STATISTICS 542 Introduction to Clinical Trials

CLINICAL TRIAL DESIGN

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Types of Clinical Research

1. Case Reports Anecdotal Problem 2. Observational
a. Case Control/Retrospective (lung cancer) b. Cross Sectional (WESDR) Beaver Dam c. Prospective (Framington) WESDR-II Risk Factor Associations

3. Drug Development (Phase 0, Phase I, & Phase II)

Dose and activity

4. Experimental (Clinical Trial) Phase III

Effect

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Phases of Clinical Trials (Cancer) [1]

Phase 0 - Preclinical Preclinical animal studies Looking for dose-response Phase I Seeking maximum tolerated dose (MTD) Patients usually failed other alternatives Phase II Estimate of drug activity Decide if drug warrants further testing (Phase III) Estimate of serious toxicities 542-03-#3

Phases of Clinical Trials (Cancer) [2]

Phase III Provide effectiveness of drug or therapy Various designs No control Historical control Concurrent Randomized Testing for treatment effect Phase IV Long term post Phase III follow-up Concern for safety 542-03-#4

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Design
The choice of design depends on the goal of the trial Choice also depends on the population, knowledge of the intervention Proper design is critical, analysis cannot rescue improper design
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Phase I Design
Typical/Standard Design
Based on tradition, not so much on statistical theory Dose escalation to reach maximum tolerated dose (MTD) Dose escalation often based on Fibonacci Series 1 2 3 5 8 13 . . . .
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Typical Scheme
1. 2. 3. Enter 3(5) patients at a given dose If no toxicity, go to next dosage and repeat step 1 a. If 1 patient has serious toxicity, add 3 more patients at that does (go to 4) b. If 2/3 have serious toxicity, consider MTD a. If 2 or more of 6 patient shave toxicity, MTD reached (perhaps) b. If 1 of 6 has toxicity, increase dose and go back to step 1 542-03-#8

4.

Standard Phase I Design

Designed to find dose where 1/3 of patients experience dose limiting toxicity (DLT) Standard escalation design tends to underestimate target dose Ref: Storer, Biometrics, 1989
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Dose-response curves used in simulations (1)

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Dose-response curves used in simulations (2)

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Summary of Designs Considered (1)

(Storer, Biometrics 45:925-37, 1989) A. Standard Observe group of 3 patients No toxicity increase dose Any toxicity observe 3 or more One toxicity out of 6 increase dose Two or more toxicity stop B. 1 Up, 1 Down Observe single patients No toxicity increase dose Toxicity decrease dose

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Summary of Designs Considered (2)

(Storer, Biometrics 45:925-37, 1989) C. 2 Up, 1 Down Observe single patients No toxicity in two consecutive increase dose Toxicity decrease dose D. Extended Standard Observe groups of 3 patients No toxicity increase dose One toxicity dose unchanged Two or three toxicity decrease dose 542-03-#13

Summary of Designs Considered (3)

(Storer, Biometrics 45:925-37, 1989) E. 2 Up, 2 Down Observe groups of 2 patients No toxicity increase dose One toxicity dose unchanged Both toxicity decrease dose B, C, D, E - fixed sample sizes ranging from 12 to 32 patients Can speed up process to get to target dose range 542-03-#14

Phase II Design (1)

References:
Gehan (1961) Journal of Chronic Disorders Fleming (1982) Biometrics Storer (1989) Statistics in Medicine

Goal
Screen for therapeutic activity Further evaluate toxicity Test using MTD from Phase I If drug passes screen, test further

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Phase II Design (2)

Design of Gehan
No control (?) Two stage (double sampling) Goal is to reject ineffective drugs ASAP Decision I: Drug is unlikely to be effective in x% of patients Decision II: Drug could be effective in x% of patients
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Phase II Design (3)

Typical Gehan Design
Let x% = 20% That is, want to check if drug likely to work in at least 20% of patients 1. Enter 14 patients 2. If 0/14 responses, stop and declare true drug response 20% 3. If 1+/14 responses, add 15-40 more patients 4. Estimate response rate & C.I. 542-03-#17

Phase II Design (4) (Why 14 failures?)

