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sizes must be carefully calculated to offer the necessary statistical power for detecting the minimum therapeutic effect compatible with the approval criteria or a commercially viable product. In drug comparison studies, special attention must be given to the choice of the most suitable comparative drug. Different comparative drugs may be required in different regions or countries. Some of the most spectacular progress in reducing total drug development time has been made by shortening the time for trial data evaluation through continuous and/or remote entry of data during the study. In particular, this applies to interim analyses which may allow the next consecutive study to start earlier, when, for example, the effective dose range is sufficiently well established. The price for this faster study evaluation, however, is more work in the study planning and setup phase which, therefore, must be started early enough. The full benefit of a rapid study evaluation is obtained only when the next study is ready to start immediately. For this purpose, the design and preparations must also be as flexible as possible to allow for some last minute adjustments. For example, additional dose strengths of the formulation may be manufactured and stocked to avoid delays by a late change in the dosing scheme. |
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4.
Manufacturing Development |
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Generally, clinical and toxicological studies are the most time consuming, and, typically, are the critical path activities of drug development. They also carry the highest risk of negative outcomes leading to project delay or even termination. However, drug substance and drug manufacturing issues are becoming increasingly complex and need careful attention in planning. Some reasons for this are more complex chemical structuresoften stereoisomersleading to larger number of synthesis steps and increased manufacturing cost, more frequent demand for controlled release or other special formulations, and more stringent regulatory requirements for GMP manufacturing. Newly developed technologies for advanced formulations often require lengthy optimization and scale-up, with considerable risk of unexpected problems and resulting delays. Every effort has to be made to use the final formulation in the large-scale, pivotal, phase III trials. Final formulation means that this formulation is supported by a sufficiently validated manufacturing scale process and sufficient stability data to minimize the need for further optimizations at the risk of changed properties. This rule is especially important for controlled release formulations because almost every formulation change requires a proof of bioequivalence with its inherent high risk of failure and the consequent repetition of clinical trials. For example, if development of the final formulation determines the initia- |
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