Published on June 12, 2019
1. Randomized Control Trial Presentation By: Bikram Adhikari MPH-2018 1
2. Research Design
3. RCT in Hierarchy of Evidence
4. Randomized Control Trial • It is a trial in which subjects are randomly assigned to one of two groups: • Experimental group receiving the intervention • Comparison group or control receiving an alternative/conventional treatment • The two groups followed up to see any differences in outcome. • The results and subsequent analysis of the trial: • Used to assess the effectiveness of the intervention (treatment, procedure, or service does patients more good than harm) • Used to determine whether a cause-effect relation exists between the intervention and the outcome.
5. Randomized Control Trial
6. Types of RCT • According to the aspects of the interventions they evaluate • Explanatory and pragmatic trials • Efficacy and effectiveness trials • Phase I, II, and III trials • According to how the participants are exposed to the interventions • Parallel trials • Crossover trials • Trials with factorial design
7. Types of RCT • According to the number of participants • From n-of-1 to mega-trials • Fixed size • Sequential trials • According to whether the investigators and participants know which intervention is being assessed • Open trials • Single blind trials • Double blind trials • Triple and quadruple-blind trials
8. • According to whether the preferences of non-randomised individuals and participants are taken into account • Zelen's design • Comprehensive cohort design • Wennberg's design
9. RCT according to the aspects of the interventions Explanatory trials • Address whether or not an intervention works. If the intervention works, then these trials attempt to establish how such intervention works. • It tend to use placebos as controls, fixed regimens (that is, 20 mg by mouth every 6 hours), long washout periods (if patients have been taking diuretics, for instance, those drugs will be stopped for a sufficient period of time to ensure that they are ‘washed out’ of their bodies), intention to treat analysis, and focus on ‘hard’ outcomes (that is, blood pressure recorded at specific times after a detailed and standardised process).
10. RCT according to the aspects of the interventions Pragmatic trials (aka. management trials): • Designed not only to determine whether the intervention works, but also to describe all the consequences of its use, good and bad, under circumstances mimicking clinical practice. • To achieve this, pragmatic studies tend to use more lax criteria to include participants with heterogeneous characteristics, similar to those seen by clinicians in their daily practice. • In addition to the more lax inclusion criteria, pragmatic trials tend to use active controls (that is, the new antihypertensive drug vs a b-blocker), flexible regimens (that is, 20 mg orally every 6 hours, reducing or increasing the dose by 5 mg according to the degree of blood pressure control and adverse effects), and analysis of the patients who received the interventions. Pragmatic trials do not preclude the use of ‘soft’ outcome measures, such as measures of sexual function or quality of life.
11. Explanatory Vs Pragmatic
12. RCT according to the aspects of the interventions Efficacy trial • Efficacy refers to whether an intervention works in people who receive it. • Trials designed to establish efficacy • Tend to be explanatory trials, because they are designed to yield a ‘clean’ evaluation of the effects of the intervention. • Investigators are not so interested in finding out how the intervention works. Instead, their main goal is to include participants who will follow their instructions and who will receive the intervention.
13. RCT according to the aspects of the interventions Effectiveness trial • Effectiveness refers to whether an intervention works in people to whom it has been offered. • Tend to be pragmatic, because they try to evaluate the effects of the intervention in circumstances similar to those found by clinicians in their daily practice. • The design of effectiveness trials is usually simpler than the design of efficacy trials, because effectiveness trials tend to follow lax inclusion criteria, include flexible regimens, and allow participants to accept or reject the interventions offered to them. • Typically, effectiveness trials evaluate interventions with proven efficacy when they are offered to a heterogeneous group of people under ordinary clinical circumstances.
14. Phases of Clinical Trial
15. Phases in Trial
16. • Parallel trial: RCT according to how the participants are exposed to the interventions This design is appropriate for chronic conditions that are stable over time and for interventions that last a short time. A drawback of the factorial design is the concern over potential drug interactions; however, this design also allows for the determination of synergies between two This design is simple and eliminates the potential for drug interaction.
17. RCT according to the number of participants n-of-1 trials • Aka. individual patient trials. • Basically, they are crossover trials in which one participant receives the experimental and the control interventions, in pairs, on multiple occasions and in random order. • These trials provide individual, rather than generalizable, results. • They can be very useful when it is not clear whether a treatment will help a particular patient.
18. Mega-trial • Term is being used increasingly to describe RCTs with a simple design (usually very pragmatic) which include thousands of patients and limited data collection. • Usually, these trials require the participation of many investigators (sometimes hundreds of them) from multiple centers and from different countries. • The main purpose is to obtain ‘increased statistical power’ and to achieve wider generalizability. • Its main aim is to increase the chances of finding a difference between two or more interventions, if such a difference exists.
19. • A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers. • Benefits: • Larger number of participants • Different geographic locations • Possibility of inclusion of a wider range of population groups • Ability to compare results among centers • All of which increase the generalizability of the study.
20. A sequential trial • It is a study with parallel design in which the number of participants is not specified by the investigators beforehand. Instead, the investigators continue recruiting participants until a clear benefit of one of the interventions is observed, or until they are convinced that there are no important differences between the interventions. • These trials allow a more efficient use of resources than trials with fixed numbers of participants, but they depend on the principal outcome being measured relatively soon after trial entry.