Compute probability of consecutive failures
Patient 1 2 3 --8 --14 Prob 0.8 0.64 (0.8 x 0.8) 0.512 (0.8 x 0.8 x 0.8) --0.16 --0.044

If drug 20% effective, there would be ~95.6% chance of at least one success If 0/14 success observed, reject drug
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Phase II Design (5)

Stage I Sample Size
Table I
Rejection Error 5 5% 59 10% 45 Effectiveness (%) 15 20 25 40 50 19 14 11 6 5 15 11 9 5 4

10 29 22

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Stage II Sample Size (1)

Based on desired precision of effectiveness estimate r1 = # of successes in Stage 1 n1= # of patients in Stage 1
1 = r1/n1 p

SE( p1 ) =

p1 (1 p1 ) n1

Now precision of total sample N=(n1 + n2)

* (1 p * ) p *) = SE(p N

=p Let p
*

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Stage II Sample Size (2)

To be conservative, Gehan suggested

=p 1 + 1.15SE( p 1) p
*

upper 75% confidence limit from first sample Thus, we can generate a table for size of second stage (n2) based on desired precision
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Additional Patients for Stage II (n2) (Rejection Rate 5% for Stage I)

Required Precision (SE) Number of Successes Stage I Therapeutic Effectiveness (%) 5 59 0 0 0 0 0 0 0 0 0 0 10 29 4 17 28 38 46 0 0 0 0 0 15 19 30 45 58 67 75 0 0 1 3 5 20 14 45 63 76 83 86 1 6 9 11 11 25 11 60 78 87 89 89 7 12 14 14 14 30 9 70 87 91 91 91 11 15 16 16 16

n1 +1 SE 5% 1 2 3 4 5 1 +1 SE 10% 2 3 4 5

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Additional Patients for Stage II (n2) (Rejection Rate 5% for Stage I)

We might require 10% precision with 20% desired effectiveness. Assuming 4 or 5 successes in the first stage .... n1 = 14 n2 = 11 N = 25

We will use estimate p (= r/N) to design a Phase III study where r = r1 + r2. 542-03-#23

Phase II Trials
Many most cancer Phase II trials follow this design Many other diseases could there seems to be no standard non-cancer Phase II design Might also randomize patients into multiple arms each with a different dose can then get a dose response curve
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Phase III Introduction

The foundation for the design of controlled experiments established for agricultural experiments The need for control groups in clinical studies recognized, but not widely accepted until 1950s No comparison groups needed when results dramatic:
Penicillin for pneumococcal pneumonia Rabies vaccine

Use of proper control group necessary due to: Natural history of most diseases Variability of a patient's response to intervention 542-03-#25

Phase III Design

Comparative Studies Experimental Group vs. Control Group Establishing a Control
1. Historical 2. Concurrent 3. Randomized

Randomized Control Trial (RCT) is the gold standard

Eliminates several sources of bias
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Purpose of Control Group

To allow discrimination of patient outcomes caused by experimental intervention from those caused by other factors
Natural progression of disease Observer/patient expectations Other treatment

Fair comparisons
Necessary to be informative
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Choice of Control Group

Goals of Controlled Clinical Trials Types of Control Groups Significance of Control Group Assay Sensitivity
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Considerations in Choice of Control Group

Available standard therapies Adequacy of the control evidence for the chosen design Ethical considerations
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Significance of Control Group

Inference drawn from the trial Ethical acceptability of the trial Degree to which bias is minimized Type of subjects Kind of endpoints that can be studied Credibility of the results Acceptability of the results by regulatory authorities Other features of the trial, its conduct, and interpretation
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Type of Controls
External Historical Concurrent, not randomized Internal and concurrent No treatment Placebo Dose-response Active (Positive) control Multiple Both an Active and Placebo Multiple doses of test drug and of an active control 542-03-#31

