Blinding or Masking of
Treatments and of Other Aspects
of the Trial
Two Important Methods for Removing Bias in Clinical Trials
1. Randomization
2. Blinding
– Treatment assigned and application
– Endpoint assessment
Bias (def.) - A systematic error usually introduced (conscious or unconscious) by investigator / trial participant which leads to incorrect estimates of the treatment effect
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
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
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.
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<0.001); and 2) trials that were not double-blind resulted in more extreme treatment differences than double-blind studies (p=0.01).
* Schulz et al., JAMA, pp.408-412, 1995.
Pocock identifies four areas to consider to determine whether
blinding is feasible1) Ethics - undue harm to patient
2) Practicality - similarity of treatments
3) Avoidance of bias - How much bias?
4) Compromise – partial blinding
MRC Trial on Tuberculosis
• MRC committee considered whether the trial on streptomycin should be blinded and whether the investigator should be allowed to modify therapy (e.g., collapse therapy).
• Use of placebo would have required IM injection 4xday for 4 months
• Hill argued “no need in the search for precision to throw common sense out the window”
FDA Panel Discussion on Blinding• A randomized trial (RE-LY) was carried out for patients with
atrial fibrillation comparing dabigatran, an oral direct thrombin inhibitor that provides stable anticoagulation at a fixed dose without any need for laboratory control, with warfarin,a vitamin K antagonist, that requires strict laboratory control.
• The trial was not blinded and the FDA asked the panel to consider if open-label warfarin was reasonable.
• The trial was published in Lancet 2010; 376:975-983. Panel questions can be found at ww.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM226006.pdf
Blinding
1) of study participant
2) of treatment team
3) of endpoint assessment (e.g., endpoint review committee)
4) of data monitoring committee
5) of data analysts and management staff
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
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).
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 (?)
Example: Non-Blind Study
Aspirin trial in British male doctors
No. 3429 1710
Age < 60(%) 46.8 47.0
Never smoker 25.1 23.1
Hypertension 10.2 9.3
Diabetes 2.0 1.9
Aspirin(500 mg Daily)
Control(Avoid Aspirin)
BMJ 1988; 296: 313-316.
British Aspirin Study
Stopped taking 44.3* –aspirin(%)
Started taking – 12aspirin(%)
19.5% in first year
Aspirin Control
*
The potential for non-compliance with the treatmentassignment needs to be considered in the design – very
important in a non-blind study of a readily available treatment.
Physician’s Health StudyDouble-Blind Study
Compliance 85.7185.74
Aspirin (N=11,037)
Placebofor Aspirin (N=11,034)
N Engl J Med 1989; 321: 129-135.
Example: Non-Blind Study
MRFIT
∆ DBP (mm Hg) -10.5 -7.4
∆ cholesterol (mg/dl) -12.3 -6.4
% quitting smoking 46 29
SI
Risk Factor ChangesAfter 6 Years
UC
JAMA 1982; 248: 1465-1477.
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
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)
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.
Example: Single Blind StudyPulmonary Embolism Trial
(UPET)
12 hours urokinase + heparin
vs.
heparin alone
Endpoint: 24-hour clot resolution;symptom relief;complications
Circulation 1973; Supplement II
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.
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?
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
TOMHS
Weight Loss + Na Reduction +Alcohol Reduction
and
(1) (2) (3)Placebo Acebutolol Amlodipine
(400 mg) (5 mg)
(4) (5) (6)Chlorthalidone Doxazosin Enalapril
(15 mg) (2 mg) (5 mg)
TOMHS: Double-Dummy
Weight Loss + Na Reduction +Alcohol Reduction
and
(1)Placebo ( )Placebo ( )
(2) Acebutolol ( )
Placebo ( )
(3)Placebo ( )
Amlodipine ( )
(4)Placebo ( )
Chlorthalidone ( )
(5)Placebo ( )Doxazosin ( )
(6)Placebo ( )Enalapril ( )
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.
Blinding can complicate the treatment regimen and change the nature of the
question being addressed
Design Considerations for theAlzheimer’s 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.
Obtain drug in powder form and repackage.
Obtain in existing formulation and encapsulate.
Partially blinded with existingformulations.
Fully blinded, double dummy.
Prevention of Toxoplasmic EncephalitisDesign and Recruitment Goals
Lancet 1992; 339:333-334 and JID 1994;169:384-394
750 Patients
Unblinded
375 Clindamycin Arm 375 Pyrimethamine Arm
Blinded Blinded
250 ActiveTreatment
250 ActiveTreatment
125Placebo
125Placebo
Combination Nucleoside (NuCombo) StudyN Engl J Med 1996;335:1099-1106
No. Tablets
Morning 4 4 4 4
Afternoon 2 2 4 4
Evening 4 4 4 4
10 10 12 12
Unblinded
Blinded Blinded
ddI+
AZT
ddC+
AZT
Placebo (ddI)+
AZT
Placebo (ddC)+
AZT
ddI Arm ddC Arm
NuCombo StudyAlternative Design“Double-Dummy”
No. Tablets
Morning 6 6 6
Afternoon 4 4 4
Evening 6 6 6
16 16 16
Blinded
ddI+
ddC Placebo+
AZT
ddI Placebo+
ddC+
AZT
ddI Placebo+
ddC Placebo+
AZT
NuCombo StudyAlternative Design
Unblinded
No. Tablets
Morning 4 4 2
Afternoon 2 4 2
Evening 4 4 2
10 12 6
ddI+
AZT
ddC+
AZT AZT
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
Time
Schwartz D and Lellouch J, J Chronic Dis, 1967.
Vaginal Microbicideto Prevent HIV Infection
Concern: Use of microbicides might decrease use of condoms.
Microbicide Placebo
Microbicide “Condom only”(no gel)
Double blind
Non- blind
Partially blindMicrobicide Placebo “Condom only”(no gel)
(1)
(2)
(3)
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
Maintenance of Blindin the CPPT Study of Cholestyramine
Patients 56.0 54.6
Treatment team 55.2 52.9
% assignments guessed correctly
Cholestryamine Placebo
JAMA 1984; 251:351-64
Maintenance of Blindin Mt. Sinai Hypertension Trial:
Potassium Supplementation versus Placebo
Participant 60
Nutritionist 49
Nurse 56
% Correct
N Engl J Med 1990; 322: 569-574.
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?
Evaluation of Blinding in 191 TrialsPublished 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.
Evaluation of Methods of Blinding in 819 Trialsof 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.
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”.
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 arm…The 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 assignments…The 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 investigators…were kept masked to outcome measurements and trial results.”
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.