Phase I submissions

Phase I includes all of the clinical pharmacology studies that in many cases were conducted within 12 months of the NDA BLA submission. 

Subsequent to the submission of this manuscript, Pharmacyclics Inc. announced the results of the Phase I clinical study of Lu(III) texaphyrin 10.4. A total response (partial and complete) rate of 78% and 50% for skin or subcutaneous breast cancer and melanoma lesions, respectively. 

The European Clinical Trials Directive has now standardized the submissions to regulatory authorities needed for phase I studies within the European Community. The data in support of such submissions are now more or less the same as for an IND in the United States, and there is comparable institutional review board/ethics committee review and oversight on both sides of the North Atlantic. The preclinical manager must keep a close eye on the pace of such studies so that the preclinical testing for phase I in humans, which is usually rate limiting, causes as little delay as possible. 

In Western Europe, in spite of the Clinical Trials Directive, there is still no uniformity in the order of approval/submission of documentation by the various parties involved. For example, although all countries now require review and approval of phase I clinical protocols, in some countries, approval of a study by the local or national ethics committee is required before documentation is submitted to the competent national authorities, whereas in others, this order is reversed. The documentation that is required to be submitted to the authorities is also quite variable (Table 50.2). Some countries require brief summaries of available information, whereas others require detailed information on the preclinical, pharmacy, chemistry and other clinical data to be submitted. 

There is a considerable difference in the standard and type of information required by the various national regulatory authorities throughout the world. For example, until recently it was possible to perform clinical trials within some European countries without submission of any manufacturing information in other European countries Phase I clinical trials could be performed solely on the permission of a local ethics committee or just a doctor or dentist s approval. Requirements have now been harmonised across the EU with the Clinical Trials Directive discussed previously. Further attempts at harmonisation continue through ICH or are being driven by various MRAs. In the USA, a considerable amount of information has always been required for all phases of clinical trial from Phase I to Phase III. 

On Figure 2 I have shown the number of these new chemicals which have actually been commercialized by the manufacturer or importer as of March 1st of this year. About 30% of the total submissions were commercialized through the end of the 3rd quarter of last year. This seems like a very slow rate of commercialization but the reasons for some companies not following through the development phase with a commercialization phase are common-place in the industry. We made a spot telephone survey of a number of these manufacturers and received the following answers to our questions (Tablell). The chemical industry would say that these reasons are par for the course and undoubtedly could add a few more. 

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