PubH 7420 Clinical Trials: Supplemental Notes for Lecture 7
1. Friedman, Furberg, and DeMets. Fundamentals of Clinical Trials, Chapter7.
Supplemental Reading References
1. Schulz KF, Grimes DA. Blinding in randomized trials: hiding who got what.
Lancet 359:696-700, 2002.
2. Boutron I, Estellat C, Guittet L, et al. Methods of blinding in reports of
randomized controlled trials assessing pharmacologic treatments: a systematic
review: PLoS Medicine 10;e425, 2006.
3. Hróbjartsson A, Boutron I. Blinding in randomized clinical trials: imposed
impartiality. Clin Pharmac and Ther 2011;90: 732-736.
4. Pocock SJ: Clinical Trials. A practical approach. John Wiley and Sons, Ltd.
Chapter 3, pages 38-49, Chapter 6.
5. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and
elaboration: updated guidelines for reporting parallel group randomized trials.
BMJ 340: c860, 2010.
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BLINDING OR MASKING
First, consider some definitions.
1.
Bias - a systematic error which results in a difference between the "true" value
and the value actually obtained (as opposed to sampling variability in which the
error is assumed random). In clinical trials, this error can result from a
preconceived, sometimes unconscious preference, on the part of the patient or
investigator which influences the way in which a treatment is evaluated. This
bias may manifest itself in the way a response variable is measured, how data is
analyzed or how the results of a trial are reported.
2.
Blinding or Masking of Treatments - a feature of a trial's design which is
introduced to eliminate the bias associated with the patient and/or the therapist
having knowledge of the treatment being given (after randomization), i.e., to
assure that patients in all treatment groups are treated and evaluated in a similar
way. Recall that one of the advantages of randomization was that it eliminated
the bias associated with assigning patients to treatments. These two forms of
bias are different and can exist together or separately. The term “mask” is
preferred by some instead of “blind” because of negative connotations associated
with the term blind and because in some trials blindness is an endpoint.
3.
Double Blind (Masked) Study - neither the patient nor the person(s) responsible
for assessing the benefits/risks of treatment are aware of the random
assignment.
4.
Single Blind (Masked) Study - the patient is not aware of the random treatment
assignment but the physician/investigator is (this could be reversed, but this is
more typical). This design can be useful in trials where the major response
variable is based on the patient's self-evaluation, e.g., pain relief.
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5.
Non-blinded (Non-masked) Study - both the patient and the person(s)
responsible for assessing the benefits/risks of treatment are aware of the random
assignment. This is also referred to as an open study or an “open label” study.
6.
Triple-Blind Study - this term is sometimes used to refer to double-blind studies in
which the persons responsible for monitoring the trial for treatment effects are
also blinded to treatment. This is usually accomplished by presenting coded data
to monitoring groups (e.g., A and B) in summary interim analyses.
Nature of Treatment Blinding
Examples of Sources of Bias
Non-blind
Single
Blind
Double
Blind
Concomitant Therapy
Chosen by patient
X
Chosen by evaluator
X
X
Treatment Modification
Chosen by patient
X
Chosen by evaluator
X
X
Treatment evaluation (This should be considered regardless of
the nature of treatment blinding)
X denotes that the design eliminates/reduces the potential bias.
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In a review of 81 clinical trials in 5 major medical journals published in the 1980's,
Neaton, Guallar and Wentworth found the following:
-
46% of trials reported were double-blind
-
2% were single-blind
-
38% were non-blind
In 11 studies the nature of the blinding could not be ascertained. In the trial report, it is
important to state who was blinded and how in addition to using terms like “single blind”.
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Examples of Use of Blinding (Masking) in Clinical Trials
Non-blind Trials
1.
MRFIT - assessment of endpoints (cause of death, non-fatal MI) was made
without knowledge of treatment assignment; the number of persons at the
Coordinating Center unblinded to endpoint data was kept to a minimum; interim
results were monitored by a group of scientists not directly involved in the study.
2.
Streptomycin trial of tuberculosis - chest x-rays evaluated by two independent
observers blinded to patient's treatment.
Single Blind Trials
1.
Urokinase Pulmonary Embolism Trial (UPET) - patient was blinded; endpoints
which related to clot burden (review of angiograms and lung scans) made without
knowledge of treatment. Trial actually could be considered "modified" double
blind design as an attempt was made to have someone who did not administer
treatment assess clinical signs, symptoms and complications.
2.
Diabetic Retinopathy Study - patients asked not to inform treatment evaluator
which eye had been treated.
3.
CPCRA trial on acupuncture for the relief of pain due to peripheral neuropathy.
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Double-blind trials
The Aspirin Myocardial Infarction Study (AMIS) is an example of a double-blind trial. In
order to carry out some trials as double-blind, multiple placebos may have to be used if
medications cannot be packaged to look alike, e.g., TOMHS employed a "doubledummy".
In the CPCRA TOXO and NuCOMBO studies a modified double-blind design was used.
For example, in the TOXO study patients were randomly assigned to one of 4 groups:
1) clindamycin; 2) placebo for clindamycin; 3) pyrimethamine; or 4) placebo for
pyrimethamine. Patients and clincians knew whether they were in the clindamycin arm
(active clindamycin or placebo for clindamycin) or the pyrimethamine arm, but did not
know whether they were taking active drug or placebo.
Triple-blind trials
In a few studies monitoring groups were also blinded to treatment results; i.e., in data
reports treatments were coded. There is disagreement among investigators on whether
treatments should be coded in interim analyses reviewed by external monitoring groups.
