Doctors Express Concerns Over Proposed Research Regulations

Steve Kraske

Well, in October, the Office for Human Research Protections of the U.S. Department of Health and Human Services proposed updates regarding disclosure of risk to human subjects involved in research of medically recognized standards of care. The reason for wanting to make these changes, what they could mean for persons involved in these research studies, and the impact they could have on doing studies are what make our next two guests co-author an article disagreeing with the proposed guidance. That article was just published in the New England Journal of Medicine. Our guests are Dr. John Lantos. He's a board-certified pediatrician, and he's director of the Children's Mercy Bioethics Center at the Children's Mercy Hospital. And John Lantos, so good to have you here again. Great to be here, Steve. And also with us is Dr. John Spertus. He's a board-certified specialist in cardiovascular disease. He's on staff at the cardiology department at St. Luke's Hospital. And Dr. John Spertus, nice to have you too. Welcome.

John Spertus

Thanks so much for having me.

Steve Kraske

Well, Dr. Lantos, what's the issue here? What's the problem?

Dr. John Lantos

The issue is there's a lot of medical treatments that are in common use. Doctors disagree about which ones are preferable. And people... People think, doctors think the best way to figure that out is to study them. The question is, how much risk is involved in a study when the two treatments are in common use and doctors prescribe one or the other almost at random?

Steve Kraske

Dr. Spertus, explain that to me. What does that mean exactly? Give me an example of what John Lantos is talking about here.

John Spertus

So one of the real challenges in medicine today is that the FDA goes through rigorous trials to approve a therapy. And when that therapy is released, some doctors use it, some don't. And so there's enormous variation in how different doctors will choose to use new therapies in patients. And so the exact same patient being treated by one doctor might be treated with one medicine, but if the same patient went to a different doctor, would just get a different medicine. And so comparative effectiveness research, this field that we're concerned about, tries to say, we don't know which of these approved drugs is best for particular patients. Let's figure it out and let's study it. And the concern that we have is that OHRP, the agency that's regulating research, is saying, if you want to study it and the choice of treatment is going to be given by random chance rather than the doctor's personal belief, that is is a kind of research where you have to disclose to the patient not only that they're in the study, which we agree with, but all the risks of the therapy that they would be getting anyway. And that's what your concern is, right? How much you disclose to that patient. Well, and the way you frame it, it's as if we're trying to hide something from the patient. It's not that we want to hide anything from the patient, but if a patient needs a treatment and you're going to get one of two approved therapies, Those treatments have some risk with them, as all treatments do. But the fact that you would be essentially randomly given a treatment depending which doctor you said versus systematically being randomized to one treatment or another, to me, there's no difference. And so you don't – you never get disclosed

John Spertus

whether or not the – what the risks and benefits are of each treatment. If you had high blood pressure and – there are 20 different treatments for high blood pressure, I think the doctor would not go into great detail about the chance that your blood pressure might get very low, you might pass out, you might get a heart rhythm problem. They would just say, let's try this medicine, see how it works. And then if it worked well, terrific. If it didn't work well, they'd say, okay, well, let's try this one. Let's add a new one. And there's a certain randomness to what that doctor's preferences are for what medicine they'll start with first. And a different doctor might start with another medicine first. And so we want you to know that we would like to disclose to the patient, we're not sure which of these approved therapies are best. We would like to have you in a study where we randomly give one of these therapies and study how well it works for you so we can compare these two treatments.

John Spertus

We feel the patient should be known, should be informed that they're in the study. We want their participation in the study. But we don't feel that the inherent risks of the treatment are what's important to disclose because you're going to get the treatment regardless.

Steve Kraske

And so, Dr. John Lantos, the pressure right now is you have to disclose more than what you're suggesting should be disclosed.

Dr. John Lantos

Right. The assumption today that's built into these new draft guidelines is that being in a research study is much riskier than getting standard treatment because getting standard treatment, the theory goes, your doctor is talking to you. They're making a very educated, informed decision based on their knowledge and understanding of you as an individual. But what we've learned from studies is doctors don't, in fact, do that very well. And doctors who do research actually do it much more carefully. So for this particular type of research, that is research on therapies that have already been approved or in widespread use, we think being in a research project is often, not always, but often safer than getting treatment as chosen by a doctor who's not carefully thinking about the alternatives and carefully evaluating which is better.

Steve Kraske

And so, Dr. Lantos, the risk to medical research is what? That you're discouraging? What you're saying is by disclosing all of this information, you're going to wind up discouraging the kinds of trials and studies that you think need to be conducted.

Dr. John Lantos

Exactly right. So if you were the patient and you went to the good Dr. Spertus in his hypertension example, and he said, we're going to put you on hydrochlorothiazide. That's the treatment I think is best. Right. You'd probably say, I love Dr. Spertus. He's a great guy. He's a smart guy. Put me on hydrochlorothiazide. But if you happen to go to Dr. Jones, he'd say, I'm going to put you on Avopro. That's my favorite hypertension drug. He wouldn't say, we don't know which is better as a first-line drug. They'd recommend it. You'd trust them. You'd go on the drug. Right. There'd be risks. You went to a third doctor and he said, we don't know which is better. So what we'd like to do is evaluate it. We'll flip a coin to figure out which one to put you on and carefully monitor you to see if you have any of the side effects. It seems like you'd be safer. But the current regulations say in that third situation, you have to be told about all the risks of all the different treatments, and you'd probably say, whoa, that sounds awful. Just give me what you think is best.

Steve Kraske

And so the danger here, Dr. Spertus, is what? What kind of dampening effect would there be on medical research under these new guidelines as far as you're concerned?