Use of Placebo Control

The placebo effect is well documented Could be
No treatment + placebo Standard care + placebo

Matched placebos are necessary so patients and investigators cannot decode the treatment E.g. Vitamin C trial for common cold Placebo was used, but was distinguishable Many on placebo dropped out of study Those who knew they were on vitamin C reported fewer cold symptoms and duration than those on vitamin who didn't know 542-03-#32

Historical Control Study (1)

A new treatment used in a series of subjects Outcome compared with previous series of comparable subjects Non-randomized, non-concurrent Rapid, inexpensive, good for initial testing of new treatments Two sources of historical control data: Literature Subject to publication bias Data base 542-03-#33

Historical Control Study (2)

Vulnerable to bias Changes in outcome over time may come from change in:
underlying patient populations criteria for selecting patients patient care and management peripheral to treatment diagnostic or evaluating criteria quality of data available

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Changes in Definitions

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Time Trend
Age-adjusted Death Rates for Selected Causes: United States, 1950-76

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Stat Bite

Cancer and Heart Disease Deaths

Cancer and heart disease are the leading causes of death in the United States. For people less than age 65, heart disease death rated declined greatly from 1973 to 1992, while cancer death rates declined slightly. For people age 65 and older, heart disease remains the leading killer despite a reduction in deaths from this disease. Because cancer is a disease of aging, longer life expectancies and fewer deaths from competing causes, such as heart disease, are contributing to the increasing cancer incidence and mortality for those age 65 and older

JNCI 87(16): 1206, 1995

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Historical Control Study (3)

Tend to exaggerate the value of a new treatment Literature controls particularly poor Even historical controls from a previous trial in the same institution or organization may still be problematic
Pocock (1977, Brit Med J) In 19 studies where the same treatment was used in two consecutive trials, differences in survival ranged from 46 to 24 , with four differences being statistically significant

Adjustment for patient selection may be made, but all other biases will remain 542-03-#39

PRAISE I vs. PRAISE II Placebo arms

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Concurrent Controls
Not randomized Patients compared, treated by different strategies, same period Advantage
Eliminate time trend Data of comparable quality

Disadvantage
Selection Bias Treatment groups not comparable

Covariance analysis not adequate

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Biases in Concurrent Control Study

Types Magnitude of effects False positive Sources Patient selection Referral patterns Refusals Different eligibility criteria Experimental environment Diagnosis/staging Supportive care Evaluation methods Data quality

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Randomized Control Clinical Trial

Reference: Byar et al. (1976) New England Journal of Medicine Patients assigned at random to either treatment(s) or control Considered to be Gold Standard
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Advantages of Randomized Control Clinical Trial

1. Randomization "tends" to produce comparable groups Design Randomized Concurrent (Non-randomized) Historical (Non-randomized) Sources of Imbalance Chance Chance & Selection Bias Chance, Selection Bias, & Time Bias

2. Randomization produces valid statistical tests

Reference: Byar et al (1976) NEJM

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Disadvantages of Randomized Control Clinical Trial

1. Generalizable Results? Subjects may not represent general patient population volunteer effect 2. Recruitment Twice as many new patients 3. Acceptability of Randomization Process Some physicians will refuse Some patients will refuse 4. Administrative Complexity 542-03-#45

Bias of Non-RCTs
Example - Peto (1979) Biomedicine Trials of anticoagulant therapy Design Effect 18 Historical 8 Concurrent 50% 6 Randomized 20% Biases 3000 1/6 #Patients 900 P<0.05 15/18 3000 5/8 Observed 50%

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Ethics of Randomization (1)

Statistician/clinical trialist must sell benefits of randomization Ethics MD should do what he thinks is best for his patient
Two MD's might ethically treat same patient quite differently

