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.

Introduction

One of the key steps in any pharmaceutical drug development program is the elucidation of the dose–response relationship. In dose finding trials the optimal dose has to be determined. On the one hand, choosing a dose too low might result in a failure in the subsequent phase III clinical trials due to inefficacy. On the other hand, choosing a dose too high might lead to unnecessary safety problems during subsequent drug development or even after the drug has being marketed; see, e.g. Bretz et al. (2008) for a comprehensive overview.

Dose finding for classical hormonal contraceptives is usually done by investigating ovulation inhibition in healthy female volunteers; see, e.g. Heger-Mahn et al. (2004). Ovulation inhibition is a broadly accepted surrogate endpoint since ovulation is an absolute precondition for conception. In addition ovulation inhibition can be rapidly and reliably assessed within two cycles of pill intake.

For novel non-ovulation-inhibition contraceptive approaches, e.g. methods impacting endometrial, cervical, or male reproductive parameters, such an approach is not feasible. These new strategies do not necessarily inhibit ovulation and yet no other surrogate endpoint for contraceptive efficacy is available. Similar to phase III clinical trials on contraceptives, the only way to assess the efficacy of such a product is the direct measurement of the contraceptive efficacy, by the Pearl Index (PI), i.e., the number of pregnancies per 100 women-years; see Gerlinger et al. (2003). The PI is the ultimate clinically relevant endpoint and in contrast to the surrogate parameter ovulation inhibition, it encompasses also all non-ovarian contraceptive effects, e.g. effects on cervical mucus sperm permeability, endometrial receptivity, fallopian tube function and all male reproductive factors. Phase III trials typically assess the contraceptive efficacy over a treatment period of one year.

A classical parallel group dose–response trial investing several doses including at least one ineffective dose would lead to a number of contraceptive failures, i.e., unplanned pregnancies, especially in women randomized to an ineffective dose. Such a dose–response trial design does not seem to be practicable nor does it seem acceptable from an ethical point of view. The strategy to identify the maximum tolerated dose (MTD) used frequently in early drug development, e.g., in oncology, is used as the basis for the concept. While the MTD is found by applying increasing doses, starting from a well-tolerated dose up to a point of intolerance, the approach presented here applies decreasing doses, starting from a presumed effective dose down to an ineffective dose. Thus, the least-effective dose (LED) is zeroed in. A trial design that minimizes the (absolute) number of unwanted pregnancies is presented. However, given the limited extend of our simulation study, further research is warranted.