 It's my turn. As many of you know and some of you do not know, I am the hospital epidemiologist at the University of Chicago and I first became interested in ethics because I found that I was making a lot of decisions that affected many, many groups of people at the hospital and I wasn't sure there was no one in my field really talking about what the ethics were, what ethical considerations needed to be included in making these kinds of decisions. And I want to talk to you today about something that's relatively new on the field of American medicine. It's not new to me, we've been doing this for a couple of years at the University of Chicago and I wanted to present it to you as something that I think we should know a little bit more about. So I have nothing to disclose as it relates to this topic except that it is my job to make sure that everyone's protected when we study or use these viral vector agents at the University of Chicago. And I do have a vested interest in that. Anyway, protecting people. So let's talk a little bit, let's go back, step back and talk a little bit about human subjects research which we talk about it endlessly in the fellowship not endlessly but enough. And we all know here that a human subject is a living individual about whom an investigator conducting research obtains data through an intervention or interaction with the individual or obtains identifiable private information about that person. And we know that every single study that includes any sort of human subject research needs to go through the IRB and we have a robust and wonderful IRB system that sometimes irritates clinical researchers but generally does good. It's a committee that systematically and prospectively reviews research proposals to ensure that appropriate steps are taken to protect the rights and welfare of human subjects. This is what we do. It's been proscribed and recommended that this is how we protect people from research and as much as we talk about how we could improve our informed consent for research and all of the things that we could do better, we still have this as our main system. There's another system that you don't know about most likely and it's the Institutional Biosafety Committee. Now you don't know about this because many of you don't do biological research with live agents, right? People know that every institution doesn't just have an IRB, they have an IBC. And this Institutional Biosafety Committee meets and they review proposals for research that include any sort of biohazardous material including any recombinant DNA, any agents infectious to humans or animals or plants and any other genetically altered organisms or agents. Every protocol that includes one of those things has to go through another review process called the IBC. And they decide what level of protection is required for the researchers who are working with these agents because we would like to protect our researchers from the work that they do, right? And so this is what they decide. They decide what sort of biosafety level people need to work under in order to handle these particular agents. And some of these sorts of things are going to be familiar to you because we use a little bit of this in clinical medicine but not a lot. And I've talked about isolation here and things like that. But this is a typical biosafety level one lab. It's much like the microbiology lab that you worked in in your medical school class. If you went to medical school, your undergrad micro or physics lab, it has maybe sinks, sometimes people wear eye protection if they need to. You just walk right in the door, you're in the lab, you're supposed to clean your hands. There's probably an eye wash station in there and that's to be able to protect you. People usually wear lab coats when they're close. That's a biosafety level one lab. A biosafety level two lab is a little different. This, you'll notice, now we've got a door, right, that has a sign on it that says there's biohazards in this room. Outside the door is a shower and an autoclave, which you didn't see in the last lab. There's also now not just lab coats on people but they've got gloves and eye protection and there's signs and special waste containers. This is what you might see in a biohazard level, biosafety level two lab. A lot of work is done inside of these hoods, which allow you to do sort of biosafety level two lab with biosafety level three practices because you only ever open up the infectious agent when it's in a hood that has special ventilation to pull it away from you. This is a biosafety level three lab. We're going to get fours most. This will not go on forever. In a biosafety level three lab, it looks a little bit like a containment isolation room that we might have in the hospital. We now have an anti-room. There's fancy ventilation that happens in these kinds of labs that draw air away from the outside and into the lab and then out through an exhaust system sort of like we do for preventing spread of TB, right? It's all very familiar except there's a lot of stuff. Now you see people have solid front gowns and they've got respirators on. They're covered all the way up. They have an autoclave inside the lab. There's a fume hood. There's a biosafety cabinet and there's additional biohazard containers. This is what it looks like in real life. This is a typical example of a biosafety level three lab. These people are covered head to toe. They're wearing full protective gear. They're still working inside that biosafety cabinet or hood, as you might have learned it in chemistry class. And they're protected all the time. They have to change their clothes before they go in and then they have to take off all their clothes before they leave. There's a big process involved in this where someone has to watch you put on the clothes and they have to watch