[MUSIC] So along with the Belmont report, Congress develop some regulations and they were first codified as 45 CFR 46 and that's under the Department of Health and Human Services. And it's referred to now as the Common Rule, that is referred to as a Common Rule because other funding agencies adopted it. In fact, most funding agencies have adopted 45 CFR 46. It might be listed under different numbers or chapters, and then, it just might refer to 45 CFR 46 in a specific regulation. But 45 CFR 46 is referred to as the Common Rule and the human subject protection regulations. And so, it applies really only to federally funded studies. I think I've said this earlier, but it is considered the basic threshold for people conducting research. And here at UC Davis, we apply 45 CFR 46 to all research and I believe all the other campuses apply it too. And so, it has protections that include requirement for informed consent and for minimizing risks and maximizing the benefits during the research. It talks a lot about there's criteria for approval that, before the study can be approved, you have to meet very specific criteria. One of them for justice is selection of subjects is equitable. So you have to make sure that when you're enrolling, people are developing your inclusion criteria that your selection is equitable. You have to either get informed consent, in some instances informed consent can be waived but those censuses are pretty rare. And the biggest change there is that it required a group of people to look at your research. Look at your protocol, look at your background. Look at the resources that you have and then consider all of that against 45 CFR 46 in the criteria for approval. And determine whether this research can be conducted and that's called the Institutional Review Board, or the IRB. A lot of people think of the IRB is a black hole. They send their sub, their research to it and maybe a few months later, they'll get something back. But really, the IRB is a group that looks really hard at all the research submissions and they ensure that subjects are protected. The science is valid and that risks are minimized, benefits are optimized. And every UC campus has an IRB and they do require review of research involving human subjects before you can start it. There is also FDA regulations. These were promulgated about 10 years later and they include regulations very similar to the Common Rule. The little bit of differences are because the risk are usually higher in FDA research because you're looking at drugs or devices. And that's very important for the data to be correct. So, you're protecting the subjects as much as possible from harm at the same time, you're trying to make sure the data you get from this study is valid and will show if a drug is good or drugs bad, if they're effective, what the risks are, so people can be warned. And so the data in an FDA investigation is really, really important. So it also has a specific regulation for informed consent and it has additional protections for children. I didn't mention before the Common Rule has additional protections for children, for prisoners, and for pregnant women in neonates. FDA has specific regulations for investigator conflict of interest. So sometimes, investigators might be the inventor of a drug or a device, or some other thing and they expect maybe to make money if their research is successful. And so, that can sometimes result in investigator bias, when they're looking at whether a person meets the criteria to be in the research, or even when they're evaluating the outcome of the research. They might see benefit maybe when there's not really a benefit there. And so, we look at investigator conflicts of interest and even research staff conflicts of interest, and we try to manage them as appropriately as much. And the IRB does that, the FDA considers that when they're looking at a drug or a device, when you're looking at the data. And so, the FDA regulations also include very specific regulations for involving humans and research experiments with drugs. And biologics and they also have a separate regulation for involving humans and experiments with devices. I mean, drugs and biologics can be pretty bad in some instances and devices, if they're implantable can be terribly bad, if they're not safe and effective. And so you have to go through steps before you can even get to the human subject aspect of clinical investigation. So I've talked a lot about the regulations and the history. And so we've got these wonderful regulations where we protect everybody and that data are good, but really does that take care of everything and that's old news, right? All that ethical stuff does bad things are old news. And unfortunately, it's an evolving world and it's really not old news. Here are some more recent examples of some pretty bad things that have happened. Most of these are clinical investigations involving the FDA. But I can also tell you much about other investigations that were psychological or social behavior studies too, but these are a little bit more stirring. I think one, I was really involved in was a woman was in a gene therapy study back. I think was around 2011 and she received edited gene through a vector. She had rheumatoid arthritis. She was in constant pain and this was a phase one study. A phase one study is where you're just trying to see how the drug works in the body and whether the body can tolerate it. You might see a little bit about whether the drug works to cure the disease but really, it's just, will the body tolerate it. And she thought she was going to get well from this, at least that's what her husband said, which wasn't the purpose of the study at all. And so, how did she get that in her mind, did what she told that or was she really told the real reason for this research, or does she just want to believe? We don't know at this point because she died, she got an injection. She got ill, she went camping, the illness became worse and to the point where she was infected everywhere in her body and she died. And at this instance, it was her own doctor who enrolled her in the study. She had been seeing this doctor for many years and he was the one enrolled. And so that might have a little bit of effect on her belief that she would get well from the study. So, did she go into the study knowing the risks, knowing the discomfort she might have endured? And knowing that she could really die in the study and we don't really know at this point what she believed. Another study was a young man and he had a genetic disorder and he's really wasn't very bad. His was controlled and he decided to go into research though when he turned 18, he signed up for studying. It was other gene transfer study and that's where they edit a gene and they get it into the body. And in this study, it was a little bit different because one of the physicians that was on the study and that was providing care to him had a financial interest in that gene therapy test article, the thing they were injected into him. And so if this turned out to be good, that physician could make a lot of money off of that experiment. And unfortunately, it turned out to be bad. This young man who went into the study to help others and not really help himself ended up dying. And there was a little bit more data about the effect of the drug on animals that maybe people didn't look at closely. There's also this conflict of interest. There's a few other stories on here and I don't want to bore you by going over all of them and stuff. But look at the slides and you might want to look up some of the results of these studies and actually, see what happened in these to know the ethical consequences that people could face.