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not known at the beginning, and an intelligent choice may only be made based on some structural similarity to drugs investigated earlier. Therefore, most initial studies are done with the standard species rat and dog. However, human kinetic and metabolism data should be collected as early as feasible in phase I to make the most appropriate species choices for longer term studies. The required duration of toxicological studies is determined by the intended treatment duration. For short treatment courses up to four weeks as with most antibiotics, three-month toxicological studies are sufficient for the clinical program and approval. Differences among the requirements for longer term clinical studies in different countries must be taken into account when coordinating the toxicological and clinical programs. The largest difference is in the requirement for Phase II trials of more than 4 weeks duration: US FDA guidelines require toxicological study durations identical to the intended human application, whereas EU and Japanese guidelines require 6- or even 12-month studies independent of treatment duration. This offers the possibility of an earlier phase II start in the U.S. It is good common practice to determine target organs and appropriate dose levels in shorter term or smaller pilot studies before embarking on the more costly long-term studies. However, the risk of missing the appropriate dose range can also be minimized by using more than the required minimum three doses in a study. A further option is to add additional animals to a longer term (e.g., 6-month) study and sacrifice some animals at half time to get an early indication that the study is on the right track. However, for ethical reasons, the toxicological program should be designed to avoid unnecessary repetition of studies with large numbers of animals. Generally, the most efficient toxicological program for a particular drug development should be planned by the toxicological expert with input by the whole project team rather than following a traditional standard pattern. |
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Originally, the main objective of phase I studies was to establish the safety and tolerability of a new drug in healthy human volunteers. After starting with a single dose one to two orders of magnitude below the no effect dose in animals, this dose is increased in small steps with careful measurement and observation of a large number of laboratory and clinical parameters. Several such steps may be required until therapeutic drug levels are reached. After establishing single dose tolerability, this must be repeated in multi-dose studies whose treatment duration depends on the intended therapeutic dosing scheme. The total duration of this program depends greatly on the time required to evaluate a completed study sufficiently to justify initi- |
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