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RCT A randomized controlled trial (RCT) is a type of scientific experiment most commonly used in testing the efficacy or effectiveness of healthcare services (such as medicine or nursing ) or health technologies (such as pharmaceuticals , medical devices or surgery ). RCTs are also employed in other research areas, such as judicial, educational, and social research. As their name suggests, RCTs involve the random allocation of different interventions (treatments or conditions) to subjects . As long as numbers of subjects are sufficient , this ensures that both known and unknown confounding factors are evenly distributed between treatment groups FOR NEXUS CRI


TYPES OF TRIALS Open trial: In an open trial, also called an open-label trial, the researcher knows the full details of the treatment, and so does the patient. These trials are open to challenge for bias, and they do nothing to reduce the placebo effect. However, sometimes they are unavoidable, as placebo treatments are not always possible. Usually this kind of study design is used in bioequivalence studies. Single-blind trial: In a single-blind trial, the researcher knows the details of the treatment but the patient does not. Because the patient does not know which treatment is being administered (the new treatment or another treatment) there might be no placebo effect. In practice, since the researcher knows, it is possible for him to treat the patient differently or to subconsciously hint to the patient important treatment-related details, thus influencing the outcome of the study. FOR NEXUS CRI


TYPES OF TRIALS Double-blind trial: In a double-blind trial, one researcher allocates a series of numbers to 'new treatment' or 'old treatment'. The second researcher is told the numbers, but not what they have been allocated to. Since the second researcher does not know, he cannot possibly tell the patient, directly or otherwise, and cannot give in to patient pressure or to give him the new treatment. In this system, there is also often a more realistic distribution of sexes and ages of patients. Therefore double-blind trials are preferred, as they tend to give the most accurate results FOR NEXUS CRI


TYPES OF TRIALS Triple-blind trial: Some randomized controlled trials are considered triple-blinded, although the meaning of this may vary according to the exact study design. The most common meaning is that the subject, researcher and person administering the treatment (often a pharmacist ) are blinded to what is being given. Alternately, it may mean that the patient, researcher and statistician are blinded. The team monitoring the response may be unaware of the intervention being given in the control and study groups. These additional precautions are often in place with the more commonly accepted term "double blind trials", and thus the term "triple-blinded" is infrequently used. However, it connotes an additional layer of security to prevent undue influence of study results by anyone directly involved with the study. FOR NEXUS CRI

Randomization in clinical trials:

Randomization in clinical trials There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate a random and unpredictable sequence of allocations. This may be a simple random assignment of patients to any of the groups at equal probabilities, or may be complex and adaptive. A second and more practical issue is allocation concealment , which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed to the study investigators prior to definitively allocating them to their respective groups. FOR NEXUS CRI

Randomization procedures :

Randomization procedures There are a couple of statistical issues to consider in generating the randomization sequences. Balance : since most statistical tests are most powerful when the groups being compared have equal sizes, it is desirable for the randomization procedure to generate similarly-sized groups. FOR NEXUS CRI


RANDOMIZATION PROCEDURES Selection bias : depending on the amount of structure in the randomization procedure, investigators may be able to infer the next group assignment by guessing which of the groups has been assigned the least up to that point. This breaks allocation concealment (see below) and can lead to bias in the selection of patients for enrollment in the study. Accidental bias : if important covariates that are related to the outcome are ignored in the statistical analysis, estimates arising from that analysis may be biased . The potential magnitude of that bias, if any, will depend on the randomization procedure. FOR NEXUS CRI

Complete randomization:

Complete randomization In this commonly used and intuitive procedure, each patient is effectively randomly assigned to any one of the groups. It is simple and optimal in the sense of robustness against both selection and accidental biases. However, its main drawback is the possibility of imbalances between the groups. In practice, imbalance is only a concern for small sample sizes ( n < 200). FOR NEXUS CRI

Sir Ronald Aylmer Fisher: randomized controlled agricultural trials The Design of Experiments(1935) Statistical Methods for Research Workers (1925):

Sir Ronald Aylmer Fisher: randomized controlled agricultural trials The Design of Experiments (1935) Statistical Methods for Research Workers (1925) FOR NEXUS CRI

Permuted block randomization:

Permuted block randomization In this form of restricted randomization , blocks of k patients are created such that balance is enforced within each block. For instance, let E stand for experimental group and C for control group, then a block of k = 4 patients may be assigned to one of EECC , ECEC , ECCE , CEEC , CECE , and CCEE , with equal probabilities of 1/6 each. Note that there are equal numbers of patients assigned to the experiment and the control group in each block. Permuted block randomization has several advantages. In addition to promoting group balance at the end of the trial, it also promotes periodic balance in the sense that sequential patients are distributed equally between groups. This is particularly important because clinical trials enroll patients sequentially, such that there may be systematic differences between patients entering at different times during the study. FOR NEXUS CRI

Permuted block randomization:

