Choice Of Endpoints Research Articles

Real-world effectiveness of new medicines should be evaluated by appropriately designed clinical trials

Objectives Health care providers, policy makers, and importantly patients themselves are increasingly interested in the outcomes of clinical trials yet often expect different questions to be addressed than those commonly asked in conventional phase 3 trials. Study Design and Setting Review of methodological articles. Results Conventional randomized controlled trials (RCTs) emphasize internal validity through standardization and control but by design reduce external validity, that is, generalizability of results and conclusions. Ongoing uncertainty about effectiveness or safety of medical interventions in the real world is the major driver for developing improved phase 3b and phase 4 study designs. Factors that should improve the relevance of these real-world trials (RWTs) include choice of endpoints; investigator specialty, appropriate patient selection criteria; emphasis on patient–physician interaction; admittance of relevant interventions in all study groups; and more flexible, simple, and possibly event-driven study visits and procedures, while maintaining randomization as a critical element to address confounders. Conclusion Although we do not believe that RWTs will supplant conventional RCTs, properly designed RWTs will enrich our understanding of the effectiveness of new health care interventions and better inform patients and health care providers alike.

Balancing the Risks and Benefits of Thromboprophylaxis in Patients Undergoing Podiatric Surgery

Balancing the Risks and Benefits of Thromboprophylaxis in Patients Undergoing Podiatric Surgery

To Phase 3 or Not to Phase 3?

See related article, pages 1803–1810. Decisions to progress new chemical entities, biologicals, or new treatment modalities into Phase 3 are usually based on small Phase 2 studies that are designed to assess safety and to explore efficacy.1–3 Based on these Phase 2 safety studies, both large and small companies have launched large Phase 3 programs that include 2 concurrently run studies, ie, Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II ASP I and Ancrod Stroke Program (ASP) II. When Phase 3 studies have failed to demonstrate efficacy for the whole population under study, subgroup analysis to identify patients who may have benefited from treatment has led to additional Phase 3, subsequently negative studies.4 In part as a result of this approach, the number of failed studies for treatment of acute ischemic stroke, especially for neuroprotection, has become legendary. In this issue, Mandava and Kent5 present a model to predict if the results of a single study are different from a pooled control population. The model calculates expected outcome using a pooled control population and the ±95% “prediction interval surfaces” using the baseline variables of the National Institutes of Health Stroke Scale and age. The outcome variables assessed in the model are mortality and the 90-day modified Rankin …

Anesthetic Effects on the Developing Brain

Anesthetic Effects on the Developing Brain

Optimising the design of phase II oncology trials: The importance of randomisation

Oncology trial end-points continue to receive considerable attention, as illustrated by the development and revisions to the RECIST criteria. In this article, we focus the reader away from the issue of end-points for phase II trials and towards what we believe to be an even more important issue, the fundamental need for randomisation in phase II oncology trials, ideally with blinding and dose-ranging. We present arguments to support the proposition that randomisation will enable greater clarity in the interpretation of the phase II trial results, as well as allowing for more precise estimates of the effect size and sample size requirements for definitive phase III trials. Randomisation will also reduce potential bias resulting from inter-trial variability, which inflates both type I and II errors if historical controls are utilised. In the context of a randomised blinded trial, the exact choice of end-point is less critical, although we favour end-points such as the change in tumour size or progression status at a fixed early time point (i.e. 8–12 weeks after randomisation). Although end-points based on RECIST criteria can and should be utilised in randomised phase II trials, we do not believe that revision of the RECIST criteria will result in a fundamental improvement in drug development decisions in the absence of randomised clinical trials at the phase II stage of drug development.

Somatisation in functional dyspepsia: integrating gastric physiology with psychological state

Functional dyspepsia is considered to be the result of a complex interaction between biological, psychological and social factors. In this issue of the journal, Van Oudenhove and colleagues1 ( see...

