Welcome back. In this last section of ethical issues, we're going to talk about some come contemporary issues in clinical trials. An ongoing controversy in clinical trials is what to select as the control therapy. The placebo orthodoxy is that placebo should be used unless there is an increased risk of serious harm. Meaning death or irreversible morbidity, in the absence of a therapy. And the argument for this is that without a placebo, the finding of no difference between a new and standard therapy is difficult to interpret and can be misleading. In addition because we are expecting to see a bigger difference between a placebo experimental treatment than we would see between an active control and in experimental treatment. Placebo designs are more efficient in determining efficacy meaning that they require fewer people. And we'll discuss that more when we talk about sample size. Another argument for using the placebo is that the standard of car is not universal. The act of control orthadoxy says that if an effective therapy exists, the use of placebo should be prohibited. And the argument for this orthodoxy is that the clinically relevant question is not whether a new therapy is better than nothing. Which is the placebo. But whether the new therapy is better than the standard treatment. But, again, the problem is if you find no difference between the experimental treatment and the active control, the interpretation of the results can be difficult because you don't know whether either treatment is better than nothing in the current setting. As I mentioned on a previous slide, the standard of care is not uniform. It differs greatly between countries and there's particularly a, a big gap between developed and developing countries and even within a country there can be a lot of variability in the standard of care. An example of where this caused a controversy was in the prevention of maternal tranmission of HIV. In developed countries, a high dose of oral AZT in late pregnancy, and IV AZT during birth was considered the standard of care. But in developing countries, there was no therapy because the AZT therapy required a lot of infrastructure and was very expensive to provide. So, in this setting, investigators wanted to be able to provide a treatment regimen that was more practical to deliver in developing countries. For example, a low dose oral therapy. And the question was, should a trial of the low dose oral therapy proposed for use in a developing country be compared to the high dose AZT therapy, which was standard of care in the developed world. Or to a placebo, because the standard of care in the developing world was no therapy. Clinical trials are occurring increasingly on a more global scale. In an article published in the New England Journal in 2009, the authors pulled trials from clinicaltrials.gov which is a site that registers clinical trials. And they looked at industry sponsored phase three trials and found that industry sponsored trials and the 20 largest U.S. pharmaceutical companies were being done increasingly outside of the U.S.. They found that more than a 3rd of the trials recruited solely outside of the U.S. And the majority of the clinical sites were outside of the U.S.. And they thought that this was the because in the developing world, there is a large pool of untapped participants, and that there is substantial cost savings. Medical care in many developing countries costs only a fraction of what it costs in the United States. And the bureaucracy and regulatory environments are much more complicated in wealthy nations. This globalization of research has some benefits, but also is a cause for some concern. Doing research around the world helps to build global collaborations. And it also helps to make the results more generalizable, because we are answering questions that are of interest throughout the world. But ethically and practically there are some concerns as well. The regulatory bodies that are used in monitoring trials are used to what is requred in their domestic markets. And they may have limited knowledge of procedures in people in other markets. The financial compensation for participation may be large in a clinical trial with respect to what people make in their regular wages and this could be coercive. And participation in a trial may be the only way that some of the people would have access to adequate healthcare for their condition. The local standards of care may be lower than what is required in the developed world. And it may lead to research that would not be permissible in wealthier countries. And finally, research should be applicable to the needs and priorities of the community in which it's being conducted. So that the results will be useful in that setting. Now we've come to the end of the lecture on ethical issues in clinical trials. That's all for now. Thank you.