Chalmers & Shaw (1970) Annals New York Academy of Science

1. 2. 3. If MD "knows" best treatment, should not participate in trial If in doubt, randomization gives each patient equal chance to receive one of therapies (i.e. best) More ethical way of practicing medicine

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Ethics of Randomization (2)

Byar et al. (1976) NEJM 1. RCT honest admission best is not known! 2. RCT is best method to find out! 3. Reduces risk of being on inferior treatment 4. Reduces risk for future patients

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Ethics of Randomization (3)

Classic Example Reference: Silverman (1977) Scientific Amer 1. High dose oxygen to premature infants was common practice 2. Suspicion about frequency of blindness 3. RCT showed high dose cause of blindness

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Comparing Treatments
Fundamental principle
Groups must be alike in all important aspects and only differ in the treatment each group receives In practical terms, comparable treatment groups means alike on the average Randomization Each patient has the same chance of receiving any of the treatments under study Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned Blinding Avoidance of psychological influence Fair evaluation of outcomes

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Randomized Phase III Experimental Designs

Assume:
Patients enrolled in trial have satisfied eligibility criteria and have given consent Balanced randomization: each treatment group will be assigned an equal number of patients

Issue
Different experimental designs can be used to answer different therapeutic questions 542-03-#51

Commonly Used Phase III Designs

Parallel Withdrawal Group/Cluster Randomized Consent Cross Over Factorial Large Simple Equivalence/Non-inferiority Sequential
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Parallel Design
Screen

Trt A Randomize Trt B H0: A vs. B Advantage Simple, General Use Valid Comparison Disadvantage Few Questions/Study

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Fundamental Design
Yes Yes R A N D O M I Z E A

Eligible

Consent

No

No

Dropped

Dropped

Comment: Compare A with B

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Examples of Parallel Designs

VEST CAST DCCT NOTT IPPB

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Run-In Design
Problem:
Non-compliance by patient may seriously impair efficiency and possibly distort conclusions

Possible Solution: Drug Trials

Assign all eligible patients a placebo to be taken for a brief period of time. Patients who are judged compliant are enrolled into the study. This is often referred to as the Placebo Run-In period. Can also use active drug to test for compliance 542-03-#56

Run-In Design
R A Run-In Satisfactory N Period D O M I Unsatisfactory Z E Dropped
Note: It is assumed that all patient entering the run-in period are eligible and have given consent

Screen & Consent

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Examples of Run-In Trials

Cardiac Arrhythmia Suppression Trial (CAST) Diabetes Control and Complications Trial (DCCT) Physicians Health Study (PHS)

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Withdrawal Study
I Trt A Not Trt A

Trt A II

H0: How long should TRT A continue? Advantage

Easy Access to Subjects Show continued Tx Beneficial

Disadvantage
Selected Population Different Disease Stage

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Cluster Randomization Designs

Groups (clinics, communities) are randomized to treatment or control Examples:
Community trials on fluoridization of water Breast self examination programs in different clinic setting in USSR Smoking cessation intervention trial in different school district in the state of Washington

Advantages
Sometimes logistically more feasible Avoid contamination Allow mass intervention, thus public health trial

Disadvantages
Effective sample size less than number of subjects Many units must participate to overcome unit-to-unit variation, thus requires larger sample size Need cluster sampling methods

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Randomized Consent Design

Zelen (NEJM, 1979)
Group I: Regular Care (TRT A) Patient Randomize Group II: Experimental (TRT B)
Consent YES (TRT B)

NO (TRT A)

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Randomized Consent
(Zelen, 1979 NEJM)
Usual Order Screen Proposed Order Screen Randomize Consent (from Exp. Group only)

Consent

Randomize

Advantages Easier Recruitment Disadvantages Need Low Refusal Rate Control Must Be Standard Unblinded Ethical? Refusal Rate Dilution Increase Sample Size 15% 2x

