The rule of thumb in life is to not talk in polite society about race, religion, politics, money, FDA regulatory affairs, reproduction, taxes, and probably quite a few other hot button topics. However, I feel compelled to break life rule number 1: don't talk about race.
J11 dares to speak the truth and will not be silenced.
I have been reading up on African American (AA) Alzheimer's. What is of great interest is that AA AD is very different from European AD. For example, research has found that for AA, epsilon 4 is not typically a risk factor. It has also been found that an African specific APOE variant exists dubbed R145C. So basically there are 3 important APOE SNPs; there is the rs7412 SNP, the rs429358 SNP (these are the two generally recognized SNPs) and then there is the R145C variant found in some with African backgrounds. The R145C variant apparently only occurs on the epsilon 3 strand. Research has also found that e3 (R145C) with e4 in Africans increases AD risk significantly. Surprisingly, research has found that e4 in Africans with surrounding DNA from European ancestors causes European like e4 risk, while from African ancestors causes African like AD risk (i.e., small risk increase).
An additional difference involves tau. tau levels do not seem as overly predictive of AD in African derived populations as in European ones. In summary, AA AD appears to be complicated even while it has not as yet even been explored that much. There is quite likely a large amount more to learn (which could take some time).
All of the above can be easily found with an internet search so I will not post extensive referencing.
This is now where the difficult and highly murky aspect of race enters the scene. If we assume that everyone is just the same and that race does not matter in the pathological development of amyloid dementia, then anti-amyloid treatment might not (as a very rough first round guesstimate) work to plan.
Yet, the CMS has requested that clinical trials have populations with diversity reflective of the Medicare AD population. This on the face would seem a worthy goal. However, what the above description of African specific AD suggests is that such hasty inclusion (without enabling clinical results) might merely result in trial failure. CMS is creating the environment for an Aducan trial is not a clear replication of the original studies; this clearly increases the risk of missing toplines. One can only guess with some cynicism that this is not a bug but a feature: Claim to champion diversity, deny treatment to desperate AD patients (of all races for years), let the clinical trial drift for years and then feign surprise when the trial reads out negative. Anti-amyloid clinical research is still in its formative stage, it would probably be best to replicate results with great attention to the conditions of the original result.
The last two decades of anti-amyloid research has largely been focused on European populations. It has taken these 20 years to figure out how anti-amyloid treatment works-- largely in white people. Not that much clinical research has been done for other racial groups. The assumption has simply been that treatment should more or less have the same efficacy across racial and other groups. The above research that I noted suggests this might not be true. I had speculated that such group differences might exist earlier on thread, though I never got around to investigating the idea further (until recently).
Merely wishing something to be true does not make it to be true. As a first guess, if epsilon 4 does not pose an increased risk for AA than it is hard to predict that including AA with epsilon 4 in an anti-amyloid treatment arm would result in treatment efficacy. With the current research it might almost be thought unethical to do so because there is no enabling research to suggest it will be effective and it could then have a low a priori probability of success. This, however, is what the CMS has requested.
As also noted elsewhere, pharma companies typically have developed products with this monoracial focus in the past during the clinical trial stage and then moved into a more diverse focus once they have banked a new product. Why do they do this? Is it racist to do this? Not really. Typically science is complicated. You can't merely snap your fingers and say: "Scientists fix this. Give me the results tomorrow." It doesn't work like that. It has taken decades since the first Alzheimer vaccine to reach the point where we have an effective anti-amyloid treatment (in white people) with Aducan.
With anti-amyloids (and much other pharmaceutical research) what happens is that you have a pay day and then you can do near endless amounts of research for subgroups. Once you have the money in the bank you can solve African Alzheimer's and other types as well. Without the money and merely doing another clinical trial what could happen is that after YEARS of clinical research they will report back that Aducan appears ineffective in subgroups and that "oh by the way" the phase 4 trial also showed a negative top line primary as a result. Yeah! /s The tens of millions of desperate amyloid dementia patients and their families/caregivers will be so happy. /s
Forcing this research at the coverage with development stage would mean that the pharmas are further stressed for yet more money without any obvious in-revenue to support the expense. This is almost the perfect strategy to shut down all further research effort (even beyond Alzheimer's to include many other serious health challenges). It's a feature not a bug. One would then tend to expect a reduction and not enhancement in the research effort. From the previous experience researching European dementia, sorting through the logic of AD in other racial groups could easily prove to be equally frustrating. It is even possible that for some groups anti-amyloid treatment will not show any efficacy. One can only hope that even more research confusions can be avoided by carefully planning future clinical trials.
How can such basic knowledge appear to have alluded the CMS? One could do better by simply living in a shack in the woods and reading pubmed. Haven't they read the research noted above. CMS: Do better! Is the CMS truly so far out of the loop that an interested person could out-research them? Don't they have any contact with the AD research leaders? From their comments page I am guessing not.
I am at a loss for words; How could this even be possible? If they really need helpful advice, what they could do is setup a booth or something at ICAD, grab some AD thought leaders and toss them 1 large and chat over a cup of tea. Not the best idea, though at least it's a start. Perhaps setup their own AD expert advisory counsel or something. They appear to have simply thrown out bullet points into the discussion to appear "with it" about diversity and wokeness and then actually seem very far out of the picture; apparently they lack any meaningful understanding of the available evidence. Of course, not providing anti-amyloid treatment on the basis of race would be close to the worst possible outcome from the point of view of wokeness ; yet, the even worser outcome would be providing treatment to groups who had no potential of gain and perhaps would only experience side-effects (no gain only pain).
The CMS briefing document also seems to be constantly out of step with where the thought leaders are in Alzheimer's. Considering that Alzheimer's could easily cost into the tens of billions of dollars, building out high level AD expertise in house would be a good game plan. Why do all the top AD researchers (we all have a fairly good idea of whom they might be) only have industry sponsors and not CMS sponsorship? CMS is the ultimate payer here; why not be closer to the dementia research frontier? All of these comments might be off-base (as these comments are only from my perspective); I hope that I am off-base; I would prefer to be wrong than right-- yet, more often than you might like you are right and are quiet about it and then a bigger problem then happens because you were silent. My overall impression is that CMS needs to enhance their understanding of amyloid dementia.
Back to the main topic. The problem as stated above is that adding in African Americans into a clinical trial could introduce data noise. The expected relationships that have been found in Europeans populations might not be present in African Americans. The research to my best knowledge does not support benefits of anti-amyloid treatment in the same way in AA as in Europeans, though this is very uncertain as the clinical research has not been done.
What could be done to increase equity and avoid negative trials? One workaround is to fast walk the enrollment of AA into the upcoming ICARE trial while slow walking possible CMS and Biogen enrollments of AA in upcoming Aducan trials. {Perhaps an even better workaround is to do a focused phase 2 in AA and then use this result to determine the statistical plan of any phase 3/4 plan (just as taurx did with its phase 3 trials). If the phase 2 trial found that AA AD was largely indecipherable at that time then the phase 3/4 trials could move the AA out of the topline results.} This would allow at least some knowledge to accumulate regarding efficacy patterns in AA populations. In the ICARE trial all patients would be on treatment, so one might be able to rapidly develop understanding of how effective Aducan might be in different genotypes etc.. Once sufficient insight had been gained, then it could be applied to other trials which could then be fast walked. If the insight were still considered too preliminary and uncertain, then perhaps the AA results from the trials (e.g. the phase 4 Envision) could be set aside and analyzed separately from the topline primary.
