Randomized trials are important for evaluating the effectiveness of new medical treatments compared to existing options. Key considerations in randomized trials include sample size, type I and type II errors, power, and internal and external validity. Sample size calculations require estimates of expected outcomes under different treatments and specifications of acceptable error rates and desired power. Randomization helps reduce bias but poses ethical issues that must be addressed through informed consent and oversight. Registration of all clinical trials helps reduce publication bias.

1. Randomized Trials:
Some Further Issues
Dr. Win Aye Hlaing
Lecturer
Department of Epidemiology
University of Public Health, Yangon

2. • Sample Size
• Type I Error
• Type II Error
• Power
• External Validity (Generalizability)
• Internal Validity

3. Sample Size
• two jars of beads, each containing 100
• some white and some blue
• jars are opaque
• cannot see the colors

5. • 10 from A – 9 B & 1 W
• 10 from B – 2 B & 8 W
• Can we conclude that 90% of the beads in jar
(A) are blue and 10% are white?
• Clearly, we cannot
• by chance

7. • 10 from A – 7 B & 3 W
• 10 from B – 7 B & 3 W
• It clearly could concluded color distribution be
the same
• We are looking at samples and trying to draw a
conclusion regarding a whole universe
• We want to draw a conclusion from the study
results that goes beyond the study population—is
• treatment (A) more effective than treatment (B)

14. • 2 × 2 table
• Two columns —therapy A differs from therapy
B, or
• therapy A does not differ from therapy B
• Two rows - our decision to conclude
• four possibilities – a,b,c,d

15. • Not differ (-) --- differ (+) ----Type I Error (α)(c)
• differ (+) --- not differ (-) ----Type II Error (β)(b)
• α = p value (probability)
• α ‹ 0.05
• Therapy differ (+) - (2) groups-----probability = 1
• b cell = β
• d cell = 1-β = Power

17. Estimate the Sample Size
1. must specify the expected difference in response rate
• existing therapy cures- 40%
• expect new therapy cure-50%, 60%
• expect 10% or 20% better than current therapy
• A new therapy
– no prior experience
– to search data in human populations
– To search data from animal studies
– No way of producing such an estimate
– Can make a guess [estimate] --- bracket the estimate

18. 2. must have an estimate of the response rate
• E.g. current cure rate is 40%.

19. 3. must specify the level of (α)
• P = 0.05 or 0.01

20. 4. must specify the power (1-β)
• (TP)Power increase=FN decrease=FP decrease
• (1-β) increase = β decrease = α decrease

21. 5. must specify the test - one-sided or two-
sided
• Current T/m — cure rate — 40%
• New therapy—cure rate—50% or 60%

22. • one-sided test
– Cure rate – difference between (2) T/m
– Cure rate in New? --- better
• two-sided test
– Cure rate – difference between (2) T/m
– Cure rate in New? --- better or worse

23. • not only for a difference that is better than the
current cure rate
• but also for one that is worse than the current
rate

24. • One-sided test
– Require smaller sample sizes
– Attractive
– E.g. Disease – 100% fatal
• Only be the direction of improvement
• One-sided test

25. Gehan Table (Sample Size Table)
• Lower of the two cure rates=higher and lower
Choose lower one
– E.g. Lower = 40%
– Higher = 60%
– Choose lower one --- 40% = 0.4

26. • Difference in cure rates = higher – lower
– E.g. Lower = 40%
– Higher = 60%
– Choose --- 60-40 = 20% = 0.2

27. • Choose the intesect row of 0.4 & column of
0.2
97
• We need 97 subjects in each of our study
groups (Sample Size)

29. Alternative
• If the sample size is too small
– Decide not to do the study (or)
– Decide to extend the study (or)
– Decide to collaborate with investigators at other
Institutions to increase the total no.of subjects
– Test -- single site (bias – difficult to detect)
-- multicentre (bias – readily to detect)
– Sample size – Use – in RCT, Cohort, Case-Control

30. Recruitment and Retension of Study
Participants
• A major challenge in RCT - to recruit the
sufficient no. of eligible and willing volunteers
• Failure to recruit – trial without sufficient no.
of volunteers to yield statistically valid results

31. • Trials may be significantly delayed – by limited
recruitment and costs of completing such
trials may be increased
• High level of vigilance is needed
– No coercion, either overt or convert
– By study investigators consciously or
subconsciously
– To enroll the subjects (Bias)

32. • Participants must be fully informed of the risks
& what arrange/m have been made
• If untoward effects occur (Consent)

33. • Appropriate arrangements - cover participants’
expenses such as transportation,
accommodations, etc.
payment of cash incentives to prospective
volunteers
will risk or overt coercion
biases and distortion may occur, if large
incentives (+)

34. • conducting RCT is that we do not know which therapy
is better
Losses to follow-up and other forms of noncompliance
major concern
Participants may lose interest in the study over time
drop out of studies
appropriate measures to prevent losses to follow-up

35. Ways of Expressing the Results of RCT

36. I. Reduction in Risk (Efficacy)
• can be expressed as rates of developing disease in the
vaccine and placebo groups
• Showed the extent of the reduction in disease by use
of the vaccine
• Risks are calculated per person-years of observation
• Effectiveness
– ideal conditions ≠ real-life situations
• evaluate efficacy of a treatment
– Efficacious
– Effective

