Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Placebo may be a medicine
- Bill D. Misner (7 December 2002)
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Informing Paticipants of Treatment Allocation in Clinical Trials
- Bruce V. Stadel, MD, MPH, Eric Colman, MD (18 December 2002)
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Informing participants about their trial status
- Julian T Hart (24 December 2002)
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Recruiters are often left ignorant also
- Tim M Reynolds (30 December 2002)
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Bill D. Misner, Director R & D E-CAPS Inc. 99205/99009/59937
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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 |
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Bruce V. Stadel, MD, MPH, Medical Officer Food & Drug Administration, 5600 Fishers Lane, Rockville, Maryland, 20857, USA, Eric Colman, MD
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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 |
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Julian T Hart, retired general practitioner Gelli Deg, Penmaen SA3 2HH
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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 |
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Tim M Reynolds, Professor of ChemicalPathology Queen's Hospital, Burton-on-Trent, DE13 0RB
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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 |
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