Fundamentals of Clinical Trials by Lawrence M. Friedman Curt D. Furberg David L. DeMets David M. Reboussin & Christopher B. Granger

Fundamentals of Clinical Trials by Lawrence M. Friedman Curt D. Furberg David L. DeMets David M. Reboussin & Christopher B. Granger

Author:Lawrence M. Friedman, Curt D. Furberg, David L. DeMets, David M. Reboussin & Christopher B. Granger
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham


Length of Follow-up

The duration of a trial has a substantial impact on adverse event assessment. The longer the trial, the more opportunity one has to discover adverse events, especially those with low frequency. Also, the cumulative number of participants in the intervention group complaining will increase, giving a better estimate of the incidence of the adverse event. Of course, eventually, most participants will report some general complaint, such as headache or fatigue. However, this will occur in the control group as well. Therefore, if a trial lasts for several years, and an adverse event is analyzed simply on the basis of cumulative number of participants suffering from it, the results may not be very informative, unless controlled for severity and recurrences. For example, the incidence could be annualized in long-term trials.

Duration of follow-up is also important in that exposure time may be critical. Some drugs may not cause certain adverse effects until a person has been taking them for a minimum period. An example is the lupus syndrome with procainamide [32]. Given enough time, a large proportion of participants will develop this syndrome, but very few will do so if treated for only several weeks. Other sorts of time patterns may be important as well. Many adverse effects even occur soon after initiation of treatment. In such circumstance, it is useful, and indeed prudent, to monitor carefully participants for the first few hours or days. If no effects occur, the participant may be presumed to be at a low risk of developing these effects subsequently.

In the Diabetes Control and Complications Trial (DCCT) [33], cotton exudates were noted in the eyes early after onset of the intervention of the participants receiving tight control of the glucose level. Subsequently, the progression of retinopathy in the regular control group surpassed that in the tight control group, and tight control was shown to reduce this retinal complication in insulin-dependent diabetes. Focus on only this short-term adverse effect might have led to early trial termination. Fortunately, DCCT continued and reported a favorable long-term benefit-harm balance.

Figure 12.1 illustrates the first occurrence of ulcer symptoms and complaints of stomach pain, over time, in the Aspirin Myocardial Infarction Study [30]. Ulcer symptoms rose fairly steadily in both the aspirin and placebo groups, peaking at 36 months. In contrast, complaints of stomach pain were maximal early in the aspirin group, then decreased. Participants on placebo had a constant, low level of stomach pain complaints. If a researcher tried to compare adverse effects in two studies of aspirin, one lasting weeks and the other several months, the findings would be different. To add to the complexity, the aspirin data in a study of longer duration may be confounded by changes in aspirin dosage and concomitant therapy.

Fig. 12.1Percent of participants reporting selected adverse events, over time, by study group, in the Aspirin Myocardial Infarction Study



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