No one seems to be making these talking points, so I am unclear whether these comments are valid. How could such an important topic have been completely disregarded? The above research related to different manifestations of AD was widely reported over the last 10 years in the research literature.
Celebration Thread! Biogen is going to the FDA with Aducan.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Last edited by J11 on Thu Feb 24, 2022 3:52 pm, edited 2 times in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
I have had so many ideas about anti-amyloids recently it is difficult to keep up to date on thread. I thought perhaps I should start posting in point form and not overly elaborate on my many ideas.
One of my better ideas is that perhaps the CMS could propose a highly reasonable offer.
Possible Agreement Outline
1. Biogen would open up its patent on Aducanumab in the US for roughly the next ~5 months.
This could allow possibly tens of millions of Americans to access the drug.
Access would be based upon understandings developed with the patient doctor relationship.
(This idea was highlighted by the Down Syndrome Association's comment to the CMS during the first round of comments and it seemed to me to be a quite powerful way to frame how treatment access should be managed.
There would be latitude in accessing treatment based upon what the patients and doctors could agree upon.)
Basically, let patients and physicians think up what makes sense for the patient. This would take away the highly politicized arena in which Aducanumab has been discussed to date. In such a context perhaps microdosing Aducanumab in the context of early Down's might seem reasonable. Bottom line give patients and doctors some lead way in working out what they felt was best as a treatment regimen.
2. Biogen could charge a nominal production fee. This could be perhaps close to marginal cost though this would not need to be directly specified as such.
3. Biogen would be allowed to sell product "as is" just like with vaccines and would not be held to account for damages arising for side effects etc. given reasonable care is satisfied.
4. On the basis of achieving some indicator of anti-amyloid success (perhaps a positive readout on Clarity), CMS would agree to pay out a sum to Biogen. Perhaps $5 billion would be reasonable.
Everyone wins!
1. Patients would clearly win. They would have near term access to an anti-dementing product that has substantial supporting evidence and would pay a minimal amount to access the product.
2. Biogen would also clearly win. They would be in for the $5 billion pay day if they could establish with yet more evidence that anti-amyloids were effective. They would also rapidly be able to accumulate a massive amount of clinical evidence rapidly. This would allow deep insights into the efficacy of Aducanumab into different patient populations. It would also be an overwhelming public relations win.
3. CMS would also win . They would be seen as unlocking population scale Aducanumab treatment, while only paying out for treatment that subsequently demonstrated efficacy. It would be a mechanism that allowed treatment now and definitive evidence later.
Happy patients; Happy everyone.
This idea largely parallels the wine street scene from a Tale of Two Cities (hopefully, without the need for an ensuing revolution). It would somewhat put it to the man, though at the same there is the recognition that we clearly need to reward pharma if we want cures for difficult neurodegenerative and other illnesses. Overall then the idea is really a win for everyone.
One of my better ideas is that perhaps the CMS could propose a highly reasonable offer.
Possible Agreement Outline
1. Biogen would open up its patent on Aducanumab in the US for roughly the next ~5 months.
This could allow possibly tens of millions of Americans to access the drug.
Access would be based upon understandings developed with the patient doctor relationship.
(This idea was highlighted by the Down Syndrome Association's comment to the CMS during the first round of comments and it seemed to me to be a quite powerful way to frame how treatment access should be managed.
There would be latitude in accessing treatment based upon what the patients and doctors could agree upon.)
Basically, let patients and physicians think up what makes sense for the patient. This would take away the highly politicized arena in which Aducanumab has been discussed to date. In such a context perhaps microdosing Aducanumab in the context of early Down's might seem reasonable. Bottom line give patients and doctors some lead way in working out what they felt was best as a treatment regimen.
2. Biogen could charge a nominal production fee. This could be perhaps close to marginal cost though this would not need to be directly specified as such.
3. Biogen would be allowed to sell product "as is" just like with vaccines and would not be held to account for damages arising for side effects etc. given reasonable care is satisfied.
4. On the basis of achieving some indicator of anti-amyloid success (perhaps a positive readout on Clarity), CMS would agree to pay out a sum to Biogen. Perhaps $5 billion would be reasonable.
Everyone wins!
1. Patients would clearly win. They would have near term access to an anti-dementing product that has substantial supporting evidence and would pay a minimal amount to access the product.
2. Biogen would also clearly win. They would be in for the $5 billion pay day if they could establish with yet more evidence that anti-amyloids were effective. They would also rapidly be able to accumulate a massive amount of clinical evidence rapidly. This would allow deep insights into the efficacy of Aducanumab into different patient populations. It would also be an overwhelming public relations win.
3. CMS would also win . They would be seen as unlocking population scale Aducanumab treatment, while only paying out for treatment that subsequently demonstrated efficacy. It would be a mechanism that allowed treatment now and definitive evidence later.
Happy patients; Happy everyone.
This idea largely parallels the wine street scene from a Tale of Two Cities (hopefully, without the need for an ensuing revolution). It would somewhat put it to the man, though at the same there is the recognition that we clearly need to reward pharma if we want cures for difficult neurodegenerative and other illnesses. Overall then the idea is really a win for everyone.
Last edited by J11 on Sun Feb 13, 2022 9:59 am, edited 1 time in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.
The above figures are from the Gantenerumab clinical trials.
In the top figure we see serial SUVR imaging of AD patients during anti-amyloid treatment. We have talked so much about amyloid SUVR imaging it is nice to actually take a look at a few. What these images suggested to me was that even with a given amyloid level the pattern itself of amyloid in the brain might help to add additional information. for example the subfigure on the bottom row two from the left shows an 11 SUVR while the subfigure to the right diagonal from the first subfigure has a 7 SUVR. As can be seen even while the two subfigures have similar SUVRs they have somewhat different patterns of amyloid deposition. I think that I have mentioned this idea before but one certainly wonders whether an artificial intelligence program could take the totality of the Alzheimer datasets and create an accurate model of human cognition based upon the information. Roughly, AlphaAD -- a very advanced AI model of Alzheimer's. This could go well beyond simply looking at summary statistics. Patterns of amyloid deposition could inform exactly how patients would experience cognitive deficits. The imaging clearly shows that there are clear variations on how amyloid deposits in the brains of different patients.
The bottom figure shows the temporal change in amyloid centiloids in AD patients on the right. Typically amyloid treatment might be thought a success once reaching 0 centiloids, though one does wonder how going below zero might help to accrue more benefit. Shouldn't removing more amyloid help to seeding more tau? Wouldn't it help AD patients to remove more amyloid? Such research will be of interest to read.
