Blinding or Masking of Treatments and of Other Aspects of the
Trial
Slide 2
Two Important Methods for Removing Bias in Clinical Trials
1.Randomization 2.Blinding Treatment assigned and application
Endpoint assessment
Slide 3
Bias (def.) - A systematic error usually introduced (conscious
or unconscious) by investigator / trial participant which leads to
incorrect estimates of the treatment effect
Slide 4
Blinding of Treatments Feature of design to eliminate bias
associated with physician/patient being aware of treatment that is
given Note: This is different from the type of bias that
randomization prevents and from allocation concealment
Slide 5
Examples of Bias Eliminated or Reduced with Blinding
Differential/preferential ancillary/compensatory treatment (co-
intervention bias) Psychological impact of being treated with what
might be perceived to be superior treatment (placebo effect)
Differential ascertainment/diagnosis of endpoints (primary outcomes
and toxicities) particularly important for subjective outcomes
Differential compliance/visit attendance/record
keeping/withdrawal
Slide 6
ICH Guidelines (E 10) Potential biases blinding can
prevent/minimize: Patients may be more likely to report benefit on
active drug. Observers may be more likely to report favorable
outcomes and adverse effects on active drug. Knowledge of treatment
may affect rigor of follow-up. Knowledge of treatment could affect
decisions to use concomitant treatment or to stay on study drug.
Knowledge of treatment could affect decision to leave in the
analysis. Knowledge of treatment could affect choice of statistical
analysis.
Slide 7
Overview of Trials in Pregnancy or Childbirth * 250 trials;
authors studied the association of methodological rigor with
treatment effect as measured by odds ratio (i.e., interaction of
treatment effect with quality measure) Two significant predictors:
1) unclear allocation concealment resulted in more extreme
treatment differences than adequate measures (p
Blinding of Treatments Non-blind - Investigator and patient
know treatment assigned (open label) Single-blind - Investigator
knows treatment assigned but patient does not (in some cases
participants knows and investigator does not) Double-blind -Neither
investigator nor patient knows treatment assigned General
view-Double-blind > single blind > non- blind
Slide 13
Slide 14
Blinding in a Non-Blind Study 1.Accumulating data:
investigators should be blinded to group data; an external
independent data monitoring committee (DMC) should not be.
2.Endpoint committee assessments and laboratory measurements (can
be performed blinded to treatment group even in an open
trial).
Slide 15
PROBE Design Prospective, Randomized, Open-label, Blinded
Endpoint Design Phrase coined by Hannsson et al (Blood Pressure
1992) Motivation: More similar to clinical practice Easier to
enroll trials Better patient compliance Cheaper (?)
Slide 16
Example: Non-Blind Study Aspirin trial in British male doctors
No.34291710 Age < 60(%)46.847.0 Never smoker25.123.1
Hypertension10.29.3 Diabetes2.01.9 Aspirin (500 mg Daily) Control
(Avoid Aspirin) BMJ 1988; 296: 313-316.
Slide 17
British Aspirin Study Stopped taking44.3* aspirin(%) Started
taking12 aspirin(%) 19.5% in first year AspirinControl * The
potential for non-compliance with the treatment assignment needs to
be considered in the design very important in a non-blind study of
a readily available treatment.
Slide 18
Physicians Health Study Double-Blind Study Compliance85.7185.74
Aspirin (N=11,037) Placebo for Aspirin (N=11,034) N Engl J Med
1989; 321: 129-135.
Slide 19
Example: Non-Blind Study MRFIT DBP (mm Hg)-10.5-7.4 cholesterol
(mg/dl)-12.3-6.4 % quitting smoking4629 SI Risk Factor Changes
After 6 Years UC JAMA 1982; 248: 1465-1477.
