John Lantos

Dr. John Lantos

Don't underestimate yourself. There's that

John Birch

and yeah,

Dr. John Lantos

there we go. Let me start with a trigger warning. This will be a deeply impractical talk. I will argue that our current system of research regulation is outdated and dysfunctional but also say that researchers have to follow it so this might cause some moral distress. In some cases that leads people to be hostile to the speaker. Don't do that, I'm just the messenger here. I never know what to call a disclosure these days since I've been accused of conflict of interest for every one of the things on this slide, so now I put them all up there. This is everybody I've gotten money for or given time to.

Dr. John Lantos

So foundational assumptions of current research regulation I think are these. In clinical care doctors know the risks and benefits of treatment. They can and do explain this to their patients in the course of clinical care and then together in a process of shared decision making the patient and doctor decide on the best treatment for that patient in that circumstance. Whereas in research investigators acknowledge that they don't know which treatment is best and to find out they are happy, willing, even eager to sacrifice patient's interest for the sake of the science that allows them to get an answer to an important research question. In other words, clinicians are smart, good communicators and can be trusted while researchers are heartless, don't care about patients and thus are in constant need of moral supervision. There's a deep history of this sort of philosophical distrust. It goes back to the 50s, but in its modern version, that would be post-Belmont. Larry Churchill, I think, is one of the first who articulated it. And

Dr. John Lantos

this deep history sees the moral obligations of clinicians and the moral obligations of researchers as being very different. The acknowledged goal of the physician-patient relationship is healing or the health of the patient. The scientific investigator cannot claim this goal or the moral authority that goes with it. Or Brody and Miller, what defines a doctor-patient relationship is the overriding commitment of the physician to that individual patient's benefit. Research participants form a different sort of relationship with the professionals in charge. Failing to see the difference between these two sorts of relationships creates a fundamental problem for protecting patients or subjects. from exploitation. This way of framing the problem is deeply embedded in the DNA of current research regulation so that it doesn't look so much at the risks of particular clinical trials, but it looks at is the risks of being taken care of by somebody whose fundamental moral commitments are not to the well-being of the patient. I think this is a narrow and outdated view. It was really a response to the sorts of abuses that got famous in Tuskegee and Willowbrook, which were non-therapeutic studies taking advantage of vulnerable populations in the name of science. And I think this approach to research regulation has been pretty good at curtailing those kinds of research abuses. But it doesn't make sense for most type of clinical research now, particularly the kind of research that we're talking about with learning healthcare systems. Furthermore, nine out of 10 clinical researchers disagree with this view. This is a non-scientific finding. But they say things like, this is Jay Katz, who was one of the strongest advocates for doctor-patient communication and shared decision-making informed consent. Research and therapy, pursuit of knowledge and treatment are not separate but intertwined. For Keith Barrington, a neonatologist in Canada, I have a fiduciary obligation to provide optimal treatment. I also have a moral obligation to know what optimal treatment is. I also simultaneously have a moral obligation as a researcher to keep trying to find out what the best treatments may be. He doesn't see these as being in conflict but sees them as being thoroughly harmonious and even synergistic. Or this quote from a role in a paper in the New England Journal about 10 years ago, the alternative to clinical research is not individualized and thus better patient care, but merely the pretense of omniscience that physicians do not and cannot possibly have.

Dr. John Lantos

So there are all these different kinds of inquiries that should, I think, lead to different sorts of regulation, but what we do today is try to cram them all into one model of what research is and then apply the sorts of regulation that are appropriate for some small subset of them to all the others. Traditional clinical research assumes that we know what the best is, what the standard of care is, and want to compare it to some new or innovative drug or treatment. Quality improvement assumes that we know what is best and want to figure out how to achieve it. Comparative effectiveness research assumes that we don't know what is best among widely used alternatives and learning healthcare systems I think assume that we're not even sure which questions to ask and therefore how to prospectively gather data instead they use an ongoing iterative process to try to even figure out where the problems lie.

