Randomised Controlled Trials.pptx

Randomised Controlled Trial for Undergraduate Medical Students

1. Randomised Controlled Trials Dr Abinesh V Dept of CM SVMCH&RI

2. Presentation Outline Why do Randomized Controlled Trials? Randomization why and how it is done RCT classification Study design & Steps of RCT Minimizing bias in intervention studies Allocation concealment and blinding

3. Human Experiment Can you identify the experiment?

4. In 1947 Lind tested the effect of lime juice on the occurrence of Scurvy on Royal Navy ships - a major health problem on long voyages. Crucially Lind randomised which of his patients received the treatment (lime juice plus several other liquid tested)

5. 1948: Sir Austin Bradford Hill - streptomycin for TB The first published RCT in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hil, who is credited as having conceived the modern RCT.

6. Definition of RCT An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or therapeutic procedure, maneuver, or intervention -John M.Last, 2001

7. Uses of RCT Evaluate the safety of a new drug in healthy human volunteers. Assess treatment benefits in patients with a specific disease. Compare a new drug against existing drugs or against dummy medications (placebo).

8. Ethics in RCT Al most always provide informed consent for their participation in an RCT. In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005 must be registered. Clinical trial registry of India - (CTRI), hosted at the ICMR's National Institute of Medical Statistics (http://nims-icmr.nic.in), is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007 (www.ctri.nic.in).

9. Randomized Eliminate bias in selection/allocation Balances all confounders: known or unknown Controlled Intervention compared to a control Control: active or placebo Both groups identical except for intervention/exposure Investigator has control over the process Trial Experimental intervention Effects unknown to investigator

10. Randomization Process by which, allocation of subjects to treatment groups is left to chance (or randomness) The major purpose of random assignment Ensure that the study groups are comparable on baseline characteristics. Reduce selection bias in allocation to groups Facilitate double blinding Facilitate measurements of outcome variables

11. Types of Randomization A . Fixed Allocation Randomization Simple Randomization Block Randomization Stratified Randomization B. Adaptive random allocation a) Baseline Adaptive Randomization Biased Coin Urn Design Minimization b) Response Adaptive randomization Play the Winner Two-armed bandits Biased urn model

12. Simple Randomization This method is equivalent to tossing a coin for each subject that enters a trial, such as Heads = Active, Tails = Placebo. However, imbalanced randomization can happen in smaller trials, reducing statistical power. In trial of 10 participants, instead of 5-5 split 7-3 or 8-2 split can occur.

13. Block Randomization Block randomization is balanced within each block The basic idea of block randomization Divide potential patients into m blocks of size 2n Randomize each block such that n patients are allocated to A and n to B Then choose the blocks randomly Example: Two treatments of A, B and Block size of 2 x 2 = 4 Possible treatment allocations within each block are (1) AABB, (2) BBAA, (3) ABAB, (4) BABA, (5) ABBA, (6) BAAB

14. Stratified Randomization An RCT may not be considered valid if it is not well balanced across prognostic factors. E.g., Age Group: < 40, 41-60, >60; Sex: M, F; Total No. of strata = 3 x 2 = 6 Stratification can balance subjects on baseline covariates, tend to produce comparable groups with regard to certain characteristics (e.g., gender, age, race, disease severity)thus produces valid statistical tests. The block size should be relative small to maintain balance in small strata.

15. Allocation Concealment Refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. P revent selection bias by concealing the allocation sequence. Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE)

16. Parallel group design E ach participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.

17. Crossover design O ver time, each participant receives or does not receive an intervention in a random sequence.

18. Cluster design P re-existing groups of participants (e.g., villages, schools) are randomly selected to receive or not receive an intervention.

19. Factorial design E ach participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions.

20. On basis on hypothesis A Superiority RCT aims to show that a new drug is more effective than the comparative treatment (placebo or current best treatment) An Equivalence RCT is designed to prove that two drugs have the same clinical benefit. A Non inferiority RCT aims to show that the effect of a new treatment cannot be said to be significantly weaker than that of the current treatment.

21. On basis of outcome of interest Explanatory RCT: test efficacy in a research setting with highly selected participants and under highly controlled conditions. Pragmatic RCT: test effectiveness in everyday practice with relatively unselected participants and under flexible conditions.

22. Clinical Trials Concerned with evaluating therapeutic agent, mainly drugs. Example: Evaluation of β-blockers in reducing cardiovascular mortality.

23. Preventive Trials Trial of primary preventive measures. Example: Vaccines.

24. Risk factors Trials Investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have risk factor for developing the disease. Example: Primary prevention of CHD using clofibrate to lower serum cholesterol.

25. Cessation Experiment An attempt is made to evaluate the termination of a habit which is considered to be causally related to disease. Example: Cigarette smoking and lung cancer.

26. Evaluation of Health services Domiciliary treatment of PTB was as effective as more costlier hospital or sanatorium treatment.

27. Phases of RCT Phase - I: Trial done on group of healthy individuals to know safety, efficacy and the side effects Phase - II: Carried in diseased group to know safety and efficacy done in multiple centers.