Slide 20
MRFIT Endpoint Ascertainment Mortality review blinded to
treatment group for assigning cause of death Issues which had to be
dealt with: Rapidity with which deaths were ascertained
Completeness of data Assuring blinded review
Slide 21
Examples of Studies Where Blinding of Treatment is Difficult or
Impossible Surgical (e.g., device) vs. medical treatment (even in
this situation, one may be able blind some members of the treatment
team) Non-pharmacologic and behavioral interventions (e.g., diet,
rehabilitation) Utility of genotypic resistance testing versus not
using it for choosing salvage treatments for patients with HIV
Interventions to improve patient adherence Strategic trials of how
to use treatments based on disease markers (e.g., START trial on
when to start ART)
Slide 22
Design: Randomized, single/double-blind 2x2 factorial,
multi-center clinical trial. Randomization Placebo + Alt Points
Amitriptyline + Acupuncture Placebo + Acupuncture Amitriptyline +
Alt Points Sample Size: 260 patients (65 in each arm) JAMA 1998;
280: 1590-1596.
Slide 23
Example: Single Blind Study Pulmonary Embolism Trial (UPET) 12
hours urokinase + heparin vs. heparin alone Endpoint:24-hour clot
resolution; symptom relief; complications Circulation 1973;
Supplement II
Slide 24
Nature of Blinding Patient was blinded Two members of medical
staff were aware of treatment because of clotting studies for
patient management Daily evaluations of symptoms by blinded staff
Blinded evaluation of angiograms and lung scans.
Slide 25
How well was the blind maintained? of patient? Very well; no
objective data of treatment team? Not very well because of bleeding
complications of endpoint evaluation?
Slide 26
Example: Double Blind Study TOMHS AIM: Among mild hypertensive
men and women does the addition of drug to intensive nutrition
intervention result in a reduction of CVD morbidity/mortality? JAMA
1993; 270:713-724
Slide 27
TOMHS Weight Loss + Na Reduction + Alcohol Reduction and
(1)(2)(3) PlaceboAcebutololAmlodipine (400 mg)(5 mg) (4)(5)(6)
ChlorthalidoneDoxazosinEnalapril (15 mg)(2 mg)(5 mg)
Blinding in Influenza-IVIG Study INSIGHT 005: FLU-IVIG Pilot
Study * PID Number: [write 8-digit PID number here] Anti-Influenza
Hyperimmune IVIG or Placebo Directions for use: Infuse entire
contents over a continuous period (approximately 2 hours) Start
infusion as soon as possible after the date and time treatment was
prepared FOR INVESTIGATIONAL USE ONLY Time for preparing placebo
should mimic that for IVIG (e.g., thawing and preparing proper dose
weight based dose.
Slide 30
Blinding can complicate the treatment regimen and change the
nature of the question being addressed
Slide 31
Design Considerations for the Alzheimers Disease
Anti-inflammatory Prevention Trial (ADAPT) Randomization to
naproxen (220 mg bid), celecoxib (200 mg bid) or placebo (1:1:1.5)
Four placebo design options were considered to allow masking Cont
Clin Trials 2002; 23:93-99.
Slide 32
Obtain drug in powder form and repackage. Obtain in existing
formulation and encapsulate. Partially blinded with existing
formulations. Fully blinded, double dummy.
Slide 33
Prevention of Toxoplasmic Encephalitis Design and Recruitment
Goals Lancet 1992; 339:333-334 and JID 1994;169:384-394 750
Patients Unblinded 375 Clindamycin Arm375 Pyrimethamine Arm Blinded
250 Active Treatment 125 Placebo
Slide 34
Combination Nucleoside (NuCombo) Study N Engl J Med
1996;335:1099-1106 No. Tablets Morning4444 Afternoon2244 Evening 4
4 4 4 10101212 Unblinded Blinded ddI + AZT ddC + AZT Placebo (ddI)
+ AZT Placebo (ddC) + AZT ddI ArmddC Arm
Slide 35
NuCombo Study Alternative Design Double-Dummy No. Tablets
Morning666 Afternoon444 Evening 6 6 6 161616 Blinded ddI + ddC
Placebo + AZT ddI Placebo + ddC + AZT ddI Placebo + ddC Placebo +
AZT
Slide 36
NuCombo Study Alternative Design Unblinded No. Tablets
Morning442 Afternoon242 Evening 4 4 2 10126 ddI + AZT ddC +
AZT
Slide 37
Example: Clinical Trial of Radiotherapy (R) Alone vs.