you take off the clothes to make sure that you don't contaminate yourself. But there's not necessarily a requirement for a shower before and after and these people have on N95 respirators. You can see them, they're rather uncomfortable. A lot of labs just use pappers when they do this. Some of you know what I'm talking about. Personalized air purified respirators. It basically looks like the stuff you wear when you take care of an Ebola patient. And this is where you take care of things when you're at level three. Now biosafety level four is exactly what you see in all the movies about outbreaks. There's a shower outside. You've got a shower, get dressed in the fancy clothes and you put on one of those things that's hooked up to the ventilation system above you and it's like all one piece and everything's crazy, it looks like that. And they really exist. We have a biosafety level three and level four labs out at Argonne where Olaf Schneewand works with his team on select agents. And they work with them there safely following all of these things. And that's how we allow people to do research on things that would otherwise be very dangerous, right? So now we have a system for protecting patients who might be a participant in a trial and also for protecting researchers. The question becomes when we give a patient a treatment that is contagious, what happens? In the history of medicine we've done a lot of things to people. We've bled them. We've done all sorts of things to them. But we really haven't given them infectious diseases on purpose until now. So viral vectors are genetically engineered viruses that are designed to introduce new genetic material into a target cell. This is not new. You've heard of it before. It's called gene therapy. All of you know of the case of the kid who had the adenovirus vector injected into his knee in order to treat a condition where his or her sepsis and died, right? And then sort of gene therapy kind of ended for a while and we didn't worry about it. Well, it's back. And now we use it to treat cancer. The two goals are that we take these viruses and we want to inject them into people either into their cancer or into their body in order to target the cells that are cancerous. They modify these viruses much more than they could back in the 90s. They actually target the cancerous cells and kill them directly. They have a secondary benefit and some are more on one side and some are more on the other that are naturally immunogenic because they're viruses. They take advantage of the immune system and teach your immune system to attack all cells that are cancerous. And they work pretty well in animals that are kept in biosafety level three labs. So there's three ways you can do this for people. You can either genetically modify a virus directly into the tumor. The actual effect of that is limited to the amount of virus that you inject. It can only kill as many cells as you've injected. They can't reproduce. You can't get any more. That clearly limits the amount of the tumor you can kill. Then the last one on this list is what you actually have heard about in the news a lot, which are CAR T cells. That's where they take the... This is very simplified, all of this. So if someone knows about a more specific way of saying this, please correct me. But you remove the patient cells. They actually get transduced by... None other than HIV. Didn't know that, did you? They use HIV to transform the cells into cancer-killing white blood cells and give them back to the patient. It works beautifully. They don't end up with HIV. It's beautiful. It's wonderful. You kill the HIV in the cells before you give them back. It's fabulous. It's going to revolutionize the way we take care of cancer. And it's not so much of a concern. But these genetically modified viruses that can reproduce that we're putting into patients is another story entirely. I don't think they're all bad. In fact, if I thought that they weren't useful, there's no way I would even agree that we should try having them at the University of Chicago. But the problem is, they're actually pretty good. So let's talk about some examples that we've studied here at the University of Chicago. Now, I'm not a PI or an investigator on any of these trials. I am only just the person who has to try and figure out how to make it safe. So HSV is herpes simplex virus because it causes skin and mucous membrane lesions and healthy individuals. And you can inject it once it's been genetically modified into melanoma cells. And yes, it can reproduce, but it's very selective. And it can really only reproduce in the cancer cells or so they say. And if you want to build this in the lab and work with it in the lab, it needs to be in a BSL2 or BSL3 lab. Adnovirus causes conjunctivitis, diarrhea, upper and lower respiratory tract infection, a very easy virus to manipulate. Cancer target here that we're talking about specifically is ureothelial cancer, or bladder cancer. It can be instilled into the bladder via cystoscope, a genetically modified one. It is sometimes they use a transmissible form, sometimes a non-transmissible form. And this is recommended to be used only in a biosafety level to lab when working with it as a researcher. Vaccinia, the very first vaccine known to man. It is a virus, dry-vax, otherwise known as. It is what we use to vaccinate people against smallpox. We don't do widespread smallpox vaccinations anymore because you can actually get very disseminated infection from cowpox. And it's a pretty virulent virus and it has some pretty interesting limitations in that you are likely to have this problem if you have something as common as eczema. We can genetically modify it, either through venous infusion or directly injected into the tumor, and yes, it is still contagious and it still is able to reproduce and is