scholarly journals Are clinical trial results transferable in the real life?

2016 ◽  
Vol 84 (1-2) ◽  
Author(s):  
Enrico Natale ◽  
Alfiera Marsocci
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Recurrent Events ◽  
Randomized Clinical Trials ◽  
Real Life ◽  
Recurrent Event ◽  
The Real ◽  
Number Of Patients ◽  
Clinical Trial Results

<p>Generally in the clinical practice patients are more complex in comparison with those included in the clinical trials. In this article, we discuss three relevant items, which may implement the transferability of the clinical trial results in the real world. The observational studies have fewer restrictions on the number of patients included, due to more relaxed inclusion and exlusion criteria than in randomized clinical trials. The absence of randomization however may lead to potential for bias. The recurrent event analysis may extend the positive results of clinical trials regarding the reductions of the first primary endpoint event to total events, including those beyond the first event. This analysis is of great interest in the clinical practice, where recurrent events are common. Finally the reliability of subgroup analysis is discussed. Pre-specified subgroup analyses are more credible and valuable than <em>post-hoc</em> analyses.</p><p><strong>Riassunto</strong></p><p>Nella pratica clinica i pazienti sono generalmente più complessi rispetto alle popolazioni studiate nei trial clinici. Si rendono necessari pertanto strumenti di analisi che integrino i trial clinici. In questo articolo vengono esaminati alcuni punti di rilevante importanza nella definizione di una corretta applicabilità dei risultati dei trial clinici al mondo reale. Il primo punto riguarda il ruolo e i limiti degli studi osservazionali. Il secondo tratta delle analisi degli eventi ricorrenti, una modalità di analisi dei trial clinici che rende i risultati più aderenti alla vita reale, nella consapevolezza che limitare i dati di outcome al primo evento sia riduttivo rispetto alla necessità di stabilire che l’intervento studiato nel trial confermi la sua efficacia anche sugli eventi successivi al primo. Il terzo punto riguarda la controversa questione delle analisi per sottogruppi, uno strumento utile per generare ipotesi, ma discutibile quando impiegato per rimediare a trial con risultati negativi o estendere i risultati di trial positivi a sottopopolazioni particolari di pazienti. </p>

Survival among metastatic colorectal patients in clinical trials compared to the real world.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 673-673
Author(s):  
Ziwei Wang ◽  
Lindsay Hwang ◽  
James Don Murphy
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Median Survival ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
The Real ◽  
Clinical Trial Results

673 Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p<0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p<0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p<0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.

scholarly journals Comparison of Time-to-First Event and Recurrent-Event Methods in Randomized Clinical Trials

Circulation ◽  
2018 ◽  
Vol 138 (6) ◽  
pp. 570-577 ◽  
Author(s):  
Brian Claggett ◽  
Stuart Pocock ◽  
L.J. Wei ◽  
Marc A. Pfeffer ◽  
John J.V. McMurray ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Statistical Power ◽  
Recurrent Events ◽  
Randomized Clinical Trials ◽  
Cox Model ◽  
Study Drug ◽  
Recurrent Event ◽  
Drug Discontinuation ◽  
Patient Heterogeneity ◽  
Study Drug Discontinuation

