three ingredients: a, b, and c, and chemical b was in particular short supply. 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".: 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: 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: 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".: 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,: 90 having identified 120 "placebo reactors", went on to suppose that all of them may have had either "psychological headaches" (with or without attendant "hypochondriasis") or "true physiological headaches accessible to suggestion". thus, according to this view, the degree to which a "placebo response" is present tends to be an index of the psychogenic origins of the condition in question.: 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 that the first-ever randomized clinical trial was the trial conducted by the medical research council (mrc) in 1948 into the efficacy of streptomycin in the treatment of pulmonary tuberculosis. in this trial, there were two test groups: those "treated by streptomycin and bed-rest", and those " 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 has been suggested to have been the first randomized trial. another early and until recently overlooked randomized trial was published on strophanthin in a local finnish journal in 1946. 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, 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 helsinkithe 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 hypnotherapy, psychotherapy, counseling, and non-drug psychiatry) are now required to have scientific validation by clinical trial. however, there is controversy over what might or might not be an appropriate placebo for such therapeutic treatments. furthermore, there are methodological challenges such as blinding the person providing the psychological non-drug intervention. in 2005, the journal of clinical psychology, devoted an issue to the issue of "the placebo concept in psychotherapy" that contained a range of contributions to this question. as the abstract of one paper noted: "unlike within the domain of medicine, in which the logic of placebos is relatively straightforward, the concept of placebo as applied to psychotherapy is fraught with both conceptual and practical problems."