Clinical trials documentation

In a similar manner, QA departments and consultants paid for by the sponsor will conduct audits of investigator sites. Again, as with the clinical trial monitor, there may be some annoyance among the investigator and his staff that some person, who may not be a physician, should be appointed by the sponsor to review the clinical trial documentation at the site. 

Other chapters describe the regulatory governance of clinical trials, and little needs to be added here. These clinical trial documents are central to these processes. Equally, the regulatory requirements (which still vary from country to country), and the documents needed to support them, must be taken into account when constructing the clinical development plan. 

As a consequence of the new legislation for clinical trials, documentation on the quality and preclinical (i.e., toxicological) data of investigational medicinal products, including radiopharmaceuticals, needs to be submitted to obtain approval from the national health authorities in the member states prior to initiating a clinical study in humans. Furthermore, all clinical trials which started in the European Union after 1 May 2004 need to be recorded in the European EudraCT database (European Commission 2003 b). 

EC Amendment on 2001/83/EC. Part 1, 5.2.C defines holding period of essential clinical trials document... 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

The effect of statins on plasma lipids and lipoproteins is rapidly seen and fully achieved after 4-6 weeks of treatment. The effect persists unchanged during continued use for several years, but after stopping the diug, LDL-cholesterol rapidly increases to pretreatment levels. Treatment with statins is therefore usually continued indefinitely and not as a short-term cure. Finally, it is generally advisable to use the statins that have documented their efficacy in clinical trials (evidence-based medicine). 

Figure 5.4 A checklist of documentation to be provided with a Clinical Trial Application.

During the course of its conduct, the sponsor may need to amend a clinical trial, as a consequence of the emergence of new information. If the amendments are deemed to be substantial, in that they may impact on the safety of trial subjects, or change the interpretation of the scientific documents in support of the conduct of the trial, or are otherwise significant, the sponsor shall notify the Competent Authority and the Ethics Committee, using a Trial Amendment Form. The Ethics Committee are permitted 35 days to approve the amendment. 

In accordance to GCP, the sponsor should appoint clinical trial monitors. These act as the main communication interface between the sponsor and the trial site, and should regularly visit the site to oversee that the trials are being conducted and correctly documented in accordance with the protocol and GCP. Reports should be supplied to the sponsor after each visit. It is also good practice for the sponsor to establish an auditing system for independently verifying that the activities in relation to the collection and processing of data at the trial site, and at related laboratories or sponsor s facilities, are conducted in accordance with applicable protocols, procedures, regulations, GCP and GLP. 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

Heart failure is more prevalent and associated with a worse prognosis in African-Americans compared to the general population.1 Unfortunately, deficiencies in disease prevention, detection, and access to treatment are well documented in minority populations. African-Americans and other races are underrepresented in clinical trials, compromising the extrapolation of results from these studies to ethnic subpopulations. The influence of race on efficacy and safety of medications used in HF treatment has received additional attention with... 

The E6 (or GCPs) discusses the overall standards for implementing a clinical trial. Anyone who works on a clinical trial needs to understand this document. Of particular interest to the statistical programmer are the following parts of E6. The italics have been added for emphasis. 

In summary, for data to be useful in clinical trial analyses they need to be quantifiable. The data must be either a continuous measure or a categorical value. Free text poses a problem for analysis, and if it is a valuable variable for the statistical analyses it really must be coded. Finally, hardcoding should be used only when absolutely necessary, because it is inherently problematic. Organizations that do allow hardcoding should document in their standard operating procedures (SOPs) that it is an approved business practice and how it is to be used. 

Program 4.3 for creating study day variables for the SDTM data sets. However, the General Considerations document from the CDISC Analysis Data Set Modeling Team states that you should use the algorithm in Program 4.2 for analysis data sets. Whether you are deriving data based on the CDISC models or not, you should calculate study day variables in a consistent fashion across a clinical trial or set of trials for an application. 

Unfortunately, clinical trials in human volunteers usually have small sample sizes and adverse reactions are poorly documented. Also, adverse effects that have a long latency period such as carcinogenicity are difficult to account for. 

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