Current Status and Future Prospects for Cell Transplantation to Prevent Congestive Heart Failure

Although most cardiac cell therapy trials have focused on patients with acute myocardial infarction, attempts at "regenerating" chronically failing hearts have also been performed. These studies have entailed use of skeletal myoblasts and bone marrow-derived cells. In the case of skeletal myoblasts, the randomized placebo-controlled myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial has failed to show that myoblast injections increased ejection fraction beyond that seen in controls but the finding that the highest dose of myoblasts resulted in a significant antiremodeling effect compared with the placebo group provides an encouraging signal. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have not shown a substantial benefit but positive results have been reported with intraoperative epicardial injections of CD133(+) progenitors. There are three possible reasons for these mixed results. The first is the marked heterogeneity of cell functionality (particularly in the case of bone marrow), which would expectedly translate into variable clinical outcomes. The second reason is the low rate of sustained engraftment. The third possible explanation is a mismatch between the choice of end points and the presumed mechanism of action of the cells. The initial assumption that adult stem cells could effect myocardial tissue regeneration has led to usual focus on ejection fraction as the major surrogate endpoint. It is now increasingly recognized that adult stem cells, in contrast to their embryonic counterparts, have little if any regenerative capacity and that their presumed beneficial effects more likely involve paracrine signaling, in which case infarct size, perfusion, or left ventricular volumes might be more appropriate markers. Altogether, these observations provide a framework for future research, the results of which will then have to be integrated in the protocol design of second-generation clinical trials.

An epistemology of patient safety research: a framework for study design and interpretation. Part 3. End points and measurement

This article builds on the previous two articles in this series, which focused on an evaluation framework and study designs for patient safety research. The current article focuses on what...

Pharmacogenetics: potential role in the treatment of diabetes and obesity

Background: Common genetic variation is associated with increased risk of common metabolic diseases such as type 1 and type 2 diabetes, and obesity. Increasing experience with genetic association studies has led to an understanding of the large sample sizes required to detect a weak to moderate genetic predisposition to disease, the need to reproduce such associations in independent cohorts, and the statistical criteria required to detect a true association. This approach has been used successfully to identify disease-associated gene variation usually in representative populations of large numbers. Objective: To review the current understanding of how common genetic variation influences predisposition to, and treatment of, metabolic disease. Methodology: Review of scientific literature. Results: While there has been progress in understanding how genetic variation predisposes to diabetes and obesity, and how candidate genes may alter drug response, several caveats limit the interpretation and significance of pharmacogenetic studies published to date: those caveats typically include relatively small numbers of participants and choice of endpoints in determining gene-associated differences in response, which may not be clinically significant or relevant as a biomarker or predictor of a desired clinical effect. The genetic variants studied at a given locus are often limited in number and may not represent a comprehensive map of the region under study. Conclusions: The pharmacogenetic associations in diabetes and obesity that have been reported to date have had limited impact on the choice of individual treatments. We perceive, however, that this field is in its infancy in these multifactorial metabolic diseases, and with further advances and future drug intervention trials designed in a way that allows a more clear interpretation of the impact of genetic variation on differences in drug response in obesity and diabetes, it is anticipated that pharmacogenetics will have a significant impact on individualizing medical care.

Invited Commentary

Invited Commentary

Cardiac Cell Therapy Trials: Chronic Myocardial Infarction and Congestive Heart Failure

Although most cardiac cell therapy trials have focused on patients with acute myocardial infarction, attempts at "regenerating" chronically failing hearts have also been performed. These studies have entailed use of skeletal myoblasts and bone marrow-derived cells. In the case of skeletal myoblasts, the randomized placebo-controlled MAGIC trial has not achieved its primary end point as 6-month ejection fractions did not significantly differ between patients receiving cells or placebo, but the finding that the highest dose of myoblasts resulted in a significant anti-remodeling effect (a prespecified secondary end point) compared with the placebo group provides an encouraging signal. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have failed to show any substantial benefit. A catheter-based trial using a cross-over type of design has reported more successful outcomes, but its results will then have to be confirmed. Indeed, the most positive results have been reported with intraoperative epicardial injections of CD133 progenitors, which is probably explained by the angiogenic potential of these cells. There are three possible reasons for these mixed results. The first is the marked heterogeneity of cell functionality (particularly in the case of bone marrow), which would expectedly translate into variable clinical outcomes. The second reason is the low rate of sustained engraftment caused by early mechanical leakage followed by biologically induced cell death. The third possible explanation is a mismatch between the choice of end points and the presumed mechanism of action of the cells. The initial assumption that adult stem cells could affect myocardial tissue regeneration has led to the usual focus on ejection fraction as the major surrogate end point for treatment efficacy. It is now increasingly recognized that adult stem cells, in contrast to their embryonic counterparts, have little if any regenerative capacity and that their presumed beneficial effects more likely involve paracrine signaling and/or limitation of remodeling, in which case infarct size, perfusion, or left ventricular volumes might be more appropriate markers. Altogether, these observations provide a framework for future research the results of which will then have to be integrated into the protocol design of second-generation clinical trials so as to maximize their likelihood of yielding more successful results.

