Randomized Controlled Trials (RCT)

1. Randomized Controlled Trials (RCT)

2. Definition of levels of evidence and grading of recommendation

3. Study Designs Exposure NOT manipulated by Investigator OBSERVATIONAL Descriptive Analytic • Case-series • Cross-sectional • Ecological • Cohort • Case-control EXPERIMENTAL Exposure manipulated by Investigator • Clinical trials

4. Association The results of any epidemiological study may reflect the true effect of an exposure on the development of disease It is also possible that the findings may have an alternative explanation ! Three possibilities ??

5. Three possibilities • Chance • Bias • Confounding

6. Bias in epidemiological studies Bias is systematic error(or non-random error) that introduces distortion in estimates/results of study •  Selection bias •  Information bias • Confounding bias

7. Randomized Controlled Trials (RCT) • The methodologic standard of excellence for scientific experiments • ‘RCT has probably contributed more than any single scientific discovery to the improvement in medical care’ ( Lancet, 1987)

8. Randomized Controlled Trials •One of the main scientific advances in methods of clinical research in the 20th century • RCT is considered as the Gold standard for demonstrating therapeutic efficacy for a pharmaceutical agent • Efficacy is not transferable from one goal to another ( e.g. Lowering of blood glucose and prevention of vascular complications)

9. RCT A clinical trial is a planned experiment designed to assess the efficacy of a treatment in humans by comparing the outcomes in a group of patients treated with a test treatment with those observed in a comparable group of patients receiving a control treatment where patients in both groups are enrolled, treated and followed over the same period. Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986

10. RCT “ A scientific research activity undertaken to define prospectively the effect and value of prophylactic / diagnostic / therapeutic agents, devices, regimens, procedures etc. applied to human subjects. It is essential that the study be prospective and that intervention of some sort occur” NIH (1980)

11. RCT Paradigm Population of Interest Child <5 year presenting at hospital with severe malaria Randomize Placebo Tx Outcome Assessment Death within 7 days

12. Randomized (controlled) clinical trials are described often as Phase III clinical trials • Phase I Clinical Trial is usually carried out in ‘normal’ • human volunteers to examine clinical pharmacology of a new drug. This phase is concerned with Safety of the drug in humans, and studies • - Drug metabolism, Bio-availability • - Dose ranging and Multiple Doses

13. Phases of trial Phase I• Clinical pharmacology & toxicity • Human volunteers • Hospital study Phase II• Initial clinical investigation for treatment effects • Patients • Hospital study Phase III• Full-scale evaluation • Patients • Hospital study Phase IV• Post-marketing surveillance

14. Phase I Clinical Trials • Usually carried out in ‘normal’ Human volunteers to examine clinical pharmacology of a new drug • Concerned with Safety of the drug in humans, and studies Drug metabolism, Bio-availability, Dose ranging and Multiple Doses

15. Phase II Clinical Trials It evaluates • Effectiveness of a drug based on Clinical Endpoints • Dosing Ranges and Doses for Phase III trial • Common Short-term Side Effects and Risks associated with the drug

16. Phase III Clinical Trials • The final stage in testing a new treatment in humans • Is primarily concerned with assessment of efficacy and safety studied under controlled conditions

17. Phase IV trials • Post-marketing trials assess incidence of adverse reactions and effect on morbidity and mortality in the population

18. Classification of RCT

19. Assures Comparability • In observational studies, statistical methods allow investigators to control for confounding factors • Must be measured

20. Randomized Trials Require Methodological Rigor • Improperly conducted RCTs yield biased results • Researchers must devote assiduous attention to design and conduct of RCTs • Only properly conducted RCTs will fulfill their promise of minimizing bias

21. Advantages of Randomized Trials • First and foremost, the only effective method known to control selection bias • Controls confounding bias without adjustment • Facilitates effective blinding in some trials • Theoretically attractive -many statistical methods assume random assignment • Maintains advantages of cohort studies

22. Disadvantages of Randomized Trials • May be complex and expensive • Prohibitively difficult and expensive with low incidence outcomes • May lack representativeness - volunteers may differ from population of interest • Ethical challenges of experimental research • Sometimes impossible or impractical to conduct

23. Study outcome measures • Quantitative • Qualitative • Primary • Secondary

24. Study outcome measures (contd.) • Multiple outcomes • Intermediate endpoints • Misclassification

25. •We deal mostly with Phase III trials • Comparative or Controlled trials • Variations are kept under control • Groups differ only with respect to “treatment” • Integration of statistical ideas and methodology • Elimination of bias at Design and Analysis Stages

26. Steps in RCTs • Define purpose of the trial (General – Specific objectives) • Design the trial (Written protocol, Work instructions etc.,) • Conduct the trial (Good organization) • Interim analyses (Stopping rules) • Analyse the data (Descriptive statistics, Test the hypothesis) • Draw conclusions • Publish results

27. Interventions amenable to be studied using clinical trials • Life style • Diet • Drugs • Operational factors • Surgical procedures • Rehabilitation

28. Randomization • Blind assessment • Length of follow-up Specific issues • Sample selection • Sample size • Control groups • Uncertainty principle:Definite indications and contraindications

29. Specific issues (cont) • True effect may not be ascertained for many years • Study power is dependent on number of events observed during the study • Random allocation