recommended to be used only in a BSL3 lab or in a BSL2 lab if you get a yearly smallpox vaccine. So when we decided it was time to start testing these in patients, we had a researcher who was definitely protected by the IBC rules wearing all of the PPE that they need to wear to carry it out of the lab and give it to a patient who is protected at least as much as we expect participants in research trials to be protected by asking them to sign a lot of informed consent explaining to them that they could have a transmissible form of a virus that they could spread to their family and we asked them to consent on behalf of their family themselves, their close contacts, although it isn't phrased quite as such. It's any sort of informed consent. And then you have your clinicians, right? So the doctors and nurses who work in the clinic are not the researchers who develop this agent and work in the BSL2 lab. They are the regular clinic nurses and doctors that work with whoever the PI is on whatever studies they do in clinical patients. And they sometimes don't know everything that you might want them to know and no one's consenting them. That's what we have now. And then there's the community. Either the other patients in the hospital, the next patient that goes into that room, the next patient that uses the bathroom after someone pees out their genetically modified adenovirus and the person you meet at the store or someone that might share the seat with you or on a bus coming back to the hospital for your visit. And I think that there are a lot of questions here about who's participating in this research. It's really not just the patient and yet we're really only consenting the patient. Who's protecting these other participants? And is participation even voluntary? You don't know who you're coming into contact with, granted, most of these patients the risk is going to be quite low for just casual contact outside the hospital, but these clinicians are regular clinicians who may not even know they're taking care of a patient that's received one of these viruses. I'll show you this slide again to remind you that there's a big difference between public health ethics and medical ethics or epidemiologic ethics and medical ethics. The epidemiologist in me is really uncomfortable with people walking around with genetically modified viruses and public not really knowing about it. And the medical ethicist in me is really glad that we have a better treatment for cancer that may be safer and easier for patients to tolerate. So how do we go about protecting these other people? Well, most of the studies recommend precautions for healthcare workers families, proactive steps for the patient to take to protect the broader community. Most studies include, interestingly, some sort of assessment of the healthcare workers. All the healthcare workers can be if they desire to participate in the study they can have their blood drawn and see if they've actually contracted the thing. If they don't want to participate, they don't have to. They still have to do their job. They just don't get their blood drawn. And sometimes family members can be consented to have their blood drawn as well. Sometimes we have to make sure that the lab protections are always greater than the clinic protections which are even greater than the home and community protections. So some of the things that we recommend people do like pouring bleach into the toilet every single time they pee for seven days and then waiting 30 minutes to flush the toilet are a lot more feasible for us to do in the clinic than they are for people to do at home. And we have no idea whether we have no way of controlling what people actually do at home. In the clinic we can make sure it happens. In the home it can't be made a requirement. What if they have to go to the bathroom while they're at target? Are they supposed to bring bleach? Then there's the fact that they have resource abundance during clinical trials where you've got clinical trials coordinators who can follow the patients who can meet them at the door, who can call them up and ask them if they have symptoms before they come into the hospital so we can make sure they're masked up if they might be spreading vaccinia to other patients. But once things are FDA approved those resources go away. And now it's just any old clinic can provide any of these medications to anyone, anytime they want with whatever protections they can. And there's really no official oversight for anyone aside what's been afforded by the IRB and the IBC. So this is a sample of one of the study recommendations for people which includes the add four ounces of bleach to the toilet bowl and underwear should be washed at 140 degrees in a standard washing machine for seven days. This is what our recommendations look like because we did, we sent recommendations to the study protocol people and said not only do we want to know what you're going to do to follow this we want to know exactly how you're going to make sure it happens and how you're going to check up on it afterwards. Because I can do that inside our hospital but I can't do that for the whole world. Not every medical center has a secure specifically designed clean facility where we store and prepare these products. You don't even know it exists probably it's the center for good manufacturing processes and island cells for transplantation in a super clean environment with incredibly trained staff. It has very fancy sort of ventilation systems to help manage this and air locks. Some agents have very specific and unusual recommendations like it might be reasonable to expect that people would know if I'm pregnant I probably shouldn't be I may not want to be participating in this kind of study but eczema has anyone ever felt like their eczema was a reason not to take care of a specific