Alternative Primary Endpoint Research Articles

Randomised controlled trials evaluating anticancer therapies in haematological cancers: an overview of global research activity.

Design, results, and interpretation of oncology randomised controlled trials (RCTs) have changed substantially over the past decade. In this study, we describe all RCTs evaluating anticancer therapies in haematological cancers published globally during 2014-2017 with comparisons with solid tumours RCTs. A PubMed literature search identified all phase 3 RCTs of anticancer therapy for haematological cancers and solid tumours published globally during 2014-2017. Descriptive statistics, chi-square tests and the Kruskal-Wallis test were used to compare RCT design results, and output between haematological cancers and solid tumours as well as for different haematological cancer subtypes. 694 RCTs were identified; 124 in haematological cancers and 570 in solid tumours. Overall survival (OS) was the primary endpoint in only 12% (15/124) of haematological cancer trials compared to 35% (200/570) in solid tumours (p < 0.001). Haematological cancer RCTs evaluated the systemic novel therapy more often than the solid tumour RCT (98% versus 84%, p = 0.002). Use of surrogate endpoints like progression-free survival (PFS) and time to treatment failure (TTF) were more common in haematological cancers than solid tumours (47% versus 31%, p < 0.001). Within haematological cancers, the use of PFS and TTF was more prevalent in chronic lymphocytic leukaemia and multiple myeloma as compared to others (80%-81% versus 0%-41%, p < 0.001). Seventy-eight percent of haematologic trials were funded by industry as compared to 70% of solid tumour trials. Only 4% (5/124) of haematologicalcancer trials were led by investigators in upper-middle and lower-middle-income countries as compared to the 9% of solid tumour trials. The fact that only 12% of haematological cancer RCTs are designed to show improvements in OS is of grave concern for the field and the care of future patients. This is further compounded by the highly prevalent use of alternative primary endpoints that are rarely valid surrogates for OS in haematological cancers.

Simultaneous population enrichment and endpoint selection in phase 3 randomized controlled trials: An adaptive group sequential design with two binary alternative primary endpoints

Population enrichment designs can play a vital role in detecting treatment benefits, if present, by selecting a study population where the treatment is more likely to show a benefit compared to the unselected population. While population enrichment designs with one primary endpoint have been studied in the current literature, there are limited research on population enrichment with alternative primary endpoints. Many diseases have multiple sequelae and it can be sufficient to show treatment benefits on at least one of these consequences. In this manuscript, we provide the theoretical basis and development of a two-stage adaptive design with two binary alternative primary endpoints that simultaneously evaluates two subgroups for enrichment, selects one or both endpoints for efficacy assessments at the time of the interim analysis using pre-specified decision rules, and maintains an overall type I error rate. Treatment benefits can be declared in one or both endpoints in a selected subgroup or in the overall population at the time of interim or final analyses. We provide stage-wise boundary values for futility and efficacy and rejection probabilities under heterogeneous treatment effects in the subgroups. We further demonstrate the implementation of the proposed design and discuss venues for future development on this topic.

Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications.

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.

Should Overall Survival Remain an Endpoint for Multiple Myeloma Trials?

While the traditional gold standard for demonstrating clinical benefit of a therapy has been to show prolongation of overall survival (OS), there are multiple factors which can hinder the use of OS as a primary endpoint in randomized clinical trials (RCTs). Here, we analyze recent myeloma RCTs and evaluate the issues relevant to current and future myeloma RCT design. A review of recent phase III RCTs that led to approval of new agents/combinations reveals that none were designed with OS as the primary endpoint, but instead utilized time to progression (TTP) or progression-free survival (PFS). These studies illuminate the inherent difficulties of designing trials with the primary endpoint of OS/PFS in a disease characterized by increasingly prolonged survival times, availability of effective salvage therapies, and competing events such as co-morbid conditions. Alternative primary endpoints other than OS or PFS need to be developed for future myeloma RCTs. Validated surrogate endpoints with novel clinical trial designs will help improve the feasibility of conducting comparative clinical trials in a timely manner.