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Cross Over Design

H0: A vs. B
Scheme Period
Group I II

AB BA

1 TRT A 2 TRT B

TRT B TRT A

Advantage Each patient their own control Smaller sample size Disadvantage Not useful for acute disease Disease must be stable Assumes no period carry over If carryover, have a study half sized (Period I A vs. Period I B)

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Factorial Design
Schema
Factor I Placebo Placebo Factor II Trt A N/4 N/4 N/4 Trt B N/4 A vs. Placebo

B vs. Placebo 542-03-#64

Factorial Design
Advantages
Two studies for one Discover interactions

Disadvantages
Test of main effect assumes no interaction Often inadequate power to test for interaction Compliance

Examples
Physicians' Health Study (PHS) NEJM 321(3):129-135, 1989. Final report on the aspirin component Canadian Cooperative Stroke Study (1978) NEJM p. 53

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Physicians Health Study

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Physician Health Study

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Physicians Health Study

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Physicians Health Study

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Superiority vs. Non-Inferiority Trials

Superiority Design: Show that new treatment is better than the control or standard (maybe a placebo) Non-inferiority: Show that the new treatment
a) Is not worse that the standard by more than some margin b) Would have beaten placebo if a placebo arm had been included (regulatory) 542-03-#70

Non-inferiority Trial
Trial with active (positive) controls The question is whether new (easier or cheaper) treatment is as good as the current treatment Must specify margin of equivalence or noninferiority Can't statistically prove equivalency -- only show that difference is less than something with specified probability Historical evidence of sensitivity to treatment Small sample size, leading to low power and subsequently lack of significant difference, does not imply equivalence 542-03-#71

Possible outcomes in a non-inferiority trial (observed difference & 95% CI - Pocock)

Superior Non-inferior Non-inferior Tricky (& rare) Inconclusive Inconclusive Inferior, but Inferior
0 Treatment Difference Delta

A B C D E F G H

New Treatment Better New Treatment Worse

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Difference in Events Test Drug Standard Drug

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Superior vs NonInferiority Designs

Benefit
.8 1.0 Placebo ( ( ( X X ) Benefit 1.25 X ) Non-significant ) Harm Harm RR

Better

Active Control
Worse 1.0 Standard ( RR

X ) Non-Inferior

) Worse

( Better( X )

Modified from Fleming, 1990

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Non-Inferiority Challenges (1)

Requires high quality trial Poor execution favors non-inferiority Requires strong control; weak control favors non-inferiority

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Non-Inferiority Challenges (2)

Treatment margin somewhat arbitrary Imputed Trt vs. Plbo effect
Uses historical control concept Imputed estimate not very robust

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OPTIMAAL
OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan Steering Committee
J. Kjekshus (Chair), K. Dickstein (Coordinator), S. G. Ball, A. J. S. Coats, R. Dietz, A. Kesniemi, E. S. P. Myhre, M. S. Nieminen, K. Skagen, K. Swedberg, K. Thygesen, H. Wedel, R. Willenheimer, A. Zeiher, J. C. Fox and K. Kristianson

Endpoint Committee
J. G. F. Cleland and M. Romo

Data Safety and Monitoring Board

D. Julian (Chair), A. Bays de Luna, D. L. DeMets, C. D. Furberg, W. W. Parmley and L. Rydn
Lancet 2002; 360:752-60

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Rationale
ACE inhibitors reduce mortality in high risk post MI patients Selective Angiotensin II Receptor Antagonists are an alternative because of more complete blockade of tissue RAAS Better tolerability
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Hypothesis
Losartan (50 mg) is superior or non-inferior to captopril (150 mg) in decreasing all-cause mortality in high-risk patients following AMI

