drugs or treatment options promise significant benefits to both trial sponsors and patients, but complicate resource allocation. We study the patient enrollment and trial termination decision in a Phase 3 group sequential adaptive trial, which allows for early trial termination due to established efficacy or anticipated futility. Our objective is to quantify the impact of interim analyses on key performance metrics, including the new drug’s misclassification risk and time-to-market, and the firm’s profit. To this end, we build a stochastic dynamic programming model that incorporates Bayesian updates on the drug’s efficacy. The patient enrollment decision in this setting is characterized by endogenous uncertainty, and a trade-off between the incentive to establish the drug’s efficacy early on (exploitation), due to a time-decreasing market revenue, and the benefit from collecting information on the drug’s performance (exploration) prior to committing a large amount of resources. We characterize important structural properties of an optimal patient enrollment policy and perform a numerical study utilizing realistic data. Our results suggest that sequential adaptive clinical trials, even with a single interim analysis, outperform their traditional counterparts (i.e., fixed sample size trials) across all metrics, because patient enrollment is re-optimized adaptively, based on updated information on the drug’s efficacy.

A review of cardiovascular outcome trials in type 2 diabetes.

Type 2 diabetes is a complex metabolic disorder associated with a high risk of cardiovascular complications. In December 2008, due to concerns about the cardiac safety of antihyperglycaemic therapies, the Food and Drug Administration (FDA) published a new guidance on special requirements for the demonstration of cardiovascular safety for these medications. In 2012, similar recommendations were made for antidiabetic drug manufacturers by the European Medicines Agency (EMA). Since then, both FDA and EMA recommendations have been applied in cardiovascular outcome trials (CVOTs) for several new antihyperglycaemic drugs. Unlike conventional trials, CVOTs are usually placebo controlled, non-inferiority trials that examine the cardiovascular safety of a drug compared to standard of care in large cohorts of patients with high cardiovascular risk or established cardiovascular disease. Patients in CVOTs are also monitored for a longer observation period than in typical randomised controlled trials to provide data on long-term cardiovascular risk. To date, nine CVOTs involving patients with type 2 diabetes have been completed, and at least 13 are still ongoing. These studies focus on a variety of antihyper-glycaemic drugs, including incretin-based agents, sodium-glucose cotransporter 2 inhibitor (SGLT-2) inhibitors, and insulin formulations. This article takes a critical look at these CVOTs and summarises the results of the completed trials.

Pathophysiology and therapeutic progress of diabetic macular edema

Diabetic macular edema (DME) is the leading cause of vision loss in diabetics. The destruction of blood retinal barrier is the primary pathological feature. At present, a large number of animal experiments and clinical studies show that DME not only has abnormal vascular structure, but also is an inflammatory disease. A variety of inflammatory media and chemokine are involved in the process of DME. With the extensive clinical application of anti-vascular endothelial growth factor (VEGF), the treatment of DME got a revolutionary breakthrough. However, unlike proliferative diabetic retinopathy (PDR), DME patients response intensively to anti-VEGF agents and couldn't resolve completely despite of multiple injections. Therefore, in addition to VEGF, other possible therapeutic targets and clinical trials of new drugs are also widely carried out. This article reviews the therapeutic process of DME. (Chin J Ophthalmol, 2018, 54: 625-630).

Dr. Joseph Siu-Kie Au: beyond immunotherapy—discovering new possibilities

Dr. Au ( Figure 1 ) is a consultant clinical oncologist in Hong Kong Adventist Hospital. He has special interest in bioinformatics, translational research, clinical trials of new drugs and radiotherapy.