28. Phases of RCT Phase - III : Carried in thousands of people to study safety, efficacy and whether fit for manufacturing. Determine the effectiveness (overall benefit/risk-cost assessment) of new therapies relative to standard therapy Phase - IV Post-marketing study as the drug has already been granted regulatory approval/license. Continuous ongoing process to know the long term effects, additional safety information, rare side effects. Often non randomized

29. Steps of conducting RCT

30. Drawing up a protocol Step One Selecting reference & experimental population Step Two Randomization Step Three Manipulation or Intervention Step Four Followup Step Five Assessment of Outcome Step Six

31. Drawing up a Protocol Rationale Aims and objectives Research questions Design of the study: selection of study and control groups Size of the sample & allocation of subjects in both groups Treatment to be applied - when, where, how Standard of Operations (SOP) Ethics: patient consent, confidentiality, adverse events Documentation Procedure

32. 2. Selecting population Reference or Target population: Population to which the findings of the trial, if found successful, are expected to be applicable (eg. drugs, vaccines, etc.)

33. Experiment or Study population Actual population that participates in the experimental study. Derived from the reference population. Has same characteristics as the reference population. Must give informed consent. Should be qualified or eligible for the trial. Effectiveness of drug in treating anemia - subjects should be anemic Effectiveness of a vaccine against a disease - subjects should not be already immune

34. 3. Randomization Heart of the control trial. Participants are allocated into study and control groups. Eliminates bias and allows comparability. Both groups should be alike with regards to certain variables that might affect the outcome of the experiment.

35. 4. Manipulation/Intervention Deliberate application or withdrawal or reduction of a suspected causal factor It creates an independent variable (drugs, vaccine, new procedure) whose effect is measured in final outcome constituting the dependent variable (incidence of disease, survival time, control of events, etc.,)

36. 5. Followup Implies examination of the experimental and control group subjects at defined intervals of time in a standard manner with equal intensity under the same given circumstances Attrition: Inevitable losses to follow up (death, migration, loss of interest

37. 6. Assessment of Outcome Positive results: Reduced incidence or severity of disease Reduced cost to health service Appropriate outcome in the study Negative results: Increased severity or frequency of side effects Complications Death

38. 1. Sequence generation Generate the random allocation sequence by some random procedures Participants should be assigned to comparison groups in the trial on the basis of a chance (random) process characterised by unpredictability 2. Allocation concealment Develop allocation concealment mechanism (such as numbered, identical bottles or sequentially numbered, sealed, opaque envelopes) 3. Implementation Enrol participants Assess eligibility Discuss the trial Obtain informed consent Enrol participant in trial Ascertain intervention assignment Administer intervention

39. Advantages & Disadvantages Advantages: Randomization tends to balance prognostic factors across study groups. Detailed information can be collected on baseline and subsequent characteristics of participants. Dose levels can be predetermined by the investigator. Blinding of participants can reduce distortion in assessment of outcomes

40. Disadvantages: Subject exclusions may limit ability to generalize findings to other participants. A long period of time is often required to reach a conclusion. A large number of participants usually required. Financial costs are typically high. Ethical concerns may arise. Compliance

41. Bias Selection Bias - Bias in patients. Hawthorne effect - improved performance in intervention subjects due to psychological benefit that he/she is receiving some new treatment. Observer bias bias in outcome assessment may report favourable outcome for new treatment

42. Potential sources of bias Methods to minimize bias in RCT Selection bias (biased allocation to comparison groups) Randomization (Generation of allocation sequence and allocation concealment) Performance bias (unequal provision of care apart from treatment under evaluation) Blinding of care providers and patients Single blind (either subjects or assessors blind) Double blind (both subjects or assessors blind) Detection bias (biased outcome assessment) Blinding of outcome assessors Triple blind (Analysis team is also blind) Attrition bias (biased occurrence & handling of protocol deviations, withdrawals and losses to follow up) Intention-to-treat analysis (Analysis based on treatment allocation, not adjusted for compliance)

43. Outcome Clinical outcome (e.g, death, stroke, BP) Symptom/sign Lab abnormality 2 types, depending on nature: Hard endpoints Surrogate endpoints

44. Endpoints Hard Endpoints Generally clinical end-points Death due to any cause Death due to cardiovascular/diabetic causes Non-fatal myocardial infarction/stroke End stage renal disease Time to clinical event Surrogate Endpoints A biomarker intended to substitute for a clinical endpoint HbA1c Serum cholesterol levels

45. Measures of Effect To compare frequency of outcome between two groups. Magnitude of relationship generally expressed as: Relative measures of Effect Relative Risk Odds ratios Absolute measure effect Risk difference Number needed to treat (NNT)

46. Event Rates Event rates - to compute measures of risk Experimental event rate (EER) The proportion of people with intervention who develop the outcome. Control event rate (CER) The proportion of people without the intervention who develop the outcome.

47. Relative Risk The ratio of incidence of outcome in those exposed to those not exposed. RR = EER / CER RR applies to cohort study or clinical trial.

48. Relative Risk Reduction The reduction in risk with a new therapy relative to the risk without the new therapy RRR = (EER - CER) / CER