The Ethics of Placebo-controlled Trials: Methodological Justifications

The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling

The Challenge of Assuring Continued Post-Trial Access to Beneficial Treatment

Sam Jones has agreed to participate in a clinical trial testing an experimental drug as a possible treatment for his chronic disease. The primary outcome of effectiveness is a decrease in a specific disease marker after two months of taking the drug. Soon after Sam begins to take the drug, he reports feeling better and the level of disease marker in his blood is significantly lower at each study interval. The study reaches its predetermined endpoint, is stopped as planned, and the sponsor submits an application to a regulatory agency to license the drug for this indication. It is clear that Sam would clinically benefit from continuing to take the drug. Is it the responsibility of the investigator or the research sponsor to ensure that Sam and other participants in this study continue to receive the drug or even to provide it to them after a study ends? This question is at the heart of recent controversy regarding post-trial benefits and may be one of the biggest ethical challenges facing clinical investigators, especially those involved in international research, over the next several years

Introduction: The Fogarty International Research Ethics Education and Curriculum Development Program in Historical Context

In response to the increasing need for research ethics expertise in low and middle income countries (LMICs), the NIH's Fogarty International Research Ethics Education and Curriculum Development Program has provided grants for the development of training programs in international research ethics for LMIC professionals since 2000. This collection of papers draws upon the combined expertise of Fogarty grantees, trainees, and other experts to assess the state of research ethics in LMICs, and the lessons learned over 12 years of international research ethics education; to assess future needs; and to chart a way forward to meet those needs. In this introductory paper we briefly sketch the evolution of research ethics as applied to LMIC research, the underpinning and evolution of the Fogarty bioethics program, and summarize key conclusions from the other papers in the collection

Generalizations of Permutation Statistics to Words and Labeled Forests

A classical result of MacMahon shows the equidistribution of the major index and inversion number over the symmetric groups. Since then, these statistics have been generalized in many ways, and many new permutation statistics have been defined, which are related to the major index and inversion number in may interesting ways. In this dissertation we study generalizations of some newer statistics over words and labeled forests. Foata and Zeilberger defined the graphical major index, majU , and the graphical inversion index, invU , for words over the alphabet {1, . . . , n}. In this dissertation we define a graphical sorting index, sorU , which generalizes the sorting index of a permutation. We then characterize the graphs U for which sorU is equidistributed with invU and majU on a single rearrangement class. Bj¨orner and Wachs defined a major index for labeled plane forests, and showed that it has the same distribution as the number of inversions. We define and study the distributions of a few other natural statistics on labeled forests. Specifically, we introduce the notions of bottom-to-top maxima, cyclic bottom-to-top maxima, sorting index, and cycle minima. Then we show that the pairs (inv, BT-max), (sor, Cyc), and (maj, CBT-max) are equidistributed. Our results extend the result of Bj¨orner and Wachs and generalize results for permutations. Lastly, we study the descent polynomial of labeled forests. The descent polynomial for per-mutations is known to be log-concave and unimodal. In this dissertation we discuss what properties are preserved in the descent polynomial of labeled forests

Clinical research: Should patients pay to play?

We argue that charging people to participate in research is likely to undermine the fundamental ethical bases of clinical research, especially the principles of social value, scientific validity, and fair subject selection

When to start ART in Africa.

To the Editor: In their Perspective article, De Cock and El-Sadr (March 7 issue)1 highlight the need for data on when to start antiretroviral therapy (ART) for HIV-infected people in Africa who have CD4+ counts above 350 cells per cubic millimeter. However, their proposed solution — a new randomized, controlled trial in Africa — is flawed

The Invisible Hand in Clinical Research: The Study Coordinator's Critical Role in Human Subjects Protection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74962/1/j.1748-720X.2002.tb00410.x.pd