Estimation after subpopulation selection in adaptive seamless trials

During the development of new therapies, it is not uncommon to test whether a new treatment works better than the existing treatment for all patients who suffer from a condition (full population) or for a subset of the full population (subpopulation). One approach that may be used for this objective is to have two separate trials, where in the first trial, data are collected to determine if the new treatment benefits the full population or the subpopulation. The second trial is a confirmatory trial to test the new treatment in the population selected in the first trial. In this paper, we consider the more efficient two-stage adaptive seamless designs (ASDs), where in stage 1, data are collected to select the population to test in stage 2. In stage 2, additional data are collected to perform confirmatory analysis for the selected population. Unlike the approach that uses two separate trials, for ASDs, stage 1 data are also used in the confirmatory analysis. Although ASDs are efficient, using stage 1 data both for selection and confirmatory analysis introduces selection bias and consequently statistical challenges in making inference. We will focus on point estimation for such trials. In this paper, we describe the extent of bias for estimators that ignore multiple hypotheses and selecting the population that is most likely to give positive trial results based on observed stage 1 data. We then derive conditionally unbiased estimators and examine their mean squared errors for different scenarios.

Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Two Faces of AIDS in Hong Kong: Culture and the Construction of the `AIDS Celebrity'

Since the first reported case of HIV infection in Hong Kong in 1985, only two HIV-positive individuals in the territory have voluntarily made public their seropositivity: a British dentist named Mike Sinclair, who disclosed his condition to the media in 1992 and died in 1995, and J.J. Chan, a local Chinese disc-jockey, who came forward in 1995 and died just a few months later. When they made their revelations, both became instant media personalities and were invited by the Hong Kong Government to act as spokespeople for AIDS awareness and prevention. Mike Sinclair worked as an education officer for the Hong Kong AIDS Foundation, and J.J. Chan appeared in Government television commercials about AIDS. This article explores how the public identities of these two figures were constructed in the cultural context of Hong Kong where both Eastern and Western values exist side by side and interact. It argues that the construction of `AIDS celebrities' is a kind of `identity project' negotiated among the players involved: the media, the Government, the public, and the person with AIDS (PWA) himself, each bringing to the construction their own `theories' regarding the self and communication. When the players in the construction hold shared assumptions about the nature of the self and the role of communication in enacting it, harmonious discourses arise, but when cultural models among the players differ, contradictory or ambiguous constructions result. The effect of culture on the way `AIDS celebrities' are constructed has implications for the way societies view the issue of AIDS and treat those who have it. It also helps reveal possible sites of difficulty when individuals of different cultures communicate about the issue.