TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, 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 giving radiation after breast-conserving surgery in breast cancer, respiratory syncytial virus (RSV) vaccines in adults, FDA approvals of drugs, and screening for genital herpes.
1:38 Pre-fusion F protein
2:38 Big problem in adults
3:15 Screening for genital herpes
4:15 Neonatal outcomes
4:45 FDA approved drugs not recommended for use in other countries
5:44 Five approved drugs refused
6:45 Domestic approval process different
7:45 210 new drugs approved with null findings
8:45 Hard clinical endpoints
9:17 Radiation or not in early breast cancer
10:17 Followed for 10 years
Elizabeth: Vaccines for RSV in adults.
Rick: Refining breast cancer therapy so we don’t need radiation.
Elizabeth: Let’s look a little more closely at FDA approvals of drugs and their prices and their utility.
Rick: And should we be doing blood screening for genital herpes?
Elizabeth: That’s what we’re talking about this week on TTHealthWatch, 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: And I’m Rick Lange, president of Texas Tech University 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 New England Journal of Medicine? These are two studies that we’re going to treat together and they are taking a look at two vaccine candidates for respiratory syncytial virus (RSV) in adults.
I’d like to first draw attention to the editorial, interestingly, because it educated me about RSV in adults. I had no idea that it was a major cause of death that rivals seasonal influenza among frail, older adults.
There is of course, a really big need to develop vaccines for this. These are two vaccine candidates that are in two different types of trials. One of them is a phase II and the other one is a phase III. In one of them, they had just shy of 25,000 participants, and this is an RSVPreF3 OA vaccine.
Wow, that’s a lot of stuff. Basically, what it reflects is the fact that in studying respiratory syncytial virus, it became clear that the prefusion F protein, the thing that is there on the virus before it fuses to cells and becomes infectious, is the thing against which we really need to direct these antibodies. This is the one that’s in the phase III trial.
They were able to prevent RSV-related lower respiratory tract disease in almost 83% of these folks. Their efficacy was 94%. Prevention of severe RSV-related lower respiratory tract disease was almost 72%. They didn’t have a whole lot of adverse vaccine side effects.
The next one, also using the prefusion F protein and an adenovirus vector, was a phase II trial just shy of 6,000 participants. In this one, they calculate their efficacy at 80%, a similar kind of a side effect picture.
Rick: I think that’s terrific news. By the age of 3, pretty much everybody has had an RSV infection, but as you mentioned, it’s a big problem in adults as well. As you mentioned, really little in the way of side effects, some local side effects, but really nothing systemic. It’s effective in the much older individuals. These are the ones that have fewer T-cells and are less likely to be able to fight off the infection. I would be very surprised if these aren’t out on the market pretty soon.
Elizabeth: Many of these folks also had comorbidities that would predict a more severe outcome from RSV disease. They also were able to tolerate this vaccine just fine.
Rick: Yeah. They decreased the risk of infection and the severity of infection across all morbidities and across all age groups over the age of 60.
Elizabeth: Let’s turn then to JAMA and take a look at this issue from the USPSTF. Should we be screening people for genital herpes?
Rick: That’s HSV-2. There has been a huge push that maybe we need to screen, just a routine blood test, to look for the presence of HSV-2. That would allow us to either put people on antiviral agents or provide them recommendations about how to avoid passing it on to partners.
Originally in 2016, the USPSTF said there really wasn’t good evidence to suggest that screening for it would be helpful. Now they are updating. They are looking at all the recent data over the last 6 to 7 years. What they have determined is those recommendations are still the same. The reason for that is, it’s got a high false-positive rate that creates a lot of anxiety, so at this particular time the USPSTF is saying it’s really not going to be helpful to do routine screening for HSV-2.
Elizabeth: Let’s talk about some of the consequences of this infection because, of course, many people are on acyclovir and other things to make sure that the virus doesn’t recrudesce. I’m wondering about the neonatal outcomes.
Rick: That’s the most concerning. It could be passed to the infant through the birth canal when the child is born. There may be some high-risk individuals that we should be screening for, those that have other sexually transmitted diseases and then we ought to be examining mothers to see if there are any lesions. But there is really no evidence to date that routine screening of mothers, all of them, looking for HSV-2 is going to be helpful. Now, it’s different for those mothers who have had known genital lesions.
Elizabeth: Let’s turn now to JAMA Internal Medicine, two studies that we’re going to treat together. One of them is an assessment of FDA-approved drugs not recommended for use or reimbursement in other countries. The authors put forward the notion that because of the Inflation Reduction Act and powers that are going to be granted to Medicare to start negotiating drug prices, taking a look at what other countries do with regard to utilization of newly-approved drugs is probably something that might be informative.
