Changes in the characteristics of approved New Drug Applications for antihypertensives

Abstract

In this thesis, the control of hypertension provides the backdrop for my effort to investigate how clinical trial design has evolved for antihypertensive drug submissions reviewed and approved by the Food and Drug Administration between 1988 and 2001. To do this, I have constructed and undertaken a preliminary analysis of a number of quantitative surrogate measures of complexity and scale, such as trial design, numbers of patients, treatment lengths, active drug comparators, number of indications pursued, number of indications approved, and approval times. In addition, I review how practice guidelines for the treatment of hypertension have changed with advancing clinical and biological knowledge. I attempt to investigate whether a link exists between the changing characteristics of clinical trials for antihypertensive therapies and the evolving guidelines for treating hypertension, promulgated by the Joint National Committee Report on the Detection, Evaluation, and Treatment of High Blood Pressure, (JNC), a committee assembled by the National Heart, Lung, and Blood Institute.

(cont.) Although the number of New Drug Applications (NDAs) examined in the antihypertensive class is too small to permit rigorous statistical analyses, I am nonetheless able to observe a number of apparent trends within the set of NDA submissions for antihypertensives approved by the FDA. Specific trends I observe in support of increasing trial complexity include: 1) trial sizes increase over time as measured by patient enrollments per trial (p-value = 0.003); 2) clinical trial designs over time have included greater numbers of arms per trial (p-value = 0.022); and 3) the number of drug-drug interaction studies in antihypertensive NDAs has increased with time (p-value = 0.027). These trends offer preliminary support for the hypothesis that clinical trials associated with NDA applications for antihypertensives have become more complex over the last two decades. The mechanisms responsible for the observed increase in complexity are less clear. Based on available information, I cannot determine if FDA guidance documents or informal correspondence were responsible for making antihypertensive clinical trials more complicated, or whether pharmaceutical companies introduced greater complexity into the trial design for commercial reasons.

(cont.) Furthermore, while I observe that FDA guidelines did not precisely track changes in JNC guidelines for treating hypertension, it is not clear whether the discrepancies are meaningful. Future research might attempt to identify more precisely the causes of increasing clinical trial complexity, and attempt to relate trial complexity to the cost of drug development more generally.