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ating the next step. This can be done most efficiently if the whole sequence of studies is done in the same institution and by the same investigator, perhaps even within the company. Another consideration for the choice of study site may be the fact that phase I studies can be started in some European countries, such as Germany and U.K. approximately six months earlier than in the U.S. because extensive manufacturing and analytical reports on the formulation are not required in the data submission. In addition to safety information, many other valuable data are derived from phase I studies. Pharmacokinetic measurements give critical information on bioavailability and half life not infrequently very different from the animal data. This is important early guidance for formulation development. A low oral bioavailability of a costly drug substance may jeopardize the commercial success of a project unless a formulation with improved bioavailability can be developed. Low bioavailability also carries an increased risk of safety problems because of larger interindividual variations. If marketing considerations require a once daily dosing and a short half life makes this unlikely, the development of controlled release formulations should be started early. When possible, companies increasingly design their phase I programs to collect pharmacodynamic information, relevant to the intended therapeutic use, from healthy subjects. For example, bronchoprovocation or challenge studies give an important indication of the efficacy of asthma drugs. It may even be possible to determine the effective dose range with sufficient accuracy so that pivotal efficacy studies may be started immediately, parallel to formal dose finding studies, with considerable saving in total development time. Careful judgment by clinical experts is required in such decisions. |
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Clinical development is the subject of a specific chapter in this book. Therefore, only a few general comments will be given. The duration of clinical studies determines most of the critical path for the largest part of the development program, and initially planned times for completing studies are often exceeded because estimated enrollment rates were too optimistic and countermeasures to prevent further delay were started too late. Important choices to be made, especially by companies doing parallel international development, are the country or continent for the study and whether to perform it through its own organization or contract it totally or in part to a Clinical Research Organization (CRO). In an international development effort, common understanding of goals and good coordination of activities between the regional departments are prerequisites for efficiency. Study |
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