Radiotherapy Preceded by Drug Treatment (DR) for 30 Days Which
treatment is better when administered under usual conditions? Does
drug have a sensitizing effect? Pragmatic Approach DR R Drug R R DR
R Drug No Drug R Explanatory Approach R Time Schwartz D and
Lellouch J, J Chronic Dis, 1967.
Slide 38
Vaginal Microbicide to Prevent HIV Infection Concern: Use of
microbicides might decrease use of condoms. MicrobicidePlacebo
MicrobicideCondom only (no gel) Double blind Non- blind Partially
blindMicrobicidePlaceboCondom only (no gel) (1) (2) (3)
Slide 39
Implementation of Double Blind Design 1.Maintenance of blind
Intermediate response variables Laboratory data 2.Preparation and
packaging of drugs Similar in appearance, taste, weight Labeling;
unique bottle numbers Quality control 3.Breaking the blind (this
should be tracked and reported) 4.Evaluation of blinding
Slide 40
Maintenance of Blind in the CPPT Study of Cholestyramine
Patients56.054.6 Treatment team55.252.9 % assignments guessed
correctly CholestryaminePlacebo JAMA 1984; 251:351-64
Slide 41
Maintenance of Blind in Mt. Sinai Hypertension Trial: Potassium
Supplementation versus Placebo Participant60 Nutritionist49 Nurse56
% Correct N Engl J Med 1990; 322: 569-574.
Slide 42
How Blind is Blind? Should the blind be assessed? before the
trial begins? as the trial is ongoing? at the end? Is the bias that
results from unblinding different if it is due to substantial
efficacy versus minor side effects? How should the blind
assessment, if done, be used to adjust/interpret the primary
results?
Slide 43
Evaluation of Blinding in 191 Trials Published in General
Medicine and Psychiatric Journals 7 of 97 trials (7%) in general
medicine journals reported success of blinding 8 of 94 (9%) in
psychiatric journals reported success of blinding Ferguson D et
al., BMJ 2004;328:432-437.
Slide 44
Evaluation of Methods of Blinding in 819 Trials of
Pharmacologic Treatments Published in Major Journals in 2004
Reporting of blinding in trials is poor 58% of trials reported
method of blinding (should always state who was blinded and how in
addition to using terms like single- and double-blind). 28%
blinding of patients, health care providers and outcome assessors;
14% blinding of patients and health care providers. 24% patients
only 0.1 % health care providers only 21% outcome assessors but not
health care providers Boutron et al., PLoS Med
2006;3:1931-1939.
Slide 45
CONSORT Guidelines for Reporting Results of Trials Blinding Who
was blinded to the interventions and how was the blind implemented.
If relevant, description of the similarity of the interventions.
TOMHS: To facilitate the double-blind design, active drugs and
placebo were prepared in capsule form. Since all active treatments
could not be provided in the same size capsule, participants took
two different-sized capsules daily as the initial dose.
Slide 46
Trial Reports of Blinding (cont.) Acupuncture study: To
maintain blinding and to determine the need for supplemental
points, the acupuncturists asked all patients a series of standard
questions, irrespective of treatment armThe placebo capsules were
identical in appearance and taste to the active capsules. Weight
loss diets (N Engl J Med 2009;360:859-873): Except for the
interventionists (dieticians and behavioral psychologists)
investigators and staff were kept blind to diet assignmentsThe
trial adhered to established procedures to maintain separation
between staff that take outcome assignments and staff that deliver
the intervention. Staff who obtained outcome assignments were kept
blind to diet group assignment. All investigatorswere kept masked
to outcome measurements and trial results.
Slide 47
Summary Blinding is an effective way to reduce/eliminate bias
in clinical trials do it when you can. Blinding does not guarantee
valid results Willingness to compromise is essential Feasibility
(cost, time, patient/investigator interest, patient safety)
Necessity and common sense (how much bias) In some circumstances,
blinding can change the nature of the research question. Consider
opportunities for blinding carefully before the trial begins.