In the top figure we see serial SUVR imaging of AD patients during anti-amyloid treatment. We have talked so much about amyloid SUVR imaging it is nice to actually take a look at a few. What these images suggested to me was that even with a given amyloid level the pattern itself of amyloid in the brain might help to add additional information. for example the subfigure on the bottom row two from the left shows an 11 SUVR while the subfigure to the right diagonal from the first subfigure has a 7 SUVR. As can be seen even while the two subfigures have similar SUVRs they have somewhat different patterns of amyloid deposition. I think that I have mentioned this idea before but one certainly wonders whether an artificial intelligence program could take the totality of the Alzheimer datasets and create an accurate model of human cognition based upon the information. Roughly, AlphaAD -- a very advanced AI model of Alzheimer's. This could go well beyond simply looking at summary statistics. Patterns of amyloid deposition could inform exactly how patients would experience cognitive deficits. The imaging clearly shows that there are clear variations on how amyloid deposits in the brains of different patients.
The bottom figure shows the temporal change in amyloid centiloids in AD patients on the right. Typically amyloid treatment might be thought a success once reaching 0 centiloids, though one does wonder how going below zero might help to accrue more benefit. Shouldn't removing more amyloid help to seeding more tau? Wouldn't it help AD patients to remove more amyloid? Such research will be of interest to read.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
One of the larger strategic errors that I think has been made during the advocacy of anti-amyloids is missing the chance to lobby harder for advancing Lecanemab.
Lecanemab is a second generation anti-amyloid and it appears to be safer and probably somewhat more effective than Aducanumab. Earlier in the thread we anticipated that possibly Lecanemab would be the first frontline treatment for AD.
The problem that occurred was that anti-amyloids such as Lecanemab and Donanemab received accelerated approval designation soon after Aducanumab's approval, though the meaning of this accelerated approval was not clearly understood by the thread. Apparently accelerated approval designation means that no additional clinical results are required for Lecanemab. The phase 2 is enough for an FDA approval.
This means that Lecanemab could possibly have completed its rolling submission back in October. There was no clear need to wait for a readout on Clarity. Lecanemab could be approved first and then Clarity could roll out as a confirmatory study. Yet, the obvious tact that we took and most others as well was to sit back and let the Clarity trial finish up and then have this dataset to refer to. This was not necessary. What might have been worth considering was to take an early peak at the trial by perhaps removing a sample of 200 placebo and 200 APOE4s. This could have been particularly effective after the CMS questioned the efficacy of the anti-amyloids. Lecanemab demonstrated large cognitive benefits in the APOE 4s and the Mild AD subgroups. To keep the conversation honest it could have been (could be) helpful to release results early. The CMS seemed to assume that additional evidence was not available to support anti-amyloid treatment. That is untrue. There is substantial locked results from 3 phase 3 clinical trials that could be brought forward for discussion. From the previous research, even 200 APOE4s would be expected to have highly statistically significant results. There does not seem to be an especially persuasive reason why this research is not reported.
Given this, the thread should have been more forceful on getting Lecanemab filed. There is no reason to wait to be in the September window of the end of Clarity. This is the last day of January; so we now have reached this time window. Yet, it was not necessary. It would have been much better for us if we could have pushed more for an April Lecanemab approval. Admittedly, the evidence would have been somewhat thin, though for accelerated approval all that was needed was strong evidence of amyloid clearance which has abundant supporting evidence. Lowering the amyloid biomarker is easily achieved. The cognitive result could then have confirming evidence with Clarity.
Lecanemab is a second generation anti-amyloid and it appears to be safer and probably somewhat more effective than Aducanumab. Earlier in the thread we anticipated that possibly Lecanemab would be the first frontline treatment for AD.
The problem that occurred was that anti-amyloids such as Lecanemab and Donanemab received accelerated approval designation soon after Aducanumab's approval, though the meaning of this accelerated approval was not clearly understood by the thread. Apparently accelerated approval designation means that no additional clinical results are required for Lecanemab. The phase 2 is enough for an FDA approval.
This means that Lecanemab could possibly have completed its rolling submission back in October. There was no clear need to wait for a readout on Clarity. Lecanemab could be approved first and then Clarity could roll out as a confirmatory study. Yet, the obvious tact that we took and most others as well was to sit back and let the Clarity trial finish up and then have this dataset to refer to. This was not necessary. What might have been worth considering was to take an early peak at the trial by perhaps removing a sample of 200 placebo and 200 APOE4s. This could have been particularly effective after the CMS questioned the efficacy of the anti-amyloids. Lecanemab demonstrated large cognitive benefits in the APOE 4s and the Mild AD subgroups. To keep the conversation honest it could have been (could be) helpful to release results early. The CMS seemed to assume that additional evidence was not available to support anti-amyloid treatment. That is untrue. There is substantial locked results from 3 phase 3 clinical trials that could be brought forward for discussion. From the previous research, even 200 APOE4s would be expected to have highly statistically significant results. There does not seem to be an especially persuasive reason why this research is not reported.
Given this, the thread should have been more forceful on getting Lecanemab filed. There is no reason to wait to be in the September window of the end of Clarity. This is the last day of January; so we now have reached this time window. Yet, it was not necessary. It would have been much better for us if we could have pushed more for an April Lecanemab approval. Admittedly, the evidence would have been somewhat thin, though for accelerated approval all that was needed was strong evidence of amyloid clearance which has abundant supporting evidence. Lowering the amyloid biomarker is easily achieved. The cognitive result could then have confirming evidence with Clarity.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
So much to comment on.
One of the more central points in many of the comments to the CMS comment page has been about the cost implications of Aducan for those on medicare. Originally the increase in monthly cost related to Aducan to those on Medicare was suggested to be $21.60 per monthly. However, in fact only half of the increase was directly related to Aducan -- $10.60. Yet, with Biogen's price reduction in Aducan's price from $56,000 to $28,000 the premium increase even with coverage would only be a $5.40 monthly increase. Are the commenters truly complaining about $5.40 per month?
This also got me thinking as to why CMS had never considered creating a funded plan for AD. Couldn't some legislation have required this? CMS could have pre-funded AD treatment to the tune of $100 billion in a locked box and then premium increases might have not been necessary. Government constantly uses a pay as you go approach, and never saves ahead. Even children understand the importance of saving their money in a piggy bank. Thinking ahead for these known liabilities to Medicare then would make the arrival of effective treatments less of a fiscal crisis and more the celebration that they should be. The next generation of anti-amyloids are already in sight and the cost implications for the unfunded liability clearly are large. How will the CMS justify not covering anti-amyloids when they are proven beyond all reasonable doubt effective?
AD research is an off-line budget item, why not make AD treatment a pre-funded off-line item as well? How is it that CMS just woke up one sunny day to realize that they had a liability that probably amounts into the tens of billions of dollars at least. It has been clear to those of paying attention that a cure for AD has been emerging for over the last 20 years with the original publication of the AD vaccine. It was widely recognized by the field 5 years ago that Aducanumab was an approaching treatment. Why was thought completely unnecessary to prepare for this? Not providing full coverage for this merely excuses a large oversight by CMS. How much of the complaint about Aducan would exist if this had all been pre-funded ahead of time? Possibly the CMS could show that they have learned this lesson by developing a policy of pre-funding other emerging cures. Doing so might encourage pharma to invest in the disease selected as it would then be clear to all that financing would be in the bank.
