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.