TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.
This week’s topics include pay for clinical trials, hospitalizations and death among COVID vaccinated people, using catheter techniques for valve replacement in some people, and how long cancer drugs that have had accelerated approval but found not useful remain on the market.
0: 56 Vaccination and hospitalization and death in COVID
1: 53 Less than 4% of hospitalized people
2: 51 Do preventative social things
3: 07 Accelerated approval for cancer drugs but not proven efficacious
4: 07 Failed in post-approval trials
5: 07 Use of surrogate markers
6: 08 Confirmatory trials also use surrogates
6: 45 TAVR in subpopulations
7: 45 Use in younger patients
8: 45 Mechanical valves with catheters?
10: 18 Incentives increased consent rates in smoking cessation trial
11: 10 Begs issue of social justice
12: 06 Why smoking cessation but not ambulation?
13: 01 End
Elizabeth: Should we pay people to participate in clinical trials?
Rick: In individuals that have received COVID vaccination, can we predict those that may be hospitalized or die from COVID?
Elizabeth: How long do cancer drugs that have been given accelerated approval but then subsequently shown not to be helpful remain on the market?
Rick: And using catheter techniques to replace aortic valves in people that are otherwise at low risk for having surgery.
Elizabeth: That’s what we’re talking about this week on TT HealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.
Rick: I’m Rick Lange, president of Texas Tech University of Health Sciences Center in El Paso where I’m also dean of the Paul L. Foster School of Medicine.
Elizabeth: Rick, how about if we turn right to the BMJ and this is taking a look at risk prediction for people who have been vaccinated for COVID.
Rick: Elizabeth, we have talked a lot about individuals that are unvaccinated and develop COVID infection, and are at increased risk of having severe infection or dying. Now, unfortunately, as we know that the vaccines are very effective — the most effective way we have of preventing COVID infection. But nevertheless, there is a small percentage of individuals who will develop COVID infection because the vaccine is only about 95% effective or their effects wane over time. Hence, the need for boosters.
So what this particular study attempted to do was to provide a risk prediction of COVID-19-related death and hospital admission in adults who have already received the COVID vaccination. This was a national prospective cohort study. The primary outcome was COVID-19-related deaths. The secondary outcome was COVID-19-related hospitalizations. To derive this information, they evaluated almost 7 million vaccinated patients.
Here is what they found out: the number of deaths and hospital admissions was incredibly low. It accounted for less than 4% of the hospital deaths and or hospital admissions among the patients. What factors predicted those that may have a poor outcome? Increased age; male sex; interestingly enough, Indian and Pakistani ethnic origin; and what was known as deprivation — that is, individuals who are more likely to be unemployed or not own their car or home, or to have household crowding.
Then there were some cause-specific predictors. Individuals that had Down syndrome had a 13-fold increase in having these complications. Kidney transplant, an 8-fold increase. Individuals that are in nursing homes, 4-fold. Sickle cell disease, 7-fold. Chemotherapy, 4-fold. HIV or liver disease, about 3-fold and neurologic conditions about 2 ½-fold.
Elizabeth: I think this is really important information. I would say that it could help inform all of these different patient populations, so maybe we ought to say to them, “Look, if you become infected with COVID, you should seek care right away.”
Rick: That’s right. I mean, identifying these individuals helps either increase prevention or making sure these are individuals that really do the preventative social things we talked about. But as you said, these may be the ones that we target for early, for example, monoclonal antibody therapy as well. So having this information is really helpful. By the way, when you look at it, it’s really not terribly different from those that are more likely to do poorly from initial infection as well.
Elizabeth: OK. Since we are in the BMJ, let’s take a look at this issue of “Your drug has gotten accelerated approval by the FDA and one of the requirements of that is that you have to perform confirmatory trials to prove that this drug actually is going to have meaningful impact on whatever the endpoint is.” We are in the midst of addressing this right now with the Alzheimer’s drug Aduhelm, which received accelerated approval. The predictors that I see say that its confirmatory trials could take up to 7 years. I would say that in the middle of all of that, the company is going to be reaping huge profits by the use of this particular drug.