John Spertus

I'm most concerned that people will be scared off of it. not only participating in the trial, but any therapy for their blood pressure if they were disclosed to all these risks, even though the benefits of preventing heart attacks, preventing strokes are very, very clear. If I walked in and saw a six-page consent form to participate in a trial and it disclosed all the risks that any lawyer had ever thought of could be done. And I'd be saying,

Steve Kraske

no, thank you, Dr. Spertus.

John Spertus

Yes. And I don't want to be in the trial. I don't want to be treated for my blood pressure. I'll just keep going as I'm going. I mean- That's a real concern. Plus, from the researcher side, it creates a tremendous amount of administrative burden, a lot of complexity, when in fact what we're trying to do is far simpler. And so I think it will discourage these kinds of studies from ever happening, and we need this kind of research to know what are the best treatments for not only patients in general, but for specific types of patients, because the treatment for, you know, elderly black patients with multiple comorbid conditions might be different than sort of young white women with no other medical problems. And we can't start to collect the data to know how to personalize care without doing the kind of research that's called comparative effectiveness research. And if we create burdens to doing that kind of work, I think we all suffer.

Steve Kraske

We're talking about new guidelines required by the federal government when it comes to medical research with Dr. John Lantos with Children's Mercy Hospital, Dr. John Spertus with St. Luke's Hospital. I'm wondering, Dr. Lantos, I mentioned in the intro that the article the two of you wrote was just published in the New England Journal of Medicine. What kind of reaction have you had? Are you guys two voices in the wilderness here currently? calling out about this, or are lots of colleagues joining you now saying, yes, there's something out of whack here?

Dr. John Lantos

controversy that led to the new proposed regulations from the federal government was a controversy about a study done in tiny babies, premature babies. And

Steve Kraske

oxygen use.

Dr. John Lantos

I was going to ask you about that. Yeah. And as a result of what that study showed was that babies who were treated with different levels of oxygen had different mortality rates. So it was an important study that helped doctors learn what the best dose of oxygen is for premature babies. But the feds found that the consent form for that study was inadequate because it didn't disclose all the risks, which were all the risks, as we've been talking about, of being a premature baby and getting oxygen in general. The babies in the study weren't worse off than the babies who were not in the study. They had all the same problems. As a result of that controversy, many doctors in bioethicists were sort of split down the middle. Half of them thought OHRP got it just right, that... the consent forms were inadequate, that you need to disclose all

Steve Kraske

these

Dr. John Lantos

risks, and that research is in general riskier than standard therapy. Half the bioethicists in the country thought that OHRP got it just wrong, so they would have agreed. So this is very much in play as a matter of public policy.

Steve Kraske

In

Dr. John Lantos

fact, the guidelines that we're talking about are draft guidelines that are open for public comment right now.

Steve Kraske

And that spurred your article

Dr. John Lantos

in the New England Journal of Medicine. Right. So the editors of the New England Journal had a companion piece with ours, and they agreed with our position for the most part. But many of the people who have written into the federal website take the

Steve Kraske

other point of view. Dr. Spertus, I imagine if we're sitting here talking about transparency when it comes to medical research and the use of patients, I'm just guessing here that if you want to open up the door to transparency when it comes to medical science in general in this country, you're talking about a box that all kinds of things would pop out of it and all kinds of issues here that might be very much in play if you want to walk down that road.

John Spertus

Well, that's true. I will just harken back to the last comment that Dr. Lantos made. Just imagine if the – so this study of oxygen levels in premature babies clearly showed that one treatment strategy was better than the other in allowing babies to live. Had all of that – the current OHRP regulations been applied to that study and – all of these other concerns were disclosed, it may have taken several more years to find enough participants willing to participate in that study. And for that delay in several years, many, many more babies may have died by not having the knowledge that came from this study. So I don't I'm going to answer your question in a second, but I just want to make very concrete what the implications are to us as a society of professionals learning how best to treat our patients if we create more barriers for people to participate in the research. You know, it is an interesting issue

John Spertus

that you asked about, sort of, are we going to open up a Pandora's box? And we had a A very interesting study where at St. Luke's we've been leading really the nation in cardiology on delivering personalized medicine. And every patient who goes through our cath lab when they have coronary artery disease, there's a personalized estimate of their risk of getting a bleeding complication. And when people are at higher risk for bleeding, you would treat them differently than if they were at lower risk for bleeding. We have done a nine-center study funded by the National Institutes of Health and the American Heart Association to look at the impact of giving these risks on care. And in fact, there was a 45% reduction in bleeding when the doctors knew the risk of the patient. What was remarkable was the variation across doctors. So even in the highest risk patient, if you're mom had a 10% risk of bleeding, which is a very high risk, you would want her to get some bleeding avoidance strategy. And these were premier centers. I mean, the Mayo Clinic and Washington University and Yale and Baylor. Across these centers, if your mom saw one doctor, her chance of getting... bleeding preventive strategies was 100%. But another random doctor from the same study, it was 0%. And that variation was so great that when we tried to publish the article, one of the reviewers wrote back and said, it seems to me that the biggest risk here is which doctor the patient is seeing, not their inherent risk for bleeding. And so do we need to start disclosing to the patients the likelihood that this doctor will treat you Well or not. Dr. Lantos, we're about out of time. Quick follow-up

Dr. John Lantos

on

Steve Kraske

that. Very

Dr. John Lantos

quickly. So the question that we are addressing in criticizing the OHRP guidelines is whether the patients who are getting treatments chosen by their doctor almost at random are at higher risk or lower risk than patients enrolled in a study. We say they're at higher risk. OHRP says they're lower risk. And those are just draft

Steve Kraske

guidelines we're talking about, so you're hoping to have some impact on what these guidelines actually wind up saying here. I want to thank Dr. John Spertus from St. Luke's Hospital, Dr. John Lantos from Children's Mercy. Thank you both for coming on. Thanks for having us.