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Journal of Biopharmaceutical Statistics 2012A clinical trial might involve more than one clinically important endpoint, each of which can characterize the treatment effect of the experimental drug under... (Comparative Study)
Comparative Study
A clinical trial might involve more than one clinically important endpoint, each of which can characterize the treatment effect of the experimental drug under investigation. Underlying the concept of using such endpoints interchangeably to establish an efficacy claim, or pooling different endpoints to constitute a composite endpoint, is the assumption that findings from such endpoints are consistent with each other. While such an assumption about consistency of efficacy findings appears to be intuitive, it is seldom considered in the design and analysis literature of clinical trials with multiple endpoints. Failure to account for consistency of efficacy findings of two candidate endpoints to establish efficacy, at the design stage, has led to difficulties in interpreting study findings. This article presents a flexible testing strategy for accommodating findings of an alternative to the designated primary endpoint (or a subgroup) to support an efficacy claim. The method is built on the following two premises: (i) Efficacy findings of the designated primary endpoint, although nonsignificant, need to be supportive of those of the alternative endpoint, and (ii) the significance level allocated for testing the second endpoint is determined adaptively based on the magnitude of the p-value for the designated primary endpoint. The method takes into account the hierarchical ordering of the hypotheses tested and the correlation between the test statistics for the two endpoints to increase the chance of a positive trial. We discuss control of the type I error rate for the proposed test strategy and compare its power with that of other methods. In addition, we consider its application to two clinical trials.
Topics: Clinical Trials as Topic; Decision Support Techniques; Endpoint Determination; Humans
PubMed: 22204533
DOI: 10.1080/10543406.2010.513464 -
Current Oncology (Toronto, Ont.) Oct 2011In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been...
In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the "gold standard"-the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer.
PubMed: 21969810
DOI: No ID Found -
Statistics in Medicine Dec 2017The Food and Drug Administration in the United States issued a much-awaited draft guidance on 'Multiple Endpoints in Clinical Trials' in January 2017. The draft guidance...
The Food and Drug Administration in the United States issued a much-awaited draft guidance on 'Multiple Endpoints in Clinical Trials' in January 2017. The draft guidance is well written and contains consistent message on the technical implementation of the principles laid out in the guidance. In this commentary, we raise a question on applying the principles to studies designed from a safety perspective. We then direct our attention to issues related to multiple co-primary endpoints. In a paper published in the Drug Information Journal in 2007, Offen et al. give examples of disorders where multiple co-primary endpoints are required by regulators. The standard test for multiple co-primary endpoints is the min test which tests each endpoint individually, at the one-sided 2.5% level, for a confirmatory trial. This approach leads to a substantial loss of power when the number of co-primary endpoints exceeds 2, a fact acknowledged in the draft guidance. We review approaches that have been proposed to tackle the problem of power loss and propose a new one. Using recommendations by Chen et al. for the assessment of drugs for vulvar and vaginal atrophy published in the Drug Information Journal in 2010, we argue the need for more changes and urge a path forward that uses different levels of claims to reflect the effectiveness of a product on multiple endpoints that are equally important and mostly unrelated. Copyright © 2017 John Wiley & Sons, Ltd.
Topics: Atrophy; Bias; Endpoint Determination; Female; Guidelines as Topic; Humans; Limit of Detection; Pharmaceutical Preparations; Research Design; Sample Size; United States; United States Food and Drug Administration; Vagina; Vulva
PubMed: 28722159
DOI: 10.1002/sim.7383 -
Zeitschrift Fur Evidenz, Fortbildung... 2010The use of a combined (composite) endpoint as a primary outcome in clinical studies offers many advantages, e.g., increased statistical efficiency, smaller sample sizes,...
The use of a combined (composite) endpoint as a primary outcome in clinical studies offers many advantages, e.g., increased statistical efficiency, smaller sample sizes, shorter study completion times, and the possibility for a summary measure of different treatment effects. However, basic clinical and statistical requirements need to be respected in order to obtain valid results and to avoid difficulties in their interpretation later. Each component of a combined endpoint must be clinically meaningful. Patients must be followed up until death or to the planned end of the trial; these rules also apply to premature treatment withdrawal or after occurrence of the first pre-defined component event. All components of the composite endpoint need to be analysed separately in order to find out how they contribute to the overall result and to avoid the masking of negative effects on one or more components. Difficulties in interpretation may arise when the results for single components of the combined endpoint head in opposite directions, and when "hard" clinical outcomes are combined with "soft" endpoints, particularly if the latter occur much more frequently but are of minor clinical relevance.
Topics: Humans; Problem Solving; Reproducibility of Results; Research Design; Treatment Outcome
PubMed: 20608253
DOI: 10.1016/j.zefq.2010.03.007 -
Alzheimer Disease and Associated... 2020This study examined the primary and secondary endpoints used by recent phase II/III randomized controlled trials (RCTs) of drugs for the Alzheimer disease. We searched...
