Optimal, minimax, and Bayesian two-stage designs in two-dose phase II clinical trials

Background: For most cytotoxic and biologic anti-cancer agents, the response rate of the drug is commonly assumed to be non-decreasing with an increasing dose. However, an increasing dose does not always result in an appreciable increase in the response rate. This may especially be true at high doses for a biologic agent. Therefore, in a phase II trial the investigators may be interested in testing the anti-tumor activity of a drug at more than one (often two) doses, instead of only at the maximum tolerated dose (MTD). This way, when the lower dose appears equally effective, this dose can be recommended for further confirmatory testing in a phase III trial under potential long-term toxicity and cost considerations. A common approach to designing such a phase II trial has been to use an independent (e.g., Simon's two-stage) design at each dose ignoring the prior knowledge about the ordering of the response probabilities at the different doses. However, failure to account for this ordering constraint in estimating the response probabilities may result in an inefficient design. In this dissertation, we developed extensions of Simon's optimal and minimax two-stage designs, including both frequentist and Bayesian methods, for two doses that assume ordered response rates between doses. ^ Methods: Optimal and minimax two-stage designs are proposed for phase II clinical trials in settings where the true response rates at two dose levels are ordered. We borrow strength between doses using isotonic regression and control the joint and/or marginal error probabilities. Bayesian two-stage designs are also proposed under a stochastic ordering constraint. ^ Results: Compared to Simon's designs, when controlling the power and type I error at the same levels, the proposed frequentist and Bayesian designs reduce the maximum and expected sample sizes. Most of the proposed designs also increase the probability of early termination when the true response rates are poor. ^ Conclusion: Proposed frequentist and Bayesian designs are superior to Simon's designs in terms of operating characteristics (expected sample size and probability of early termination, when the response rates are poor) Thus, the proposed designs lead to more cost-efficient and ethical trials, and may consequently improve and expedite the drug discovery process. The proposed designs may be extended to designs of multiple group trials and drug combination trials.^

The Study of International Cultural Relations of Postwar Japan

The paper examines policies and activities of cultural exchange carried out by Japanese national, local and private agents since the end of WWII. Methodologically, we distinctively use the notion culture as a tool and as an object of study, and to synthesize the two in full intention, based on the debate among IR students about so called Cultural Turn in IR theories. As case studies, the Japanese experiences are examined from two points. Firstly, it is compared with the German experiences in Europe, with special attention to the construction of national identity.In both countries, the peoples tried to make use of cultural exchange activities in the management of international relations. The actual developments of cultural relations by the two countries, however, were in striking contrast to each other. Secondly, our study focuses on the explosive expansion of private sector's international cultural exchange in the 1980s in association with so called "emerging civil society" phenomenon observed worldwide throughout 1970s and 1980s. By using our original approach mentioned in the Chapter 1, the paper tries to sketch out that the increase of the private organizations is largely the response of the Japanese society to outside influences, not something genuinely outgrown from within the society itself due to mainly domestic causes.