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XIX. From Trial Results to Approval |
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The development process is unending and needs to be attended to throughout its course. Once the critical pivotal studies are ongoing, the next step needs to be planned. Adequate patient exposure needs to be ensured. Many of the patients need not be exposed to controlled randomized trials, but could be exposed through treatment studies or prolonged chronic exposure. However failure to maintain contemporaneous control groups can be quite devastating to a program. If liver enzyme elevations are noted just in a few patients, a program could be placed in severe jeopardy. However, if it is clear that both in the control group and in patients receiving the drug under development there is an elevation in liver enzymes, then the drug would appear exonerated and the development program would proceed unhindered. Controls are critical for the evaluation of adverse side effects as well as for the evaluation of drug efficacy. |
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Beside establishing safety through patient exposure, adequate drug interaction studies are needed. In cardiology, several drug-interaction studies are standard such as evaluating a possible interaction with digoxin. Others can be predicted by knowing the route of elimination of the new agent and if, for instance, the liver is involved, there is likely a need to study interactions with drugs that induce liver enzymes. If a drug is significantly protein bound, then agents that may displace it from its protein binding need to be evaluated. From the known pharmacodynamic and kinetic properties of the drug, potential interactions can be determined. Another aspect of the drug-interaction evaluation comes from the pharmacodynamic properties of a drug. For instance, if a drug is going to be used as an antianginal, it may be used in combination with a calcium channel blocker or beta blocker. Clearly, concomitant studies with the use of these combined agents are indicated to see if there is a dynamic interaction. These studies go a long way toward placing the drug in the proper context, aiding the physician in its use, and reassuring them in terms of safety. |
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Another critical aspect at this time is the exposure of special populations. Women need to be included in the drug development process at all stages, but especially in terms of drug efficacy and safety, adequate numbers of women are needed. While most antianginal, antihypertensive, and heart failure studies are performed on men, it turns out that as many, if not more, women are being treated with these medical therapies. It is appropriate to suspect that the pharmacodynamic response, as well as the kinetic handling of the drugs, may be different between genders and thus adequate exposure and careful comparison of the female group to the male group needs to be undertaken. In terms of kinetics the effect of drugs in other special populations, such as orientals and blacks, is most important. There is a well-known belief that the oriental population handles drugs in terms of elimination much more poorly and there- |
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