Background: Most phase-3 trials feature time-to-first event end points for their primary and secondary analyses. In chronic diseases, where a clinical event can occur >1 time, recurrent-event methods have been proposed to more fully capture disease burden and have been assumed to improve statistical precision and power compared with conventional time-to-first methods. Methods: To better characterize factors that influence statistical properties of recurrent-event and time-to-first methods in the evaluation of randomized therapy, we repeatedly simulated trials with 1:1 randomization of 4000 patients to active versus control therapy, with true patient-level risk reduction of 20% (ie, relative risk=0.80). For patients who discontinued active therapy after a first event, we assumed their risk reverted subsequently to their original placebo-level risk. Through simulation, we varied the degree of between-patient heterogeneity of risk and the extent of treatment discontinuation. Findings were compared with those from actual randomized clinical trials. Results: As the degree of between-patient heterogeneity of risk increased, both time-to-first and recurrent-event methods lost statistical power to detect a true risk reduction and confidence intervals widened. The recurrent-event analyses continued to estimate the true relative risk (0.80) as heterogeneity increased, whereas the Cox model produced attenuated estimates. The power of recurrent-event methods declined as the rate of study drug discontinuation postevent increased. Recurrent-event methods provided greater power than time-to-first methods in scenarios where drug discontinuation was ≤30% after a first event, lesser power with drug discontinuation rates of ≥60%, and comparable power otherwise. We confirmed in several actual trials of chronic heart failure that treatment effect estimates were attenuated when estimated via the Cox model and that increased statistical power from recurrent-event methods was most pronounced in trials with lower treatment discontinuation rates. Conclusions: We find that the statistical power of both recurrent-events and time-to-first methods are reduced by increasing heterogeneity of patient risk, a parameter not included in conventional power and sample size formulas. Data from real clinical trials are consistent with simulation studies, confirming that the greatest statistical gains from use of recurrent-events methods occur in the presence of high patient heterogeneity and low rates of study drug discontinuation.

Primary Stroke Prevention in Nonvalvular Atrial Fibrillation: Implementing the Clinical Trial Findings

1997 ◽  
Vol 31 (10) ◽  
pp. 1187-1196 ◽  
Author(s):  
Patricia A Howard ◽  
Pamela W Duncan
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Cost Effectiveness ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Randomized Clinical Trials ◽  
Nonvalvular Atrial Fibrillation ◽  
Risk Patients

OBJECTIVE: To review the clinical trials evaluating warfarin for primary stroke prophylaxis in nonvalvular atrial fibrillation (NVAF), to discuss the relative benefits and risks of warfarin versus aspirin therapy, and to review the clinical practice guidelines and identify potential barriers to their implementation in clinical practice. DATA SOURCES: A MEDLINE literature search was performed to identify clinical trials of antithrombotic therapy for NVAF, clinical practice guidelines, studies evaluating physician practices and attitudes, cost-effectiveness studies, and pertinent review articles. Key search terms included atrial fibrillation, stroke, antithrombotic, warfarin, aspirin, and cost-effectiveness. DATA EXTRACTION: Prospective, randomized clinical trials were selected for analysis. Clinical practice guidelines from recognized panels of experts were reviewed. Comprehensive review articles were selected. DATA SYNTHESIS: NVAF is a common arrhythmia that is associated with a substantial risk for stroke. Seven prospective, randomized, clinical trials have conclusively demonstrated the efficacy of warfarin for stroke prevention. The greatest benefits are achieved in older patients and those with comorbidities that increase their risk for stroke. The potential benefits of preventing a devastating stroke, however, must be weighed against the potential for bleeding complications. Warfarin has been shown to be cost-effective in high-risk patients, provided the rate of complications is minimized. Nonetheless, many physicians remain hesitant to implement warfarin therapy in older, high-risk patients. The clinical data on aspirin are less consistent than those observed with warfarin. Aspirin appears to be most effective in younger individuals or those considered to be at low risk for stroke. CONCLUSIONS: In patients with NVAF, the personal, social, and economic consequences of stroke are often devastating. Clinical trials have provided definitive proof that the risks of stroke can be significantly reduced through the use of appropriate antithrombotic therapy. Despite this evidence and the recommendations of a number of clinical practice guidelines, variations in care exist that continue to place patients at risk. Additional outcomes research is needed to evaluate the impact of the clinical trial findings and practice guidelines on clinical practice and to develop methods for overcoming barriers to implementation.

scholarly journals Approaches to Assessing the Quality of Observational Studies of Clinical Practice Based on the Big Data Analysis

2021 ◽  
Vol 17 (4) ◽  
pp. 584-593
Author(s):  
S. R. Gilyarevsky
Keyword(s):  
Clinical Trials ◽  
Big Data ◽  
Clinical Practice ◽  
Observational Studies ◽  
Randomized Clinical Trials ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Real Life ◽  
Hierarchy Of Evidence

The article is devoted to the discussion of the problems of assessing the quality of observational studies in real clinical practice and determining their place in the hierarchy of evidence-based information. The concept of “big data” and the acceptability of using such a term to refer to large observational studies is being discussed. Data on the limitations of administrative and claims databases when performing observational studies to assess the effects of interventions are presented. The concept of confounding factors influencing the results of observational studies is discussed. Modern approaches to reducing the severity of bias in real-life clinical practice studies are presented. The criteria for assessing the quality of observational pharmacoepidemiological studies and the fundamental differences between such studies and randomized clinical trials are presented. The results of systematic reviews of real-life clinical trials to assess the effects of direct oral anticoagulants are discussed. 

