Optimal dose de-escalation trial designs for novel contraceptives in women

Abstract

Dose finding for classical hormonal contraceptives for women is usually done by investigating the surrogate endpoint inhibition of ovulation. For novel compounds such an approach is not feasible because they do not necessarily inhibit ovulation and no other surrogate endpoint for pregnancy is available. The only way to assess the efficacy of such a product is the direct measurement of the contraceptive efficacy. However, a classical parallel group dose response trial investing several doses including at least one ineffective dose is not possible due to ethical considerations. Therefore, an alternative trial design to determine the lowest effective dose of a new compound that minimizes the number of unwanted pregnancies occurring during the trial is needed. Seven dose escalation designs used to find the maximal tolerated dose in cancer trials were investigated for our problem of determining the minimal effective dose (LED) in preventing pregnancies over 1 year. The statistical properties of these designs were elucidated by a simulation study. The most suitable dose de-escalation designs to determine the LED of a new contraceptive that minimizes the number of unwanted pregnancies occurring during the trial were the continual reassessment method and a design derived from the classical “ 3+3” design in cancer, but with a cohort size of 100 instead of 3. Both dose-finding designs substantially reduced the expected number of pregnancies to less than 4 pregnancies compared to 16.9 in the classical dose-finding design. However, this clear advantage comes at the price of a 5-fold increase in trial duration.