Dr. John Lantos

So what is research? And this is to compare research and QI. This is from the federal regulations and the key element of research is that it's designed, it's a systematic investigation designed to develop or contribute to generalizable knowledge. Those of you who aren't steeped in the arcana of federal regulations may not know that As long as you promise not to try to learn anything, you can do anything you want and it's not research. You can try innovative treatments. You can try things that haven't been studied before. You just can't

Dr. John Lantos

have a goal of creating generalizable knowledge. What is quality improvement then? Systematic data-guided activities designed to bring about immediate improvements in healthcare delivery in particular settings. and therefore not generalizable and therefore not research. So in a sense, quality improvement is kind of local knowledge, but it's an odd distinction between particular settings and generalizable knowledge since most of us work in particular settings that look a lot like every other particular setting. So that if we do learn something about what improves the quality of care in one setting, were tempted to tell other people about it, at which point it becomes generalizable knowledge, at which point we were doing research without IRB approval and consent. And Bailey wrote, usually the knowledge that results from QI is most applicable to the local situation, but insights about one setting ordinarily have applicability in other setting. I'll skip over comparative effectiveness research quickly, only to say that It is sort of somewhere in between, I think, traditional innovative therapy research, or what do you guys call it? RENT and ROMP? Research on... That's ROMP versus...

Dr. John Lantos

To evaluate new treatments. Comparative effectiveness research has also been called ROMP, and we'll hear more about that later today. So why is there such overlap between all these things? Another key feature of the current system of research regulation is that it was developed before we understood the widespread and now quantified phenomenon of practice variation. Practice variation was, the study of small area practice variation was pioneered by Jack Wenberg and others at Dartmouth and they've now quantified how for almost any procedure you look at, you can find idiosyncratic, inexplicable, and pretty dramatic practice variations. They started doing their studies in small counties in New England, and they found, for example, that children in Littleton, New Hampshire were four times as likely to get tonsillectomies as children in neighboring Burlington, or twice as likely to get chest X-rays in Springfield as in neighboring Townsend. that the number of admissions was highly correlated with the number of acute care beds that were available in any geographic service area rather than any indication of medical need. Now, in thinking about the implications of this for the current system of research, when Wenberg first did these studies, no medical journal would publish them because nobody believed it could be true. So they rejected the papers at the New England Journal at JAMA, and the poor guy had to publish in Science and Nature.

Dr. John Lantos

Now it is so widely accepted that it raises the question, does research, whatever that is, inevitably increase risk compared to standard or individualized care, whatever that is? Or to put it another way, if somebody proposed a randomized trial in New England between a more aggressive or less aggressive approach to tonsillectomy, in which all the children in Littleton and Burlington would be randomized, to either approach, would they be at higher risk than they are now when they're not randomized but instead

Dr. John Lantos

subject to one approach or another based simply on their zip code? If so, if research is more risky, if randomizing them would be more risky, then the extra layer of protection are sensible. But if not, then the extra layers of protection for research are actually deceiving. because they suggest that clinical care is safer and research is riskier than either truly are. And that's a problem for truth telling and that's a problem for the fundamental basis of the way we think about the ethics of research and regulate it. It's based on these two views of what's going on today. Try summarize and simplify here. One view is doctors know what they're doing and the other is No, they don't. Doctors know what they're doing. This was at the HHS meeting about the support study controversy where

Dr. John Lantos

premature babies were randomized to two levels of oxygen saturation targets. And George Annis who's a regular writer for the New England Journal of Medicine and thus I think should know better. says, how worried are we about the loss of the physician's individual decision making when nobody really knows what the right answer is? We're really worried about it. A doctor's judgment matters. We have trained them. We think medical education means something. We put them through residency and fellowships. We want their judgment over our own. We value that very highly. They know what they're doing. Or Alice Drager at that same meeting said, It may be the case that individual care is not very evidence-based, but in the cases where you are not in research, your physician is attempting to individualize your care. And as soon as you go into a randomized system, that ceases. On the other side, Keith Barrington says you could call this individualized care, but in reality it's haphazard variation in practice which is due to the lack of good data. Or Norm Faust says, it would not be responsible to give an unstudied treatment to you in an uncontrolled way because neither you nor I nor future patients would ever know whether it helped or hurt.

