Clinical trials documentation labelling

The author of the FDA memo revealing the decision to hide the existence of the clinical trials that had failed to find a difference between drug and placebo was Dr Paul Leber, Director of the FDA Division of Neuropharmacological Drug Products. Here is what he wrote about the labelling of Cipramil, which is referred to by its generic name, citalopram, in the document ... 

The basic structure of the ICH GMP guideline for API production is shown in Table 15. It consists of 19 chapters, which cover the requirements for quahty management, personnel, premises, equipment, documentation, materials, production and process controls, packaging and labeling, storage and distribution, laboratory controls, validation, change control, complaints, recalls, contract services, cooperators, APIs manufactured by cell culture/fermentation, and APIs used in clinical trials [52]. 

Premature ventricular contractions (PVCs) are commonly recorded in patients convalescing from myocardial infarction. Since such arrhythmias have been associated with an increased risk of sudden cardiac death, it had been the empiric practice of many physicians to treat PVCs, even if asymp-tomatic, in such patients. In CAST (Cardiac Arrhythmia Suppression Trial [CAST], Echt et al, 1991), an attempt was made to document the efficacy of such therapy in a controlled clinical trial. The effects of several antiarrhythmic drugs on arrhythmia frequency were first evaluated in an open-label fashion. Then, patients in whom antiarrhythmic therapy suppressed PVCs were randomly assigned, in a double-blind fashion, to continue that therapy or its corresponding placebo. 

Phase III Clinical Trials Consist of controlled and uncontrolled trials that are performed after preliminary evidence of effectiveness of a drug has been established. They are conducted to document the safety and efficacy of the drug, as well as to determine adequate directions (labeling) for use by the physician. A specific patient population needs to be clearly identified from the results of these studies. Trials during Phase III are conducted using a large... 

Disease was labeled not severe when MDF < 54, severe at 55-92 and probably lethal at > 93. In practice, most modem clinical trials will document... 

An adverse event is unexpected when its nature or severity is not consistent with information in the relevant source document(s) . Relevant source documents include the investigator s brochure for investigational drugs, and the master data sheet or core safety data sheet, or local product labeling for marketed products. The determination of whether an adverse event is unexpected usually resides with the company that sponsors the clinical trial or markets the product. 

Both retrospective surveys and ongoing monitoring of newly approved products are important in marketplace analysis and forecasting, as well as in gauging the relative productivity and potential profitability of individual companies. Documents associated with registration, such as copies of approved labeling and summaries of data submitted to support applications, can also provide useful models for companies planning clinical trials and subsequent submissions for comparable and competitive products. 

In case of use date extension an additional label should be affixed to the investigational medicinal product. This additional label should include the new use date and repeat the batch number. It may be superposed on the old use date, but, for quality control reasons, not on the original batch number. This operation may be performed on site by the clinical trial monitor(s) or the clinical trial site pharmacist, in accordance with specific and standard operating procedures and under contract if applicable. The operation should be checked by a second person. Documented evidence of this additional liability should be available in the trial documentation and in the batch records. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

Labeling, retrieval, and storage of samples should be regulated in detail, just as sample flow. Equipment should be maintained and calibrated regularly the personnel operating them should be trained properly. Note that these not just have to be performed adequately, but have to be documented in detail. Clinical work should typically be performed according to GCP an international ethical and scientific quality standard. Its main objective is to ensure that the data and reported results are credible and accurate, and that the rights of trial subjects are adequately protected. 

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