That’s what they did. They looked at international regulatory and reimbursement decision-making relative to new drugs. They have this mechanism that’s called health technology assessments (HTAs). It’s in Australia, Canada, and the UK. How were those applied to drugs that were approved by the FDA here between 2017 through 2020?
What they found out was that there were five FDA-approved drugs that were refused marketing authorization by an international regulatory agency in one of those three countries because of unfavorable benefit-to-risk assessments. There were 42 additional drugs that were approved here in this country that did not get reimbursement because of uncertainty relative to clinical benefits or unacceptably high prices. They note that the median U.S. cost of these 47 drugs that were refused was $115,281 per patient per year. A large number of these were for oncology indications. Do you want to comment on that before I talk about the other one?
Rick: How we approve drugs and devices in this country is different than in many other countries. As you and many of our listeners are aware, I had the privilege of chairing one of the FDA panels looking at approving circulatory devices. In all of our discussions, we were not allowed to consider the cost of the device. We just consider the benefit-risk ratio with regard to the health of the patient. If you don’t do that, oftentimes you end up approving either drugs or devices that are extremely expensive. We don’t have a mechanism yet in the U.S. of dealing with that. Now, other countries do and other countries say, “For us, we just can’t afford that.” I think at some point we’re going to need to get to the point where we actually look at the cost-benefit ratio for all the drugs and devices we’re approving.
Elizabeth: Would you suggest that this idea of examining how other countries are looking at this might be efficacious here?
Rick: I think it will be very helpful. They have done it for years. We spend more on healthcare than any other developed country in the world without significantly better health results, so we need to address this.
Elizabeth: Let me just go forward to this research letter that’s also in JAMA Internal Medicine examining a similar related issue and that’s FDA approval of drugs that don’t meet pivotal trial primary endpoints. Of course, the poster child for this is aducanumab for Alzheimer’s disease.
These authors looked at — between 2018 and 2021 — 210 new drugs that were approved by the FDA. They found out that 10% of those were approved with null findings for one or more primary efficacy endpoint. How do we need to change this so that we don’t go ahead and approve things that may or may not end up being very helpful? The authors come to this somewhat lukewarm conclusion where they say greater transparency regarding FDA decision-making could increase clinician, patient, and payer confidence in novel drugs.
Rick: One of the things that the FDA has taken advantage of is the use of panels, for example, to review this to see whether drugs should be approved or not. As you mentioned, in the case of aducanumab the panel recommended it not be approved, but the FDA approved it nevertheless with a great amount of consternation because it didn’t meet the primary endpoint.
Does it improve the Alzheimer’s symptoms? People oftentimes use surrogate endpoints. Well, it looks like the amyloid protein went down. Really, what you’re concerned about are the hard clinical endpoints. Any of these drugs that were approved without meeting the endpoints were orphan drugs, new drugs, and expedited reviews. Because there is always this balance, only approving drugs that are efficacious and hopefully cost-effective, but not delaying things too long. The general public, especially for diseases or conditions in which it’s terminal, or there is no other treatment, they want to get drugs even if there is a possibility they could be beneficial. That’s the balance that the panel and the FDA are trying to weigh when they are approving drugs.
Elizabeth: Okay. What’s our final one?
Rick: Elizabeth, we’re going to talk about breast-conserving surgery with or without radiation in early breast cancer. This is a study that’s in the New England Journal of Medicine. We would like to identify women who have breast cancer where we can provide them the optimal amount of therapy they need to prevent recurrence, but not additional therapy they don’t need.
In particular, there is a group of women over the age of 65 who have what is called T1 or T2 primary breast cancer, with a tumor that’s less than 3 cm, who don’t have any metastasis to the lymph nodes. They are usually treated by having the lump removed, and if the cancer is estrogen receptor-positive, putting them on endocrine therapy. Oftentimes, these women will receive radiation therapy, and the question is do they really need to receive radiation therapy because it has some side effects with it.
The study looked at over 1,300 women who had the breast cancer that I described, small, no nodes, and estrogen receptor-positive. They had it removed and then they randomized them to radiation therapy or no radiation therapy, and followed them for 10 years.
The 10-year incidence of either distant metastasis or risk of death from breast cancer was the same in both groups. Now, local recurrence occurred more often in those that did not have radiation therapy, about 9%, versus about 1% in those that had radiation. That local recurrence can be treated very easily either by a resection or by additional therapy, but the radiation therapy did not provide long-term significant benefits in those women that had this type of cancer.
Elizabeth: It’s rather onerous to have to undergo radiation therapy, at least according to the dosage schedules that are frequently seen. Was there anything else that they discerned among them that was a difference in outcome?
Rick: The only difference, Elizabeth, was the local recurrence rate. What they have done is they’ve identified a group of women who have a low risk of recurrence. What they’d like to be able to do is besides just choosing the physical characteristics of tumors, maybe we can add some biomarkers later on that will even give us more insight.
Elizabeth: On that note then, that’s a 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.