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Disease-Modifying Therapy: Defining Response


Expert panelists consider how to define response to disease-modifying therapies and discuss the threshold for treatment ineligibility due to lack of response.

Neil Minkoff, MD: At some point, we are going to need to start thinking collectively about when we begin disease-modifying therapy, and if there is there a point where it is too late to start disease-modifying therapy. I hate to say that, but it is probably true. Could you give this a little high-level look at how you have been thinking about how that would look, what the great patient would be, and how you would follow that patient to see how you would define response?

Richard Isaacson, MD: That is a great question because I can tell you this: when the news headlines hit, and the headlines say that one of these drugs is positive in a trial and the FDA is going to review it, the meter of that interest is our phone calls the next morning. Our voicemail gets full at 30 calls, and we hit the full voicemail. It happens almost every time.

Neil Minkoff, MD: Yes, boom.

Richard Isaacson, MD: We have someone checking voicemail and monitoring it, it is a whole thing. I can tell you that two-thirds of those calls are from people with dementia because they cannot tease out what that means: “What is MCI [mild cognitive impairment]? What does that mean for me?” I can tell you that some of the patients who are the most steadfast, most interested and invested in trying to do anything to get this treatment are those with severe dementia. I can tell you that for a fact.

Neil Minkoff, MD: Right.

Richard Isaacson, MD: For example, when the drug is going to be FDA-approved for mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. Let’s say that, at some point, a disease-modifying therapy is approved for those 2 classifications, what do I do as a clinician when I have someone with severe dementia who is begging me? They will do anything, they will pay anything, and they will mortgage their house. When it is not FDA approved, then it is generally not covered by insurance. It is not FDA approved for that condition for the patient with severe Alzheimer disease, for example. I can tell you that the doctors’ hands are going to be tied because you are going to have patients who are begging and pleading, “Please, no. Do not withhold this. Do not do that to me. Please, she deserves this. This is my mom. We need to do everything. I do not care what the FDA said.” Doctors get stuck. Doctors get stuck, and you have to talk about the evidence.

What I am trying to say is that doctors prescribe drugs off-label all the time. The COVID-19 [coronavirus disease 2019] pandemic was a good representation of this, where no one knew what the heck to use. We did not have treatment, so doctors said, “Let’s use that drug, this supplement, and that vitamin, and maybe it will work. I read it online.” Using something off-label that has that type of cost and complexity, meaning coming in every month for an infusion and getting surveillance MRI scans and whatever else, is going to be a challenging situation.

Mona, you were going to say something?

Mona Chitre, PharmD: No, I was agreeing with you. Hope is a beautiful thing. It puts the system at strain when we know that we want to follow evidence.

Richard Isaacson, MD: Yes.

Michael Cantor, MD: We have examples of this today though. If you look at what happens when people come into their primary care doctor and have some memory loss, they are usually put on a drug, most commonly Aricept [donepezil]. They may or may not meet the criteria, but that is what primary care doctors know what to do in most cases. As the disease then progresses, oftentimes despite the treatment with the donepezil, you reach a point even if you add memantine, where they are not benefitting from the drug. You can see that, however you want to measure their cognitive function, it is getting worse despite the treatment. With the decision to take that away, Neil, not only is it that you do not want to start it too late, but if it does not work after a certain point, that is a horrible, horrible place to be. And all the clinicians who have dealt with people with dementia and their families have been in that situation, trying to have a discussion about why it is OK to stop this medicine because it does not appear to be working. It is what Mona said: it is people’s hope. That is what my attending physicians said so me as a resident: “Never take away people’s hope.”

Neil Minkoff, MD: I understand. I do not want to take anybody’s hope away, but we are going to need to be thinking about who the target population is and how we do that. To Richard’s point, the potential drugs are not going to be easy. It is not going to be like handing out a prescription for which you show up at your local apothecary and go on your way. There is going to be a lot of follow-up. It is going to be burdensome on all sides of this.

Michael Cantor, MD: I agree, and those decisions will be made. There will be rules. There will be payment policies put into place. Some people will like them, but most people will not, especially those who do not get their treatment paid for under those payment policies. We will start with a payment policy, and there will be a lot of back-and-forth and push-and-pull. This is usually how it goes, then it evolves, and then there are new things. We are going to go through that with dementia treatments just like we have done with some of the others that you mentioned earlier, Neil, with multiple sclerosis treatment, rheumatoid arthritis treatments, etc. The distribution of scarce resources in our society is determined by these battles over coverage policies and payment policies, so I anticipate that we will see the same thing here and the same growing pains that we have experienced with other similar situations with biological agents.

Neil Minkoff, MD: Then to complicate things further, there will be a larger dose of federal involvement.

Michael Cantor, MD: Yes. The new sheriff in town, right?

Mona Chitre, PharmD: Yes.

Neil Minkoff, MD: Even beyond that, with the patient population and the Medicare ramifications, there is going to be a political policy aspect to this as well beyond just the medicine.

Transcript edited for clarity.

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