Novel 1 L polyethylene glycol-based bowel preparation NER1006 for overall and right-sided colon cleansing: a randomized controlled phase 3 trial versus trisulfate

NER1006 is the first 32 fluid ounce (1 L) polyethylene glycol-based bowel preparation. This randomized, multicenter, colonoscopist/central reader-blinded phase 3 non-inferiority trial assessed the efficacy, safety, and tolerability of NER1006 versus trisulfate for bowel cleansing. Patients undergoing colonoscopy were randomized (1:1) to receive NER1006 or trisulfate, using evening/morning split-dosing administration. Blinded central readers used the validated Harefield Cleansing Scale to evaluate 2 alternative primary endpoints: overall bowel-cleansing success and high-quality cleansing of the ascending colon/cecum. Secondary endpoints included lesion detection, Boston Bowel Preparation Scale (BBPS) assessment, and adherence. The non-inferiority margin was 10% and the significance threshold was P< .025. Of 621 patients randomized (NER1006, n=310; trisulfate, n=311), 556 were evaluated for efficacy (NER1006, n=276; trisulfate, n=280). NER1006 achieved non-inferiority versus trisulfate for both primary endpoints of overall bowel-cleansing success (85.1% vs 85.0%; difference, 0.14%; one-sided 97.5% lower confidence limit [LCL],-8.15%; P= .528) and high-quality cleansing of the ascending colon/cecum (35.9% versus 29.3%; difference, 6.58%; LCL,-1.69%; P = .059). BBPS assessments supported overall bowel-cleansing success rates. Lesion detection rates were similar between the groups. The percentage of patients with treatment-related adverse events was 14.9% with NER1006 and 9.4% with trisulfate. Both bowel preparations showed similar overall tolerability and safety profiles. Adherence was very high in both arms. With evening/morning split dosing, NER1006 was as effective as trisulfate for overall bowel and right-sided colon cleansing. Adverse event rates were slightly higher with NER1006 than trisulfate, but did not compromise tolerability, adherence, or efficacy. (Clinical trial registration number: NCT02254486.).

New Low-Volume Bowel Cleansing Solution (NER1006) Versus Trisulfate, Polyethylene Glycol 3350+Ascorbate or Sodium Picosulfate/Magnesium Salt: 3 Multicenter Randomized Parallel Group Ph3 Studies in 1,865 Colonoscopy Patients

Introduction: A Phase 3 program aims to establish efficacy, safety, tolerability of NER1006, a new oral low-volume polyethylene glycol (PEG) solution with ascorbate (Asc), in a large adult colonoscopy patient population Methods: Three multicenter, randomized, colonoscopist-blinded parallel group studies in males/females (18-85 years) are underway. Main inclusion criteria: screening, surveillance or diagnostic colonoscopy patients. Main exclusion criteria include: history (≤12 months) or current severe constipation episode; known/suspected ileus; gastrointestinal (GI) obstruction; gastric retention; bowel perforation; toxic colitis or megacolon; ongoing severe acute inflammatory bowel disease; previous significant GI surgeries. NOCT (NCT02254486) will randomize (1:1) ≤620 US patients to NER1006 (2-day split dosing starting evening of the day before colonoscopy) or trisulfate solution (per label). MORA (NCT02273167; 2014-002185-78) will randomize (1:1:1) ≤850 European patients to NER1006 (2-day evening/morning splitdosing and 1-day morning on day of colonoscopy) or PEG3350+Asc (per label). DAYB (NCT02273141; 2014-002186-30) will randomize (1:1) ≤530 European patients to NER1006 (1-day, day before-only split dosing starting evening of the day before colonoscopy) or sodium picosulfate/magnesium salt (per label). Study duration: ≤4 clinic visits/patient for ≤40 days. Alternative primary endpoints: 1. NER1006 overall bowel cleansing success rate is non-inferior to comparator using the Harefield Cleansing Scale (HCS); 2. NER1006 ‘Excellent plus Good' cleansing rate in colon ascendens is non-inferior to comparator using HCS segmental cleansing scoring system. Central readers will score colonoscopy videos. Key secondary endpoints include: adenoma and polyp detection rates in colon ascendens and overall. Results: As of May 2015, number of patients randomized were: 610/620 at 12 US sites (NOCT); 507/850 at 30 sites in Belgium, France, Germany, Italy, Poland, Spain and UK (MORA); 369/530 at 20 sites in Germany, Italy, Netherlands, Poland, Spain, and UK (DAYB). Studies are due to complete by September 2015. Conclusion: Quality of bowel preparation is an important factor for a successful colonoscopy but lavage solution volume required to achieve efficacy/tolerability is often a barrier. Findings from these pivotal Phase 3 studies of a new low-volume bowel preparation may provide a better understanding of what is required in an optimal bowel preparation.

