Regulatory requirements case report form

Setting up clinical studies is a lengthy process, as there are many documents to prepare [e.g. protocols and case report forms (CRFs)], study facilities to be assessed (e.g. study sites, CROs, clinical laboratories, phase I units), regulatory review to be considered and negotiations and agreements with study sites (e.g. contracts, finances, confidentiality, indemnity, insurance) to be undertaken. In addition, as will be dealt with in subsequent sections, ethical aspects of the study must be considered (e.g. ethics committee and IRB review and informed consent requirements), and study medications/devices must be organized. 

The pathway as presented in Table I shows that it is linear for the first 10 steps with no branch points before the pivotal IMP is formed. However, a branch point does exist for the synthesis of the pyrimidine moiety (Bi-pyrimidine) of thiamine. Convincing evidence has been obtained to indicate that AIR also serves as a precursor to Bi-pyrimi-dine [27]. This explains the concomitant growth requirement for thiamine for most of the mutants blocked in any one of the first five enzymes [27-29]. A complication in regulatory control is thus introduced in that any attempt to control purine biosynthesis at the first five steps would have dire consequences on the formation of thiamine. This has indeed been found in the often-reported cases where inhibition of growth by adenine and its derivatives can be reversed by thiamine or its pyrimidine moiety [29-31]. The situation is more complicated in a special class of adenine-sensitive mutants where the sensitivity appears to be related to disturbances in folic acid metabolism [32]. Mutations in the AICAR formyltransferase complex (steps 9 and 10) also create a pleiotropic thiamine requirement which is not due to a deficiency in the synthesis of thiamine but rather to an unexplained phenotypic... 

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