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In part 2 of this Instagram Live interview, Jeremy Faust, MD, editor-in-chief of 名媛直播, sits down to talk with and , about how the uncertainties and potential pitfalls of drugs approved under the accelerated approval pathway are often not made clear to the general public and patients. You can view part 1 of this discussion here.

Fernandez Lynch is an assistant professor of medical ethics and health policy at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Kesselheim is the director of the Program on Regulation, Therapeutics, and Law (PORTAL) of Harvard Medical School and Brigham & Women's Hospital in Boston.

The following is a transcript of their remarks:

Faust: Do you think, Aaron, that there's a bent towards exuberance?

Patient advocates are a big area here. On one hand I think patient advocacy is just so important -- getting attention, moving things forward, pulling the levers and making things happen. On the other hand, I often worry that there is a bias towards, "It's new, it works, I want it."

Do you feel like that sort of pressure from people who mean well, but maybe might be a little too optimistic and downplaying of the possible harms, can -- I won't say tank the process -- but can influence the process in an undue manner?

Kesselheim: Well, I think that that is part of an educational gap. I think that, unfortunately, all too often when a drug is approved by the FDA, no matter how it's approved or what mechanism it's approved from, there is not enough information that is made well-available to patients, to the patient groups, even to clinicians that describe the basis on which the drug was approved.

I think that part of the exuberance that can come with accelerated approval drugs is, oftentimes it's important. It can be a new drug. But I think that if people understood more about the nature on which the drug was approved and the special pathway that was used to approve the drug, then people might understand more about what the remaining uncertainties are and the possibility that these drugs might not work.

So I think that to the extent that that's true -- that what you're talking about is the case, that there is unnecessary exuberance or however you put it -- I think that's just because as a healthcare system, as a regulatory system, we have not educated the public well enough about the drugs and the basis on which drugs are approved.

Faust: Someone in the comments put something interesting, which is: doesn't the FDA just require all this information to be on the inserts of the packages of the drugs? I think the answer to that is yes, but it doesn't really matter because no one reads them. Patients very rarely open those up and know what they mean, the doctors certainly very rarely do.

This is kind of like -- Holly, correct me if I'm wrong -- but this is taught in contracts. If there's an 8,000-page contract and on page 7,000 there's some fine print, it's not necessarily enforceable because no one was ever expected to read that part. Is that right?

Fernandez Lynch: Well, you're still supposed to read it. And it doesn't matter if it's eight pages or 8,000 pages, people are still not reading it, right?

And so there are all these communication challenges around labels. We have boxes and key fact summaries and those types of things, but on the one hand, it's asking a lot of physicians to be aware at the fine level of detail about the trial data that's supporting these various products. On the other hand, you think -- well, that's the responsibility in treating patients.

But often, the expectation is that you can rely on FDA approval as the heuristic. Right? People assume that it's safe and effective because the FDA allowed this on the market. We have trust in the agency. And so there may not be a lot of awareness about the different pathways for approval -- recognizing that the accelerated approval pathway has evidence behind it that's not as high-quality as other types of approval.

In some important ways, FDA may be kind of shooting itself in the foot on that communications struggle. Which is to say, if there was an FDAer on this call, and Aaron and I were to say, "Accelerated approval is a lesser standard," the FDA folks would say, "No, no, no, it's the same standard. It's substantial evidence of effectiveness. You still have to show the drug is safe and effective."

That has been in part to get payers to pay for accelerated approval drugs, to insist that it's the same standard. Aaron, I don't know if you agree with me -- I think I do know if you agree with me on this, but I won't speak for you. It's not the same standard, right? I mean, you're still meeting the substantial evidence of effectiveness standard under the statute, but you're using an endpoint that's not as reliable or high-quality as that required for traditional approval.

Faust: Did she get your opinion correct, Aaron?

Kesselheim: Yeah. I mean, I think that this goes to the point that there are different standards that are used for regulatory approval of a drug and then whether or not a drug should be paid for, given the fact that these are max-priced drugs, because in the U.S. we allow drugs to be priced at whatever the company wants [them] to be priced at a lot. Whether or not a drug is approved through accelerated approval or it's approved through regular approval, often the drugs are set at the maximum price they can [be]. What that means is that the decision about whether or not the drug is covered doesn't necessarily have to do with the same kinds of decisions that the FDA is making when it's approving the drug in the first place.