Permuted block randomization Unfortunately, by enforcing within-block balance, permuted block randomization is particularly susceptible to selection bias. That is, since toward the end of each block the investigators know the group with the least assignment up to that point must be assigned proportionally more of the remainder, predicting future group assignment becomes progressively easier. The remedy for this bias is to blind investigator from group assignments and from the randomization procedure itself. Strictly speaking, permuted block randomization should be followed by statistical analysis that takes the blocking into account. However, for small block sizes this may become infeasible. In practice it is recommended that intra-block correlation be examined as a part of the statistical analysis. A special case of permuted block randomization is random allocation , in which the entire sample is treated as one block. FOR NEXUS CRI

Covariate-adaptive randomization:

Covariate-adaptive randomization When there are a number of variables that may influence the outcome of a trial (for example, patient age, gender or previous treatments) it is desirable to ensure a balance across each of these variables. This can be done with a separate list of randomization blocks for each combination of values - although this is only feasible when the number of lists is small compared to the total number of patients. When the number of variables or possible values are large a statistical method known as Minimisation can be used to minimise the imbalance within each of the factors. FOR NEXUS CRI

Hierarchy of Study Types:

Hierarchy of Study Types Descriptive Case report Case series Survey Analytic a) Observational Cross sectional Case-control Cohort studies. FOR NEXUS CRI

Slide 15:

Experimental Studies: Randomized controlled trials FOR NEXUS CRI

Ethics of Clinical Research:

Ethics of Clinical Research Ethical principles and Norms 2. Role of IRB/IEC 3. Ethical issues Balance of risk and benefit Informed Consent Selection of subjects Compensation for research related injury Confidentiality and Information security Research integrity Ethical problems with Randomized Trials Use of animal, human tissue and biological sample FOR NEXUS CRI

Ethical problems with Randomized Controlled Trial (RCT):

Ethical problems with Randomized Controlled Trial (RCT) RCT is the gold standard method for demonstrating safety and efficacy of treatment. Features of RCT design that makes it a gold standard method: controlled, randomized, blinding. Yet, the design of RCT presents a spectrum of unique ethical problems. Levine R. Ethics and Regulation of clinical research. “In considering the RCT, the average IRB member must be baffled by its complexity and by the manifold problems it represents” FOR NEXUS CRI

Unique ethical issues:

Unique ethical issues 1. Equipoise: ethical justification of RCT 2. Physician as clinical investigator 3. Randomization and Blinding 4. Preliminary data and emerging trends 5. Placebo and/or “Best current” control treatment 6. Continuation of treatment after trial end. FOR NEXUS CRI

What should we do and How?:

What should we do and How? Be aware of the tension inherent in dual role Inform subject accordingly Rely on other members of team Separating roles of clinician and investigator Refer to other investigator for inclusion in trial FOR NEXUS CRI

Ethical problems with Randomization & Blinding:

Ethical problems with Randomization & Blinding 1. Preferences for treatments and information about which treatment a subject is receiving are relevant to autonomous decisions 2. Information about which treatment the subject is receiving may be important in managing an adverse event or a medical emergency, consistent with a concern about safety and welfare of subjects. FOR NEXUS CRI

What should we do and How?:

What should we do and How? Informed consent all important randomization and suspension of knowledge about treatment Have procedure to allow breaking of blind? Have procedure to handle emergency? FOR NEXUS CRI

Outcome-adaptive randomization:

Outcome-adaptive randomization For a randomized trial in human subjects to be ethical, the investigator must believe before the trial begins that all treatments under consideration are equally desirable. At the end of the trial, one treatment may be selected as superior if a statistically significant difference was discovered. Between the beginning and end of the trial is an ethical grey zone. As patients are treated, evidence may accumulate that one treatment is superior, and yet patients are still randomized equally between all treatments until the trial ends. FOR NEXUS CRI

Out come-Adaptive randomization:

Out come-Adaptive randomization Outcome-adaptive randomization is a variation on traditional randomization designed to address the ethical issue raised above. Randomization probabilities are adjusted continuously throughout the trial in response to the data. The probability of a treatment being assigned increases as the probability of that treatment being superior increases. The statistical advantages of randomization are retained, while on average more patients are assigned to superior treatments. FOR NEXUS CRI

Allocation concealment:

Allocation concealment In practice, in taking care of individual patients, clinical investigators often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient [2] . This introduces selection bias and confounders and distorts the results of the study. Breaking allocation concealment in randomized controlled trials is that much more problematic because in principle the randomization should have minimized such biases. FOR NEXUS CRI

Allocation concealment:

Allocation concealment Some standard methods of ensuring allocation concealment include: Sequentially-Numbered, Opaque, Sealed Envelopes (SNOSE) Sequentially-numbered containers Pharmacy controlled Central randomization Great care for allocation concealment must go into the clinical trial protocol and reported in detail in the publication. Recent studies have found that not only do most publications not report their concealment procedure, most of the publications that do not report also have unclear concealment procedures in the protocols FOR NEXUS CRI

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