Dr. John Lantos

So here's the fundamental tension this leaves us with. The ethics of research are such that research is seen as risky and totally optional. Nobody has an obligation to participate in research. Patients are mandatorily protected from participating in research, even if they want to participate, they're not allowed to unless the research goes through the various approval processes which require special permission to do research and then rigorous oversight. Whereas the ethics of quality improvement are that we are obligated to do quality improvement. It's a core competency now of residency training. It's a requirement for maintenance of certification by the American Board of Pediatrics and the American Board of Internal Medicine, and thus patients are obligated to participate in quality improvement projects with no consent, no oversight, and no prior approval by an IRB. But many of the activities that we do as part of research and that we do as part of quality improvement are exactly the same activities. How do you know if you're improving quality if you don't study it? And if you study it, you're doing research. So we may have an ethical obligation to do something that we are ethically and legally prohibited from doing. That is studying outcomes in ordinary practice settings in order to improve quality and save lives. So my view on this is that unstudied treatments have unknown risks and research studies, whatever you call them, to discover and quantify those risks are generally as safe or safer than providing those treatments in an unstudied way that we all have an obligation to do and to participate in those studies and we need a new system of oversight that recognizes that. If you're interested, here are four recent papers that compared the risks to people in studies to the risks of people with similar conditions who were eligible for those studies and not enrolled and showed that being in the studies was generally, had no increased risk. So the key need is to change the culture and develop ethics of learning healthcare systems. Ray mentioned this Fade and Cast paper. The key element of that is that traditional presumptions need to change and that health professionals and organizations have an obligation to learn and patients have an obligation to contribute, participate and otherwise facilitate learning. In some ways, it's the same ethics that we apply to medical education which has many of the same tensions inherent in it. That is, it's an activity done for the benefit of future patients training new physicians. for which current patients are put at risk, but we consider it obligatory and don't require IRB review or consent. So we're moving towards transparency by engaging patients in research. This approach has been endorsed by the Robert Wood Johnson Foundation, by the Institute of Medicine, and by PCORI. I mean, I think it's coming. It's just coming. Slowly, the next steps I think are new governance systems that thoroughly engage patients or surrogates, parents in all aspects of these activities, whatever you want to call them, including study design, consent, data interpretation, communication of results, dealing with IRBs and federal agencies, looking at adaptive and pragmatic study designs and creative use of big data. I'll finish with a quote that a patient advocate gave at an IOM meeting about this where she said, Look, we want safety. We want seatbelts and airbags, but we don't need five seatbelts and seven airbags, which is what the current system seems to be. Thanks.

Andrew Shuman

Great. I'd like to thank everyone for really thoughtful and provoking questions and comments. I will invite anyone who's interested to please work their way to the microphones to ask any questions to our group. But I'll take the prerogative of asking the first question and I'll address it to Professor Jacobson. In light of what we've heard this morning, I am having difficulty reconciling what is right versus what is practical versus what is allowed in the context of the pursuit of knowledge, whether or not we're calling it research. And I would love to hear your comments on that.

Peter Jacobson

Thanks. Pleasure to be here. Thanks for a nice, easy question.

Peter Jacobson

You'll find the answer at the back of my next book. Okay. We just heard three absolutely first-rate presentations raising lots of issues that pertain to that. And let me be clear. I don't have the answer to that question, and I'm not sure, as I listened to all three, that we'd get much agreement on that. Anyway, but let me respond by talking about some things that I heard from this presentation. I don't want to call the themes in a sense. First of all, what's the role of an IRB slash institutional control oversight with regard to all of the issues here. By way of background, I spent a little more than 20 years on the Rand Corporation's IRB, both as a Rand employee and then as an outside member when I came to the University of Michigan. And while I'm not a clinical researcher, I am a researcher, and while Rand doesn't and do much clinical research, per se. It did and does a lot of quality improvement work, and so a lot of the issues that we dealt with at the Rand IRB pertain to these kinds of issues. So the first issue is the role of oversight. The second is, of course, the trust.

Peter Jacobson

How do we maintain trust? The third is around informed consent generally separate and apart from an IRB process. So what are the common links here? First, choice. Who chooses? Under what circumstances? Second, how do we think about informed consent in a couple of ways? One analogy, used to emergency preparedness. So you have an outbreak, let's say, an epidemic, or let's say a bioterrorist

Peter Jacobson

outbreak, and you quarantine. Let's just keep it with an epidemic. You quarantine people. I'm sorry, I don't believe in quarantine, so I'm entitled to due process. But now we have hundreds of people who are quarantined. Can we have some type of collective due process so that people aren't detained improperly? I think the analogy is to the biobanks issue. How do we develop a collective informed consent process? And then the oversight. I did miss one. A consistent theme here is the definition of risk. And that's something that pervades IRBs. So I'm not going to spend time discussing cases where researchers differed with the IRB on whether any particular intervention constituted more than minimal risk. Suffice it to say that there were any number of cases where researchers wanted to waive informed consent based on impracticality, impracticability. You can't conduct the research. Well, that gets the institutional control. I think, just two final comments on this. One is,

Peter Jacobson

on the control side, it may be that IRBs are dysfunctional in some ways and inhibit research. But if we're going to replace them, we better replace that sort of repeal and replace. We better replace them with something that makes sense, that does provide some level of institutional control. That includes, I think, Dr. Lantos, the issue of QI research. There's got to be some institutional mechanism protecting patients. We can discuss what that is. But my work on the IRB suggests that. The second is that while it's important not to overplay the horror cases that Dr. Botkin mentioned and the support trial, Kennedy Krieger, those are still warnings. They're warning signs that if we don't give patients some information, maybe the transparency issue, some information by which they can determine whether to accept the risk in the support trial of oxygenation levels.