One of the other issues that’s brought up by this accelerated approval pathway is that surrogate endpoints are used to determine whether the drug is having an impact. The model for this clearly is cancer drugs.
This study is taking a look at cancer drugs that received accelerated approval, but failed to improve their primary endpoint in their post-approval trials. First of all, they identified 18 indications in 10 cancer drugs that had been in this specific circumstance. When they followed this up, they found out that 61% of them were voluntarily withdrawn by the manufacturer. The remaining six of them, 33% the indications remained on the label for these drugs even after the post-approval trials had shown that they did not meaningfully impact on the endpoint. This is not a good situation and, again, illustrates what in my mind really looks like a paucity of oversight where we really need it.
Rick: This is a complicated issue. The reason we have accelerated approval is, if you have a terminal disease and there is a hope that a drug could be effective, people want them to be on the market. There has been a big push for the FDA to do this. As you mentioned, they use surrogate markers.
Now, what is a surrogate marker? Well, you give a drug and if the tumor looks like it shrinks, you go, “Oh, great, that drug is beneficial.” You’re not really interested in whether the tumor shrinks. You want to know, does it improve the patient’s overall survival? Who cares that the tumor shrinks if the person doesn’t live any longer? That should be the primary endpoint.
Surrogate endpoints and primary endpoints sometimes don’t match. It looks like the tumor shrinks, but the person doesn’t have a better survival. Many of these companies now don’t want to have primary survival as their endpoint. Again, that’s not good enough for patients.
The last thing is there is a lot of public pressure. When the FDA recommends withdrawing a drug, there are some people feel like they have received a clinical benefit from it and they don’t want to take it off the market. Ultimately, what happens is this goes to a committee that decides whether to take it off the market or not, so it’s really not left in the FDA’s hands at all. But I agree with you, you don’t want to raise people’s hopes and give a drug that in the overall outlook isn’t going to prove their survival.
Elizabeth: Absolutely. The other thing that they point out is most of these confirmatory trials that are conducted subsequent to the accelerated approval continue to use the surrogate measures. And as you’ve already said, that may not be the meaningful thing. Again, I would go to the Aduhelm situation. If we deplete amyloid, but we don’t slow the progression of Alzheimer’s disease, then that’s not really adequate.
Rick: Right. Again, it’s not that the FDA wants that. It’s because that’s what the pharmaceutical companies were pushing for. One of the reasons why they are pushing for that is because it’s easier to measure. Overall survival — it takes years to do those studies and they are expensive. Sometimes, occasionally, they are hiding behind it as well.
Elizabeth: Speaking of important outcomes, let’s turn to JAMA, taking a look at transaortic valve replacement.
Rick: When people have a blockage or there is a stenosis of the aortic valve — the main valve between the left ventricle and the aorta — one of the ways to treat that is to obviously to do surgery to replace that. Alternatively, we now have catheter techniques where we can load a valve on a catheter, insert it in the femoral artery up into that — where the native aortic valve is, and implant that valve, and we do it without any surgery. The patient usually goes home in 2 or 3 days.
It was usually oftentimes used for high-risk patients. Now, it has become so ubiquitous, it’s even oftentimes recommended in low-risk surgical patients that are elderly — 80 or 85 years of age — because they can avoid having surgery, and oftentimes in those individuals the surgery can lead to complications.
What this particular study said is, “OK, well, those are older individuals who have a calcified valve with three leaflets — that’s normal. What about in younger individuals that have two leaflets, called a bicuspid aortic valve?” They oftentimes develop stenosis at a younger age, 50 or 60, and is the outcome as good in those patients as it is in the older?
They looked at over 159,000 patients that had had the transcatheter aortic valve replacement, most of them in the older individuals, but some of the younger individuals [with] the bicuspid valve. What they determined is that they had very similar outcomes; the individuals did just as well when they were implanted in the bicuspid valve, as in the younger patients, as opposed to the tricuspid.
