Drug placebo

When you control for differences in side effects, drug-placebo differences in improvement are not statistically significant. 

Another trick was to publish only some of the data from a clinical trial, a manoeuvre that researchers call cherry-picking the data. Some clinical trials are conducted in more than one location. These are called multi-centre studies. Multi-centre studies make it easier to find sufficient patients to conduct the trial. They also make it easier to cherry-pick the data. For example, one multi-centre study of Prozac was presented to the FDA as showing a drug-placebo difference of three points on the Hamilton scale. When data from this clinical trial was published, the difference was reported as 15 points - a five-times increase in effectiveness. How was this magical augmentation of the benefits of Prozac accomplished The full study was conducted on 245 patients. The published paper reported data from only 27 of these patients. In the published version, the data from the bulk of the patients were left out, making the drug seem much more effective than it really was. 

This is the basic problem with any attempt to evaluate the overall effectiveness of placebos, as Beecher and the Danish researchers had tried to do. There is not just one placebo effect. Instead, the placebo effect depends on a host of factors. It depends, for example, on the condition being treated, the way in which the placebo is administered, the colour of the placebo, its price, whether it has a recognized brand name and the dose that is prescribed. Studies of the placebo effect reveal that, all else being equal, taking placebo pills four times per day is more effective than taking them only twice a day brand-name placebos are more effective than placebos presented as generic drugs placebo injections are more effective than placebo pills and more expensive placebos are better than cheaper ones.16... 

The protocol should specify what should be recorded directly into the CRF and what will also be recorded in the medical records. The CRF will contain all the pertinent data associated specifically with the clinical trial but some will be repeated in the medical records, for example, the protocol identification number, date of consent, date of commencement of the study, key baseline medical findings, visit dates, start and finish dates of the study drug/placebo or treatment, concurrent medication, adverse events and key efficacy and any unscheduled or scheduled actions or interventions (such as escape medication). Additional information obtained from biopsy reports, radiographs and similar documents will provide confirmation that the data in the CRF are recorded correctly. Monitors, QA auditors and inspectors need to see all the medical records available to the investigator. It is not appropriate to create copies of data from CRFs or checklists derived from medical records and claim that these are source documents. 

While the issue of the ethical conduct of clinical trials in pediatric psychopharmacology is addressed comprehensively elsewhere in this book, it is important to present an FDA perspective on this important matter. It is also important to have the issue of ethics discussed in the context of the scientific needs for trials presented to the FDA in support of new drug applications. These trials must be adequate and well-controlled (U.S. Department of Health and Human Services, 2001). What this requirement essentially means is that, in order to support an efficacy claim, the trials must be interpretable and must be able to document efficacy. For treatments that are intended to improve symptoms, as is almost always the case for psychotropic drugs, placebo-controlled trials are the usual standard. This is especially true when there is a substantial failure rate in placebo-controlled trials for the drugs known to work in a particular therapeutic area, as again is the case for most psychotropic drugs. Where that is true,... 

Invitation of investigators who have previously demonstrated drug placebo differences in other trials... 

Avoidance of active concomitant medication is the next important requirement. Such medication constitutes a major artifact because it can markedly weaken the drug—placebo difference. Thus, compared treatments may appear equally efficacious due to the concomitant medication and not any inherent efficacy of the experimental agent. Some studies have used multiple agents, in different doses, with some known to be specifically effective for the disorder under investigation. For example, in some studies, comparing carbamazepine or valproate with placebo or lithium, patients have also received adjunctive antipsychotics, making firm conclusions difficult (see the section Alternative Treatment Strategies in Chapter 10). 

Equally critical to a properly designed study is sample adequacy (i.e., size and appropriateness). It is hard to make definitive conclusions with very small sample sizes (e.g., five per group) because variation is too great. The minimal sample size needed to make inferences also depends on how large the experimental drug-placebo effect size is (i.e., the larger the effect size, the smaller the sample needed). 

The effect size of a continuous variable is frequently expressed as the difference between the mean of the experimental minus the mean of the control group divided by the pooled standard deviation. For example, in Chapter 5, data from the National Institute of Mental Health collaborative study demonstrated that antipsychotic-treated patients averaged a 4.2-point increase on a 6-point improvement scale, whereas the placebo patients averaged only a 2.2-point increase (i.e., an average difference of 2 points). The standard deviation of these data was approximately 1.7, so in effect size units, the improvement was approximately 1.2 (i.e., 2.0 1.7) SD units. For discontinuous data, the effect size for a drug-placebo comparison is usually expressed as the difference between the percent improvement with the experimental drug and the percent improvement with placebo. 

The authors have encountered some patients refractory to all other therapies who had a dramatic, full, rapid, and sustained response to methylphenidate. One study found methylphenidate effective in treating mildly depressed outpatients, particularly those who drank three or more cups of coffee a day ( 191). A replication study did not find a drug-placebo difference on the physician s ratings, but did demonstrate one for the patients subjective assessment of improvement ( 192). Another blind study of methylphenidate found improvement in an outpatient group (193). Finally, two of three trials of methylphenidate in apathetic, senile geriatric patients showed that this drug produced more improvement than placebo (194). To date, no evidence indicates that it is beneficial in cases of moderate-to-severe depression. 

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