21. Fixed size trial • The investigators establish deductively the number of participants that they will include. • This number can be decided arbitrarily or can be calculated using statistical methods. • The main goal of using statistical methods to calculate the sample size is to maximize the chance of detecting a statistically and clinically significant difference between the interventions when a difference really exists
22. RCT according to whether the investigators and participants know which intervention is being assessed
23. Zelen’s Design
24. Wennberg’s Design
25. Comprehensive cohort Design
26. A) Zelen's design B) Comprehensive cohort design C) Wennberg's design
27. Types of RCT • Prophylactic Trials • Evaluate the efficacy of intervention that is designed to prevent disease • Example: Vaccine trials, patient education, screening, vitamin supplement • Curative Trials • Evaluate the efficacy of the curative drugs or intervention designed to manage or mitigate the sign and symptoms of disease • Example: Arthritis, Hypertension drug trials
28. RCT on the basis of Hypothesis • Superiority studies • It aims to show that a new drug is more effective than the comparative treatment (placebo or current best treatment) • Non Inferiority studies • It is designed to prove that two drugs have the same clinical benefit. • Equivalence studies • It aims to show that the effect of a new treatment cannot be said to be significantly weaker than that of the current treatment.
29. Features of a well designed RCT • The sample to be studied will be appropriate to the hypothesis being tested so that any results are appropriately generalizable. The study will recruit sufficient patients to allow it to have a high probability of detecting a clinically important difference between treatments if a difference truly exists. • There will be effective (concealed) randomization of the subjects to the intervention/control groups (to eliminate selection bias and minimize confounding variables). • Both groups will be treated identically in all respects except for the intervention being tested and to this end patients and investigators will ideally be blinded to which group an individual is assigned.
30. Features of a well designed RCT • The investigator assessing outcome will be blinded to treatment allocation. • Patients are analyzed within the group to which they were allocated, irrespective of whether they experienced the intended intervention (intention to treat analysis). • Analysis focuses on testing the research question that initially led to the trial (that is, according to the a priori hypothesis being tested), rather than “trawling” to find a significant difference.
31. Randomization in RCT Advantages • Eliminates selection bias, balancing both known and unknown prognostic factors, in the assignment of treatments. • Random assignment permits the use of probability theory to express the likelihood that any difference in outcome between intervention groups merely reflects chance • Random allocation, in some situations, facilitates blinding the identity of treatments to the investigators, participants, and evaluators, possibly by use of a placebo, which reduces bias after assignment of treatments Confidently attribute to cause and effect
32. Randomization in RCT • Randomization tends to distribute potential confounders similarly among exposure groups, which removes this necessary precondition.
33. Randomization in RCT Successful randomization in practice depends on three interrelated aspects: • Adequate generation of an unpredictable allocation sequence • Concealment of that sequence until assignment occurs • Implementation- Who generated random allocation sequence and who enrolled participants
34. Randomization in RCT • Several types of Randomization present in RCT but choice depends on two goals: • Balance : There should be balance of measured and unmeasured characteristics between intervention and control group. • Unpredictability: There should not be no predictability for enrollment of intervention and control group.
35. Types of Randomization • Simple Randomization • Simple (or unrestricted) randomization is tantamount to flipping a coin. • Every subject has an equal chance of being assigned to either group, and all assignments are independent of one another. • Simple randomization thus maximizes unpredictability: the sequence of past assignments provides no clue about the group to which the next patient is likely to be assigned • Possibility of chance imbalances, particularly with small sample sizes.
36. Types of Randomization • Restricted randomization • It refers to the use of another procedure along with random assignment in order to promote balance in the sizes or composition of study groups.
37. Types of Randomization • Block Randomization: • Block randomization, the most common form of restricted randomization, involves first grouping study subjects into sets, or blocks. • Within each block, an equal number of subjects is then randomly assigned to each treatment group. • Block randomization gives priority to keeping the sizes of treatment groups balanced. However, it does so at the expense of unpredictability. • One way to help prevent corruption of block randomization is to use larger block sizes.
38. Types of Randomization Stratified Randomization • It guarantee that a strong potential confounding factor will be balanced between groups. • Each level on the confounding factor becomes a stratum, and randomization is carried out separately within each stratum. • Block randomization (or some other form of restricted randomization) must be used within each stratum to assure that the ratio of experimental to control subjects is equal across strata.
39. Sample size Calculation Dichotomous Variable
40. Sample size Calculation Continuous Variable
41. References • https://www.quantics.co.uk/blog/what-is-a-pp-population-or-per-protocol-population-in- a-clinical-trial/ • https://link.springer.com/referenceworkentry/10.1007%2F978-1-4419-1005-9_1041 • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359056/ • https://emj.bmj.com/content/20/2/164 • https://www1.cgmh.org.tw/intr/intr5/c6700/OBGYN/F/Randomized tial/chapter2.html • https://i1.wp.com/basicmedicalkey.com/wp- content/uploads/2017/09/A306168_1_En_14_Fig2_HTML.gif?w=960 • https://rwe-navigator.eu/use-real-world-evidence/generate-real-world-evidence/study- design-pragmatic-trials/structured-summary-study-design-comprehensive-cohort-study/ • https://basicmedicalkey.com/trial-design-overview-of-study-designs-phase-i-ii-iii-iv- factorial-design/
42. References • https://irb.research.chop.edu/sites/default/files/documents/classificatio nclinicalresearch_0.jpg • https://images.slideplayer.com/32/10081697/slides/slide_6.jpg • https://cdn.ttgtmedia.com/rms/onlineimages/healthit-clinical-trial.png • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256489/