Effects of catecholamines on cerebral blood vessels in patients with traumatic brain injury

Data on the cerebrovascular effects of catecholamines after head injury are difficult both to interpret and to compare. Diverse parameters with regard to brain trauma animal models, methods of determining the effects on the cerebral blood flow and metabolism and choice of end-points have been used. Many studies investigate the cerebrovascular effects of catecholamines over a range of cerebral perfusion pressures above the range recommended by current guidelines. The relationship between patient outcome and the use of a specific substance to improve cerebral perfusion has not been investigated. Dopamine, norepinephrine and phenylephrine all seem to increase cerebral blood flow in various animal models and in patients. The data suggest that norepinephrine may be the most predictable. It is associated with an improved restoration of global and regional oxygenation when compared to dopamine. Dopamine has been associated with an increase in brain oedema. There is further evidence that dopamine has many disadvantages in critically ill patients due to its ability to suppress circulating concentrations of most anterior pituitary-dependent hormones. Both aspects would further discourage its use. Data on phenylephrine are scarce. It has been associated with increased intracranial pressure and a failure to improve cerebral oxygenation despite markedly improved cerebral perfusion pressure. For all other catecholamines and related substances there are insufficient data on the cerebrovascular effects after head injury. This suggests that norepinephrine may be the catecholamine that is the most suitable substance to maintain or restore adequate cerebral perfusion. The data, however, are insufficient to formulate a guideline.

Improving clinical trial design for hepatocellular carcinoma treatments

Despite its place as the third leading cause of cancer deaths worldwide, there are currently no approved chemotherapeutic agents, devices or techniques to treat hepatocellular carcinoma. Importantly, there have been no phase III studies demonstrating survival benefit, nor any randomized studies of treatment except for transarterial chemoembolization and most recently sorafenib. The importance of well-designed clinical trials of agents to treat HCC has never been greater. However, general clinical study design issues, combined with HCC-specific issues pose significant challenges in structuring such studies. HCC-related challenges include the heterogeneity of this cancer and the fact that it is frequently accompanied by significant comorbidities at diagnosis, such as active hepatitis B or C virus replication, substantial past or on-going alcohol use, and cirrhosis, itself often a fatal disease. The recently published comparison of a newer treatment, nolatrexed to doxorubicin, and comments about this study’s initial HCC diagnostic criteria, staging system, comparator therapy and choice of endpoints have provided a platform to discuss the challenges unique to the design of HCC clinical trials. The difficulty in accurately framing study results obtained from the constantly changing HCC clinical landscape and approaches to meet these challenges will be reviewed.

End points to establish the efficacy of new agents in the treatment of acute leukemia

AbstractFederal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure “reasonably likely” to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort.

Clinical trials in systemic sclerosis: lessons learned and outcomes

The pathogenesis of systemic sclerosis (SSc) is complex and largely unclear. The clinical heterogeneity of the disease and its progression over a number of years makes the choice of endpoints in the design of clinical trials difficult. The overwhelming need in this disease is to diagnose it early and identify those patients who will benefit most from early, aggressive treatment that potentially can alter the clinical disease course. To achieve this, innumerable challenges must be overcome. This article reviews data from recent clinical trials and the lessons derived from retrospective observational studies, databases, and patient registries. Taken together, these observations will help to improve our understanding of the diverse clinical course of SSc and permit refinement of existing outcome measures for the design of future clinical trials, in which the likelihood of observing a positive treatment effect with the drugs at our disposal will be maximized.