Peter Jacobson

We do risk losing trust in the system. Final point, what about population health? How does all this apply more broadly to public health? I think the clearest example Of course, it would be the newborn screening. But as we talk about these issues, I think it's really important to see how can we bring in public health? How can we use this to improve population health?

Pat Rinvelt

Good morning. My name's Pat Reinvelt, and I run the National Network of Depression Centers. And we focus, one of our focuses is on employing these learning health system constructs to advance the research on depression and bipolar. Thank you for the thought-provoking presentations this morning. And one of the things that occurred to me as we were having this conversation about ethics is I didn't hear any reference to the Hippocratic Oath, which was one of the earliest ethical, oaths that physicians took. And I was wondering if you could comment on how that still applied or if it needed to be moderated as a part of this whole construct.

Dr. John Lantos

Well, most people who cite the Hippocratic oath pick and choose carefully among its recommendations and its prohibitions. So that

Dr. John Lantos

abortion, for example, is prohibited. Surgery is prohibited.

Dr. John Lantos

I think many people would have trouble with both those prohibitions today. Having sex with your patients has gotten to be even a stronger prohibition. So Hippocrates in modern times seemed to be aligned on that one.

Dr. John Lantos

I think it's one of many codes. It was for a particular time in a particular place and has subtle meanings that may or may not be relevant today.

Dr. Jeffrey Botkin

Yeah, I think it's a really interesting question about what the role of oaths ought to be within the system. And one of the interesting aspects of the research oversight system is that the regulations speak to institutional responsibilities and don't speak to responsibilities of individual investigators. So I think SACCARP has recommended that there be more attention to the whole notion of individual responsibilities, investigator responsibilities. Colleague Aaron Rothwell, University of Utah, is working on the notion of a investigator's oath, where an investigator will explicitly

Dr. Jeffrey Botkin

proclaim his or her allegiance to a set of ethical principles in the conduct of that research, and the question is, Is that meaningful for people? Do they want to have some sort of commitment to a set of standards? And will that change investigator behavior in any particular way? But it may well increase trust and confidence in the research system. We'll see.

Andrew Shuman

And I'll address that with another question. So the concept of first to no harm is not technically part of the oath, but it's in many ways part of the spirit of where that's coming from. And I think a lot of the talks this morning were addressing what is and how do we define harm. And I will turn that question to Dr. Kim in relation to what you've been talking about in terms of practicality, as well as implementation and understanding harm in that setting.

Dr. Scott Kim

Oh, gosh. I don't know if this is answering your question, but I can't help but notice that like all good, discussions about ethics in liberal societies, we keep coming down to freedom and welfare, harm, free, you know, choice. So, you know, that's the perennial tension. And honestly, I think that what we have learned over the years is that if you only look at harm or risk as your only guiding star in ethics, you're going to ignore other very important things. And especially things that happen to do with people's sense of trust, relationships, which require transparency, give and take, shared decision making. So I think that regardless of what the outcomes are, no matter how good the intentions are, you can't ignore that aspect of what people expect. So I would just sum up. I think all three of our talks actually speak to that.

John Birch

I just wanted to add that I thought these were absolutely great talks this morning. The ability to bring clarity to some of these issues is really, really essentially important. My name is John Birch. I'm actually from Kansas City, although I don't really know John very well. I'm an angel investor, and I'm looking at opportunities to do something about some of these problems that make economic sense. And I want to just, I was at the AMIA conference over in Chicago the early part of this week.

John Birch

And one of the, a couple points were made there, well, lots of points, but one in particular here. It's amazing the extent to which we are still prisoners of the past. And I think it may be true here as well. What I mean is this, that we imagine electronic, we imagine medical data in terms of electronic medical records. It's very clear to most, to an awful lot of people working in that field that probably 60% of what is needed for medical decision making is not in the electronic medical record anyway. It's social and behavioral determinants, it's psychosocial vitals and so on, the sorts of things that 150 years ago maybe doctors really did have in their heads the primary care docs that came to visit you, but it's not there today. So the objective is to try to find some way to collect that data and make it usable for medical decision making. To bring it back to the points here,