Transforming Clinical Trial Eligibility Criteria to Reflect Practical Clinical Application

2016 ◽  
pp. 83-90 ◽  
Author(s):  
Edward S. Kim ◽  
Jennifer Atlas ◽  
Gwynn Ison ◽  
Jennifer L. Ersek
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Diagnostic Testing ◽  
Standard Of Care ◽  
Trial Participation ◽  
Eligibility Criteria ◽  
Number Of Patients ◽  
Oncology Clinical Trials ◽  
Clinical Trial Accrual ◽  
Clinical Trial Results

Historically, oncology clinical trials have focused on comparing a new drug’s efficacy to the standard of care. However, as our understanding of molecular pathways in oncology has evolved, so has our ability to predict how patients will respond to a particular drug, and thus comparison with a standard therapy has become less important. Biomarkers and corresponding diagnostic testing are becoming more and more important to drug development but also limit the type of patient who may benefit from the therapy. Newer clinical trial designs have been developed to assess clinically meaningful endpoints in biomarker-enriched populations, and the number of modern, molecularly driven clinical trials are steadily increasing. At the same time, barriers to clinical trial enrollment have also grown. Many barriers contribute to nonenrollment in clinical trials, including patient, physician, institution, protocol, and regulatory barriers. At the protocol level, eligibility criteria have become a large roadblock to clinical trial accrual. Over time, eligibility criteria have become more and more restrictive. To accrue an adequate number of patients to molecularly driven trials, we should consider eligibility criteria carefully and attempt to reduce restrictive criteria. Reducing restrictive eligibility criteria will allow more patients to be eligible for clinical trial participation, will likely increase the speed of drug approvals, and will result in clinical trial results that more accurately reflect treatment of the population in the clinical setting.

Leveraging historical data to optimize the number of covariates and their explained variance in the analysis of randomized clinical trials.

2021 ◽  
pp. 096228022110652
Author(s):  
Samuel Branders ◽  
Alvaro Pereira ◽  
Guillaume Bernard ◽  
Marie Ernst ◽  
Jamie Dananberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Degrees Of Freedom ◽  
Randomized Clinical Trials ◽  
Historical Data ◽  
Cost Benefit ◽  
Patient Characteristics ◽  
Cost Ratio ◽  
Optimum Number ◽  
Number Of Patients

The amount of data collected from patients involved in clinical trials is continuously growing. All baseline patient characteristics are potential covariates that could be used to improve clinical trial analysis and power. However, the limited number of patients in phases I and II studies restricts the possible number of covariates included in the analyses. In this paper, we investigate the cost/benefit ratio of including covariates in the analysis of clinical trials with a continuous outcome. Within this context, we address the long-running question “What is the optimum number of covariates to include in a clinical trial?” To further improve the benefit/cost ratio of covariates, historical data can be leveraged to pre-specify the covariate weights, which can be viewed as the definition of a new composite covariate. Here we analyze the use of a composite covariate to improve the estimated treatment effect in small clinical trials. A composite covariate limits the loss of degrees of freedom and the risk of overfitting.