TRANSCRIPTOMICS RESEARCH IN THE CLINICAL AND EXPERIMENTAL INVESTIGATION OF PATHOGENETIC MECHANISMS OF ALIMENTARY OBESITY

The review considers the significant role of changes in the transcriptome of organs and tissues for studying the molecular mechanisms of obesity development. Modern methods of transcriptomics including technologies for quantitative RT-PCR and DNA microarrays provided a new approach to the search for sensitive molecular markers as obesity predictors Differential gene expression profiles are mostly organo- and tissue-specific for adipose tissue, liver, brain, and other organs and tissues; can significantly differ in animal in vivo models with genetically determined and dietary induced obesity. At the same time, coordinated regulation is registered in the organs and tissues of expression of extensive groups of genes associated with lipid, cholesterol, and carbohydrate metabolism, the synthesis and circulation of neurotransmitters of dopamine and serotonin, peptide hormones, cytokines which induce systemic inflammation. For systemic regulation mechanisms causing a concerted change in the transcription of tens and hundreds of genes in obesity, the adipokines effects should be pointed out, primarily leptin, as well as pro-inflammatory cytokines, the micro-RNA (miRs) system and central effects developing at NPY/AgRP+ and POMC/CART+ neurons of the arcuate nucleus of the hypothalamus. Results of transcriptomic studies can be used in preclinical trials of new drugs and methods of dietary correction of obesity in animal’s in vivo models, as well as in the search for clinical predictors and markers of metabolic abnormalities in patients with obesity receiving personalized therapy. The main problem of transcriptomic studies in in vivo models is incomplete consistency between the data obtained with full-transcriptional profiling and the results of quantitative RT-PCR expression of individual candidate genes, as well as metabolic and proteomic studies. The identification and elimination of the causes of such discrepancies can be one of the promising areas for improving transcriptomical research.

Urine IP-10 as a biomarker of therapeutic response in patients with active pulmonary tuberculosis

BackgroundPrior to clinical trials of new TB drugs or therapeutic vaccines, it is necessary to develop monitoring tools to predict treatment outcomes in TB patients. Urine interferon gamma inducible protein 10 (IP-10) is a potential biomarker of treatment response in chronic hepatitis C virus infection and lung diseases, including tuberculosis. In this study, we assessed IP-10 levels in urine samples from patients with active TB at diagnosis, during treatment, and at completion, and compared these with levels in serum samples collected in parallel from matched patients to determine whether urine IP-10 can be used to monitor treatment response in patients with active TB.MethodsIP-10 was measured using enzyme-linked immunosorbent assays in urine and serum samples collected concomitantly from 23 patients with active TB and 21 healthy adults (44 total individuals). The Mann-Whitney U test and Wilcoxon matched-pairs signed rank test were used for comparisons among healthy controls and patients at three time points, and LOESS regression was used for longitudinal data.ResultsThe levels of IP-10 in urine increased significantly after 2 months of treatment (P = 0.0163), but decreased by the completion of treatment (P = 0.0035). Serum IP-10 levels exhibited a similar trend, but did not increase significantly after 2 months of treatment in patients with active TB.ConclusionsUnstimulated IP-10 in urine can be used as a biomarker to monitor treatment response in patients with active pulmonary TB.

Demographic composition of lung cancer trials: FDA analysis.

9088 Background: Lung cancer is the leading cause of cancer death; in the US non-small cell lung cancer (NSCLC) accounts for 80% of the lung cancer diagnoses. Enrollment of a diverse population in clinical trials (CTs) of new cancer drugs may provide information regarding the safety and efficacy of treatments in demographic subgroups that are disproportionately represented among new cases of, and deaths from, cancer. This analysis characterizes the demographics of patients enrolled in CTs submitted to FDA in support of marketing applications for FDA-approved NSCLC drugs. Methods: Reviewed datasets in the applications of original approval for new NSCLC drugs (2011- 17), and pooled demographic data from CTs that provided primary safety and efficacy data for drug approval. Results: This table illustrates enrollment by demographics at all sites and in the US. Conclusions: Enrollment of females is slightly higher (54%) than predicted based on corresponding incidence rates (48%) for this subgroup in the Surveillance, Epidemiology, and End Results database. Enrollment of younger patients is also higher than predicted based on incidence rate; patients < 65 years comprise 68% of all enrolled patients compared to 28% of new cases. These differences may be attributable, in part, to the number of CTs for new drugs for biomarker-defined NSCLC subtypes that occur more frequently in females and younger patients than in NSCLC in general. In contrast, there is lower representation of racial/ethnic minority patients ( < 1%) and patients ≥ 65 years of age (32%) in these CTs than predicted by incidence rates (65.9, 83.7, 312 and 15 cases per 100,000 in patients who are White male, Black male, > 65 years, and < 65 years, respectively). Targeted enrollment of racial/ethnic minorities and older patients is needed to improve their access to CTs; such efforts may facilitate an assessment of safety and efficacy in these subgroups. All n = 9711% US n = 1149% Age < 65 years 68 72 65-80 years 31 25 > 80 years 2 2 Sex* Female 54 55 Race# American Indian/ Alaskan Nativea < 1 < 1 Asian 43 10 Black/African American < 1 2 Native Hawaiian / Other Pacific Islandera < 1 < 1 Other 2 4 White 50 82 Ethnicity Hispanic 2 3 Not Hispanic 19 21 Other 3 12 Missing/Not Collected 76 65 *Missing ‘Sex’ (n = 2); #Missing ‘race’(n = 484). a (n = 3).

