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 feasible

1) 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/CommitteesM eetingMaterials/Drugs/CardiovascularandRenalDrugsAdvis oryCommittee/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

Non-blind

Blinding of Treatments

- 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

• P rospective, R andomized, O pen-label, B linded E ndpoint 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

No.

Aspirin trial in British male doctors

Aspirin (500 mg Daily) 3429 Control (Avoid Aspirin) 1710 Age < 60(%) Never smoker Hypertension Diabetes 46.8

25.1

10.2

2.0

47.0

23.1

9.3

1.9

BMJ 1988; 296: 313-316.

British Aspirin Study

Stopped taking aspirin(%) Started taking aspirin(%) * 19.5% in first year Aspirin 44.3* – Control – 12 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.

Physician’s Health Study

Double-Blind Study

Aspirin (N=11,037) Placebo for Aspirin (N=11,034) Compliance 85.71

85.74

N Engl J Med 1989; 321: 129-135.

Example: Non-Blind Study MRFIT

∆ DBP (mm Hg) ∆ cholesterol (mg/dl) % quitting smoking Risk Factor Changes After 6 Years SI UC -10.5

-7.4

-12.3

46 -6.4

29 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 Placebo + Acupuncture Amitriptyline + Alt Points Sample Size: 260 patients (65 in each arm)

JAMA 1998; 280: 1590-1596.

Amitriptyline + Acupuncture

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

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) Placebo (2) Acebutolol (400 mg) (3) Amlodipine (5 mg) (4) Chlorthalidone (15 mg) (5) Doxazosin (2 mg) (6) Enalapril (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 the Alzheimer’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 existing formulations.

Fully blinded, double dummy.

Prevention of Toxoplasmic Encephalitis Design 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 Active Treatment 125 Placebo 250 Active Treatment 125 Placebo

Combination Nucleoside (NuCombo) Study N Engl J Med 1996;335:1099-1106

Unblinded ddI Arm Blinded ddC Arm Blinded ddI + AZT Placebo (ddI) + AZT ddC + AZT Placebo (ddC) + AZT No. Tablets Morning Afternoon Evening 4 10 4 2 4 10 4 2 4 12 4 4 4 12 4 4

No. Tablets Morning Afternoon Evening

NuCombo Study Alternative Design “Double-Dummy”

Blinded ddI + ddC Placebo + AZT 6 16 6 4 ddI Placebo + ddC + AZT 6 16 6 4 ddI Placebo + ddC Placebo + AZT 6 16 6 4

No. Tablets Morning Afternoon Evening 4 2 4 10

NuCombo Study Alternative Design Unblinded

ddI + AZT ddC + AZT 4 4 4 12 AZT 2 2 2 6

Example: Clinical Trial of Radiotherapy (R) Alone vs. Radiotherapy Preceded by Drug Treatment (DR) for 30 Days DR Drug R Pragmatic Approach R R Time Which treatment is better when administered under usual conditions?

DR Drug R Explanatory Approach R No Drug R Time Does drug have a sensitizing effect?

Schwartz D and Lellouch J,

J Chronic Dis

, 1967.

Vaginal Microbicide to Prevent HIV Infection (1) Microbicide Placebo Double blind (2) Microbicide “Condom only” (no gel) Non- blind (3) Microbicide Placebo “Condom only” (no gel) Partially blind Concern: Use of microbicides might decrease use of condoms.

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 Blind in the CPPT Study of Cholestyramine

Patients Cholestryamine 56.0

Placebo 54.6

Treatment team 55.2

52.9

% assignments guessed correctly JAMA 1984; 251:351-64

Maintenance of Blind in Mt. Sinai Hypertension Trial: Potassium Supplementation versus Placebo

Participant % Correct 60 Nutritionist Nurse 49 56 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 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.

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.

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.