patient? And then there's the medical care system that is not equipped to care for these patients because people who are undergoing treatment for bladder cancer sometimes get crushing substernal chest pain and go to the emergency room. And they need to have an EKG and they need to have a cath and they need to have their arteries fixed and none of those people were participating in the study and most hospitals don't have any sort of a system for handling it when the patient presents with the card that's usually recommended from participating in this trial that says I've been given a genetically modified adenovirus and that's about it please put me in precautions or something like that what precautions? So the real questions we need to ask those are those are logistical issues for healthcare but the real questions as an ethicist that I think we need to ask are have we as a society decided that better treatments for cancer are worth the risk of genetically modified cancer treatment viruses that could spread throughout the community? I don't know what the answer to this is I mean obviously I've answered it to a certain degree for the hospital because I think I can manage the risks and I think it's worth finding out but I've answered it that doesn't mean any of you have answered that question about your own personal lives outside the hospital and have healthcare workers bought into this risk in addition to the usual risk of being exposed to MRSA or TB I mean we think sometimes you don't wear your yellow gown when you go into the room with a patient with a CRE but you know what you're getting into you know what sorts of things the patients might have I'm mad because you might take them into the next room and give someone else that but from your own perspective I'm not too worried about you you knew what you were getting into I don't think that people know what they're getting into when they take on the care of these patients and judging from what we found in even our own Ebola epidemic problem here which was alluded to by Dr. Farmer very astutely as saying it's the control over care philosophy we definitely had many many people who were in favor of control over care and will that be the way that we approach these patients and everything else except for their one cancer treatment so these questions are being actively avoided by attempts to manage and mitigate the risk I am actively helping people to not think about these things by making it as safe as possible and it's ethically and medically good I think to try and reduce the risk as low as I can possibly get it but I don't think it should be the end of the discussion that's all okay I went way over my time that I can do that does anyone have questions or now are you afraid of me do you really have a question oh no okay okay next up oh you have a question how does healthcare work to know that they are dealing with patients who receive what they receive so we require, at University of Chicago we require everyone to be notified who's participating in the characterization when these patients return to the hospital for any other visit they have to be accompanied by a center coordinator throughout the time they head to the door through their entire stay in the hospital that's our requirement so that there's always someone knowledgeable with them who's incredibly resource intensive to say the HSV for melanoma has actually been FDA approved and is now being used in a number of different clinics private clinics everywhere now I'll say that one is sort of limited in that it can really only reproduce in cells that have the machinery there's a switch for reproduction that's specific to melanoma cells so theoretically you could catch someone's melanoma treatment and it could treat your melanoma or something else but some of these other ones are more risky and you can't imagine that that's going to be a plan when it gets approved by the FDA the FDA is not going to say sure only if you have them accompanied by a healthcare provider 24-7 oh you have a question how can the FDA exception from informed consent model be used in this situation I'm not sure what you mean so there's an exception from informed consent that the FDA allows so the model that I can think of that might be relevant to this group would be in Nashville they had community meetings about IV solution that they were going to use if you had large volume loss and trauma oh yeah yeah if you were a random patient of volume loss then you would be administered this substance that they didn't know so there were community meetings about that substance yeah I don't think it was an FDA like I think that they had the IRB said that they needed to get community buy-in on it I believe somebody might know this story better than I do and so they had to sort of do public service announcements I would propose that that would be reasonable for this but I think it's a little bit on the terrifying side and I made it terrifying because I wanted you to listen but okay up next Alexia Torque who I thought her name was said Torque but I was wrong and she corrected me so now we all have to remember is an associate professor of medicine at Indiana University and the director of the Daniel F. Evans Center for Spiritual and Religious Values in Healthcare and the Fellowship Director of the Fairbank Center for Medical Ethics that's like you don't do anything do you just kind of sit around her research focuses on end of life care patient communication, spiritual aspects of care and surrogate decision-making she was the first person to describe and analyze the relationship between doctors and healthcare surrogates. Dr. Torque has also done work in medical education designing and evaluating curricula regarding end of life care and clinical ethics for medical students, residents and fellows please welcome Dr. Torque