Placebo-controlled study
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Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate
The purpose of the placebo group is to account for the
Patients frequently show improvement even when given a sham or "fake" treatment. Such intentionally inert
Therefore, the use of placebos is a standard
This close association of placebo effects with RCTs has a profound impact on how placebo effects are understood and valued in the scientific community.[4]
Methodology
Blinding
Blinding is the withholding of information from participants which may influence them in some way until after the experiment is complete. Good blinding may reduce or eliminate experimental
During the course of an experiment, a participant becomes
Natural history groups
The practice of using an additional
- The Active drug group (A): who receive the active test drug.
- The Placebo drug group (P): who receive a placebo drug that simulates the active drug.
- The Natural history group (NH): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its natural course).
The outcomes within each group are observed, and compared with each other, allowing us to measure:
- The efficacy of the active drug's treatment: the difference between A and NH (i.e., A-NH).
- The efficacy of the active drug's active ingredient: the difference between A and P (i.e., A-P).
- The magnitude of the placebo response: the difference between P and NH (i.e., P-NH).
It is a matter of interpretation whether the value of P-NH indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". The results of these comparisons then determine whether or not a particular drug is considered efficacious.
Natural-History groups yield useful information when separate groups of subjects are used in a parallel or longitudinal study design. In
Indexing
In certain clinical trials of particular drugs, it may happen that the level of the "placebo responses" manifested by the trial's subjects are either considerably higher or lower (in relation to the "active" drug's effects) than one would expect from other trials of similar drugs. In these cases, with all other things being equal, it is reasonable to conclude that:
- the degree to which there is a considerably higher level of "placebo response" than one would expect is an index of the degree to which the drug's active ingredient is not efficacious.
- the degree to which there is a considerably lower level of "placebo response" than one would expect is an index of the degree to which, in some particular way, the placebo is not simulating the active drug in an appropriate way.
However, in particular cases such as the use of Cimetidine to treat ulcers, a significant level of placebo response can also prove to be an index of how much the treatment has been directed at a wrong target.
Implementation issues
Adherence
The Coronary Drug Project[7] was intended to study the safety and effectiveness of drugs for long-term treatment of coronary heart disease in men. Those in the placebo group who adhered to the placebo treatment (took the placebo regularly as instructed) showed nearly half the mortality rate as those who were not adherent. A similar study of women similarly found survival was nearly 2.5 times greater for those who adhered to their placebo.[8] This apparent placebo effect may have occurred because:
- Adhering to the protocol had a psychological effect, i.e. genuine placebo effect.
- People who were already healthier were more able or more inclined to follow the protocol.
- Compliant people were more diligent and health-conscious in all aspects of their lives.
Unblinding
In some cases, a study participant may deduce or otherwise obtain information that has been blinded to them. For example, a patient taking a psychoactive drug may recognize that they are taking a drug. When this occurs, it is called
An active placebo was used in the
History
James Lind and scurvy
He noted that the pair who had been given the oranges and lemons were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick.[10]
Animal magnetism
In 1784, the French Royal Commission investigated the existence of animal magnetism, comparing the effects of allegedly "magnetized" water with that of plain water.[11][12][13] It did not examine the practices of Franz Mesmer, but examined the significantly different practices of his associate Charles d'Eslon (1739–1786).[citation needed]
Perkins tractors
In 1799,
Flint and placebo active treatment comparison
In 1863 Austin Flint (1812–1886) conducted the first-ever trial that directly compared the efficacy of a dummy simulator with that of an active treatment; although Flint's examination did not compare the two against each other in the same trial. Even so, this was a significant departure from the (then) customary practice of contrasting the consequences of an active treatment with what Flint described as "the natural history of [an untreated] disease".[17]: 18
Flint's paper is the first time that he terms "placebo" or "placeboic remedy" were used to refer to a dummy simulator in a clinical trial.
... to secure the moral effect of a remedy given specially for the disease, the patients were placed on the use of a placebo which consisted, in nearly all of the cases, of the tincture of quassia, very largely diluted. This was given regularly, and became well known in my wards as the placeboic remedy for rheumatism.
Flint
Jellinek and headache remedy ingredients
Jellinek in 1946[18] was asked to test whether or not the headache drug's overall efficacy would be reduced if certain ingredients were removed. In post-World War II 1946, pharmaceutical chemicals were restricted, and one U.S. headache remedy manufacturer sold a drug composed of three ingredients: a, b, and c, and chemical b was in particular short supply.[citation needed]
Jellinek set up a complex trial involving 199 subjects, all of whom had "frequent headaches". The subjects were randomly divided into four test groups. He prepared four test drugs, involving various permutations of the three drug constituents, with a placebo as a scientific control. The structure of this trial is significant because, in those days, the only time placebos were ever used "was to express the efficacy or non-efficacy of a drug in terms of "how much better" the drug was than the "placebo".[18]: 88 (Note that the trial conducted by Austin Flint is an example of such a drug efficacy vs. placebo efficacy trial.) The four test drugs were identical in shape, size, colour and taste:[citation needed]
- Drug A: contained a, b, and c.
- Drug B: contained a and c.
- Drug C: contained a and b.
- Drug D: a 'simulator', contained "ordinary lactate".
Each time a subject had a headache, they took their group's designated test drug, and recorded whether their headache had been relieved (or not). Although "some subjects had only three headaches in the course of a two-week period while others had up to ten attacks in the same period", the data showed a "great consistency" across all subjects[18]: 88 Every two weeks the groups' drugs were changed; so that by the end of eight weeks, all groups had tested all the drugs. The stipulated drug (i.e., A, B, C, or D) was taken as often as necessary over each two-week period, and the two-week sequences for each of the four groups were:
- A, B, C, D
- B, A, D, C
- C, D, A, B
- D, C, B, A.