What is also of interest with the CMS document is the complete lack of quantification. With the FDA Briefing Document, it largely distilled down to an argument about numbers and statistical analysis. The CMS document has a near absence of numbers. The document says that they require a clinically effective treatment without ever clarifying what that would entail operationally. They also avoid any quantification of what they expect current evidence suggests for anti-amyloid treatment effects. So no mention is made that mild AD patients had a reported benefit of ~0.95 on CDR-sb in the Emerge high dose as seen in the FDA Briefing Document. The phase 2 lecanemab found a 1.2
CDR-sb benefit. What is the CMS expectation of the CDR-sb benefit for APOE4s or those with Mild AD? There entire document is literary and not number based. Yet, the entire analysis of clinical trial results is based on intense quant thinking. The FDA actually ran out of CPU on their supercomputer when they couldn't simulate more than 10 million clinical trials. They had to give up and conclude that it was essentially impossible that Aducan was not effective. I am sure we will all be interested to hear of how many tens of millions of trial simulations they have done on their super computer to refute the FDA's findings. Of course, obviously they did not do any simulations. It appears that there was no effort given to in any way consider anti-amyloids with numbers.
It is also highly disappointing that the document presents a near endless list of issues. There are so many issues that I am unsure whether we will be able to get to them all. The initial section of the document notes that only hospital based Aducan treatment would be allowed to enroll patients into their proposed clinical trials. That alone would represent a massive question to study. Hospitals as some mythic edifice that are somehow superior to all others institutional care does not correspond well to our own dementia experience. ... The CMS has so many issues that it is essentially to argue with them because they have thrown everything into one document.
{In fact, when offered free government care in such an institutional care setting we turned it down and opted to age in place even through very severe dementia; and I am still glad that we did. Our home care nurse seemed genuinely surprised that we were able to completely control problems such as bed sores before they progressed to serious medical problems. The necrotic bed sores that our nurse explained often arise in dementia wards must have been extraordinarily painful. Though from our caregiving experience we never saw anything like that even after years of home care. There should be no reason that such bed sores would ever occur. Even for someone with no medical training, bed sores can be reversed within days with a simple dressing and appropriate cream.}
That is perhaps their strategy. Create such a vastly diffuse document that no single topic can become the focus.
The FDA however was able to greatly narrow the focus down to the single topic of Aducanumab's efficacy. With only one focus a good discussion could emerge that produced a well reasoned approval. The whole FDA structure worked out great. ADCOM, Briefing Document ... It seemed like a legitimate democratic process.
With CMS not so much. The CMS document seemed to suggest that they could have called their own ADCOM though decided against it. They had a first comment period which I entirely ignored. They then have a one month comment period until February 10th and then will have a decision in April. The CMS process does not seem to have legitimacy.
The comment period could end before any meaningful discussion had occurred. There has been essentially no give and take on the main issue of Aducan efficacy. The evidence in support appears almost beyond discussion; and yet it apparently CMS has heard enough and is ready to decide on this. Clarity is expected to read out in September! How could be comfortable taking such a firm stance against the entire anti-amyloid class when an ocean of results are about to arrive so soon?
One of the more central points in many of the comments to the CMS comment page has been about the cost implications of Aducan for those on medicare. Originally the increase in monthly cost related to Aducan to those on Medicare was suggested to be $21.60 per monthly. However, in fact only half of the increase was directly related to Aducan -- $10.60. Yet, with Biogen's price reduction in Aducan's price from $56,000 to $28,000 the premium increase even with coverage would only be a $5.40 monthly increase. Are the commenters truly complaining about $5.40 per month?
This also got me thinking as to why CMS had never considered creating a funded plan for AD. Couldn't some legislation have required this? CMS could have pre-funded AD treatment to the tune of $100 billion in a locked box and then premium increases might have not been necessary. Government constantly uses a pay as you go approach, and never saves ahead. Even children understand the importance of saving their money in a piggy bank. Thinking ahead for these known liabilities to Medicare then would make the arrival of effective treatments less of a fiscal crisis and more the celebration that they should be. The next generation of anti-amyloids are already in sight and the cost implications for the unfunded liability clearly are large. How will the CMS justify not covering anti-amyloids when they are proven beyond all reasonable doubt effective?
AD research is an off-line budget item, why not make AD treatment a pre-funded off-line item as well? How is it that CMS just woke up one sunny day to realize that they had a liability that probably amounts into the tens of billions of dollars at least. It has been clear to those of paying attention that a cure for AD has been emerging for over the last 20 years with the original publication of the AD vaccine. It was widely recognized by the field 5 years ago that Aducanumab was an approaching treatment. Why was thought completely unnecessary to prepare for this? Not providing full coverage for this merely excuses a large oversight by CMS. How much of the complaint about Aducan would exist if this had all been pre-funded ahead of time? Possibly the CMS could show that they have learned this lesson by developing a policy of pre-funding other emerging cures. Doing so might encourage pharma to invest in the disease selected as it would then be clear to all that financing would be in the bank.
What is also of interest with the CMS document is the complete lack of quantification. With the FDA Briefing Document, it largely distilled down to an argument about numbers and statistical analysis. The CMS document has a near absence of numbers. The document says that they require a clinically effective treatment without ever clarifying what that would entail operationally. They also avoid any quantification of what they expect current evidence suggests for anti-amyloid treatment effects. So no mention is made that mild AD patients had a reported benefit of ~0.95 on CDR-sb in the Emerge high dose as seen in the FDA Briefing Document. The phase 2 lecanemab found a 1.2
CDR-sb benefit. What is the CMS expectation of the CDR-sb benefit for APOE4s or those with Mild AD? There entire document is literary and not number based. Yet, the entire analysis of clinical trial results is based on intense quant thinking. The FDA actually ran out of CPU on their supercomputer when they couldn't simulate more than 10 million clinical trials. They had to give up and conclude that it was essentially impossible that Aducan was not effective. I am sure we will all be interested to hear of how many tens of millions of trial simulations they have done on their super computer to refute the FDA's findings. Of course, obviously they did not do any simulations. It appears that there was no effort given to in any way consider anti-amyloids with numbers.
It is also highly disappointing that the document presents a near endless list of issues. There are so many issues that I am unsure whether we will be able to get to them all. The initial section of the document notes that only hospital based Aducan treatment would be allowed to enroll patients into their proposed clinical trials. That alone would represent a massive question to study. Hospitals as some mythic edifice that are somehow superior to all others institutional care does not correspond well to our own dementia experience. ... The CMS has so many issues that it is essentially to argue with them because they have thrown everything into one document.
{In fact, when offered free government care in such an institutional care setting we turned it down and opted to age in place even through very severe dementia; and I am still glad that we did. Our home care nurse seemed genuinely surprised that we were able to completely control problems such as bed sores before they progressed to serious medical problems. The necrotic bed sores that our nurse explained often arise in dementia wards must have been extraordinarily painful. Though from our caregiving experience we never saw anything like that even after years of home care. There should be no reason that such bed sores would ever occur. Even for someone with no medical training, bed sores can be reversed within days with a simple dressing and appropriate cream.}
That is perhaps their strategy. Create such a vastly diffuse document that no single topic can become the focus.