38. II. Ratios of Risk (Relative Risk)
• A major objective of RCT - to have an impact
on the way clinical medicine and public health

39. III. NNT
• to estimate the number of patients who
would need to be treated (NNT)
• to prevent one adverse outcome such as one
death
– E.g. Mortality in Untreated = 17%
– Mortality in treated = 12%
– NNT = 1/17-12% = 1/5% = 1/0.05 = 20

41. • used in studies of various interventions
including both treatment and prevention

42. IV. NNH
• Number needed to harm

43. Intrepreting the Results of RCT
• Ultimate objective - to generalize the results
beyond the study population itself
• Evaluate the New Drug
• Defined pop is from Total pop

44. External Validity (Generalizability)

45. External Validity (Generalizability)
• The results in the study pop can be applied to
broader pop
• Study pop is representative of Defined pop
• Patients included in study – generalized the result
– applied the patients not included in study
• Generalize the results – not only just to all
patients with disease in community – but also
total pop of patients with disease
• Defined pop is representative of Total pop

46. Internal Validity

47. Internal Validity
• A RCT is internally valid:
– if the randomization has been done and
– the study is free of other biases
– and is without any of the major methodologic
problems

48. Limiting Factors
1. Most RCT do not provide the information
2. Droup outs from trials – should be kept to
minimum
• RCT are usually not representative of General
pop (external validity)

49. Comparative Effectiveness Research
(CER)
• Some randomized trials - to compare a new
therapy to a placebo
• Other randomized trials – to compare a new
treatment with an older accepted treatment
• two or more existing interventions are
compared - to determine which intervention
would work best in a given population or for a
given patient

50. • Another issue - costs of interventions
• E.g. many treatments of HIV infections are
very expensive - affordable in developed
countries - but not affordable in many
developing countries
• Newer and cheaper medications - to
determine the new, cheaper alternatives are
as effective as the more expensive
interventions --- “Equivalence Studies”

51. Four Phases in Testing New Drugs in
USA
• Phase I Trial
– Clinical studies
– Small – 20-80 subjects
– Effects are examined, including safety and side
effects
– Go --- Phase II

52. • Phase II Trial
– Clinical
– 100-300 subjects
– Evaluate the efficacy
– Further assess its relative safety
– Go --- Phase III

53. • Phase III Trial
– Large scale RCT
– For effectiveness and relative safety
– 1000-3000 or more subjects
– Very difficult
– More than one study center-Multicenter trial
– can be approved and licensed for marketing

54. • Phase IV Trial
– Certain adverse effects of drugs
– May not become manifest for many years
– May not be detectable
– Become evident only when use by large pop after
marketing
– Post-marketing Surveillance
– Are important for monitoring new agents-general
use by the public

55. • Phase IV are not Randomized studies
• Ascertain side effects of new t/m after the
drug is being market
• A very high quality system for reporting of
adverse effects is essential
• Very valuable in providing additional evidence
on benefits and help optimize the use of the
new agent

56. • The multicenter Hypertension Detection and
Follow-up Program (HDFP) study
• benefits of treating mild to moderate
hypertension
• 22,994 subjects who were eligible because
they had elevated diastolic blood pressure
• 10,940 were randomized to the stepped care
or to the referred care group

57. The Hypertension Detection and
Follow-up Program

58. The Hypertension Detection and
Follow-up Program
• Stepped Care - according to a precisely defined
protocol, under which treatment was changed
when a specified decrease in blood pressure
• Referred care - a group receiving no care for
hypertension
• known hypertensive subjects
• the investigators believed that ethically
unjustifiable
• referred back to their own physicians

59. • the patients in the stepped care group had
lower mortality than those in the referred care
group
• untreated group for comparison
• patients referred back to their own physicians
• but there was no monitoring of the care by
their physicians

61. REGISTRATION OF CLINICAL TRIALS
• beneficial results have been published
• showing negative results (for some reason)
have not been published
• Publication Bias (or) Non-Publication Bias

62. • more eager to publish results from studies
showing dramatic effects than
• results from studies showing no benefit from a
new drug
• Both researchers and journals - excited about
studies - a new treatment is inferior to current
treatment or that the findings are not clear
one way or the other

63. • adopt a policy
• all clinical trials of medical interventions must be
registered in a public trials registry before any
participants are enrolled in the study
• Medical include drugs, surgical procedures,
devices, behavioural treatments, and processes
of health care
• at no charge
• Before publication

64. ETHICAL CONSIDERATIONS
1. Randomization is ethical?
– Randomization is ethical only when we do not know
whether drug A is better than drug B
– it is ethical to use a placebo
2. Is it ethical not to randomize?
3. Truly informed consent can be obtained?
– Whether they are capable of giving truly informed
consent
4. Under what circumstances should a trial be
stopped earlier than originally planned?
– harmful effects or beneficial effects of the agent
become apparent early

65. CONCLUSION
• the gold standard
• for evaluating the efficacy of therapeutic,
preventive, and other measures
• in both clinical medicine and public health

66. 6/26/2017 66
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