But here is the caveat, those valves typically last for no more than 10 years. If you’re putting it in an 80-year-old individual, that valve is likely going to outlive them. If you put in a 50-year-old, even though it can be just as successful, you’re likely to come back in 10 years and need another replacement at age 60 and another replacement at age 70. What it doesn’t really do is compare the transaortic catheter valve replacement versus surgery in this low-risk group. That’s really the study that we need in the future.
Elizabeth: Do you see a day when somehow things are going to be modified so that mechanical valves can be deployed, if you will, using the catheter technique?
Rick: Elizabeth, that’s a really interesting thought. I don’t see that. We are putting them in with less invasive surgery, called minimally invasive surgery and laparoscopic surgery. I see that being more likely than being able to put them in with a catheter.
Elizabeth: Maybe we’ll be around to see what happens. Finally, let’s turn to JAMA Internal Medicine. I frame this as, should we pay people to participate in clinical trials? To some degree, I guess we are already compensating people in many ways for participating in clinical trials. But in this case, they are taking a look at incentives.
Of course, all these bioethicists are out there saying we really shouldn’t incentivize or attempt to incentivize people to participate because it’s just going to skew the results by selecting the population who choose to actually participate in the trials.
In this case, they took a look at two randomized controlled trials of incentives that were embedded in two parent randomized controlled clinical trials; one was comparing smoking cessation interventions conducted at clinics in two health systems, and the other evaluating an ambulation intervention conducted in units in the hospital of the University of Pennsylvania.
Interesting, very disparate two trials. These folks were randomly assigned to incentives of nothing, $200, or $500 for the smoking cessation trial and $0, $100, or $300 for the ambulation trial.
What they found I thought was really quite fascinating. These incentives significantly increased consent rates among those in the smoking trial, at the lowest amount 21%, almost 22%, 36% and 47%. But in the ambulation trial, it really didn’t matter.
They also looked at these characteristics and found no significant effects of incentive size on things like time spent reviewing the risk sections of consent forms, perceived research risks, their understanding of the trial, coercion, or therapeutic misconceptions. So, does this open the door to say, let’s incentivize folks to participate in clinical trials?
Rick: Yeah. Elizabeth, this is really complicated. There is concern that compensating individuals may change the results. The other thing is it also begs the issue of social justice. I mean, are we now having people that would otherwise not be involved in a trial, but because they were poor or need the money, they become involved in trials — and assume the risk of a trial — when they otherwise wouldn’t do it, where the wealthy individuals wouldn’t do it?
This study would suggest that that’s not the case, but it’s probably not the end-all study to show that. You and I can both think that you can provide a big enough inducement where people would do it despite what the risk is, just because they need the money at the particular time.
The trial does suggest that modest reimbursement can help increase trial enrollment without changing the outcomes. I think that despite these initial trials I don’t think it’s going to open the door for a large amount of compensation. If you do decide to do that, which trials do you compensate and which ones do you not? Are people saying, “Well, I’m not going to enroll on that trial because I’m not getting paid, but I’m going to enroll in this trial because I am getting paid”?
Elizabeth: Yeah. I think it’s a really interesting thing. I think the editorialist also begs this question that I asked, which was why would people be incentivized in a smoking cessation trial, but not in an ambulation trial?
Rick: Yep, and it may be considering risk. This particular study leaves several unanswered questions.
Elizabeth: I think it’s worth noting that many clinical trials, of course, provide really great care to patients and that’s a wonderful incentive to participate. Anybody who is not in medicine who is listening to this, I would say it’s well worth considering regardless of whether you get stroked a check.
Rick: Elizabeth, and you’re right. I talked about the risk of a trial. These trials provide benefits oftentimes and that’s the reason we do the trial because we believe there is a benefit to a particular treatment or intervention or drug.
Elizabeth: On that note then, that’s look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.
Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.