CTA Requirements

The authors thank Dr. Christophe Lahorte for the useful discussions and his valuable information, which contributed significantly to the content of this chapter. 

l List of European Economic Council Directives and Regulations Applied to Radiopharmaceuticals 

These documents are available in the current version at http //dg3.eudra.org/eudralex Council Directive 65/65/EEC of 26 January 1965, on the approximation of provisions laid down by law, regulation, or administrative action relating to medicinal products Council Directive 75/318/EEC of 20 May 1975, on the approximation of the laws of member states relating to analytical, toxicopharmacological and clinical standards, and protocols in respect of the testing of medicinal products 

Council Directive 89/343/EEC of 3 May 1989, extending the scope of Directives 65/65/EEC and 75/ 319/EEC, and laying down additional provisions for radiopharmaceuticals 

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EIHs/IND, to NDA and postapproval marketed product support. Most of the information is based on US FDA and ICH guidelines. However, EU technical requirements are generally similar, though specific IMPD/CTA requirements may vary from coun-try-to-country. Also, the technical requirements for Japan are similar based on the ICH guidelines. 

The amount of contrast material required for CTA is comparable to that used for conventional contrast-enhanced CT imaging. The amount of scanning time required for a CTA examination of the head and neck, such as is usually performed for acute... 

The possible use of the BALB/c 3T3 CTA is mentioned in various recent testing strategies including the supplemental data for pharmaceuticals and the guidance on information requirements and chemical safety assessment for REACH [34, 35]. 

The major features for advanced photo-systems relative to the base film are a small-size thrust cartridge and return inside the cartridge. These features require low core-set curl values and high mechanical strength. The cellulose triacetate (CTA), polycarbonate and PET materials currently used in the photographic industry are not able to satisfy these requirements. Some newly developed film materials, such as modified-PET and syndiotactic polystyrene, were also unable to satisfy such requirements. It is known that annealing films just below the Tg (BTA treatment) could reduce core-set curl tendencies. BTA treatments of... 

The application for a clinical trial authorisation (CTA) for the first administration of a NME to man comprises the same elements as all other CTAs but, of course, there will be no clinical data. The regulatory authority known as the competent authority (CA) of the EU member state requires receipt of confirmation of the EU clinical trials database (EUDRACT) number, a covering letter, a completed application form, the protocol with all current amendments, the IB and a full Investigational Medicinal Product Dossier (IMPD) (see below). If the study is to be conducted in more than one member state, a list of CAs should be included. If the opinion of the lEC is available, it should be provided. 

With a view to harmonising the conduct of clinical trials across the European Union, Directive 2001/20/EEC was finally agreed on 14 December 2000 and was formally adopted in May 2001 with a 3-year transition period for its implementation. The Directive is now fully implemented in the United Kingdom and further information on clinical trials there can be accessed at the MHR A website. Under the provisions of the Directive, all clinical trials now require a Clinical Trial Authorisation (CTA). This is discussed in detail in Chapter 17. 

The discovery of DRhoGEF2 and demonstration of its requirement for gastrulation during early morphogenesis in Drosophila provided early evidence for a direct linkage between the heterotrimeric G proteins and regulation of Rho proteins (Cta and Rhol in Drosophila, respectively) (Barrett et al., 1997 Hacker and Perrimon, 1998). In these studies,... 

During preclinical development, the structure, physical and chemical characteristics, and stereochemical identity of the IND/CTA candidate are fully characterized. This information, for example, is required for the chemical manufacture and control (CMC) section of the IND. Appropriate bioanalytical methods are developed for the evaluation of pharmacokinetics, typically a series of studies focusing on absorption, distribution, metabolism, and excretion (ADME) in toxicology species, as well as systemic exposure and metabolism in toxicological and clinical studies. 

