John Lantos

Dr. John Lantos

Don't underestimate yourself. 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 I will argue that our current system of research regulation is outdated and dysfunctional, but also say that researchers have to follow it.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 patients' 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 to 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.