Intervention Studies

1
Intervention Studies

• Principles of Epidemiology
• Lecture 10
• Dona Schneider, PhD, MPH, FACE

2
Intervention Studies

• Subjects are selected from a reference
  population, the group to which investigators hope
  to extrapolate their findings
• Clear, specific definition of subjects prior to
  selection
• No subjective decision making!

3
Intervention Studies (cont.)

• Individuals are enrolled on the basis of exposure
  (the investigators control the intervention)
• Both cases and controls come from the
  experimental group
• All subjects (cases and controls) should be at
  high enough risk for manifesting the outcome so
  that the study is likely to detect a difference
  if the intervention works

4
Potential Problems

• Selection bias
• Volunteerism after screening, the experimental
  group may no longer be generalizable to the
  reference population
• Ethical considerations
• IRB issues

5
Informed Consent

• Describe the overall experience that will be
  encountered
• Describe benefits of participation
• Describe the risks of participation
• Describe alternatives to participation
• Describe the extent to which the subjects
  information will remain confidential
• Describe compensation and/or expenses that may be
  incurred

6
Informed Consent (cont.)

• Obtain informed consent prior to a subjects
  enrollment in a study
• A subject may choose not to participate or
  withdraw at any time without negative
  consequences
• Provide the subject with a list of people s/he
  can contact with further questions regarding the
  research, his/her rights as a participant, and
  potential research-related injuries
• Remember, informed consent is a process, not just
  a form!

7
Potential Problems (cont.)

• Reporting bias
• Observer bias
• Watch the experimental group more carefully than
  the control group

8
Controlling Bias and Confounding

• Randomization
• Distribute known and unknown confounders evenly
  among treatment groups
• Occurs after informed consent is provided
• Sufficient sample size
• Improves the power to detect a difference
• Improves the probability of generalizability to
  the reference population

9
Controlling Bias and Confounding (cont.)

• Masking
• Prevent subjects and study personnel from knowing
  who is in which treatment group
• Verify compliance (reduce reporting bias)
• Pill counting, laboratory studies, interviews of
  living companions

10
Controlling Bias and Confounding (cont.)

• Maintaining compliance with the intervention
• Home visits
• Payment at time of visit
• Telephone and postcard reminders
• Calendar pill packs
• Daily logs
• Pre-study compliance checks
• Document reasons for noncompliance

11
Intention to Treat Analysis

• Once randomized ALWAYS analyzed
• The analysis must always include subjects who did
  not comply with the intervention or who did not
  finish the study
• If you eliminate those who did not comply, you
  cannot address the research question whether
  offering a treatment program is of benefit
• Those who comply may be different from the entire
  experimental group
• By using only those subjects who comply, you
  introduce further selection bias and reduce the
  generalizability of your results

12
Internal vs. External Validity

• Large controlled trials usually have a high
  degree of internal validity
• Randomization and masking minimizes the risk of
  confounding and bias, and a large n makes it
  more likely that chance can be ruled out as an
  explanation of an observed association
• However, controlled trials also often have poor
  external validity (i.e., generalizability)

13
External Validity in Controlled Trials
Reference Population
Respond to letter? - Yes
Respond to letter? - No
Agree to screening? - Yes
Agree to screening? - No
Are they similar?
Meet inclusion criteria? - Yes
Meet inclusion criteria? - No
Wish to continue? - Yes
Wish to continue? - No
Agree to randomization? - Yes
Agree to randomization? - No
Experimental Population
14
Crossover Studies

• Subjects begin the study on Treatment A and later
  switch to Treatment B
• Patients serve as their own control
• Variation between individuals remains constant
• Washout period between treatments reduces
  residual carryover

15
Design of a Planned Crossover Trial
Randomized
Treatment A
Treatment B
16
Factorial Design

• Use the same study population to test Drug A
  Drug B
• Assume
• The outcomes for each drug are different
• Modes of action are independent
• If you need to terminate the study of Drug A, you
  can continue the study to determine the effects
  of Drug B instead of beginning an entirely new
  study.

17
Factorial Design (cont.)

• Example Physicians Health Study
• Test aspirin as a means of preventing
  cardiovascular disease
• Test beta-carotene as a means of preventing
  cancer
• Terminated aspirin arm early due to a significant
  drop in the risk of first myocardial infarctions
• Continued beta-carotene arm to completion

18
Factorial Design for Studying Effects of Two
Treatments

• Treatment B
• -

Both A and B (a) A only (b)
B only (c) Neither A nor B (d)

• Treatment A
• -

19
To Estimate Sample Size in a Clinical Trial You
Need

• The difference in response rates to be detected
• An estimate of the response rate in one of the
  groups
• Level of statistical significance (?)
• The value of the power desired (1 ?)
• Whether the test should be one- or two-sided

20
One-Sided Test
Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (One-Sided Test)
Lower of the Two Cure Rates Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups
Lower of the Two Cure Rates 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70
0.05 330 105 55 40 33 24 20 17 13 12 10 9 9 8
0.10 540 155 76 47 37 30 23 19 16 13 11 11 9 8
0.15 710 200 94 56 43 32 26 22 17 15 11 10 9 8
0.20 860 230 110 63 42 36 27 23 17 15 12 10 9 8
0.25 980 260 120 69 45 37 31 23 17 15 12 10 9 -
0.30 1,080 280 130 73 47 37 31 23 17 15 11 10 - -
0.35 1,160 300 135 75 48 37 31 23 17 15 11 - - -
0.40 1,210 310 135 76 48 37 30 23 17 13 - - - -
0.45 1,230 310 135 75 47 36 26 22 16 - - - - -
0.50 1,230 310 135 73 45 36 26 19 - - - - - -
Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979.
21
Two-Sided Test
Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test) Number of Patients Needed in Each Group to Detect Various Differences in Cure Rates a .05 Power (1-b) .80 (Two-Sided Test)
Lower of the Two Cure Rates Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups Differences in Cure Rates Between the Two Treatment Groups
Lower of the Two Cure Rates 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70
0.05 420 130 69 44 36 31 23 20 17 14 13 11 10 8
0.10 680 195 96 59 41 35 29 23 19 17 13 12 11 8
0.15 910 250 120 71 48 39 31 25 20 17 15 12 11 9
0.20 1,090 290 135 80 53 42 33 26 22 18 16 12 11 9
0.25 1,250 330 150 88 57 44 35 28 22 18 16 12 11 -
0.30 1,380 360 160 93 60 44 36 29 22 18 15 12 - -
0.35 1,470 370 170 96 61 44 36 28 22 17 13 - - -
0.40 1,530 390 175 97 61 44 35 26 20 17 - - - -
0.45 1,560 390 175 96 60 42 33 25 19 - - - - -
0.50 1,560 390 170 93 57 40 31 23 - - - - - -
Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979. Modified from Gehan E. Clinical trials in cancer research. Environ Health Perspect 3231, 1979.