Randomized controlled trials (RCTs) are considered the gold standard for evaluating clinical evidence because random assignment of subjects to experimental and control groups minimizes bias. RCTs manipulate the exposure by having the investigator assign subjects to different treatment groups. This allows for a direct assessment of causality between the exposure and outcome. Well-designed RCTs provide the highest quality level of evidence according to most evidence rating systems. However, RCTs also have some disadvantages such as complexity, expense, and ethical challenges of experimental research.

1. Randomized Controlled Trials
(RCT)

2. Rating of clinical evidence
Quality of evidence
I At least one properly designed randomised controlled trial
I I –1 Well-designed controlled trials without randomization
I I – 2 Well-designed cohort or case-control studies, preferably from
more than one centre or research group
I I – 3 Multiple time series with or without the intervention. Important
results in uncontrolled experiments
I I I Opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert committees
Assessment system of US Preventive Services Task Force, 1996

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

4. Association
• Results of any epidemiological study
may reflect the true effect of an
exposure on the development of
disease
• 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. RCT
• ‘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

9. 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)

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

11. 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

12. Phase II Clinical Trials
• 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

13. 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

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

15. Classification of RCT
Based on Classification
Type of intervention Therapeutic; Preventive
Unit of randomization Individual ;Community
Design Parallel; Cross-over; Factorial
Sample Size Fixed; Sequential
Randomization Fixed; Adaptive (Number, Baseline,
Outcome); Blocking
Masking Single, Double, Triple,…

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

17. Assures comparability
• No statistical method can achieve
comparability on unknown or
unmeasured factors in analysis phase
• Random allocation is the only known
method to assure comparability

18. Intervention: Exercise in men after M.I.
Outcome: Recurrent M.I.
Cohort: RR = .38 95% CI (0.18 - 0.80) p = .006
RCT: RR = 1.3 95% CI (0.73 - 2.2) p = .20
Comparison of results from
cohort study and RCT

19. RCTs Non-Random
(n=57) (n=43)
Difference in 8.8% 58%
case-fatality
rates at p < 0.05
Results favored 60% 93%
treatment over
controls (p < 0.05)
Mean differences in 0.3% 10.5%
the case-fatality rates +0.8% +1.7%
(p > 0.05) (p < 0.001)
Trials of the treatment of
acute M.I.

20. Hormone replacement therapy and
coronary heart disease (CHD)
- results of observational studies
• Three different meta-analysis of
numerous observational studies
• Hormones decrease risk of CHD by 35% to
50%
• Especially strong for secondary prevention
in women with CHD

21. Experimentation trumps
observation!
• RCT of hormone-therapy for secondary
presentation of CHD
• Relative hazard = 0.99; 95% CI 0.80 - 1.22
• No effect of hormone therapy

22. Chemotherapy for
carcinoma of the oesophagus
• A meta-analysis of 8 non-randomized
studies found a 68% reduction in death
• OR=0.32, 95% CI 0.24 - 0.42
• A meta-analysis of 12 RCTs found a 4%
reduction in death
• OR=0.96, 95% CI 0.75 - 1.22
Bhansali et al. Ann Oncol 1996;7:355-9

23. Systematic review of
randomized vs non-
randomized evidence*
• On average, non-randomized studies
result in overestimates of effect
• That bias can, however, go in either
direction
• That bias can be as large or larger than
the effects of worthwhile interventions
*Kunz R. and Oxman AD. BMJ 1998;317:1185-90.

24. 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

25. 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

26. 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