Informing participants of allocation to placebo at trial closure: postal survey
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7376.1329 (Published 07 December 2002) Cite this as: BMJ 2002;325:1329All rapid responses
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Dear editor
The paper by di Blasi, Kaptchuk and colleagues [1] deserves more
attention than it seems to have received so far. That 55% of researchers
never informed trial participants of their allocation to treatment or
placebo, or only told them if asked, and that 40% of these had never even
considered the possibility of informing them, tells us all about why
recruitment to large scale long term randomised trials is increasingly
difficult.
For human research studies it should be obvious that designers should
at each step imagine themselves in the shoes of intended participants.
This simple principle is, in my experience, rarely applied seriously. I
undertook several pilot trials for the Medical Research Council in my
practice population between 1974 and 1998. They all entailed substantial
inconvenience, discomfort, and occasionally sustained privation for
participants, though response rates were mostly over 90% and never fell
below 85%.[2] In the most challenging of these, middle-aged men were
asked first to accept screening to identify those in the top quintile of
coronary risk, then to be randomised either to low dose warfarin or
placebo in a double-blind trial, sustained in our case for 12 years.[3]
Throughout this time they had to endure venepunctures at least once every
three months, and all the worries associated with knowledge that they were
at high risk from coronary disease, with unknown benefits or risks from
experimental treatment, meanwhile from time to time seeing their friends
drop from their perches. Assuming that all researchers would gladly
subject themselves to such trials for the sake of new knowledge, would
they not expect trial organisers to appreciate their interest in exactly
what role they personally had played in this collective endeavour? Would
they accept that any researcher has the right to use their bodies but
ignore their minds? Do they even understand that research participants
have minds, just as inquisitive and sensitive as their own? If they don’t
(as in 40% of them seems the case) should they be allowed to engage in
human research?
We organised annual meetings to give participants feedback on
progress, and a final meeting to explain the results, and I’m glad to say
that MRC central staff took a lot of trouble to support these meetings.
I’m not so sure that as much happened in the rest of the MRC’s General
Practice Research Framework (GPRF), but perhaps it did. However, when I
suggested that soon after the trial results the MRC should organise a
conference of participants for them to tell us what they and their
families thought about the design and conduct of this trial, and what
lessons their experience might have for future trials, I met blank
incomprehension. Eventually it was agreed there should be a follow-up
questionnaire, to get some systematic feedback from participants. Though
such a questionnaire was designed, it was never used. The GPRF now
includes over 11% of the UK population and over 8% of all practices, but I
doubt if they were consulted about this decision, and ethical committees
were probably too busy setting limits to research, to notice this urgent
need for research to extend its scope.
Fortunately we no longer need to wait for the very intelligent but
often remote people who design and run trials to appreciate the
intelligence of their human subjects. Conducting human trials on
veterinary principles is already visibly self-limiting, and recruitment is
becoming more difficult. Unless trialists want to do all studies on
themselves, or on the limited numbers trapped in hospital beds, they will
have to start all over again where they should have begun in the first
place, treating trial participants as the intelligent and self-sacrificing
colleagues they actually are.
Yours sincerely
References
[1]di Blasi Z, Kaptchuk TJ, Weinman J, Kleijnen J. Informing participants
of allocation to placebo at trial closure: postal survey. BMJ
2002;325:1329-31.
[2]Hart JT, Smith GD. Response rates in south Wales 1950-1996: changing
requirements for mass participation in human research. In, Chalmers I,
Maynard A (eds), Non Random Reflections on Health Services Research: on
the 25th Anniversary of Archie Cochrane’s Effectiveness & Efficiency.
London: BMJ Publishing Group, 1997, pp.31-57.
[3]Meade T & the Medical Research Council's General Practice Research
Framework. Thrombosis Prevention Trial: randomised trial of low-intensity
oral anticoagulation with warfarin and low-dose aspirin in the primary
prevention of ischaemic heart disease in men at increased risk. Lancet
1998;351:233-41.
Competing interests:
None declared
Competing interests: No competing interests
Editor-Di Blasi et al. emphasize the need for “sensitive ways to
communicate treatment information to trial participants,” in the
conclusion of their paper showing that only 45% of 107 clinical trial
investigators who completed a postal survey reported that they had
informed either all or most participants of their treatment allocations.1
One approach to the need for sensitivity in communicating treatment
information to clinical trial participants would be to include a question
in the informed consent asking whether the participant wants to be
informed of the treatment allocation. At the time of completing
participation in the study, those participants who answered “yes” could be
given the treatment information unless specifically declining it, and
those who answered “no” could be given the treatment information only when
specifically requesting it. This approach would help to ensure access to
treatment information without imposing the information on patients who do
not want to know.
1. Di Blasi Z, Kaptchuk TJ, Weinman J, Kleijnen J. Informing
participants of allocation to placebo at trial closure: postal survey. BMJ
2002; 325:1-4.
The views expressed above are those of the authors and do not
represent an official position of the United States Food and Drug
Administration.
Competing interests:
None declared
Competing interests: No competing interests
If a patient reaches out for a pill or potion in hopes that it will
do this or that, then some benefit may result even if the capsule contains
no medicine whatsoever. If the patient knows that the capsule or compound
is not an active compound, then perhaps the empty capsule will exert no
effect as a true placebo should.
From a recent abstract published in FASEB J. 2002;16 1869-1873:
"Behavioral conditioning of immunosuppression is possible in humans.
Behavioral conditioned immunosuppression has been described in rodents as
the most impressive demonstration of brain-to-immune system interaction.
To analyze whether behavioral conditioned immunosuppression is possible in
humans, healthy subjects in this double-blind, placebo-controlled study
were conditioned in four sessions over 3 consecutive days, receiving the
immunosuppressive drug cyclosporin A as an unconditioned stimulus paired
with a distinctively flavored drink (conditioned stimulus) each 12 h. In
the next week, re-exposure to the conditioned stimulus (drink), but now
paired with placebo capsules, induced a suppression of immune functions as
analyzed by the IL-2 and IFN- mRNA expression, intracellular production,
and in vitro release of IL-2 and IFN-, as well as lymphocyte
proliferation. This clearly demonstrated that immunosuppression can be
behaviorally conditioned in humans."
Like early Pavlovian experiments, we humans are subject to our own
habitually conditioned responses, which with repetition clearly touch the
inner responses of the cell.
It is no wonder that a 5-30% positive "hoped-for" effects result after
subjects take a placebo di-calcium phosphate capsule as opposed to the
active ingredient. Until a means is devised to eliminate the aspect of
hope from taking medication, a pure placebo cannot be applied. On the
other hand, if more hope could be generated within the scope of active
medical compounds prior to dose, the optimal potency of the medication of
choice may be remarkably effect-enhanced.
Bill Misner Ph.D. C.S.M.T.
Competing interests:
None declared
Competing interests: No competing interests
Recruiters are often left ignorant also
I have recruited many patients into randomised clinical trials
organised by drug companies but have never informed patients of which drug
they were given.
Why?
Because I have never been informed by the clinical trial organisers!
Consequently, I increasingly feel reluctant to participate in trials
because I know I will not be informed of the patients' allocations and
therefore will have to guess what is the appropriate treatment to use
after trial completion. It is not just keeping patients in the dark that
reduces the chances of future participants being recruited...
Competing interests:
I have partcipated in drug company randomised trials in the past
Competing interests: No competing interests