The FDA however was able to greatly narrow the focus down to the single topic of Aducanumab's efficacy. With only one focus a good discussion could emerge that produced a well reasoned approval. The whole FDA structure worked out great. ADCOM, Briefing Document ... It seemed like a legitimate democratic process.
With CMS not so much. The CMS document seemed to suggest that they could have called their own ADCOM though decided against it. They had a first comment period which I entirely ignored. They then have a one month comment period until February 10th and then will have a decision in April. The CMS process does not seem to have legitimacy.
The comment period could end before any meaningful discussion had occurred. There has been essentially no give and take on the main issue of Aducan efficacy. The evidence in support appears almost beyond discussion; and yet it apparently CMS has heard enough and is ready to decide on this. Clarity is expected to read out in September! How could be comfortable taking such a firm stance against the entire anti-amyloid class when an ocean of results are about to arrive so soon?
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Welcome to February!
The positive momentum is building now for another round of FDA accelerated approval for Lecanemab and the end of Clarity in September. It is starting to get close! The submission for Lecanemab perhaps could be filed within a month. Once it's filed it will feel like the clock is ticking in our favor. I think that we should still be pulling for Biogen to unlock some of the results early. It should not take much of a sample of ɛ4s to prove beyond all reasonable doubt that Lecanemab is effective. It is nice to have the top card to play whenever talk turns to how ineffective anti-amyloid treatment is. Well if we really want to know we can always take a peek into the thousands of patients who have completed treatment in the phase 3 trials.
More great news!
Aducanumab has started another subcutaneous dosing trial (just posted to clinical trial gov today).
This one is a phase 1 trial with 120 patient enrollment that is randomized between one SC dose or two SC doses.
These SC dosing trials for Aducan are moving ahead rapidly.
The first one enrolled 30 patients with a single SC dose.
Now they have amped it up to 120.
I am surprised and encouraged how rapidly this can take place.
I was worried that this would take YEARS; perhaps not.
From a potential patient perspective, I would not be all that interested in phase 2 or phase 3 trials for SC dosing.
Those trials would take a very long time to arrive at definitive conclusions; DECADES?
Instead I would like to see a ~ 1 year safety study with multiple dosing somewhere nearish the maximal safe dose that include PET amyloid imaging and MRIs in stage 1 & 2 AD. That would be all that would be needed to move this towards ~ primary prevention. This would unlock anti-amyloid therapy to tens of millions of people. Many of those
on forum are part of the worried well who might have ɛ44 or other high risk genotype that would like to know that a treatment option were on the table so that there would be something that could actually tangibly do well ahead of age of onset. PET amyloid imaging and some safe dosing with Aducan would not seem a bad choice for someone who wanted to do something.
One concern that I have with the new trial and the one from before is that it was for "healthy" subjects. It would be quite helpful if they made a point of enrolling those with stage 1 &2 AD. Another concerns is that there was no dosing information given; was the dosing meant to therapeutic or more homeopathic? Nonetheless it is very encouraging that the SC dose is moving forward so rapidly. It will be very comforting when there is a treatment option available to those who are pre-MCI.
I also noticed on clinical trial gov that the ICARE study has already started to enroll. I thought ICARE was not expected to begin enrolling until May of this year. What I found of interest with ICARE was that they decided not to include CDR-sb. The primary endpoints were all measures that I am not that familiar with. None of these tests were used in the 301 or 302 clinical trials. I had looked forward to putting another dot on my CDR-sb versus SUVR scatter plot. I thought that CMS had requested that clinical trials should include widely used psychometric instruments. I think that problem that is probably encountered here is that observational type trials are probably not the best vehicle to report measures such as CDR-sb. With a strictly controlled clinical trial one can remove a great deal of the data noise that happens in life. With an observational trial, there is probably a great deal of data noise. Perhaps give such conditions it might have been felt that it would not be fair to pretend that there would be true comparability. Any such comparability would be unfair.
Nevertheless, observational trials in real world settings could provide a great deal of valuable information. Of particular importance will will be observing how patients chose to be dosed. In a clinical trial patients more or less most follow the dosing guidance of given. With Aducanumab we saw that the 3 mg/kg doses in the uptitration seemed to pose substantial risk of serious ARIA. I will be very interested to see how patients might choose to uptitrate slower and perhaps slower. For instance, they might ask their doctors to add in a 2 mg/kg dose or two.
In an observational trial it is no longer as necessary for their to be maximal dosing in the shortest period of time.
The positive momentum is building now for another round of FDA accelerated approval for Lecanemab and the end of Clarity in September. It is starting to get close! The submission for Lecanemab perhaps could be filed within a month. Once it's filed it will feel like the clock is ticking in our favor. I think that we should still be pulling for Biogen to unlock some of the results early. It should not take much of a sample of ɛ4s to prove beyond all reasonable doubt that Lecanemab is effective. It is nice to have the top card to play whenever talk turns to how ineffective anti-amyloid treatment is. Well if we really want to know we can always take a peek into the thousands of patients who have completed treatment in the phase 3 trials.
More great news!
Aducanumab has started another subcutaneous dosing trial (just posted to clinical trial gov today).
This one is a phase 1 trial with 120 patient enrollment that is randomized between one SC dose or two SC doses.
These SC dosing trials for Aducan are moving ahead rapidly.
The first one enrolled 30 patients with a single SC dose.
Now they have amped it up to 120.
I am surprised and encouraged how rapidly this can take place.
I was worried that this would take YEARS; perhaps not.
From a potential patient perspective, I would not be all that interested in phase 2 or phase 3 trials for SC dosing.
Those trials would take a very long time to arrive at definitive conclusions; DECADES?
Instead I would like to see a ~ 1 year safety study with multiple dosing somewhere nearish the maximal safe dose that include PET amyloid imaging and MRIs in stage 1 & 2 AD. That would be all that would be needed to move this towards ~ primary prevention. This would unlock anti-amyloid therapy to tens of millions of people. Many of those
on forum are part of the worried well who might have ɛ44 or other high risk genotype that would like to know that a treatment option were on the table so that there would be something that could actually tangibly do well ahead of age of onset. PET amyloid imaging and some safe dosing with Aducan would not seem a bad choice for someone who wanted to do something.
One concern that I have with the new trial and the one from before is that it was for "healthy" subjects. It would be quite helpful if they made a point of enrolling those with stage 1 &2 AD. Another concerns is that there was no dosing information given; was the dosing meant to therapeutic or more homeopathic? Nonetheless it is very encouraging that the SC dose is moving forward so rapidly. It will be very comforting when there is a treatment option available to those who are pre-MCI.
I also noticed on clinical trial gov that the ICARE study has already started to enroll. I thought ICARE was not expected to begin enrolling until May of this year. What I found of interest with ICARE was that they decided not to include CDR-sb. The primary endpoints were all measures that I am not that familiar with. None of these tests were used in the 301 or 302 clinical trials. I had looked forward to putting another dot on my CDR-sb versus SUVR scatter plot. I thought that CMS had requested that clinical trials should include widely used psychometric instruments. I think that problem that is probably encountered here is that observational type trials are probably not the best vehicle to report measures such as CDR-sb. With a strictly controlled clinical trial one can remove a great deal of the data noise that happens in life. With an observational trial, there is probably a great deal of data noise. Perhaps give such conditions it might have been felt that it would not be fair to pretend that there would be true comparability. Any such comparability would be unfair.
