Placebo procedural-related

Intrinsic Accuracy. Intrinsic accuracy indicates the bias caused by sample matrix and sample preparation. In this approach, a stock solution is prepared by using known quantities of related substance and drug substance. The stock solution is further diluted to obtained solutions of lower concentrations. These solutions are used to generate linearity results. In addition, these linearity solutions of different concentrations are spiked into placebo. The spiked solutions are prepared according to the procedure for sample analysis. The resulting solutions, prepared from the spiked solution, are then analyzed. If the same stock solution is used for both linearity and accuracy and all of these solutions are analyzed on the same HPLC run, the response of linearity (without spike into matrix) and accuracy (with spike into matrix) can be compared directly. Any differences in response indicate the bias caused by matrix interference or sample preparation. To determine the intrinsic accuracy at each concentration level, one can compare the peak area of accuracy (with matrix) with that of linearity (without matrix) at the same concentration (Figure 3.11). This is the simplest approach, and one would expect close to 100% accuracy at all concentration levels. 

Design Qualification (DQ) is the first validation element of a new facility system or equipment, where adherence to the user s specifications and to GMP rules is demonstrated. Installation Qualification (IQ) follows with the verification of adequacy of the area, installation of equipment pipelines, utilities, instrumentation, and conformity of the material used to the project specifications. At the Operational Qualification (OQ) phase, carried out after installation of all equipment, it is verified whether the system, when in operation, complies with the acceptance criteria defined in the validation plan. Once the OQ phase is successfully finalized it is possible to proceed with the calibration procedures, operation and cleaning, operator training, and preventive maintenance program. After IQ and OQ are concluded, it is time for the Performance Qualification (PQ), with the aim of verifying that what was designed, built, and operated results in a product that meets the expected specifications. Production and QC personnel are specially trained for these assessments. The tests can be done with the product of interest or a placebo, and are related to all operations, from raw material reception to product release (EC, 2001). 

Specificity relates to the ability of a method to measure only what it is intended to be measured with a requisite level of accuracy and precision, although the sample may contain other related compounds. The most commonly cited specificity evaluation procedure is the analysis of a placebo, wherein the sample matrix without the analyte is analyzed and the resulting system response is examined for the presence of responses, which interfere or overlap with that of the analyte of interest. Other procedures for specificity include 1) Peak reanalysis, wherein the peak of interest is collected and reanalyzed by different chromatographic conditions or with methods that are sensitive... 

In a report of two five-year periods in a single centre in France, the incidence of adverse events in 1015 healthy volunteers was 13-7% in subjects receiving active drug and 7-9% in those receiving placebo. Headache, diarrhoea and dyspepsia occurred in more than ten per thousand. Three percent of adverse events were rated severe but there were no deaths or life-threatening events. Some events such as vasovagal attacks were related to procedures rather than treatment. 

A superficially related clinical procedure for control of chronic pain is electrical transcutaneous or spinal cord nerve stimulation. A doubleblind placebo-controlled study indicated that such analgesia is not naloxone-reversible. The neurophysiological mechanisms mediating stress-induced autoanalgesia are complex and depend subtly on the parameters of the applied stress. Electrical stress-induced analgesia in animals apparently involves both opioid and non-opioid substrates. 

Placebo-controlled trial A randomised, placebo-controlled trial (N = 67) of preoperative somatostatin administration for the prevention of postoperative complications following the Whipple procedure found no evidence of improved efficacy with preoperative administration [70 ]. Three patients experienced mild side effects (nausea and vomiting) that may have been related to somatostatin treatment. The effects of the operation made it difficult to identify and properly assess side effects of somatostatin administration. 

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