The WIZARD Trial as a Case Study of Flexible Clinical Trial Design

The design of a randomized, controlled, confirmatory efficacy clinical trial is influenced by multiple competing factors, including ethical, scientific, economic, and regulatory interests. Design elements, including choice of end points, study duration, and interim monitoring plans, need to be adapted to specific circumstances. The Weekly Intervention With Zithromax for Atherosclerosis and Its Related Disorders (WIZARD) study design was initially intended to meet the sponsor's scientific goals while being subject to practical constraints. In response to changing circumstances, modifications to the study design were required. The WIZARD trial demonstrates the substantial flexibility in the design and conduct of group-sequential randomized trials not only during the design stage but also after the trial is under way, effectively satisfying evolving and competing demands while preserving the statistical and scientific validity of the study.

Designing clinical trials in women's health

Although outcomes in women's health are not as spectacular as in conditions like cancer, the large number of women who present each year means that the overall impact of these conditions is enormous. Similarly, although suboptimal therapies may not individually be much worse than best practice, the overall effect on a nation's health, wealth and happiness is substantial. There is a therefore a real need to gather evidence as to which, if any, women, benefit from any particular therapy. Well-designed randomised controlled trials (RCTs) help provide reliable evidence on a treatment's effectiveness. In this article, we consider important aspects of designing a good clinical trial; and in particular their application to women's health issues. Designed as an overview of the subject, we consider how large trials need to be; the choice of endpoints; how they should be analysed; and also more practical considerations in running a successful trial. The considerations given here are of use not only to clinicians or researchers preparing to run their own trial, but also to anyone who reads reports of trials, and should help clinicians make informed judgements about evidence presented in published reports.

Opinion of the Scientific Panel on Plant protection products and their residues (PPR) related to the choice of endpoints to assess the long term risk to mammals

EFSA JournalVolume 4, Issue 4 344 OpinionOpen Access Opinion of the Scientific Panel on Plant protection products and their residues (PPR) related to the choice of endpoints to assess the long term risk to mammals European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 10 April 2006 https://doi.org/10.2903/j.efsa.2006.344 Panel members: Damià Barceló Culleres, Robert Black, Jos Boesten, Alan Boobis, Anthony Hardy, Andy Hart, Herbert Koepp, Robert Luttik, Kyriaki Machera, Marco Maroni, Douglas McGregor, Otto Meyer, Angelo Moretto, Euphemia Papadopoulou-Mourkidou, Ernst Petzinger, Kai Savolainen, Andreas Schaeffer, John Stenström, Walter Steurbaut, Despina Tsipi-Stefanitsi, Christiane Vleminckx. Acknowledgement: The Scientific Panel on Plant health, Plant protection products and their Residues wishes to thank Richard Shore and Richard Bennett for their contributions to this draft opinion. Adoption date: 6 April 2006 Published date: 10 April 2006 Question number: EFSA-Q-2005-113A+B AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume4, Issue4April 2006344 ReferencesRelatedInformation

How to Measure Quality of Life in Integrative Oncology Research

Quality of life is an important focus of integrative oncology research. Choice of an appropriate way to measure quality of life is therefore a key concern. A common error of researchers has been to focus on whether a quality of life measure has been "validated". This may be a necessary condition for choice of endpoint, but it is certainly not sufficient. It is easily shown that interventions that undoubtedly improve quality of life, such as Epogen for chemotherapy anemia, will not have an important impact on items in some validated quality of life scales (e.g. "I trust my doctor") and therefore will not improve quality of life scores. Investigators are advised to move beyond "validation" as a criterion for choosing quality of life endpoints and focus instead on the specific content of different potential measures. A particularly important concern is whether a prior trial showing a statistically significant difference on a specific quality of life scale is published, as this would demonstrate that scores on the scale will improve if patients respond to treatment. In many cases, it is preferable to use specific symptoms, such as pain or fatigue, as opposed to more generic quality of life scales.

Is antithrombotic prophylaxis required in cancer patients with central venous catheters? Yes for special patient groups.

Is antithrombotic prophylaxis required in cancer patients with central venous catheters? Yes for special patient groups.