Nevertheless, observational trials in real world settings could provide a great deal of valuable information. Of particular importance will will be observing how patients chose to be dosed. In a clinical trial patients more or less most follow the dosing guidance of given. With Aducanumab we saw that the 3 mg/kg doses in the uptitration seemed to pose substantial risk of serious ARIA. I will be very interested to see how patients might choose to uptitrate slower and perhaps slower. For instance, they might ask their doctors to add in a 2 mg/kg dose or two.
In an observational trial it is no longer as necessary for their to be maximal dosing in the shortest period of time.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
In the last day or two the Down's advocacy community has stepped forward on the CMS comment page. Many of these comments express the concern that CMS will not provide coverage to those coping with Down's Syndrome.
From my reading of the CMS document it is not especially clear what the CMS position is with respect to Down's.
According to 2)a below those with Down's could qualify as having MCI/Mild AD with evidence of amyloid pathology consistent with AD. It is not as clear how the other CMS conditions would apply as perhaps Down's might be considered as a condition that may contribute to cognitive decline and Down's AD could be thought to increase the risk of adverse events. Also if CMS does not intend to over coverage for AD, then one would expect that Down's might be considered a class of AD.
2) All studies for CMS approval must fully describe in the protocol how the following will be carried out:
(a)Patient Criteria Patients must have:
• A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
• Evidence of amyloid pathology consistent with AD.
Patients must not have:
• Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
• Expected death from any cause during the duration of the study.
• Medical conditions, other than AD, likely to increase significant adverse events.
It is very surprising that after recognizing the NDSS (National Down Syndrome Society) the CMS then made no statement regarding anti-amyloid treatment for Down's. This has created a great amount of concern and confusion in the Down's community.
The CMS comment page is a cacophony of confusion. There is no specific focus to the discussion. The FDA ran a pretty tight ship and created a valid consultation process that instilled a sense of legitimacy. You could agree with them or disagree with them but at least there was certain fairness and integrity to the process. The FDA is good at consulting and listening to the stakeholders in their decisions- it's what they do; it's their job. The FDA was able to focus the discussion mostly on the question: Is Aducanumab effective in treating MCI/Mild AD?
The CMS appears to have made a less good effort at recreating this process. There is no central question that dominates the discussion; there is instead mostly a fairly evident tribalism with people pulling in many different directions. Fortunately the AD community, the those with Down's, and various other demographic groups are less rivals and more allies in this discussion. The CMS has multiple dimensions that is attempting to consider simultaneously including efficacy, safety, cost inter alia. Amongst all of this confusion is very unclear how we can reach any legitimate democratic consensus. Even basic questions such as the CMS' Down's policy is being left unanswered. Will there really be no feedback until they make their final ruling?
From my reading of the CMS document it is not especially clear what the CMS position is with respect to Down's.
According to 2)a below those with Down's could qualify as having MCI/Mild AD with evidence of amyloid pathology consistent with AD. It is not as clear how the other CMS conditions would apply as perhaps Down's might be considered as a condition that may contribute to cognitive decline and Down's AD could be thought to increase the risk of adverse events. Also if CMS does not intend to over coverage for AD, then one would expect that Down's might be considered a class of AD.
2) All studies for CMS approval must fully describe in the protocol how the following will be carried out:
(a)Patient Criteria Patients must have:
• A clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild AD dementia; and
• Evidence of amyloid pathology consistent with AD.
Patients must not have:
• Any neurological or other medical condition (other than AD) that may significantly contribute to cognitive decline.
• Expected death from any cause during the duration of the study.
• Medical conditions, other than AD, likely to increase significant adverse events.
It is very surprising that after recognizing the NDSS (National Down Syndrome Society) the CMS then made no statement regarding anti-amyloid treatment for Down's. This has created a great amount of concern and confusion in the Down's community.
The CMS comment page is a cacophony of confusion. There is no specific focus to the discussion. The FDA ran a pretty tight ship and created a valid consultation process that instilled a sense of legitimacy. You could agree with them or disagree with them but at least there was certain fairness and integrity to the process. The FDA is good at consulting and listening to the stakeholders in their decisions- it's what they do; it's their job. The FDA was able to focus the discussion mostly on the question: Is Aducanumab effective in treating MCI/Mild AD?
The CMS appears to have made a less good effort at recreating this process. There is no central question that dominates the discussion; there is instead mostly a fairly evident tribalism with people pulling in many different directions. Fortunately the AD community, the those with Down's, and various other demographic groups are less rivals and more allies in this discussion. The CMS has multiple dimensions that is attempting to consider simultaneously including efficacy, safety, cost inter alia. Amongst all of this confusion is very unclear how we can reach any legitimate democratic consensus. Even basic questions such as the CMS' Down's policy is being left unanswered. Will there really be no feedback until they make their final ruling?
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
VII. Evidence
B. Discussion of Evidence
2. External Technology Assessments
CMS did not request an external technology assessment (TA) on this issue.
I want to go through the Evidence section to review the logic that the CMS applied in its review process.
One of the large controversies with the FDA Aducanumab approval was how the ADCOM near unanimous vote against Aducan was overruled. An outside evaluation can add a certain reinforcement of the authority of whoever calls in the external reviewers (or with Aducan it can work in reverse). For whatever reason and perhaps unrelated to fear of an ADCOM-like rebellion, CMS did not call for an external technology assessment. I am not sure whether a TA could actually have fomented a rebellion within CMS similar to what happened at the FDA; nonetheless, it would likely have provided more insight into CMS' coverage rationale. Given the profound magnitude of the anti-amyloid issue, I probably would have called for a TA.
3. Internal Technology Assessment
Created on 01/12/2022. Page 11 of 49
We searched the data bases Academic Search Premier, CINAHL, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, for English language articles in peer-reviewed journals, published from 2010 – 2021, using the search terms ‘Phase 3 Clinical Trials’, ‘beta-Amyloid’, and ‘monoclonal antibodies’. To ensure that we captured all the relevant articles, the search was conducted independently and concurrently by a NIH librarian, the contractor International Consulting Associates (ICA), and CAG. As the searches were completed, the NIH librarian first, ICA second, and CAG last, we incorporated all the distinct, relevant references into a single reference database. The final result was the identification of over 250 peer-reviewed documents relevant to the NCD analysis.
These searches resulted in over 250 articles, including descriptions and assessments of Phase 3 clinical trials testing the efficacy and safety of using monoclonal antibodies for treatment of Alzheimer’s Disease (AD). Some of the studies, such as Konstantinos Avegerinos et al., “Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease,” a 2021 publication in Aging Research Reviews, were metanalyses that surveyed multiple clinical trials testing a variety of potential anti-amyloid drugs for treatment of AD. In addition to peer-reviewed articles, we reviewed reports from other agencies, including the FDA, the Guideline Development, Dissemination and Implementation Subcommittee of the American Academy of Neurology, the National Institute on Aging, and the National Institute for Health Care and Excellence. We also reviewed the Institute for Clinical and Economic Review’s May 5, 2021 report “Aducanumab for Alzheimer’s Disease: Effectiveness and Value.”
