scholarly journals Using numerical modelling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample

2021 ◽  
Author(s):  
Jean-Pierre Boissel ◽  
David Pérol ◽  
Hervé Décousus ◽  
Ingrid Klingmann ◽  
Marc Hommel
Keyword(s):  
Clinical Trials ◽  
Statistical Power ◽  
Controlled Trial ◽  
False Negative ◽  
Experimental Treatment ◽  
Chi Square ◽  
Randomized Controlled Clinical Trials ◽  
Randomized Controlled ◽  
Event Rates ◽  
Trial Participants

ABSTRACTIn order to explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants, including non-responders, who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are still debated. We introduce the concept of unnecessary participants, defined as those included in RCTs considered not informative with respect to efficacy, in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. Non-informative participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Non-informative participants can experience the outcome even if allocated to the experimental arm, or not present it even if allocated to the control arm. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

scholarly journals Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258093
Author(s):  
Jean-Pierre Boissel ◽  
David Pérol ◽  
Hervé Décousus ◽  
Ingrid Klingmann ◽  
Marc Hommel
Keyword(s):  
Clinical Trials ◽  
Statistical Power ◽  
Controlled Trial ◽  
False Negative ◽  
Experimental Treatment ◽  
Chi Square ◽  
Randomized Controlled Clinical Trials ◽  
Numerical Modeling And Simulation ◽  
Event Rates ◽  
Trial Participants

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Antioxidants and toxicity of cancer chemotherapy: A systematic review of the evidence from randomized controlled trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9130-9130
Author(s):  
K. I. Block ◽  
A. C. Koch ◽  
M. N. Mead ◽  
P. Tothy ◽  
R. A. Newman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Chemotherapy ◽  
Statistical Power ◽  
Meta Analysis ◽  
Controlled Clinical Trials ◽  
Randomized Controlled Clinical Trials ◽  
Randomized Controlled ◽  
Standardized Protocol ◽  
Concurrent Use ◽  
Relapsed Disease

9130 Background: Much debate has focused on whether or not antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the medical literature to compile results from randomized, controlled clinical trials evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. Methods: We performed a search of literature from 1966-December 2006 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting mitigation of chemotherapy toxicity were included in the final tally. The searches were performed in duplicate following a standardized protocol. No meta-analysis was performed due to heterogeneity of cancers and chemotherapy regimens. Results: Of 848 articles considered, 32 trials met the inclusion criteria. Antioxidants evaluated were: glutathione (9), melatonin (6), vitamin A (1), an antioxidant mixture (3), N-acetylcysteine (3), vitamin E (5), selenium (1), L-carnitine (1), Co-Q10 (2) and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. Conclusions: One of the 32 studies included reported evidence of significant increase in toxicity from the concurrent use of antioxidants with chemotherapy. In 18 studies, antioxidant groups experienced significantly lower toxicity than control groups. Statistical power and poor study quality were concerns with some of the studies. We have reported elsewhere that randomized trials of various antioxidants given with chemotherapy did not demonstrate an adverse effect on treatment response or survival. Well-designed studies evaluating larger populations of patients given antioxidants concurrently with chemotherapy are thus warranted. No significant financial relationships to disclose.

L-arginine effect on inflammatory mediators: A systematic review of randomized controlled clinical trials

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Seyed Reza Mirhafez ◽  
Mitra Hariri
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Inflammatory Mediators ◽  
Randomized Clinical Trials ◽  
Randomized Controlled Clinical Trials ◽  
Patients With Cancer ◽  
Reactive Protein ◽  
Randomized Controlled ◽  
Human Adults ◽  
Factor Α

Abstract. L-arginine is an important factor in several physiological and biochemical processes. Recently, scientists studied L-arginine effect on inflammatory mediators such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We conducted a systematic review on randomized controlled trials assessing L-arginine effect on inflammatory mediators. We searched data bases including Google scholar, ISI web of science, SCOPUS, and PubMed/Medline up to April 2019. Randomized clinical trials assessing the effect of L-arginine on inflammatory mediators in human adults were included. Our search retrieved eleven articles with 387 participants. Five articles were on patients with cancer and 6 articles were on adults without cancer. L-arginine was applied in enteral form in 5 articles and in oral form in 6 articles. Eight articles were on both genders, two articles were on women, and one article was on men. L-arginine could not reduce inflammatory mediators among patients with and without cancer except one article which indicated that taking L-arginine for 6 months decreased IL-6 among cardiopathic nondiabetic patients. Our results indicated that L-arginine might not be able to reduce selected inflammatory mediators, but for making a firm decision more studies are needed to be conducted with longer intervention duration, separately on male and female and with different doses of L-arginine.

scholarly journals Mitochondrial Reprogramming—What Is the Benefit of Hypothermic Oxygenated Perfusion in Liver Transplantation?