Frailty modelling for multitype recurrent events in clinical trials

2018 ◽  
Vol 19 (2) ◽  
pp. 140-156
Author(s):  
Paul M Brown ◽  
Justin A Ezekowitz
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Structure ◽  
Recurrent Events ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Recurrent Event ◽  
Review Of The Literature ◽  
Survival Times ◽  
The Past

Recurrent event outcomes are ubiquitous among clinical trial data which encourages a conventional approach to analysis. Yet a common feature of these data has received less attention, that is, survival times often comprise multiple types of events that may imply a disparity in cost and disease severity. Typically, we neglect this feature of the data by combining event-types or analyzing each type separately, thus ignoring any interdependence among them. This practice may reflect a dearth of readily available methods and software that more appropriately acknowledge the true data structure. We provide a review of the literature on multitype recurrent events and frailty modelling which reflects a renewed interest in the topic over the past decade and the emergence of software for estimation. Thus, a review of available methods seems timely, if not overdue.

scholarly journals Proposing Minimum Requirements for Announcing Clinical Trial Results During the COVID-19 Pandemic

2020 ◽  
Author(s):  
Mark J Siedner ◽  
Rajesh T Gandhi
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Sufficient Data ◽  
Press Releases ◽  
The Public ◽  
Unique Nature ◽  
Minimum Requirements ◽  
Clinical Trial Results ◽  
Important Purpose

Abstract Recently, results from at least six major randomized clinical trials studying management of COVID-19 have been announced via press release. Given the unique nature of the pandemic, results of such trials often have immediate and worldwide relevance. Yet, while press releases serve the important purpose of disseminating top-level results quickly, they are inherently limited in scope, and rarely include sufficient data to inform practice. Herein, we propose a minimum set of trial characteristics and results to be released simultaneously with clinical trial announcements. This practice will ensure data related to the management of COVID-19 can be used to appropriately impact care, while responding to the needs of diverse stakeholders in the scientific and publishing communities, as well as the public at large.

Repurposed Antiviral Drugs for the Treatment of COVID-19: Syntheses, Mechanism of Infection and Clinical Trials

2020 ◽  
Vol 21 ◽  
Author(s):  
Subha Sankar Paul ◽  
Goutam Biswas
Keyword(s):  
Public Health ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Small Molecule ◽  
Mode Of Action ◽  
Antiviral Drugs ◽  
Public Health Emergency ◽  
Advanced Stage ◽  
Clinical Trial Results

: COVID-19 is a public health emergency of international concern. Although, considerable knowledge has been acquired with time about the viral mechanism of infection and mode of replication, yet no specific drugs or vaccines have been discovered against SARS-CoV-2, till date. There are few small molecule antiviral drugs like Remdesivir and Favipiravir which have shown promising results in different advanced stage of clinical trials. Chloroquinine, Hydroxychloroquine, and Lopinavir-Ritonavir combination, although initially was hypothesized to be effective against SARS-CoV-2, are now discontinued from the solidarity clinical trials. This review provides a brief description of their chemical syntheses along with their mode of action and clinical trial results available in Google and different peer reviewed journals till 24th October 2020.

scholarly journals The Disclosure Decision of Foreign Clinical Trials in China: Moderating Effects of Firms’ Contingencies

SAGE Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 215824402110163
Author(s):  
Tariq H. Malik ◽  
Chunhui Huo
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Risk Taking ◽  
Academic Community ◽  
Moderating Effects ◽  
The Public ◽  
Industrial Enterprises ◽  
Unit Increase ◽  
Clinical Trial Results ◽  
Clinical Trial Activity

Result disclosure of clinical trial posts a conflicting logic between private secrecy and public interest. Despite ethical and legal requirements for disclosing clinical trial results, clinical trials’ sponsors tend to withhold the results. We explored the location, timing, and rationale behind the withheld clinical trial results. Based on the entrepreneurial orientation (EO) perspective, we propose that organizational EO contingencies moderate the disclosure decision. We used the completed clinical trial projects in China by foreign and domestic sponsors. First, we found that a unit increase in the sponsor’s experience can increase the disclosure about 1.01 times. Second, we found that industrial enterprises disclose results about 3.7 times more than universities do. Third, we found that foreign clinical trial projects in China tend to disclose 3.9 times more than domestic projects. We link these findings to two types of audience. First, we inform the academic community on the theory and empirics regarding risk-taking behavior in the biopharmaceutical industry’s clinical trial activity. Second, we address the general audiences concerned about the ethical and socioeconomic wellbeing of the public.

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