Instead of calling for an external assessment perhaps by Alzheimer thought leaders they decided to go with a DIY.
This consisted of a literature review from pubmed etc.. Assembling a massive library of resources on anti-amyloids of course is only the first step. The next step is to exhaustively analyze the documents to develop understanding into what they all meant. That would have taken many person-years of effort. My impression is that this aspect of the extensive research effort was mostly overly looked. Many of the references in their report appear to be more zoombie references which were not carefully integrated into the document. It does not seem that they carefully considered the large successes that have been posted in other trials including the Donanemab phase 2 and the Lecanemab phase 2.
If it were me I probably would have stayed away from 250 articles and focused more on the most recent documents and especially the FDA Aducan reports. So much of the rest of the literature is only derivative and to a certain extent out of date. No attempt was made in the CMS document to quantify their statements. I would have certainly tried to grapple with the numbers as I have tried to do in this thread. The CMS avoided numerical analysis entirely. The clinical trial results really can only be realistically understood from a quant heavy perspective. CMS has created an analytic approach that is largely non-falsifiable-- they aren't even wrong! Without any attempt of adding numbers, it is almost impossible to even argue with them.
What I also find of interest is that they make special reference to the FDA Aducanumab approval documents. Yet, these documents are mostly unequivocally positive. Finding that Aducanumab is not effective is less plausible when one realizes that many at the FDA were pushing for a full approval. I am not sure whether I would have supported full approval, though if full approval had been granted then it would have been close to impossible for CMS to question efficacy. I support internal disagreement and ongoing argument I think that it can be helpful to arrive at a higher level of truth; unfortunately, the lack of nuance that we have seen with the Aducan interpretation might create much more dogmatic decisions in order to preempt intellectually dishonest readings of more complex decisions.
The primary clinical review argues primarily for standard approval. ... Study 302 to be a
robust and exceptionally persuasive study that provides the primary evidence of effectiveness to support approval.
concluded that the applicant has provided substantial evidence of effectiveness to support approval of aducanumab for AD.
The clinical pharmacology review recommends approval. ... The clinical pharmacology review team notes that it is practically impossible to observe the overall pattern of results in these three studies if aducanumab is similar to
placebo.
4. Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)
A MEDCAC meeting was not convened on this issue.
They also decided to not go with a MEDCAC meeting. I am not clear what a MEDCAC meeting is, though if it were me even without knowing what it is, I would still have probably went for it. From the democratic transparency perspective it does raise certain suspicions. Why not have such a meeting? The FDA could have just decided not to have an ADCOM for Aducan and this would have saved a great deal of headaches. Most of the public would have been none the wiser. CMS appeared to avoid a few potentially difficult internal/external reviews.
Below are two Evidence Tables.
Table 1 contains summary descriptive information about individual Phase 3 RCTs.
Table 2 contains summary results from Phase 3 RCTs.
These are the tables noted elsewhere that skimmed over phase 3 clinical trials while largely overlooking the
several clinical trials (including the phase 2 donanemab, phase 2 lecanemab, the gamma entrainment trials possibly others) that did show statistically significant results.
VIII. Public Comment
Public comments sometimes cite the published clinical evidence and give CMS useful information. Public comments Created on 01/12/2022. Page 12 of 49
that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.
CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-d ... atus&bc=17.
Initial Comment Period: 07/12/2021 – 08/11/2021
During the 30-day comment period following the release of the tracking sheet, CMS received 131 comments. The majority of comments, approximately 77 commenters, did not support coverage or recommended coverage with evidence development (CED). Twenty-six comments did not state a clear position regarding coverage.
The comments included 58 from physicians, and eight from medical companies. We also received 26 comments on behalf of national associations/professional societies, including the American Academy of Neurology (AAN), UsAgainstAlzheimer’s, Biotechnology Innovation Organization (BIO), Public Citizen, Value Based Care Coalition, National Home Infusion Association (NHIA), Medical Imaging & Technology Alliance (MITA), National Association of ACOs (NAACOS), National Association of Medicaid Directors (NAMD), America’s Health Insurance Plans (AHIP), Society of Nuclear Medicine and Molecular Imaging (SNMMI), Alzheimer’s Association, National Minority Quality Forum (NMQF), Alliance for Patient Access (AfPA), Global Alzheimer’s Platform (GAP), American Geriatrics Society (AGS), Infusion Providers Alliance (IPA), Alliance for Aging Research, National Down Syndrome Society (NDSS), Duke Margolis Center for Health Policy, Alzheimer’s Foundation of America (AFA), Infusion Access Foundation (IAF), Pharmaceutical Care Management Association (PCMA), Pharmaceutical Research and Manufacturers of America (PhRMA).
In addition to the above public comments, CMS held two stakeholder meetings and met with numerous patient advocates organizations, manufactures, payers, and think tanks. See the mAB Tracking Sheet (https://www.cms.gov/medicare-coverage-d ... sheet.aspx? ncaid=305&ncacaldoctype=all&status=all&sortBy=status&bc=17) for the stakeholder meeting transcripts and a full list of the organizations.
The themes from the comments included criticism of the evidence for Aduhelm™, citing conflicting results between EMERGE and ENGAGE, and the presence of adverse events (e.g., Amyloid Related Imaging Abnormalities (ARIA)). The commenters cited that these are reasons additional evidence is needed before the drug is coverable, or expressing that coverage should be limited to CED. Commenters also expressed concerns over the price of Aduhelm™. Commenters stated that CMS should cover Aduhelm™, and future anti-amyloid monoclonal antibodies, based on FDA approval and because of the lack of available effective treatments for AD. Commenters specified that diagnostic tests for beta amyloid should also be included in coverage.
It is good to see that the CMS did get out there and conducted some listening sessions. However, one wonders how representative these listening sessions were as the comments indicate a great deal of confusion exists about what is thought to be the CMS's position. The confusion with Down's is particularly notable in this respect.
B. Discussion of Evidence
2. External Technology Assessments
CMS did not request an external technology assessment (TA) on this issue.
I want to go through the Evidence section to review the logic that the CMS applied in its review process.
One of the large controversies with the FDA Aducanumab approval was how the ADCOM near unanimous vote against Aducan was overruled. An outside evaluation can add a certain reinforcement of the authority of whoever calls in the external reviewers (or with Aducan it can work in reverse). For whatever reason and perhaps unrelated to fear of an ADCOM-like rebellion, CMS did not call for an external technology assessment. I am not sure whether a TA could actually have fomented a rebellion within CMS similar to what happened at the FDA; nonetheless, it would likely have provided more insight into CMS' coverage rationale. Given the profound magnitude of the anti-amyloid issue, I probably would have called for a TA.