2021 ◽  
Vol 2 (2) ◽  
pp. 149-161
Author(s):  
Rebecca Panconesi ◽  
Mauricio Flores Carvalho ◽  
Matteo Mueller ◽  
Philipp Dutkowski ◽  
Paolo Muiesan ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Clinical Trials ◽  
Randomized Controlled Trial ◽  
Cohort Studies ◽  
Controlled Trial ◽  
Machine Perfusion ◽  
Randomized Controlled ◽  
Hypothermic Perfusion ◽  
Underlying Mechanisms ◽  
Circulatory Death

Although machine perfusion is a hot topic today, we are just at the beginning of understanding the underlying mechanisms of protection. Recently, the first randomized controlled trial reported a significant reduction of ischemic cholangiopathies after transplantation of livers donated after circulatory death, provided the grafts were treated with an endischemic hypothermic oxygenated perfusion (HOPE). This approach has been known for more than fifty years, and was initially mainly used to preserve kidneys before implantation. Today there is an increasing interest in this and other dynamic preservation technologies and various centers have tested different approaches in clinical trials and cohort studies. Based on this, there is a need for uniform perfusion settings (perfusion route and duration), and the development of general guidelines regarding the duration of cold storage in context of the overall donor risk is also required to better compare various trial results. This article will highlight how cold perfusion protects organs mechanistically, and target such technical challenges with the perfusion setting. Finally, the options for viability testing during hypothermic perfusion will be discussed.

Testing Meldonium: Assessing Soviet pragmatic alternatives to the randomized controlled trial

2021 ◽  
pp. 174077452110085
Author(s):  
Anastasiya Chirkova ◽  
Alexander Petrenko ◽  
Pavel Vasilyev
Keyword(s):  
Clinical Trials ◽  
Randomized Controlled Trial ◽  
Soviet Union ◽  
Drug Testing ◽  
Controlled Trial ◽  
Randomized Controlled ◽  
Experimental Drugs ◽  
The Soviet Union ◽  
Experimental Drug ◽  
Second World

Background/aims Current research largely tends to ignore the drug-testing model that was developed in the “Second World” as an explicit alternative to the randomized controlled trial. This system can be described as “socialist pharmapolitics,” accounting for the specific features of state socialism that influenced the development and testing of experimental drugs. The clinical trials model employed in the “Second World” was heavily influenced by the Soviet Union, which was by far the most influential player in the socialist bloc during the Cold War. Based on extensive archival research, this article presents an empirical case of a late Soviet clinical trial as a pragmatic alternative to the randomized controlled trial model. It accounts for the divergences between the official model prescribed by the Soviet authorities and the messy realities of healthcare practice. It further outlines different factors that ultimately shaped how clinical trials were organized in Soviet institutions “on the ground.” Accordingly, this article presents a “real-life” history of “socialist pharmapolitics” and outlines the problems that this system faced in practice. Methods Archival research was conducted at the Russian State Archive of Scientific and Technical Documentation in Moscow. Archival files include scientific, technical, and registration documentation such as biochemical, pharmacological, and clinical descriptions of the experimental drug Meldonium, letters between various hospitals, research institutes and the Soviet regulatory body, as well as 26 reports of completed clinical trials. Manual content analysis was used for the interpretation of results. Results This article presents an empirical case of a late Soviet clinical trial as a pragmatic alternative to the randomized controlled trial model. It demonstrates some key differences from the randomized controlled trial model. This article also highlights some of the discrepancies between the model that was officially prescribed by the Soviet authorities and the realities of experimental drug testing in the Soviet Union in the late 1980s and early 1990s. In particular, it notes some elements of randomization, double-blinding, and the use of placebo that were present in Meldonium trials despite being formally denounced by Soviet bioethics. Conclusion The Soviet model for testing experimental drugs differed from the Western one substantially in a number of respects. This difference was not only proclaimed officially by the Soviet authorities, but was for the most part enforced in clinical trials in practice. At the same time, our research demonstrates that there were important differences between the official model and the clinical realities on the ground.

scholarly journals Long-Term Dietary and Physical Activity Interventions in the School Setting and Their Effects on BMI in Children Aged 6–12 Years: Meta-Analysis of Randomized Controlled Clinical Trials

Healthcare ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 396
Author(s):  
Purificación Cerrato-Carretero ◽  
Raúl Roncero-Martín ◽  
Juan D. Pedrera-Zamorano ◽  
Fidel López-Espuela ◽  
Luis M. Puerto-Parejo ◽  
...  
Keyword(s):  
Physical Activity ◽  
Clinical Trials ◽  
Dietary Habits ◽  
Meta Analysis ◽  
Controlled Clinical Trials ◽  
Randomized Controlled Clinical Trials ◽  
Randomized Controlled ◽  
School Based ◽  
School Based Interventions

Preventive actions and potential obesity interventions for children are mainly researched throughout the school period, either as part of the school curricula or after regular school hours, via interventions mostly lasting less than 12 months. We aimed to perform a meta-analysis on randomized controlled clinical trials to evaluate the evidence of the efficacy of long-term school-based interventions in the management of childhood obesity in terms of BMI from a dietary and physical activity-based approach. Eleven randomized controlled clinical trials were examined using the random effects model, and the results showed that there were no significant effects associated with physical activity + nutrition intervention in school children aged 6–12 years, with a pooled standardized mean difference (SMD) (95% CI) of −0.00 (−0.05, 0.04). No effects were observed after subgroup analysis based on the intervention length. The findings from our study indicate that long-term school-based interventions on physical activity and dietary habits received by children aged 6–12 years seem to have no effect on BMI. However, the promotion of such interventions should not be discouraged, as they promote additional positive health outcomes for other domains of children’s health.

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