Treatment of Menopausal Syndrome by Combined Electroacupuncture, Acupoint-injection and Fire-needle Therapies

To observe the clinical efficacy of joint application of electroacupuncture (EA), acupointinjection and fire-needle in the treatment of menopausal syndrome (MS) women. One hundred MS patients were randomized into control group and combined treatment group (n=50 patients in each). The combined treatment group was treated by joint application of EA, acupoint-injection and fire-needle stimulation, and the control group treated by EA stimulation alone. EA was applied to Shenshu (BL 23), Xinshu (BL15), Taixi (KI 3), Sanyinjiao (SP 6), Laogong (PC 8), Pishu (BL 20), etc., for 30 min, once daily for 10 days. Point-injection of red ginseng-ophiopogon root injection (0.5 mL) or red-hot needle stimulation was applied to bilateral BL15, BL 20, SP 6 and BL 23 once daily for 10 days and once every other day for 5 times, respectively. The modified Kupperman index scale was used to evaluate symptoms (hot flashes and night sweats: 4 points; paresthesia, insomnia, dyspareunia, irritability and problems of urinary system: 2 point each; depression, dizziness, fatigue, joint pain or muscular pain, headache, palpitation, skin formication: 1 point each) of the perimenopausal syndrome, and 3 months' follow-up survey was conducted after the treatment. Each symptom score was calculated as the product of the symptom severity score (0, no; 1, mild; 2, moderate; 3, severe) multiplied by the points of symptom index. The total Kupperman score was the sum of the scores of all the items. The therapeutic effect was also evaluated according to the "Guiding Principles for Clinical Trials of New Drugs of Chinese Materia Medica" (2002). The Kupperman scores were significantly decreased following the 10 days' treatment and 3 months thereafter in both control and combined treatment groups in comparison with their individual pretreatment (P<0.05), and were obviously lower in the combined treatment group than in the control group after treatment (P<0.05). Of the both 50 patients in the control and combined treatment groups, 22(44%) and 35 (70%) experienced a remarkably improvement, 18(36%) and 12(24%) were effective, and 10(20%) and 3 (6%) ineffective, with the total effective rates being 80% and 94%, respectively. The therapeutic effect of the combined treatment group was notably superior to that of the control group (P<0.05). The joint application of electroacupuncture (EA), acupoint-injection and fire needle is significantly superior to that of simple EA in improving the symptoms of patients with menopausal syndrome.

Variations in time to benefit among clinical trials of cholesterol-lowering drugs

Time to benefit (TTB) in clinical trials of cholesterol-lowering drugs is important because it may provide a clue as to the potential mechanism of action of the drug, it is helpful in determining when to stop a trial for futility, and it may inform treatment decisions in subjects with reduced life expectancy. To compare TTB among clinical trials of cholesterol-lowering drugs. We examined TTB in 24 trials of cholesterol-lowering drugs with positive outcomes. Benefit curves were constructed by subtracting the curve for a placebo or comparator drug from the curve for active treatment. TTB ranged from 1 to 30 (mean 13.1) months, being shorter in trials of statins (n=17) compared to nonstatins (n=7), 10.3 vs 20.0months. Among statin trials, TTB was shorter with atorvastatin (n=6) than in trials with other statins (n=11), 4.75 compared to 11.4months. TTB is variable among trials of cholesterol-lowering drugs, being shorter with statin compared to nonstatin drugs. TTB is shorter with atorvastatin than with other statins. For trials of new cholesterol-lowering drugs, outcome curves that do not separate for up to 30months do not preclude eventual benefit.