Coding the data helps protect the confidentiality of the data if the report is obtained by
an unauthorized person. It also may reduce bias by members of the monitoring group
in reaching a decision to terminate a study. In practice, however, it is frequently obvious
what the treatments are so the issue of bias is not relevant. Another point of view is that
since monitoring groups are charged with ensuring patient safety, they should review
"uncoded" data to maximize the information they have about the effects (untoward and
beneficial) of treatments under investigation.
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Notes:
1.
Pocock identifies 4 aspects of a trial to consider when trying to determine
whether blinding is feasible:
a)
ethics - does the blinding result in undue harm or risk to the patient?
b)
practicality - for the planned treatments is it feasible to blind them? For
example, treatment blinding is not possible in comparisons of medical vs
surgical interventions, lifestyle interventions, or if the treatments under study
have a distinctly different appearance, or if they are given by different routes
of administration.
c)
avoidance of bias - how much bias do we expect without blinding?
d)
compromise - can the bias be eliminated in an unblind study with blinded
endpoint determination?
2.
As much blinding as feasible should be used so long as study question is not
altered or jeopardized.
3.
Even though it may not be possible to blind the treatment from the therapist who
is administering the treatment to the patients, it may be possible to evaluate the
efficacy/safety of the treatments under blind conditions. For example, in the
MRFIT cause of death was determined by a Mortality Review Committee
composed of clinicians who were not participating in the trial as investigator. This
committee coded cause of death blinded to the treatment group (SI or UC).
Similarly, electrocardiograms were coded by technicians and cardiologists
masked to the treatment assignment.
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4.
In non-blind studies staff at the Coordinating or Statistical Center handling
endpoint forms should be blinded to treatment where possible. The number
persons at the Coordinating Center aware of accruing endpoint results should
also be kept to a minimum.
5.
The accruing results of a clinical trial should be kept blind to patients and
therapists. The decisions concerning the safety/efficacy of treatments and
possible early termination of a trial should be made by an external review
committee who are not involved in the care of any of the study patients. If a
physician during the course of a trial thought one therapy was superior, his
ethical participation could not be maintained, even though the data were
inconclusive.
6.
Double blind studies may be more difficult to conduct if the aim of the treatment is
to regulate a risk factor for a disease and the endpoint of the study is the disease,
not the degree of regulation, e.g., comparison of blood pressure lowering drugs
for their ability to reduce cardiovascular complications. Knowledge of the blood
pressure and or side/effects of therapy may break the blind.
Considerations in the implementation of double blind designs
1.
Preparation and Packaging of Medication
-
medications must look smell, and taste alike. Frequently, the only way this
can be accomplished is by encapsulating the study medications in opaque
capsules.
-
cannot label one drug A and the other drug B; each of the study
medications must be bottled and labeled in exactly the same way. Minor
variations in the way bottles of medication are capped, sealed or labeled
may break the blind.
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-
the usual procedure is to randomly allocate each patient to a bottle number;
ideally these bottle numbers are unique. In very large trials this may be
logistically difficult, i.e., Coronary Drug Project which involved over 8,000
patients used a 2 digit bottle number. The same bottle number was used
for more than one patient at each clinic.
-
quality control procedures have to be established to assure each
bottle/blister pack contains what you think it does.
-
the randomization schedule corresponding to the coded medications should
be kept in a confidential place.
2.
Breaking the Blind in the Event of an Emergency
-
a procedure needs to be established so that the blind can be broken for a
patient with a medical emergency.
-
care should be taken so that the blind is only broken for the concerned
patient and not several patients or all patients in the study.
-
the conditions for which the blind is broken should be agreed upon and
written down before the start of the trial.
-
when the blind is broken, senior study investigators should be informed.
-
at the end of the study all patients should be informed of their treatment.
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3.
Maintenance of the Double-Blind
-
certain laboratory measurements may reveal to the therapist which
treatment the patient is receiving; such measurements should only be seen
by the coordinating center and external monitoring committee. A procedure
may have to be established to alert the therapist if such measurements
affect the safety of the patient. For example, alert levels for serum
potassium values were defined in a trial of supplemental potassium on
blood pressure. Actual values were not provided to the investigators, only
whether the levels were elevated or not. A similar procedure was used in
the Prostate Cancer Prevention Trial with prostate-specific antigen (PSA)
levels. Results were categorized as "elevated" or "not elevated" (see Cont
Clin Trials 1995;16:150-163).
-
if dosage adjustments are permitted, care may have to be taken that the
persons performing the measurements on which the dosage adjustment is
made are not aware of the patient's current dose level or that a change was
recently made.
4.
Evaluation of Maintenance of Double-Blind
-
periodic reports on the use of concomitant medications or alternative
treatments should be produced.
-
chemical tests to detect the drugs (if possible) should be considered.
-
after the study is complete some investigators think it is a good idea to ask
patients and therapists what they think the treatment was for each patient.
Examples: Coronary Primary Prevention Trial (CPPT); Lipid Research Clinics
Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I.
Reduction in Incidence of Coronary Heart Disease. JAMA 251: 351-364, 1984.
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In this trial patients were prescribed either cholestyramine or placebo, 6 packets of
medication per day. The authors reported that over the 7-8 year study no cases of
medical emergency requiring unblinding of patient or investigator occurred. At the end
of the study a survey was conducted of patients and staff to determine if they could
correctly guess their treatment assignment. The results are below:
Percent assignment correctly guessed
Cholestyramine
Placebo
Patients
56.0
54.6
Staff
55.2
52.9
Fergusson et al (BMJ January 2004) found in a review of 191 trials that only 7-8%
provided evidence of the success of blinding.
Sackett (Int J Epid 2007) argues that end of trial tests for blinding cannot be done with
validity because you cannot distinguish blindness from hunches by the investigators
(e.g., they know at that point who did well on the treatment and who did not).
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