John Birch

one of the interesting things that I think is possible by the use of electronic data is to make medical decisions based on data that was never collected for any episode of care. Longitudinal pediatrics, pediatric-based care is one of the ones that I'm at least aware of in which data that should be collected but usually isn't in gestational history and in the first four or five years of life are often very relevant to medical conditions that arise later on in life. And yet that data is never made available. How can we justify cost-wise collection of that data in the first place, retention of it for such a long period of time? It goes to the question that Dr. Kim was talking about which is your wife you mentioned was how are we going to collect all this data that we really want on patients and how are we going to, you were talking about consenting them but collecting data is in a sense a similar problem. I guess I just wanted to say if we were to turn the learning health system on its head, instead of saying what can we learn as a secondary use from data that's collected primarily for care, episodes of care, and of course all that comes from billable transactions,

John Birch

instead of that being the primary use, the primary use of collecting data on patients is for research purposes. All 320 million patients in the United States. And the secondary use is for primary care is for the use of that data. If we were to throw, if we were to do that, how would that change some of these ethical kinds of issues as well? Thanks. Can I just say one thing?

Dr. Scott Kim

I just can't resist saying this. We assume, I think part of what you're saying is maybe limitations of electronic health records. And I just think that any electronic health record system that forces psychiatrists to make their depressed patients sound exactly the same from patient to patient is can't be a good thing. And we're just, we accept things like that now. And I think we need to think long and hard about what it is that we're actually measuring with these existing or proposed electronic health record systems because those are not really, I mean, any clinician in this room knows that EHR is not really designed to serve doctor-patient relationship. It really isn't. We know it's for other reasons. So, you know, it's something to really think about when we have this discussion.

Dr. John Lantos

I guess I'd just say don't put either one first or second, but think about systems that do both. I think that's, I think the Scandinavian countries have the model for doing that.

Andrew Shuman

Hello.

Anne Dillon

I really love hearing all of your views on everything. My name is Anne Dillon. I work at the IRB here at U of M. I'm a reg analyst. I've reviewed your studies previously, Dr. Kim.

Anne Dillon

No, no, just as a disclaimer. And I wanted to know, I heard a lot about, you know, talking about the opt out. concept for using data, using specimens and kind of helping shift the culture of how patients are thinking about what happens when they come to the hospital and they give us information because they do it all the time. And I was a bit concerned about hearing about how, you know, using the institution, institutional trust for people. and having that kind of be a base for using specimens, using our data for whatever reasons there. And how does that really tie

Anne Dillon

in with that notion of respect for people? A lot of what we're talking about here is this minimal risk research. I think we all agree if there's increased harm, like real harm, we want people to know. for all this minimal risk kind of stuff, it's not maybe about harm, but it's about that respect and when you're in a study, what are you gonna have to do? And when the institution is behind that, their interest is really the institution. It's not necessarily the subjects. The NCAA with athletes in the institution, the university works for the institution. There's no advocate for the athletes. Who's the advocate here for, the patients giving all of their data and what does it really mean when they, you know,

Anne Dillon

when the institution is behind that versus a separate body really looking out for the interests of the people providing all the data?

Dr. John Lantos

I mean, I think respect for persons honesty, transparency and disclosure are the bedrock of any system that will earn and should deserve the trust of the people that it serves. I think the system we've set up now where we make this artificial distinction between one set of activities that we call research and in my view over disclose risks and much larger set of activities that we call clinical care where we under disclose risks doesn't have that requisite respect for person's transparency or honesty.

Peter Jacobson

I agree with that. But one of the continual problems with informed consent is that it must be knowing and voluntary. And to some extent, informed consent is an oxymoron. You can have information, you can have voluntary consent, How often do we have both? How often do patients really understand what they're being told, what the context is, how it affects them? And you expand that to the biobanks type of issue where the use of the specimen is far in the future. And what are we telling patients and individuals? So I think that problem remains an issue regardless of how one addresses the institutional question.

Dr. Jeffrey Botkin

Yeah, I guess I take your question as to be how do we actually implement a meaningful, transparent system? Because I think a lot of times institutions have their hearts largely in the right place in terms of how we set up some of these structures, but yet they're very poorly informed about what it is that the public actually might need to know. And I think the informed consent criteria, for example, that we're all familiar with were developed by a number of very well-meaning people sitting around a table thinking, here's what we think people ought to be told, entirely independent of what it is that people themselves might actually need to know, and particularly around individual. So I don't have the answer. I'm sure there's people in this room who have thought much more about how to implement transparency. But obviously, it has to engage the public in a much more meaningful way than putting a lay representative on the IRB and saying, we're good, we've got public input.

Andrew Shuman

I'd like to thank everyone for their attention and thank the panel for truly outstanding talks. We have about a 10 minute break and we'll reconvene. Thank you.