Abstract
BackgroundThe assessment of treatment success in clinical trials when multiple (repeated) doses (courses) are involved is quite common, for example, in the case of infertility treatment with assisted reproductive technology (ART), and medical abortion using misoprostol alone or in combination with mifepristone. Under these or similar circumstances, most researchers assess success using binomial proportions after a certain number of consecutive doses, and some have used survival analysis. In this paper we discuss the main problems in using binomial proportions to summarize (the overall) efficacy after two or more consecutive doses of the relevant treatment, particularly for the case of misoprostol in medical abortion studies. We later discuss why the survival analysis is best suited under these circumstances, and illustrate this by using simulated data.MethodsThe formulas required for the binomial proportion and survival analysis (without and with competing risks) approaches are summarized and analytically compared. Additionally, numerical results are computed and compared between the two approaches, for several theoretical scenarios.ResultsThe main conceptual limitations of the binomial proportion approach are identified and discussed, caused mainly by the presence of censoring and competing risks, and it is demonstrated how survival analysis can solve these problems. In general, the binomial proportion approach tends to underestimate the “real” success rate, and tends to overestimate the corresponding standard error.ConclusionsDepending on the rates of censored observations or competing events between repeated doses of the treatment, the bias of the binomial proportion approach as compared to the survival analysis approaches varies; however, the use of the binomial approach is unjustified as the survival analysis options are well known and available in multiple statistical packages. Our conclusions also apply to other situations where success is estimated after multiple (repeated) doses (courses) of the treatment.
Highlights
The assessment of treatment success in clinical trials when multiple doses are involved is quite common, for example, in the case of infertility treatment with assisted reproductive technology (ART), and medical abortion using misoprostol alone or in combination with mifepristone
Depending on the rates of censored observations or competing events between repeated doses of the treatment, the bias of the binomial proportion approach as compared to the survival analysis approaches varies; the use of the binomial approach is unjustified as the survival analysis options are well known and available in multiple statistical packages
A binomial proportion is derived from a random variable X that summarizes the result of “n” independent repetitions of a Bernoulli experiment, each with probability “P” of success, by providing the total number of successes out of “n” repetitions; the binomial distribution is characterized by two parameters, “n” and “P” and is denoted as B(n,P)
Summary
The assessment of treatment success in clinical trials when multiple (repeated) doses (courses) are involved is quite common, for example, in the case of infertility treatment with assisted reproductive technology (ART), and medical abortion using misoprostol alone or in combination with mifepristone. For pregnancies of gestational age over 12 weeks (84 days), the recommended method for medical abortion is 200 mg mifepristone administered orally followed 36 to 48 hours later by an initial dose of 400 μg orally or 800 μg vaginally, with further doses of 400 μg misoprostol administered either vaginally or sublingually every three hours, up to four further doses [1] Other studies use formal survival analysis of “induction to conception expulsion” time, in hours [10, 11]
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