blinding or masking of treatments and of other aspects of the trial

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

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.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.

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.

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.

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.

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 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)(2)(3) PlaceboAcebutololAmlodipine (400 mg)(5 mg) (4)(5)(6) ChlorthalidoneDoxazosinEnalapril (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 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.

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 Arm375 Pyrimethamine Arm Blinded 250 Active Treatment 125 Placebo

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

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

NuCombo Study Alternative Design Unblinded No. Tablets Morning442 Afternoon242 Evening 4 4 2 10126 ddI + AZT ddC + 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 Schwartz D and Lellouch J, J Chronic Dis, 1967.

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)

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 Patients56.054.6 Treatment team55.252.9 % assignments guessed correctly CholestryaminePlacebo JAMA 1984; 251:351-64

Maintenance of Blind in Mt. Sinai Hypertension Trial: Potassium Supplementation versus Placebo Participant60 Nutritionist49 Nurse56 % 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 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 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.

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.

blinding or masking of treatments and of other aspects of the trial

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