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6.randomized Trials 2012
6.randomized Trials 2012
ASSESSING EFICACY
OF
PREVENTIVE MEASURES
THERAPEUTIC MEASURES
umo 2012
1
Objective of PH & Clinical Practice
• to modify natural H/O diseases
– to prevent /delay death /disability
– to improve health of individual / population
2
history …
• 1537, Paré: unintentional / unplanned trial for treatment of
treatment of the wounded after the capture of the castle of
Villaine
• 1747 , James Lind: planned trial for scurvy
• 1883, Sir Francis Galton: Research question
– Are prayers answered or are they not?
• … Do sick persons, who pray or are prayed for, recover on the
average more rapidly than others?
• 1965, Joyce and Welldon: double-blind clinical trial of the
efficacy of prayer …. No indication of benefit
• 1988, Byrd: effectiveness of intercessory prayer in a coronary
care unit population… randomized double-blind protocol …
beneficial therapeutic effect 3
basic design of a randomized trial
5
Allocation of subjects to treatment groups:
alternatives for randomization
• Studies without Comparison
– case study or case series
– Earl Peacock …
– Edere …
– Hugo Muensch, Harvard University: Second Law: “Results
can always be improved by omitting controls”
• Studies with Comparison
– Historical Controls: problems?
– Simultaneous Nonrandomized Controls
6
Simultaneous Nonrandomized Controls
• Results of a Trial of BCG Vaccination I
Selected from
TUBERCULOSIS DEATHS
health conscious
families Number of children Number %
Vaccinated 445 3 0.67
Controls 545 18 3.30
7
Randomization
Figure 7-2 How to predict the next patient's treatment assignment in a randomized study.
(PEANUTS © UFS. Reprinted by permission.)c
… hope that randomization will increase the likelihood that the groups will be
comparable in regard to characteristics about which we may be concerned
… prognostic variables
…. randomization is not a guarantee of comparability, because chance may play a
role in the process, but over the long term, the groups will tend to be similar 9
Figure 7-3 Observational versus experimental studies. I, If the study is not randomized, the proportions of
patients with arrhythmia in the two groups may differ. II, If the study is randomized, the proportions of
patients with arrhythmia in the two groups are more likely to be similar.
12
crossover
Carryover effect
Enough washout period
Order of treatment
Psychological response
Surgical or cure
Figure 7-8 Factorial design for studying the effects of two treatments.
21
noncompliance
Coronary Drug Project: Five-Year Mortality in Patients Given Clofibrate or Placebo
According to Level of Compliance
CLOFIBRATE PLACEBO
Number of Number of
Compliance Patients Mortality (%) Patients Mortality (%)
Poor (<80%) 357 24.6 882 28.2
Good (≥80%) 708 15.0 1,813 15.1
Total Group 1,065 18.2 2,695 19.4
22
Sample size
23
Figure 8-1 Two opaque jars, each holding 100 beads, some blue and some white.
27
Figure 8-4 Possible outcomes of a randomized trial.
32
TABLE 8-3 -- What Must Be Specified to Estimate the Sample Size
Needed in a Randomized Trial?
33
TABLE 8-4 -- Number of Patients Needed in Each Group to Detect Various
Differences in Cure Rates; α = .05; Power (1 - β) = .80 (Two-sided Test)
34
TABLE 8-5 -- Number of Patients Needed in Each Group to Detect Various
Differences in Cure Rates; α = .05; Power (1 - β) = .80 (One-sided Test)
35
Treatment effects
Treatment effects
• New terms were used to describe both the
good and bad effects of therapy in the current
evidence based journals. Here are some terms
of which (Evidence Based Medicine and ACP
journals Club) have achieved consensus
Sackett.D.L et al, Evidence based medicine: How to practice & Teach EBM, 2nd edt. Chrrchill Living Stone; 2000, pp 250.
Treatment effects
Event Rate. The proportion of patients in a
group in whom the event is observed.
Experimental Event Rate (EER). The
proportion of patients in experimental
group in whom the event is observed.
Control Event Rate (CER). The proportion of
patients in control group in whom the event
is observed.
Sackett.D.L et al, Evidence based medicine: How to practice & Teach EBM, 2nd edt. Chrrchill Living Stone; 2000, pp 250.
Treatment effects (bad outcomes)
42
Ways of expressing the results of randomized trials
43
GENERALIZABILITY OF RESULTS
Figure 8-9 Design of the Hypertension Detection and Follow-up Program (HDFP).
47
MRFITS
The Multiple Risk Factor Intervention Trial
Figure8-11 Mean risk factor levels by year of follow-up for Multiple Risk Factor Intervention Trial Research Group
participants. BP, blood pressure; S1, first screening visit; SI, special intervention; UC, usual care. (From Multiple Risk Factor
Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: Risk factor changes and mortality results. JAMA
Downloaded from: StudentConsult (on 7 February 2012 10:23 AM)
248:1465-1477, 1982.) © 2005 Elsevier
Figure 8-12 Cumulative coronary heart disease (CHD) and total mortality rates for Multiple Risk
Factor Intervention Trial Research Group participants. The heavy line indicates men receiving usual
care; the thin line indicates men receiving special intervention. (From Multiple Risk Factor
Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: Risk factor changes and
mortality results. JAMA 248:1465-1477, 1982.)
Downloaded from: StudentConsult (on 7 February 2012 10:23 AM)
© 2005 Elsevier
Study of Breast Cancer Prevention Using Tamoxifen
Figure 8-13 Cumulative rates of invasive and non-invasive breast cancer occurring in participants receiving
placebo or tamoxifen. (From Fisher B, Constantino JP, Wickerham DL, et al: Tamoxifen for prevention of
breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer
Downloaded from: StudentConsult (on 7 February 2012 10:23 AM)
Inst 90:1371-1388, 1998.) © 2005 Elsevier
Figure 8-14 Cumulative rates of invasive endometrial cancer occurring in participants receiving placebo or
tamoxifen. (From Fisher B, Constantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer:
Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-
1388, 1998.)
52
ETHICAL CONSIDERATIONS
• Is randomization ethical?
– Withholding a drug from patients, particularly those with serious and life-
threatening diseases?
– ethical only when we do not know whether drug A is better than drug B
• may have some indication that one treatment is better than the other (and, often, this is the
rationale for conducting a trial in the first place), but we are not certain
– when we do not have adequate evidence to support the conclusion that drug A is
better…
– is it ethical to use a placebo?
• is it ethical to withhold a treatment that has been shown to be effective
• Is it ethical not to randomize?
• Is truly informed consent can be obtained?
• under what circumstances should a trial be stopped earlier than
originally planned?
53
RANDOMIZED TRIALS FOR EVALUATING WIDELY ACCEPTED INTERVENTIONS
Figure 8-15 Design of a controlled trial of arthroscopic surgery for osteoarthritis of the knee .
(Based on Moseley JB, O'Malley K, Petersen NJ, Menke TJ, et al: A controlled trial of arthroscopic surgery for
osteoarthritis of the knee. N Engl J Med 347:81-88, 2002.)
Downloaded from: StudentConsult (on 7 February 2012 10:23 AM)
© 2005 Elsevier
Figure 8-16 Mean values (and 95% confidence intervals) on the Knee-Specific Pain Scale. Assessments
were made before the procedure and 2 weeks, 6 weeks, 3 months, 6 months, 12 months, 18 months, and
24 months after the procedure. Higher scores indicate more severe pain.
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