Over the entire population of 199 subjects, there were 120 "subjects reacting to placebo" and 79 "subjects not reacting to placebo".[18]: 89
On initial analysis, there was no difference between the self-reported "success rates" of Drugs A, B, and C (84%, 80%, and 80% respectively) (the "success rate" of the simulating placebo Drug D was 52%); and, from this, it appeared that ingredient b was completely unnecessary.
However, further analysis on the trial demonstrated that ingredient b made a significant contribution to the remedy's efficacy. Examining his data, Jellinek discovered that there was a very significant difference in responses between the 120 placebo-responders and the 79 non-responders. The 79 non-responders' reports showed that if they were considered as an entirely separate group, there was a significant difference the "success rates" of Drugs A, B, and C: viz., 88%, 67%, and 77%, respectively. And because this significant difference in relief from the test drugs could only be attributed to the presence or absence of ingredient b, he concluded that ingredient b was essential.
Two conclusions came from this trial:
- Jellinek,psychogenic origins of the condition in question.[19]: 777
- It indicated that, whilst any given placebo was inert, a responder to that particular placebo may be responding for a wide number of reasons unconnected with the drug's active ingredients; and, from this, it could be important to pre-screen potential test populations, and treat those manifesting a placebo-response as a special group, or remove them altogether from the test population!
MRC and randomized trials
It used to be thought
- those "treated by bed-rest", and
- those "[treated] by bed-rest alone" (the control group).
What made this trial novel was that the subjects were randomly allocated to their test groups. The up-to-that-time practice was to allocate subjects alternately to each group, based on the order in which they presented for treatment. This practice could be biased, because those admitting each patient knew to which group that patient would be allocated (and so the decision to admit or not admit a specific patient might be influenced by the experimenter's knowledge of the nature of their illness, and their knowledge of the group to which they would occupy).
Recently, an earlier MRC trial on the antibiotic patulin on the course of common colds[22] has been suggested to have been the first randomized trial.[23] Another early and until recently overlooked randomized trial was published on strophanthin in a local Finnish journal in 1946.[24]
Declaration of Helsinki
From the time of the Hippocratic Oath questions of the ethics of medical practice have been widely discussed, and codes of practice have been gradually developed as a response to advances in scientific medicine. The Nuremberg Code, which was issued in August 1947, as a consequence of the so-called Doctors' Trial which examined the human experimentation conducted by Nazi doctors during World War II, offers ten principles for legitimate medical research, including informed consent, absence of coercion, and beneficence towards experiment participants.
In 1964, the World Medical Association issued the Declaration of Helsinki,[25] which specifically limited its directives to health research by physicians, and emphasized a number of additional conditions in circumstances where "medical research is combined with medical care". The significant difference between the 1947 Nuremberg Code and the 1964 Declaration of Helsinki is that the first was a set of principles that was suggested to the medical profession by the "Doctors' Trial" judges, whilst the second was imposed by the medical profession upon itself. Paragraph 29 of the Declaration makes specific mention of placebos:
29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.
In 2002, World Medical Association issued the following elaborative announcement:
Note of clarification on paragraph 29 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:
- — Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
- — Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.
In addition to the requirement for informed consent from all drug-trial participants, it is also standard practice to inform all test subjects that they may receive the drug being tested or that they may receive the placebo.
Non-drug treatments
"Talking therapies" (such as
See also
- Academic clinical trials
- Bioethics
- Blinded experiment
- Clinical data acquisition
- Clinical trial management
- Confounding factor
- Experimental design
- Medical ethics
- Philosophy of medicine
- Placebo
- Randomized controlled trial
- Royal Commission on Animal Magnetism
- Scientific control
- Scientific method
References
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- ^ Reilly, David (2002). "Creative consulting: what modifies a healing response". Student BMJ. 10: 1–44. p.28
- ^ Wang T, Malone J, Fu H, Heilmann C, Qu Y, Huster WJ. Crossover design and its application in late-phase diabetes studies. J Diabetes. 2016 Sep;8(5):610-8. PubMed ID: 27100270
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- ^ Haygarth, J. (1801). Of the Imagination, as a Cause and as a Cure of Disorders of the Body; Exemplified by Fictitious Tractors, and Epidemical Convulsions (New Edition, with Additional Remarks) (PDF). Bath: Crutwell. Archived from the original (PDF) on 2008-05-16. Retrieved 2009-01-09.
- ^ a b c d Flint, A., "A Contribution Toward the Natural History of Articular Rheumatism, Consisting of a Report of Thirteen Cases Treated Solely with Palliative Measures", American Journal of the Medical Sciences, Vol.46, (July 1863), pp.17–36. [1] Archived 2009-03-01 at the Wayback Machine
- ^ a b c d e Jellinek, E. M. JSTORE "Clinical Tests on Comparative Effectiveness of Analgesic Drugs", Biometrics Bulletin, Vol.2, No.5, (October 1946), pp.87–91.
- PMID 13158365.
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- ^ Hemminki E (2005). "Commentary on an early placebo controlled trial in Finland". The James Lind Library. Archived from the original on 2008-08-28.
- ^ https://web.archive.org/web/20090220183350/http://www.wma.net/e/policy/b3.htm
- )
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External links
- James Lind Library A source of historical texts on fair tests of treatments in health care.