Study design
Double-blind, randomized, parallel, investigator initiated, no placebo control Event driven (all-cause death = 937) Multicentre (Denmark, Finland, Germany, Ireland, Norway, Sweden, UK)
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Captopril as Comparator
Captopril has well documented benefits Captopril 50 mg 3 times daily has indication for CHF worldwide Widely used, available as generic
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Statistical Methods
937 deaths required for 95% power to detect a 20% difference between groups Non-inferiority margin of 10% chosen based on placebo-controlled trials of ACE-inhibitors Analysis by Intention-to-Treat and Cox regression model
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All-cause death
25 losartan (n=499 events) captopril (n=447 events) 20 Event rate (%)

15

10

5
Relative Risk = 1.13 (0.99 to 1.28); p=0.069

0 0
losartan (n) 2744 captopril (n) 2733

6
2504 2534

12
2432 2463

18 Month
2390 2423

24
2344 2374

30
2301 2329

36
1285 1309

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Subgroup Analyses
n Age <65 2170 65-74 1840 >75 1467 Gender Female 1575 Male 3902 Diabetes Non-diabetic 4537 Diabetic 940 Killip class Killip class 1 1735 Killip class 2 3131 Killip class 3-4 609 Heart failure No heart failure 1060 Heart failure 4417 Infarct location Infarct ant/lat 3821 Infarct inf/post 1152 Prior MI No prior MI 4479 Prior MI 998 Thrombolytic use No thromb use 2499 Thromb use 2978 -blocker use No -blocker use 1171 -blocker use 4306 Overall 5477
0.6

Hazard ratio (95% CI)

1.5

losartan better

captopril better

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Effect of losartan relative to placebo?

Rel. Risk % change

captopril vs. placebo* 0.805 losartan vs. captopril (OPTIMAAL) 1.126 losartan vs. putative placebo (0.805 x 1.126)
* SAVE, AIRE. TRACE, SMILE, GISSI III, CONSENSUS II and ISIS IV

- 19.5 12.6 - 9.4

0.906

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Non-Inferiority Methodology
a) Comparison: New Treatment vs. Standard RRa b) Estimate of standard vs. placebo RRb (based on literature) c) Imputed effect of New Trt vs. placebo (RRc) RRc = RRa x RRb
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Assay Sensitivity
Ability to distinguish an effective treatment from a less effective or ineffective treatment Different implications of lack of assay sensitivity Superiority trials
Failing to show that the test treatment is superior Thus failing to lead to a conclusion of efficacy

Non-inferiority trials
Finding an ineffective treatment to be non-inferior Thus leading to an erroneous conclusion of efficacy

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Large, Simple Trial

Advocated for common pathological conditions To uncover even modest benefits of intervention That are easily implemented in a large population Intervention unlikely to have different effects in different patient subpopulations Unbiased allocation to treatments Unbiased and easily ascertained outcome Very limited data collection 542-03-#87

CAPRIE
Design

Ischemic stroke, MI, atherosclerotic PAD

Clopidogrel 75 mg/day PO Completed Trial (N = 9,577)

Aspirin 325 mg/day PO Completed Trial (n = 9,566)

Source: CAPRIE Steering Comm. Lancet. 1996; 348:1329

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CAPRIE
Risk Reduction by Major Outcomes
Ischemic stroke MI Vascular death All events 8.7 -40 -20 0 20 40 7.6 5.2 19.2 p = 0.419 p = 0.008 p = 0.29 p = 0.043

Percentage Relative Risk Reduction

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Sequential Design
Continue to randomize subjects until H0 is either rejected or accepted A large statistical literature for classical sequential designs Developed for industrial setting Modified for clinical trials
(e.g. Armitage 1975, Sequential Medical Trials) 542-03-#90

Classical Sequential Design (1)

Continue to randomize subjects until H0 is either rejected or accepted Classic
Trt Better

Net Trt Effect

20 0 -20 Trt Worse 100 200

Continue Accept H0 Continue

300

No. of Paired Observations

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Classical Sequential Design (2)

Assumptions
Acute Response Paired Subjects Continuous Testing

Not widely used Modified for group sequential designs

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Beta-blocker Heart Attack Trial (BHAT)