3. Internal Technology Assessment
Created on 01/12/2022. Page 11 of 49
We searched the data bases Academic Search Premier, CINAHL, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, for English language articles in peer-reviewed journals, published from 2010 – 2021, using the search terms ‘Phase 3 Clinical Trials’, ‘beta-Amyloid’, and ‘monoclonal antibodies’. To ensure that we captured all the relevant articles, the search was conducted independently and concurrently by a NIH librarian, the contractor International Consulting Associates (ICA), and CAG. As the searches were completed, the NIH librarian first, ICA second, and CAG last, we incorporated all the distinct, relevant references into a single reference database. The final result was the identification of over 250 peer-reviewed documents relevant to the NCD analysis.
These searches resulted in over 250 articles, including descriptions and assessments of Phase 3 clinical trials testing the efficacy and safety of using monoclonal antibodies for treatment of Alzheimer’s Disease (AD). Some of the studies, such as Konstantinos Avegerinos et al., “Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease,” a 2021 publication in Aging Research Reviews, were metanalyses that surveyed multiple clinical trials testing a variety of potential anti-amyloid drugs for treatment of AD. In addition to peer-reviewed articles, we reviewed reports from other agencies, including the FDA, the Guideline Development, Dissemination and Implementation Subcommittee of the American Academy of Neurology, the National Institute on Aging, and the National Institute for Health Care and Excellence. We also reviewed the Institute for Clinical and Economic Review’s May 5, 2021 report “Aducanumab for Alzheimer’s Disease: Effectiveness and Value.”
Instead of calling for an external assessment perhaps by Alzheimer thought leaders they decided to go with a DIY.
This consisted of a literature review from pubmed etc.. Assembling a massive library of resources on anti-amyloids of course is only the first step. The next step is to exhaustively analyze the documents to develop understanding into what they all meant. That would have taken many person-years of effort. My impression is that this aspect of the extensive research effort was mostly overly looked. Many of the references in their report appear to be more zoombie references which were not carefully integrated into the document. It does not seem that they carefully considered the large successes that have been posted in other trials including the Donanemab phase 2 and the Lecanemab phase 2.
If it were me I probably would have stayed away from 250 articles and focused more on the most recent documents and especially the FDA Aducan reports. So much of the rest of the literature is only derivative and to a certain extent out of date. No attempt was made in the CMS document to quantify their statements. I would have certainly tried to grapple with the numbers as I have tried to do in this thread. The CMS avoided numerical analysis entirely. The clinical trial results really can only be realistically understood from a quant heavy perspective. CMS has created an analytic approach that is largely non-falsifiable-- they aren't even wrong! Without any attempt of adding numbers, it is almost impossible to even argue with them.
What I also find of interest is that they make special reference to the FDA Aducanumab approval documents. Yet, these documents are mostly unequivocally positive. Finding that Aducanumab is not effective is less plausible when one realizes that many at the FDA were pushing for a full approval. I am not sure whether I would have supported full approval, though if full approval had been granted then it would have been close to impossible for CMS to question efficacy. I support internal disagreement and ongoing argument I think that it can be helpful to arrive at a higher level of truth; unfortunately, the lack of nuance that we have seen with the Aducan interpretation might create much more dogmatic decisions in order to preempt intellectually dishonest readings of more complex decisions.
The primary clinical review argues primarily for standard approval. ... Study 302 to be a
robust and exceptionally persuasive study that provides the primary evidence of effectiveness to support approval.
concluded that the applicant has provided substantial evidence of effectiveness to support approval of aducanumab for AD.
The clinical pharmacology review recommends approval. ... The clinical pharmacology review team notes that it is practically impossible to observe the overall pattern of results in these three studies if aducanumab is similar to
placebo.
4. Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)
A MEDCAC meeting was not convened on this issue.
They also decided to not go with a MEDCAC meeting. I am not clear what a MEDCAC meeting is, though if it were me even without knowing what it is, I would still have probably went for it. From the democratic transparency perspective it does raise certain suspicions. Why not have such a meeting? The FDA could have just decided not to have an ADCOM for Aducan and this would have saved a great deal of headaches. Most of the public would have been none the wiser. CMS appeared to avoid a few potentially difficult internal/external reviews.
Below are two Evidence Tables.
Table 1 contains summary descriptive information about individual Phase 3 RCTs.
Table 2 contains summary results from Phase 3 RCTs.
These are the tables noted elsewhere that skimmed over phase 3 clinical trials while largely overlooking the
several clinical trials (including the phase 2 donanemab, phase 2 lecanemab, the gamma entrainment trials possibly others) that did show statistically significant results.
VIII. Public Comment
Public comments sometimes cite the published clinical evidence and give CMS useful information. Public comments Created on 01/12/2022. Page 12 of 49
that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.
CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-d ... atus&bc=17.
Initial Comment Period: 07/12/2021 – 08/11/2021
During the 30-day comment period following the release of the tracking sheet, CMS received 131 comments. The majority of comments, approximately 77 commenters, did not support coverage or recommended coverage with evidence development (CED). Twenty-six comments did not state a clear position regarding coverage.
The comments included 58 from physicians, and eight from medical companies. We also received 26 comments on behalf of national associations/professional societies, including the American Academy of Neurology (AAN), UsAgainstAlzheimer’s, Biotechnology Innovation Organization (BIO), Public Citizen, Value Based Care Coalition, National Home Infusion Association (NHIA), Medical Imaging & Technology Alliance (MITA), National Association of ACOs (NAACOS), National Association of Medicaid Directors (NAMD), America’s Health Insurance Plans (AHIP), Society of Nuclear Medicine and Molecular Imaging (SNMMI), Alzheimer’s Association, National Minority Quality Forum (NMQF), Alliance for Patient Access (AfPA), Global Alzheimer’s Platform (GAP), American Geriatrics Society (AGS), Infusion Providers Alliance (IPA), Alliance for Aging Research, National Down Syndrome Society (NDSS), Duke Margolis Center for Health Policy, Alzheimer’s Foundation of America (AFA), Infusion Access Foundation (IAF), Pharmaceutical Care Management Association (PCMA), Pharmaceutical Research and Manufacturers of America (PhRMA).
In addition to the above public comments, CMS held two stakeholder meetings and met with numerous patient advocates organizations, manufactures, payers, and think tanks. See the mAB Tracking Sheet (https://www.cms.gov/medicare-coverage-d ... sheet.aspx? ncaid=305&ncacaldoctype=all&status=all&sortBy=status&bc=17) for the stakeholder meeting transcripts and a full list of the organizations.
The themes from the comments included criticism of the evidence for Aduhelm™, citing conflicting results between EMERGE and ENGAGE, and the presence of adverse events (e.g., Amyloid Related Imaging Abnormalities (ARIA)). The commenters cited that these are reasons additional evidence is needed before the drug is coverable, or expressing that coverage should be limited to CED. Commenters also expressed concerns over the price of Aduhelm™. Commenters stated that CMS should cover Aduhelm™, and future anti-amyloid monoclonal antibodies, based on FDA approval and because of the lack of available effective treatments for AD. Commenters specified that diagnostic tests for beta amyloid should also be included in coverage.
It is good to see that the CMS did get out there and conducted some listening sessions. However, one wonders how representative these listening sessions were as the comments indicate a great deal of confusion exists about what is thought to be the CMS's position. The confusion with Down's is particularly notable in this respect.
Last edited by J11 on Wed Feb 02, 2022 12:12 pm, edited 1 time in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
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