The secrets of a successful clinical trial: compliance, compliance, and compliance

Abstract

The high failure rate of drugs in clinical trials, especially in the later stages of development, is a significant contributor to the costs and time associated with bringing new molecular entities to market. These costs, estimated to be in excess of $1.5 billion when capitalized over the ten to fifteen years required to develop a new chemical entity, are one of the principal drivers responsible for the ongoing retrenchment of the pharmaceutical industry. Therapeutic areas such as psychiatry, now deemed very high risk, have been widely downsized, if not abandoned entirely, by the pharmaceutical industry. The extent to which patient noncompliance has marred clinical research has in some cases been underestimated, and one step to improving the design of clinical trials may lie in better attempts to analyze patient compliance during drug testing and clinical development.

Figure 1. Body weight changes in an eight-week trial of DOV 21,947 in healthy subjects

Change in body weight at study end point (left panel) and at one-week post-treatment (right panel) are shown. (ANCOVA among the three study groups; body weight at baseline and gender were applied as covariates. ^ap<0.0055 vs placebo; ^bp<0.0019 vs noncompliant; ^cp<0.044 vs noncompliant).

Figure 2. Improvement on the visual analog scale for pain in a twelve-week trial of bicifadine in patients with chronic low back pain

These data represent patients who received either a controlled release form of bicifadine (200 mg, twice daily) or placebo. The visual analog scale (VAS) ranges from 0 100 mm. For patient recruitment in the study reported here, baseline pain severity had to be at least 40 mm. Changes in VAS score was the primary endpoint measure; analysis of plasma bicifadine in this trial arm was a planned pharmacokinetic/pharmacodynamic comparison. VAS change scores as endpoint measures were compared with ANCOVA. Severity at baseline, gender and age were applied as covariates. The pattern of results shown here was largely replicated (data not shown) using the Roland-Morris Disability Questionnaire (15); see text for details. (^ap<0.01 vs placebo or noncompliant groups; ^bp<0.05 vs placebo or noncompliant groups; ^cp<0.002 vs placebo or noncompliant groups).