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Assay sensitivity is a property of a clinical trial defined as the ability of a trial to distinguish an effective treatment from a less effective or ineffective intervention. [1] Without assay sensitivity, a trial is not internally valid and is not capable of comparing the efficacy of two interventions.
Lack of assay sensitivity has different implications for trials intended to show a difference greater than zero between interventions (superiority trials) and trials intended to show non-inferiority. Non-inferiority trials attempt to rule out some margin of inferiority between a test and control intervention i.e. rule out that the test intervention is no worse than the control intervention by a chosen amount.
If a trial intended to demonstrate efficacy by showing superiority of a test intervention to control lacks assay sensitivity, it will fail to show that the test intervention is superior and will fail to lead to a conclusion of efficacy.
In contrast, if a trial intended to demonstrate efficacy by showing a test intervention is non-inferior to an active control lacks assay sensitivity, the trial may find an ineffective intervention to be non-inferior and could lead to an erroneous conclusion of efficacy. [2]
When two interventions within a trial are shown to have different efficacy (i.e., when one intervention is superior), that finding itself directly demonstrates that the trial had assay sensitivity (assuming the finding is not related to random or systematic error). In contrast, a trial that demonstrates non-inferiority between two interventions, or an unsuccessful superiority trial, generally does not contain such direct evidence of assay sensitivity. However, the idea that non-inferiority trials lack assay sensitivity has been disputed. [3] [4]
Assay sensitivity for a non-inferiority trial may depend upon the chosen margin of inferiority ruled out by the trial, and the design of the planned non-inferiority trial. The chosen margin of inferiority in a non-inferiority trial cannot be larger than the largest effect size which the control intervention reliably and reproducibly demonstrates compared to placebo or no treatment in past superiority trials. For instance, if there is reliable and reproducible evidence from previous superiority trials of an effect size of 10% for a control intervention compared to placebo, an appropriately designed non-inferiority trial designed to rule out that the test intervention may be as much as 5% less effective than the control would have assay sensitivity. On the other hand, with this same data, a noninferiority trial designed to rule out that the test intervention may be as much as 15% less effective than the control may not have assay sensitivity, since this trial would not ensure that the test intervention is any more effective than a placebo given that the effect ruled out is larger than the effect of the control compared to placebo. [5] The choice of the margin is sometimes problematic in non-inferiority trials. Given investigators desire to choose larger margins to decrease the sample size needed to perform a trial, the chosen margin is sometimes larger than the effect size of the control compared to placebo. In addition, a valid noninferiority trial is not possible in situations in which there is a lack of data demonstrating a reliable and reproducible effect of the control compared to placebo.
In addition to choosing a margin based upon credible past evidence, to have assay sensitivity, the planned non-inferiority trial must be designed in a way similar to the past trials which demonstrated the effectiveness of the control compared to placebo, the so-called "constancy assumption". In this way, non-inferiority trials have a feature in common with external (historically) controlled trials. This also means that non-inferiority trials are subject to some of the same biases as historically controlled trials; that is, the effect of a drug in a past trial may not be the same in a current trial given changes in medical practice, differences in disease definitions or changes in the natural history of a disease, differences in outcome timing and definitions, usage of concomitant medications, etc. [6]
The finding of "difference" or "no difference" between two interventions is not a direct demonstration of the internal validity of the trial unless another internal control confirms that the study methods have the ability to show a difference, if one exists, over the range of interest (i.e. the trial contains a third group receiving placebo). Since most clinical trials do not contain an internal "negative" control (i.e. a placebo group) to internally validate the trial, the data to evaluate the validity of the trial comes from past trials external to the current trial.
A placebo can be roughly defined as a sham medical treatment. Common placebos include inert tablets, inert injections, sham surgery, and other procedures.
A randomized controlled trial is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical techniques, medical devices, diagnostic procedures or other medical treatments.
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.
In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expectations, observer's effect on the participants, observer bias, confirmation bias, and other sources. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. In some cases, while blinding would be useful, it is impossible or unethical. For example, it is not possible to blind a patient to their treatment in a physical therapy intervention. A good clinical protocol ensures that blinding is as effective as possible within ethical and practical constraints.
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as effectiveness, and it has often been used synonymously, although in pharmacology a distinction is now often made between efficacy and effectiveness.
A scientific control is an experiment or observation designed to minimize the effects of variables other than the independent variable. This increases the reliability of the results, often through a comparison between control measurements and the other measurements. Scientific controls are a part of the scientific method.
In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one treatment group, more than one control group, or both.
The number needed to treat (NNT) or number needed to treat for an additional beneficial outcome (NNTB) is an epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with medication. The NNT is the average number of patients who need to be treated to prevent one additional bad outcome. It is defined as the inverse of the absolute risk reduction, and computed as , where is the incidence in the treated (exposed) group, and is the incidence in the control (unexposed) group. This calculation implicitly assumes monotonicity, that is, no individual can be harmed by treatment. The modern approach, based on counterfactual conditionals, relaxes this assumption and yields bounds on NNT.
The standard treatment, also known as the standard of care, is the medical treatment that is normally provided to people with a given condition. In many scientific studies, the control group receives the standard treatment rather than a placebo while a treatment group receives the experimental treatment. After the clinical trial, researchers compare the outcomes of the two groups to see if the experimental treatment is better than, as good as or not as beneficial as the standard treatment.
Clinical study design is the formulation of trials and experiments, as well as observational studies in medical, clinical and other types of research involving human beings. The goal of a clinical study is to assess the safety, efficacy, and / or the mechanism of action of an investigational medicinal product (IMP) or procedure, or new drug or device that is in development, but potentially not yet approved by a health authority. It can also be to investigate a drug, device or procedure that has already been approved but is still in need of further investigation, typically with respect to long-term effects or cost-effectiveness.
Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.
Vaccine efficacy or vaccine effectiveness is the percentage reduction of disease cases in a vaccinated group of people compared to an unvaccinated group. For example, a vaccine efficacy or effectiveness of 80% indicates an 80% decrease in the number of disease cases among a group of vaccinated people compared to a group in which nobody was vaccinated. When a study is carried out using the most favorable, ideal or perfectly controlled conditions, such as those in a clinical trial, the term vaccine efficacy is used. On the other hand, when a study is carried out to show how well a vaccine works when they are used in a bigger, typical population under less-than-perfectly controlled conditions, the term vaccine effectiveness is used.
Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato, Ketanest, among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.
A glossary of terms used in clinical research.
Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. Often, there is also a further "natural history" group that does not receive any treatment at all.
Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.
Eravacycline is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.
A significant amount of research has been performed on glycosaminoglycans, especially glucosamine and chondroitin, for the treatment of arthritis. These compounds are commonly marketed as nutritional supplements and numerous 'soft therapeutic claims' are made about their health benefits - especially in aging populations. Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are major components of cartilage, ingesting glucosamine might nourish joints, and thereby alleviate arthritis symptoms. Authoritative opinions on the actual therapeutic value of these compounds have been very mixed.
Equivalence tests are a variety of hypothesis tests used to draw statistical inferences from observed data. In these tests, the null hypothesis is defined as an effect large enough to be deemed interesting, specified by an equivalence bound. The alternative hypothesis is any effect that is less extreme than said equivalence bound. The observed data are statistically compared against the equivalence bounds. If the statistical test indicates the observed data is surprising, assuming that true effects are at least as extreme as the equivalence bounds, a Neyman-Pearson approach to statistical inferences can be used to reject effect sizes larger than the equivalence bounds with a pre-specified Type 1 error rate.
S-268019-b is a protein subunit COVID-19 vaccine candidate developed by Shionogi.
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