The presence of the PMMA or PET lowers the criticd concentration of the CTA. For example, a 19.6/1.2/70.2 (w/w/w) ternary solution of CTA, PMMA and TFA-CH2CI2 (6 4 v/v) and an 18.6/1.2/80.2 ternary solution of CTA, PET and TFA-CH2Q2 (6 4 v/v) were biphasic when viewed under crossed polars. Each solution appeared to be one ph but a small isotrq>ic phase may have been present, a required an extremely long time to separate due to the high viscosity of the anisotropic matrix. 

The lowering of the critical concentration of the CTA by the presence of the flexible polymer may be explained in terms of a lattice model. The large excluded volume of PMMA or PET decreases the number of lattice sites available to the semirigid CTA polymer, thus the CTA molecules are required to pack more efficiently and are more dign in the ordered phase. 

Since the technical rrq(lirclllCllt for chemical agents are common to all tlw cta.ssc., t.c., gu. ics, smokes, and incendiaries, these requirements will be considered without distuiction as to class of agent. 

Two soluble ARFs, sARFI and sARFII (Tsai et al., 1988), as well as a membrane-bound ARF (Tsai et al., 1987), were purified from bovine brain. sARFI and sARFII were later identified as ARFl and ARF3, respectively (Tsai et al., 1992). In the presence of cholate, ARF-stimulated ADP-ribosylation of Gs by cholera toxin was enhanced by DMPC (Tsai etal., 1988). However, DMPC/cholate was not required for ARF-stimulated auto-ADP-ribosylation of CTA (Tsai et al., 1988). sARFII-stimulated NAD agmatine ADP-ribosyltransferase activity was enhanced by SDS in a concentration-dependent manner 0.003 % produced maximal activity (Noda etal., 1990). 

Purified CTA or LTA is required for the assays described herein and can be generated and purified from CT or LT holotoxin using methods originally described for CT. Gel filtration in 0.1 M glycine buffer (pH 3.2) containing 6 M urea (Ohtomo ef al., 1976) or 5 % formic acid (Lai et al., 1976) results in separation of the A subunit from B subunit monomers. More recently, a reverse-phase HPLC procedure has been described for cholera toxin subunit purification (Pearson etal., 1986). Like CT, purified CTA can be purchased from several sources (see Section 2.2.3). 

Pure CTA and LTA are activated for use in these assays by incubation with thiol and proteolytic cleavage to produce the Ai and A2 peptides. After secretion, CTA is proteolytically nicked by bacterial proteases (Mekalanos etal., 1979) and thus requires only reduction to be... 

The European Commission issued a set of detailed guidelines on the requirements and format of the CTA application for use by NCAs and ethics committees, as well as templates for application forms. Directive 2001/20has also added a small but... 

The CTA procedure became mandatory on May 1, 2004 (existing trial authorizations from the pre-Directive period, for example in the United Kingdom a CTX, CTC or DDX, retained their validity, and automatically became CTAs). The CTA application process is a relatively straightforward written procedure, and requires no extensive preparatory meetings with the regulators. 

The information on the IMP in the CTA is necessarily not as complete as in a MA, and the overall intent is that the extent of information should be proportional to the clinical phase of the protocol, while complying with the new Guidance document for Good Manufacturing Practices as they apply to IMPs (Annex 13, Rev 1 of the document). A further guideline is forthcoming on the requirements to the chemical and pharmaceutical quality documentation concerning IMPs in clinical trials (see European Commission Directive 2003/94/EC). 

Conditioned taste aversion. Nachman and Hartley (1975) studied the development of a conditioned taste aversion (CTA) in rats following treatment with CN. Animals were trained to consume their daily water requirement during 10 min of access to a water bottle. On the treatment day, animals were given a 10% sucrose solution instead of water, followed by an intraperitoneal administration of NaCN (2.0 mg/kg). A subsequent decrease in sucrose solution intake, but not water intake, would be indicative of a specific CTA. In this study, no evidence of a CTA was observed, as NaCN-exposed animals consumed equivalent amounts of sucrose solution or water before and after NaCN exposure. 

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