Design Features
Mortality Outcome Randomized Double-blind Placebo-controlled Extended follow-up 3,837 patients Men and women 30-69 years of age 5-21 days post-M.I. Propranolol-180 or 240 mg/day

Preliminary Report. JAMA 246:2073-2074, 1981 Final Report. JAMA 247:1707-1714, 1982

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BHAT GSB

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Therapeutic vs. Prevention Trials

Prevention Trials
Primary - Prevent disease Secondary - Prevent recurrence

Therapeutic Trials
Treat disease

Basic fundamentals apply equally Some differences exist

Complexity Recruitment Strategies Compliance Length of Follow-up Size

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Confounding Bias
Suppose you are interested in the effects of a treatment T upon an outcome O in the presence of a predictor P Randomization takes care of bias due to factors P before treatment Blinding takes care of bias due to factors P after treatment

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Masking or Blinding (1)

Keeping the identity of treatment assignments masked for: 1. Subject 2. Investigator, treatment team or evaluator 3. Evaluation teams Purpose of masking: bias reduction Each group masked eliminates a different source of bias Masking is most useful when there is a subjective component to treatment or evaluation 542-03-#97

Blinding or Masking (2)

No Blind
All patients know treatment

Single Blind
Patient does not know treatment

Double Blind
Neither patient nor health care provider know treatment

Triple Blind
Patient, physician and statistician/monitors do not know treatment

Double blind recommended when possible

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Blinding or Masking (3)

Assures that subjects are similar with regard to post-treatment variables that could affect outcomes Minimizes the potential biases resulting from differences in management, treatment, or assessment of patients, or interpretation of results Avoids subjective assessment and decisions by knowing treatment assignment
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Feasibility of Masking
Ethics: The double-masking procedure should not result in any harm or undue risk to a patient Practicality: It may be impossible to mask some treatments Avoidance of bias: Masked studies require extra effort (manufacturing look-alike pills, setting up coding systems, etc.) Compromise: Sometimes partial masking, e.g., independent masked evaluators, can be sufficient to reduce bias in treatment comparison Although masked trials require extra effort, sometimes they are the only way to obtain an objective answer to a clinical question 542-03-#100

Reasons for Subject Masking

Those on no-treatment or standard treatment may be discouraged or drop out of the study Those on the new drug may exhibit a placebo effect, i.e., the new drug may appear better when it is actually not Subject reporting and cooperation may be biased depending on how the subject feels about the treatment

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Unbiased Evaluation
Subject Bias (NIH Cold Study) (Karlowski, 1975) Duration of Cold (Days) Blinded Unblinded Subjects Subjects Placebo 6.3 8.6 Ascorbic Acid 6.5 4.8

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Reasons for Treatment Team Masking

Treatment decisions can be biased by knowledge of the treatment, especially if the treatment team has preconceived ideas about either treatment Dose modifications Intensity of patient examination Need for additional treatment Influence on patient attitude through enthusiasm (or not) shown regarding the treatment 542-03-#103

Unbiased Evaluation
Investigator Bias - (Taste & Smell Study) (Henkin et al, 1972 & 1976) Single Blind 8/8* 0/8 Double Blind 5/8 7/8

Zinc Placebo

*Number of variables with significant improvement/Number of variables

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Reasons for Evaluator (Third Party) Masking

If endpoint is subjective, evaluator bias will lead to recording more favorable responses on the preferred treatment Even supposedly hard endpoints often require clinical judgment, e.g., blood pressure, MI

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Reasons for Monitoring Committee Masking

Treatments can be objectively evaluated Recommendations to stop the trial for ethical reasons will not be based on personal biases Sometimes, however, triple-mask studies are hard to justify for reasons of safety and ethics A policy not recommended, not required by FDA

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Design Summary
Design used must fit goals of trial RCT minimizes bias Superiority vs. Non-Inferiority trial challenges Use blinding when feasible to minimize bias after randomization

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West Campus

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