A new partition testing strategy for multiple endpoints

To evaluate efficacy in multiple endpoints in confirmatory clinical trials is a challenging problem in multiple hypotheses testing. The difficulty comes from the different importance of each endpoint and their underlying correlation. Current approaches to this problem, which test the efficacy in certain dose-endpoint combinations and collate the results, are based on closed testing or partition testing. Despite their different formulations, all current approaches test their dose-endpoint combinations as intersection hypotheses and apply various union-intersection tests. Likelihood ratio test is seldom used owing to the extensive computation and lack of consistent inferences. In this article, we first generalize the formulation of multiple endpoints problem to include the cases of alternative primary endpoints and co-primary endpoints. Then we propose a new partition testing approach that is based on consonance-adjusted likelihood ratio test. The new procedure provides consistent inferences, and yet, it is still conservative and does not rely on the estimation of endpoint correlation or independence assumptions that might be challenged by regulatory agencies.

Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer?

In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (≥30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven.

Alternative primary endpoints for cancer trials needed?

Alternative primary endpoints for cancer trials needed?

What We Want versus What We Can Get: A Closer Look at Failure Time Endpoints for Cardiovascular Studies

In this article, we review the use of all-cause mortality and the composite endpoint as the primary endpoint and propose a recurrent composite endpoint as an alternative primary endpoint. Some general suggestions to trialists and practitioners are provided. In summary, the use of the composite endpoint is an issue that needs clarification.

Fluvastatin Prevents Cardiac Death and Myocardial Infarction in Renal Transplant Recipients: Post-Hoc Subgroup Analyses of the ALERT Study

Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double-blind, placebo-controlled trial of fluvastatin (40–80 mg/day) in 2102 renal transplant recipients followed for 5–6 years. The main study used a composite cardiac end-point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end-point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end-point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL-cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre-existing CVD. These data support the early introduction of statins following renal transplantation.

Evaluation of drugs for treating obesity.

Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in relation to the realities of obesity, which is a chronic disease associated with morbidity and mortality that is increased by visceral fat deposits. The observation that patients regain weight after stopping drug treatment for obesity argues for the proposition that drugs work only when taken and NOT that the drugs are ineffective. The analogy between the development of treatments for obesity to those for the treatment of hypertension is used to highlight potential areas for new developments. Several features of an ideal drug for the treatment of obesity are suggested. Criteria for evaluating new drugs include both primary and secondary endpoints. The primary endpoint for an anti-obesity drug should be weight loss, possibly by category of success. Losses of total body fat or visceral fat might be alternative primary endpoints. Secondary endpoints include reduction in risk factors for associated diseases and improvement in the quality of life. In trials where vigorous placebo designs including highly aggressive behavior modification or very-low-calorie diets were used, it may be difficult or impossible to detect a response to a drug.