30. Good Clinical Practices (GCP) GCP are international ethical and scientific standards setting the minimum requirements for the development,conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials that involve the participation of human subjects

31. GCP standards are established by: • International Conference on Harmonization • US Food and Drug Administration • Guidelines for Clinical Trials on Pharmaceutical Products in India,Central Drugs Standards Control Organization, DGHS, Ministry of Health and Family Welfare, Govt. of India, 2001

32. GCP Synopsis • Regulations for informed consent • Regulations for Institutional Ethics Committees • Defining the responsibilities of the sponsor and investigator • Control of investigational product • Required elements of the investigator’s brochure • Essential documents

33. Patients, Treatment and Comparison (or Evaluation) are the three key words in the above definitions • Patient has to be representative of a targeted population under study. The results must be generalisable to the study population. Healthy individuals are the experimental units in prophylactic studies • Treatment may be a Placebo or a Drug or a Compound (low dose aspirin + Beta carotene) or a Diet, or a Surgical Procedure, a Medical Device, a Diagnostic test , or even no Treatment:

34. Patients, Treatment and Comparison (or Evaluation) are the three key words in the above definitions (contd.) • e.g.– Radio Therapy + Surgery for Breast Cancer • – Antiarrythmic agent + defibrillator • – MRI with or without a contrast imaging agent • Evaluation: Efficacy; safety (adverse experience). Recent years have seen evaluation encompass Assessment of Quality of Life, Cost-effectiveness and Cost- Benefit

35. Designing a Controlled Clinical Trial (RCT) • Starting point for a Controlled Clinical Trial is a clear statement of the Research Question. It is advisable to have a single Primary Research Question addressed in the trial. There may be Secondary questions also. The trial will be planned to answer the Primary Question with adequate Power.

36. Designing a RCT 2. The Primary Research Question will determine the Study Objective (s) and will help us to set up appropriate hypotheses for evaluation • e.g Sample Statement of Objectives: • Evaluate the efficacy of several lipid-influencing drugs in the long-term therapy of CHD in men ages 30 through 64 with evidence of previous myocardial infarction • State type of patients, class of treatments; But ambiguous on outcome • The next step would be to prepare a well-organised written protocol of the clinical trial

37. Contents of Protocol for Clinical Trials • Study Background • Statement of objectives • Primary objective – with a Concise and Precise statement of pre-specified hypotheses based on clinical responses for evaluation of the drug. (Patients to be studied, treatment, and outcome ) • Secondary objective (s) • (Sometimes sub-group analyses may be stated)

38. Contents of Protocol for Clinical Trials • 3. Study plan - Study design - Should permit valid Statistical Inference - Describe Patient and Control groups with rationale for choice - Single centre or Multi-centric study - Patient Inclusion and Exclusion criteria Unambiguous to define the targeted population • Method of Randomisation & Blinding - Study Subject withdrawal

39. Contents of Protocol for Clinical Trials • 4. Study Drugs • Dose and Route of administration and Duration • Method of Dispensing (Package and labeling included) • Method of Administration • Any Concomitant medications / procedures

40. Contents of Protocol for Clinical Trials • 5. Measurements and observations • Response variable – Valid and Reliable measurement; • measurement schedule • Surrogate response variable • Intermediate end point like CD 4 in AIDS or mortality in HIV +ve reduces period of follow up Impact on sample size ( Continuous Vs Qualitative variable) • Caution  Should truly reflect the Clinical outcome and be acceptable to study patients • Adverse effects of intervention may be incompletely evaluated

41. Contents of Protocol for Clinical Trials • 6. Statistical methods • Sample size; Handling Dropouts, Missing Data, • Measurement of Covariates, Sub-group analyses planned • Interim analysis (Termination), Analytical tools to be used • 7.Adverse events (Side-effects…) Reporting • Clinical / laboratory supported • 8. Institutional Review / Ethics Committee approval

42. Ethical issues in clinical trials • Ethics of Doing and not Doing a clinical trial • No harm to participants • Not missing opportunity to benefit society • If drug known to be better – no control group • Alternative treatment as a control(unrelated treatment also) • Efficacy of drug must be truly unknown Study Validity should be ensured– Sample size, Allocation, Blinding etc.

43. Ethical issues in clinical trials • 3. Informed consent Understand requirements for participation in trial. Must be clearly explained procedures to be performed. Should consent to receiving a placebo. Should be free to refuse to participate or withdraw 4. Stopping rule to be stated before start of trial • Clinical efficacy of test treatment • Toxicity of test treatment • External ( independent ) experts to do this

44. Randomisation procedures • 1.Fixed numbers to treatment regimens a) Simple randomisation b) Blocked randomisation c) Stratified allocation 2. Adaptive Randomisation - to ensure desired allocation ratio • - to ensure comparability of baseline characteristics • - outcome adaptive  not desirable

45. Bias • Selection  Incomplete review; of literature also • Observation Exposure and outcome • Statistical procedure  Analysis / Interpretation • Publication

46. Conclusions • RCT is the standard but not the only approach • Rigorous scientific assessment – absolutely essential • Involve researchers and practitioners in the concerned system of medicine • Ethics and human rights