This study examined the primary and secondary endpoints used by recent phase II/III randomized controlled trials (RCTs) of drugs for the Alzheimer disease. We searched the Clinical Trials.gov database to identify all RCTs registered from January 1, 2011 until August 19, 2018. We identified 122 RCTs and examined primary and secondary endpoints most commonly used. The median number of primary endpoints was 1 (range: 1 to 48) and the median number of secondary endpoints was 4 (range: 1 to 19). Cognitive function was used as a primary endpoint by 59% of the RCTs identified. Although few trials included a primary outcome set that fulfilled the US Food and Drug Administration (FDA) or European Committee for Medicinal Products for Human Use (CHMP) requirements, these were met by a combination of the primary and secondary outcomes of more than half of the trials.
Topics: Alzheimer Disease; Databases, Factual; Humans; Neuropsychological Tests; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic
PubMed: 30730347
DOI: 10.1097/WAD.0000000000000297 -
Clinical Trials (London, England) Feb 2010In many fields, the choice of a primary endpoint for a trial is not always the ultimate clinical endpoint of interest, but rather some surrogate endpoint believed to be... (Review)
Review
BACKGROUND
In many fields, the choice of a primary endpoint for a trial is not always the ultimate clinical endpoint of interest, but rather some surrogate endpoint believed to be relevant for predicting the effect of the intervention on the clinical endpoint. The classic example of such a field is clinical HIV treatment research, where a variety of primary endpoints are used to evaluate the efficacy of new antiretroviral drugs or new combinations of existing drugs. The choice of endpoint reflects either the goal of therapy as recommended by treatment guidelines (e.g. rapid virological suppression) or the licensing requirements of official drug approval organizations (e.g. time to loss of virological response [TLOVR]).
PURPOSE
To review the diversity of endpoints used in recent clinical trials in HIV infection and highlight the methodological issues.
METHODS
We identified articles relating to antiretroviral therapy by searching PubMed and through hand searches of relevant conference abstracts. We restricted the search to randomized controlled trials conducted in HIV-infected adults published/presented from January 2005 until March 2008.
RESULTS
We identified 28 trials in antiretroviral-naive patients (i.e. patients who were starting antiretroviral therapy for the first time at the time of randomization) and 23 trials in antiretroviral-experienced patients. Most trials were performed for purposes of drug licensing, but others were focused on strategies of using approved drugs. Most trials (40 of 51) used a composite primary endpoint (TLOVR in 13). Of note, 22 of these 40 studies reported that they had used a purely virological efficacy endpoint, but the primary endpoint was actually a composite one due to the way in which missing data and treatment switches were considered as failures.
LIMITATIONS
Examples are restricted to HIV clinical trials.
CONCLUSIONS
Whilst most current HIV clinical trials use composite primary endpoints, there are substantial differences in the components that make up these endpoints. In HIV and other fields where precise definitions are variable, guidelines for standardization of definition and reporting would greatly improve the ability to compare trial results.
Topics: Antiretroviral Therapy, Highly Active; Biomarkers; Endpoint Determination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 20156955
DOI: 10.1177/1740774509356117 -
Fundamental & Clinical Pharmacology Dec 2005This article discusses some important issues that may arise in the current usage of composite endpoints as primary endpoints for demonstrating the efficacy of new drugs... (Review)
Review
This article discusses some important issues that may arise in the current usage of composite endpoints as primary endpoints for demonstrating the efficacy of new drugs in clinical trials. The discussion focuses on time-to-event composite endpoints. Issues discussed include validity of a composite endpoint, the often lack of follow-up of patients beyond first event, the analysis of a composite endpoint, its sub-composite and individual component endpoints and their interpretation. Actual published examples in the literature are used to illustrate some of these problems. It is recommended that a clinical trial using a composite endpoint as the primary endpoint should be designed to include patient follow-up beyond the first event if possible. For data collected from such trials, basic formats for tabular presentation of trial data and for results of analysis of the composite endpoint, its sub-composite and individual component endpoints are proposed for transparency and ease of interpretation.
Topics: Clinical Trials as Topic; Drug Therapy; Endpoint Determination
PubMed: 16313272
DOI: 10.1111/j.1472-8206.2005.00370.x -
Current Problems in Cancer 2006The choice of QOL endpoints for a study should be based on which score will most likely change if the treatment is favorable. How the QOL change is calculated should be...
The choice of QOL endpoints for a study should be based on which score will most likely change if the treatment is favorable. How the QOL change is calculated should be based on the expected amount of missing data, how many time points data will be collected, and whether extreme outliers in the scores impact results. The study should have sufficient power to detect a meaningful difference between arms (typically 10 points on a 0-100 point scale) in the chosen QOL endpoint. At the conclusion of a study, several secondary endpoints can be analyzed which can provide additional information and confirm primary endpoint results.
Topics: Animals; Cartilage; Endpoint Determination; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Outcome Assessment, Health Care; Quality of Life; Radiotherapy; Randomized Controlled Trials as Topic; Recombinant Proteins; Self-Assessment; Sharks
PubMed: 17123880
DOI: 10.1016/j.currproblcancer.2006.08.006 -
Pharmaceutical Statistics 2023Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an...
Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be "significant" as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.
Topics: Humans; Prospective Studies; Sample Size; Treatment Outcome
PubMed: 37217198
DOI: 10.1002/pst.2314 -
Journal of Pain Research 2022Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into... (Review)
Review
Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.
PubMed: 35210848
DOI: 10.2147/JPR.S334840