Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions.

BACKGROUND: Noninferiority trials are becoming more common. Their design often requires investigators to "trade" a secondary benefit for efficacy. Use of mortality as an outcome of interest leads to important ethical conflicts whereby researchers must establish a minimal clinically important difference for mortality, a process which has the potential to result in problematic conclusions. OBJECTIVE: We sought to investigate the frequency of the use of mortality as an outcome in noninferiority trials, as well as to determine the average pre-specified noninferiority ("delta") values. DESIGN: We searched MEDLINE for reports of parallel-group randomized controlled noninferiority trials published in five high-impact general medical journals. MAIN OUTCOME MEASURES: Data abstracted from articles including trial design parameters, results, and interpretation of results based on CONSORT recommendations. RESULTS: One hundred seventy-three manuscripts reporting 196 noninferiority comparisons were included in our analysis. Of these, over a third (67 trials) used mortality either as their sole endpoint (11 trials) or as part of a composite endpoint (56 trials). Nine trials were consort A, 21 trials consort B, 19 trials consort C, 12 were consort F, 4 consort G, and 2 were consort H. Four analyses showed statistically significant more deaths in the new treatment arm, while meeting consort criteria as "inconclusive" (consort G), (Behringer et al. in Lancet. 385(9976):1418-1427, 2015; Kaul et al. in N Engl J Med. 373(18):1709-1719, 2015; Bwakura-Dangarembizi et al. in N Engl J Med. 370(1):41-53, 2014) and thirteen trials utilizing mortality as an endpoint and had an absolute increase of > 3%, and six had an absolute increase of > 5%. CONCLUSIONS: The use of mortality as an outcome in noninferiority trials is not rare and scenarios where the new treatment is statistically worse, but a conclusion of noninferiority or inconclusive do occur. We highlight these issues and propose simple steps to reduce the risk of ethically dubious conclusions.

Ventricular tachycardia ablation in structural heart disease: Impact of ablation strategy and non-inducibility as an end-point on long term outcome.

BACKGROUND: To investigate the long term outcomes after catheter ablation (CA) of ventricular tachycardia (VT) in the context of structural heart disease in a multicenter cohort. The impact of different ablation strategies (substrate ablation versus activation guided versus combined) and non-inducibility as an end-point was evaluated. METHODS: Data was pooled from prospective registries at 5 centres over a 5 year period. Success was defined as survival free from recurrent ventricular arrhythmias (VA). Multivariate analysis of factors predicting survival free from VA was analysed by Cox regression. RESULTS: Five hundred sixty-six patients underwent CA for VT. Patients were 64 ±â€¯15 years. Left ventricular ejection fraction was 35 ±â€¯15% and 66% had ischaemic heart disease. At 2.3 (IQR 1.0-4.2) years, success was achieved in 44% after a single procedure, rising to 60% after repeat procedures. Mortality at final follow up was 22%. Multivariate analysis showed that higher left ventricular ejection fraction, younger age, ischaemic heart disease, and non-inducibility of VA predicted long term survival free from VA (all p < 0.05). There was no impact of the approach to ablation. CONCLUSION: CA eliminates VT in a large proportion of patients long term. Ablation strategy did not impact outcome and hence substrate ablation is a reasonable initial strategy. Non-inducibility of VA predicted survival free from VA and may be worth pursuing as a procedural end-point.

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.

Milestone Survival: A Potential Intermediate Endpoint for Immune Checkpoint Inhibitors.

Recent advancements in cancer immunotherapies offer diverse strategies for cancer treatment. Among the most promising approaches is the blockade of immune checkpoint molecules to activate antitumor immunity. With targeted immunotherapies of new mechanisms of action come greater challenges in study design and statistical analysis, as well as the need for refining clinical trial endpoints. The long-term survival and delayed clinical effects demonstrated by these therapies could result in substantial prolongation of study duration and loss of statistical power if these key attributes are not accounted for in the study design and statistical analyses. In the Brookings Conference on Clinical Cancer Research held in Washington, DC, in November 2013, several intermediate clinical endpoints, including milestone overall survival, were proposed for the evaluation of cancer immunotherapies to take into account the possibility of delayed treatment effect and to better characterize the clinical activity profile of such agents, particularly immune checkpoint inhibitors. In this manuscript, the use of milestone survival is described as a potential efficacy endpoint for immune checkpoint inhibitors in late-stage drug development that could potentially mitigate the challenge of accelerating the drug development process when the strength of this class of agents is derived from long-term follow-up.

Kidney cancer: overall survival is an unsuitable primary end point.

Final results of the CALGB 90206 and AVOREN trials have failed to demonstrate an overall survival benefit for bevacizumab plus interferon compared to interferon monotherapy in patients with metastatic renal cell carcinoma. Progression-free survival or objective response rate might be more suitable primary end points in phase III trials.