So, I think that the most important thing is to try to get the information out there as clearly as possible. And as you mentioned, the drug labeling is not really designed as a way of trying to communicate information clearly. It's a way of trying to communicate information comprehensively, and there have been other mechanisms that have been proposed to try to provide a way of ensuring that this information gets communicated and taken up.

Faust: Holly, you wrote in 名媛直播 about a process like this for Duchenne muscular dystrophy. I'm wondering if you could just really quickly summarize what that was about, and as a follow-up question related to what I was saying before: how do patients react when people throw kind of cold water on something that they're excited about?

Fernandez Lynch: Well, the second question is easy, right? It's not well-received in many instances. I'm sure Aaron has experienced this as well. There are often circumstances where patient advocates will say, "We're willing to accept more risk, more uncertainty, because we don't have anything better. So step aside bioethicist or lawyer or physician or whoever says that we shouldn't have access to this thing." I think it's perfectly reasonable for individual people to make those judgments. The problem is that FDA as a public health agency has to make population-level regulatory decisions.

And when you weaken the standards for approval and allow products on the market that don't work or that will be very difficult to gather the confirmatory evidence [for], what it tells industry is, "You don't have to prove that your products are good. You can profit from them, but you don't have to prove them."

And again, if we think about economic incentives, the result of that is going to be that we might get a lot of products on the market, but we won't have any idea whether those products are actually safe and effective.

The kind of analogy that I find most salient is if I have a terrible life-threatening disease, I don't want to walk into a GNC or a Vitamin Shoppe and look at shelves and shelves of products that I have no idea work or that my clinician has no idea work, right? I want things that are proven to be beneficial, and we get that through high regulatory standards.

Very briefly on the point about Sarepta -- Sarepta is a company that has developed a number of products for different genetic mutations related to Duchenne muscular dystrophy. They have had a number of controversial accelerated approvals, going back almost a decade at this point to their very first accelerated approval, a drug called Exondys [eteplirsen], that was highly controversial even amongst the FDA reviewers. Ultimately, it was granted accelerated approval, I believe in 2016, and still has not completed its confirmatory studies.

The piece that Reshma Ramachandran and I wrote on 名媛直播 was about Sarepta's most recent accelerated approval of a drug called Elevidys [delandistrogene moxeparvovec] that was relying on an even less well-understood surrogate marker, something called micro-dystrophin. It was a very small study, very limited change in this surrogate marker, very unclear that that surrogate marker will lead to clinical benefit -- and kind of a history within a particular company of not meeting its confirmatory trial obligations in a timely fashion.

Now, FDA is supposed to consider each drug application on its own merits, and yet it does seem relevant if you have a company that has received multiple accelerated approvals in a given indication or related indication and has not been able to kind of meet the back-end obligations of this pathway.

Faust: OK. Aaron, one question that comes out of that is whether or not you think the FDA is relying on other agencies or other groups like CMS -- which is Medicare and Medicaid -- or insurance companies to say, "Look, FDA's going to say it looks safe and effective. That's all we really care about, not whether it's worth it or anything else." Is that what's happening here? That the FDA is sort of saying, "Look, it's not a perfect pathway, but we'll rely on Medicare and Medicaid to tell us whether it should be covered or not, and that's good enough?"

Kesselheim: Well, I think that you are raising the point that those are separate agencies with separate decision-making processes.

I think that the FDA is trying to make the best decision that it can based on its statute and the decision-making that it has to make. And then separately, after a drug is approved and the question is whether or not CMS should cover it, then CMS needs to make the best decision that it can based on all the data available to determine whether or not the drug is reasonable and necessary to include as something that Medicare will cover.

They're separate agencies, and historically CMS has taken FDA approval as sort of de facto evidence that something is reasonable and necessary. But the experience with the Alzheimer's drug Aduhelm [aducanumab] a few years ago -- when CMS came to the conclusion that it would not provide unfettered coverage to that Alzheimer's drug, but would only cover it in the context of additional clinical trials -- was shocking and remarkable and basically more or less the first time CMS had done that on this scale for an FDA approved drug.

And that leads to the question of if the FDA continues down the pathway of approving more accelerated approval drugs -- like the ones that Holly was talking about or like Aduhelm where the evidence is uncertain -- will CMS make separate decisions more frequently?

Whether or not CMS has the resources and ability to do that is a separate question, but I think you raise a very important point that these are separate agencies making separate determinations. Each of them try to make the best decision they can based on what they're supposed to be looking at.

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